Mystery at the heart of life

[...] non-protein-coding sequences house a set of information-rich instructions, many of which are likely to be regulatory in nature and transacted as RNA species, which have facilitated the emergence of biological complexity. [...] the protein-coding repertoire has changed little since the dawn of multicellularity [...] [...] there is a substantial problem of “missing information” that can be resolved if non-protein-coding sequences are as information rich [...] [...] the mammalian genome is nearly maximized with regulatory information bound within ncDNA.

A meta-analysis of the genomic and transcriptomic composition of complex life Ganqiang Liu, 1 , 2 John S. Mattick, 2 and Ryan J. Taft Cell Cycle. 12(13): 2061–2072. doi: 10.4161/cc.25134

Complex complexity Dionisio

(1) the number of protein-coding genes and bases does not scale with biological complexity and is in fact relatively static across all multicellular animal lineages; (2) there is a strong and statistically significant correlation between the proportion of the genome that is non-protein-coding and organismal complexity; (3) a meta-analysis of more than 170 RNA-seq data sets has revealed, consistent with other studies,4-8 that the vast majority of multicellular animal genomes are transcribed.

A meta-analysis of the genomic and transcriptomic composition of complex life Ganqiang Liu, 1 , 2 John S. Mattick, 2 and Ryan J. Taft Cell Cycle. 12(13): 2061–2072. doi: 10.4161/cc.25134

Complex complexity Dionisio

It is now clear that animal genomes are predominantly non-protein-coding, and that these sequences encode a wide array of RNA transcripts and other regulatory elements that are fundamental to the development of complex life. [...] the proportion of an animal genome that is non-protein-coding DNA (ncDNA) correlates well with its apparent biological complexity. [...] ncDNA, and the ncRNAs encoded within it, may be intimately involved in the evolution, maintenance and development of complex life.

A meta-analysis of the genomic and transcriptomic composition of complex life Ganqiang Liu, 1 , 2 John S. Mattick, 2 and Ryan J. Taft Cell Cycle. 12(13): 2061–2072. doi: 10.4161/cc.25134

Some archaic pseudoscientific hogwash in an otherwise interesting paper. Complex complexity Dionisio

The kinetochore and checkpoint proteins form a complex set of interactions that facilitate the generation of the ‘wait anaphase' signal in the form of the MCC. Understanding SAC signalling requires the elucidation of the molecular interactions between checkpoint components.

Bub1 positions Mad1 close to KNL1 MELT repeats to promote checkpoint signalling Gang Zhang,a,1 Thomas Kruse,1 Blanca López-Méndez,1 Kathrine Beck Sylvestersen,1 Dimitriya H. Garvanska,1 Simone Schopper,1 Michael Lund Nielsen,1 and Jakob Nilsson Nat Commun. 2017; 8: 15822. doi: 10.1038/ncomms15822

Complex complexity Dionisio

Proper segregation of chromosomes depends on a functional spindle assembly checkpoint (SAC) and requires kinetochore localization of the Bub1 and Mad1/Mad2 checkpoint proteins. Several aspects of Mad1/Mad2 kinetochore recruitment in human cells are unclear and in particular the underlying direct interactions. This work dissects functionally relevant molecular interactions required for spindle assembly checkpoint signalling at kinetochores in human cells.

Bub1 positions Mad1 close to KNL1 MELT repeats to promote checkpoint signalling Gang Zhang,a,1 Thomas Kruse,1 Blanca López-Méndez,1 Kathrine Beck Sylvestersen,1 Dimitriya H. Garvanska,1 Simone Schopper,1 Michael Lund Nielsen,1 and Jakob Nilsson Nat Commun. 2017; 8: 15822. doi: 10.1038/ncomms15822

Complex complexity Dionisio

The validity of the induction model should be investigated further [...] [...] more observational data are required to understand the developmental functions of eyespot organisers and differentiating epithelial cells in general in butterfly wing tissues.

Butterfly eyespot organiser: in vivo imaging of the prospective focal cells in pupal wing tissues Mayo Iwasaki,1 Yoshikazu Ohno,1 and Joji M. Otaki Sci Rep. 2017; 7: 40705. doi: 10.1038/srep40705

Complex complexity Dionisio

An organiser is a cluster of cells that can induce differentiation of their surrounding cells, and many molecules that are critically involved in the induction process have been identified. Their molecular network is fairly complex.

Butterfly eyespot organiser: in vivo imaging of the prospective focal cells in pupal wing tissues Mayo Iwasaki,1 Yoshikazu Ohno,1 and Joji M. Otaki Sci Rep. 2017; 7: 40705. doi: 10.1038/srep40705

Complex complexity Dionisio

[...] organiser cells are developmentally ahead of cells in other regions and that position-dependent heterochronic development is a general mechanism for constructing colour patterns in butterfly wings.

Butterfly eyespot organiser: in vivo imaging of the prospective focal cells in pupal wing tissues Mayo Iwasaki,1 Yoshikazu Ohno,1 and Joji M. Otaki Sci Rep. 2017; 7: 40705. doi: 10.1038/srep40705

Complex complexity Dionisio

The controlled generation of a Wnt gradient by cytonemes is a prerequisite to establishing a morphogenetic Wnt field that allows precise tissue patterning, such as in the vertebrate neural plate. [...] the next step is to substantiate our understanding of the molecular mechanisms that control the formation of these signaling filopodia. [...] it is crucial to determine whether other ligands in the Wnt pathway use a similar distribution mechanism. [...] it is important to investigate whether other delivery mechanisms, in addition to those relying on cytonemes, are used in parallel or whether there is a strict tissue-dependency for the specific transport mechanism employed. [...] further research is needed before extracellular Wnt trafficking, its impact on morphogenetic gradient formation and the effect on tissue patterning are fully understood.

Role of cytonemes in Wnt transport. Stanganello E, Scholpp S J Cell Sci. 129(4):665-72. doi: 10.1242/jcs.182469

Complex complexity Dionisio

Wnt proteins might be transported through multi-protein complexes that mask their hydrophobic lipid modifications and increase solubility. [...] exovesicles have been proposed to play a role in the passage of hydrophobic Wnt molecules through tissue [...] the delivery mode of Wnt proteins in the stem cell niche remains to be elucidated. It is, therefore, important to analyze any context-dependency on the characteristics of cytonemes and the mechanisms of transport.

Role of cytonemes in Wnt transport. Stanganello E, Scholpp S J Cell Sci. 129(4):665-72. doi: 10.1242/jcs.182469

Complex complexity Dionisio

[...] long-range spreading of Wnt proteins by diffusion is unlikely [...]

Role of cytonemes in Wnt transport. Stanganello E, Scholpp S J Cell Sci. 129(4):665-72. doi: 10.1242/jcs.182469

BTW, whatever happened with Turing’s magic “one size fit all” plain vanilla diffusion? Sometimes reductionist thinking doesn't work in biology. Plain diffusion is fine for some color patterning and stuff like that, but not for many cases where things get tough. Additional factors are required too. OK? Complex complexity Dionisio

Regulation of propagation is fundamental to the formation of a Wnt8a morphogenetic gradient. However, how Wnt proteins are distributed to form this gradient and function over tens of micrometers is still unclear.

Role of cytonemes in Wnt transport. Stanganello E, Scholpp S J Cell Sci. 129(4):665-72. doi: 10.1242/jcs.182469

Complex complexity Dionisio

During embryogenesis, all multicellular organisms face the same fundamental challenge: the development of a complex structure originating from a single cell. One of the first steps of development is the establishment of the embryonic body plan. [...] the extracellular transport mechanism of this morphogen from the signal-releasing cell to the recipient cell is still debated. [...] recent evidences of a cytoneme-mediated transport in development and in the stem cell niche. This unexpected trafficking mode raises numerous questions with regard to morphogenetic gradient formation within a growing tissue, which we will address in the concluding section of the article.

Role of cytonemes in Wnt transport. Stanganello E, Scholpp S J Cell Sci. 129(4):665-72. doi: 10.1242/jcs.182469

Did somebody say "plan"? Did somebody say "unexpected"? Why? What else did they expect? BTW, whatever happened with Turing's magic "one size fit all" diffusion? Complex complexity Dionisio

Wnt signaling regulates a broad variety of processes during embryonic development and disease. A hallmark of the Wnt signaling pathway is the formation of concentration gradients by Wnt proteins across responsive tissues, which determines cell fate in invertebrates and vertebrates. To fulfill its paracrine function, trafficking of the Wnt morphogen from an origin cell to a recipient cell must be tightly regulated. A variety of models have been proposed to explain the extracellular transport of these lipid-modified signaling proteins in the aqueous extracellular space; however, there is still considerable debate with regard to which mechanisms allow the precise distribution of ligand in order to generate a morphogenetic gradient within growing tissue.

Role of cytonemes in Wnt transport. Stanganello E, Scholpp S J Cell Sci. 129(4):665-72. doi: 10.1242/jcs.182469

A couple of years ago a Canadian professor affirmed that he knew exactly how morphogen gradients form. Or at least that's what he implicitly stated when he responded to a dishonest question that contained the tricky word "exactly" which obviously he could not notice because it was not bold text. :) Complex complexity Dionisio

While studies of stem cells have revealed a great deal about maintenance and propagation, the origin of most adult stem cell populations remains an open question. [...] local trapping of a broadly secreted signal may be a mechanism that is widely employed in a variety of embryological contexts. [...] our findings compel investigation into potential embryonic origins for other adult stem cells.

Bending gradients: How the intestinal stem cell gets its home Amy E. Shyer, Tyler R. Huycke, ChangHee Lee, L. Mahadevan, and Clifford J. Tabin Cell. 161(3): 569–580. doi: 10.1016/j.cell.2015.03.041

Note that this paper was first referenced @813, but only the summary was quoted. Complex complexity Dionisio

Surprisingly, we found that BMP activity had no effect on the total number of cells in the mesentery, despite dramatic changes in overall tissue volume. It is unclear whether such mechanisms are at work in the developing gut. An interesting, albeit at this point speculative, possibility is that the signals controlling growth of the mesentery are themselves under control of physical forces, creating a feedback loop. [...] loop morphology depends not only on differential growth, but on geometry and stiffness of the tube and mesentery as well.

BMP signaling controls buckling forces to modulate looping morphogenesis of the gut Nandan L. Nerurkar, L. Mahadevan, and Clifford J. Tabin doi: 10.1073/pnas.1700307114 PNAS vol. 114 no. 9 2277-2282

Did somebody say "Surprisingly"? Complex complexity Dionisio

Differential growth represents one of the core physical mechanisms driving morphogenesis throughout the vertebrate embryo [...] Looping maximizes the absorptive capacity of the gut by allowing intestinal length to extend well beyond the linear length of the organism, while maintaining an ordered configuration in the body cavity. [...] regulation of tissue-scale physical forces can be traced to signaling pathways during vertebrate development.

BMP signaling controls buckling forces to modulate looping morphogenesis of the gut Nandan L. Nerurkar, L. Mahadevan, and Clifford J. Tabin doi: 10.1073/pnas.1700307114 PNAS vol. 114 no. 9 2277-2282

Complex complexity Dionisio

Looping of the initially straight embryonic gut tube is an essential aspect of intestinal morphogenesis, permitting proper placement of the lengthy small intestine within the confines of the body cavity. Although the physics of this process has been studied, the underlying biology has not.

BMP signaling controls buckling forces to modulate looping morphogenesis of the gut Nandan L. Nerurkar, L. Mahadevan, and Clifford J. Tabin doi: 10.1073/pnas.1700307114 PNAS vol. 114 no. 9 2277-2282

Complex complexity Dionisio

Growth regulation is needed to form organs of correct size and proportion, but the mechanisms that define organ and organism size remain poorly understood [...] Hippo signaling is activated within faster growing clones as a consequence of cellular compression, rather than through biochemical pathways dependent upon the various genotypes analyzed. [...] when compression-induced growth suppression is bypassed by genetic manipulations that suppress mechanical feedback, higher cell proliferation is observed in the center of the wing disc.

Differential growth triggers mechanical feedback that elevates Hippo signaling. Pan Y, Heemskerk I, Ibar C, Shraiman BI, Irvine KD Proc Natl Acad Sci U S A. 113(45): E6974–E6983. doi: 10.1073/pnas.1615012113 PMCID: PMC5111668 PNAS Plus Developmental Biology, Physics

Complex complexity Dionisio

To form organs of correct size and proportion, growth must be tightly controlled. Our results support and extend a theoretical model, termed “mechanical feedback,” that described the relationship between growth rates and tissue mechanics.

Differential growth triggers mechanical feedback that elevates Hippo signaling. Pan Y, Heemskerk I, Ibar C, Shraiman BI, Irvine KD Proc Natl Acad Sci U S A. 113(45): E6974–E6983. doi: 10.1073/pnas.1615012113 PMCID: PMC5111668 PNAS Plus Developmental Biology, Physics

Complex complexity Dionisio

The striking parallelisms in the molecules and mechanisms underlying limb development in vertebrates and invertebrates have contributed to the proposal that an ancient patterning system is being recurrently used to generate body wall outgrowths. Whether the conserved JAK/STAT pathway plays a developmental role also in the specification or growth of vertebrate limbs by regulating morphogen production or activity is a tempting question that remains to be elucidated.

JAK/STAT controls organ size and fate specification by regulating morphogen production and signalling. Recasens-Alvarez C, Ferreira A, Milán M Nat Commun. 8:13815. doi: 10.1038/ncomms13815.

Complex complexity Dionisio

Morphogens of the Wnt/Wg, Shh/Hh and BMP/Dpp families regulate tissue growth and pattern formation in vertebrate and invertebrate limbs. Early in wing development, two distinct mechanisms ensure the spatial segregation of two alternative cell fates. Whether this apoptosis plays a biological role and relies on En activity requires further study.

JAK/STAT controls organ size and fate specification by regulating morphogen production and signalling. Recasens-Alvarez C, Ferreira A, Milán M Nat Commun. 8:13815. doi: 10.1038/ncomms13815.

Complex complexity Dionisio

A complex set of interactions between morphogens and their corresponding signalling pathways contributes to patterning and organizing limb growth along the dorsal–ventral, anterior–posterior and proximal–distal axes.

JAK/STAT controls organ size and fate specification by regulating morphogen production and signalling. Recasens-Alvarez C, Ferreira A, Milán M Nat Commun. 8:13815. doi: 10.1038/ncomms13815.

Complex complexity Dionisio

Despite the great differences in size and shape across the animal phyla, the body plan of most organisms is built up by a limited and conserved number of developmental toolkit genes that follow the same principles of animal design.

JAK/STAT controls organ size and fate specification by regulating morphogen production and signalling. Recasens-Alvarez C, Ferreira A, Milán M Nat Commun. 8:13815. doi: 10.1038/ncomms13815.

Did somebody say "design"? :) Complex complexity Dionisio

A stable pool of morphogen-producing cells is critical for the development of any organ or tissue. [...] JAK/STAT signalling in the Drosophila wing promotes the cycling and survival of Hedgehog-producing cells, thereby allowing the stable localization of the nearby BMP/Dpp-organizing centre in the developing wing appendage.

JAK/STAT controls organ size and fate specification by regulating morphogen production and signalling. Recasens-Alvarez C, Ferreira A, Milán M Nat Commun. 8:13815. doi: 10.1038/ncomms13815.

Complex complexity Dionisio

[...] sal promotes ban expression in the wing disc in a non-regional specific manner, unlike the manner of omb. [...] sal may mediate partial functions of Dpp in growth control. Other possibility is that sal may mediate the roles of other upstream factors such as Lines41, Wingless42, and Ubx in Drosophila43 as well as Tribolium44.

spalt is functionally conserved in Locusta and Drosophila to promote wing growth. Wang D, Li J, Liu S, Zhou H, Zhang L, Shi W, Shen J Sci Rep. 2017 Mar 16;7:44393. doi: 10.1038/srep44393.

Complex complexity Dionisio

[...] little is known about the molecular mechanism of how the Locusta wing develops into such delicate structure. The pattern formation is delicately regulated by organizers located in the anterior/posterior (A/P) and dorsal/ventral (D/V) boundaries which secrete signal molecules including the long-range morphogens Decapentaplegic (Dpp) and Wingless (Wg)11,12, and short-range morphogen Hedgehog (Hh)13. These morphogens form gradients to regulate the expression of their target genes and control almost all aspects of wing development12.

spalt is functionally conserved in Locusta and Drosophila to promote wing growth. Wang D, Li J, Liu S, Zhou H, Zhang L, Shi W, Shen J Sci Rep. 2017 Mar 16;7:44393. doi: 10.1038/srep44393.

Complex complexity [this paper was first referenced @3471] Dionisio

The Hedgehog pathway is a pivotal morphogenic driver during embryonic development and a key regulator of adult stem cell self-renewal. The identification of critical soluble factors (such as Hedgehog) and the relevant cell-cell interactions that dictate the behaviour and fate of resident vascular stem cell niches should lead to the development of diagnostic markers and new therapeutic targets for intervention in degenerative/regenerative disease of the arterial wall.

Hedgehog and Resident Vascular Stem Cell Fate Ciaran J. Mooney, 1 Roya Hakimjavadi, 1 Emma Fitzpatrick, 1 Eimear Kennedy, 1 Dermot Walls, 2 David Morrow, 3 Eileen M. Redmond, 3 and Paul A. Cahill Stem Cells Int. 468428. doi: 10.1155/2015/468428

Complex complexity Dionisio

This paper was referenced @1408 & @1124

Robust and precise morphogen-mediated patterning: trade-offs, constraints and mechanisms

Dionisio

Locusta has strong fly wings to ensure its long distance migration, but the molecular mechanism that regulates the Locusta wing development is poorly understood.

Sci Rep. 2017 Mar 16;7:44393. doi: 10.1038/srep44393. spalt is functionally conserved in Locusta and Drosophila to promote wing growth. Wang D1, Li J1, Liu S1, Zhou H1, Zhang L1, Shi W1, Shen J

Complex complexity Dionisio

The ability to recognize close kin confers survival benefits on single-celled microbes that live in complex and changing environments. Microbial kinship detection relies on perceptible cues that reflect relatedness between individuals, although the mechanisms underlying recognition in natural populations remain poorly understood. We hypothesize that the malleable property of TraA has allowed it to evolve and create social barriers between myxobacterial populations and in turn avoid adverse interactions with relatives.

Self-identity reprogrammed by a single residue switch in a cell surface receptor of a social bacterium. Cao P, Wall D Proc Natl Acad Sci U S A. 114(14):3732-3737. doi: 10.1073/pnas.1700315114.

Where's the beef? complex complexity. Dionisio

[...] we speculate that the maintenance of background biophotonic emissions may play a role in biophotonic energy storage in particular molecules such as proteins that may be involved in biophotonic signal transmission and encoding (action biophotons).

Reply to Salari et al.: Toward understanding the deep mechanisms regarding the biophotons related to human intelligence. Dai J1, Wang Z2, Li Z2, Xiao F3. Proc Natl Acad Sci U S A. 113(38):E5542-3. doi: 10.1073/pnas.1613416113.

Did somebody say "speculate"? :) Isn't that what Darwin did many years ago? Well, apparently he did worse than just speculating, because he grossly extrapolated the built-in variability framework seen in the biological systems and made up the so-called "evo theory" which is just a bunch of archaic pseudoscientific nonsensical daydreams worth much less than the ink that has been wasted to print it. complex complexity. Dionisio

We would like to thank Salari et al. for their interest in our paper (1) and to give a response to their concerns on the causation of spectral redshift of biophotons related to human intelligence (2). First, it is inappropriate to consider a brain slice (or whole brain) as a single light source to calculate the coherence length because a brain slice contains different types of neurons.

Reply to Salari et al.: Toward understanding the deep mechanisms regarding the biophotons related to human intelligence. Dai J1, Wang Z2, Li Z2, Xiao F3. Proc Natl Acad Sci U S A. 113(38):E5542-3. doi: 10.1073/pnas.1613416113.

OK, but please don't argue. Be nice to each other. :) complex complexity. Dionisio

[...] we believe that the experimental results presented do not directly support their conclusion. [...] the observed correlation does not reflect a causal relationship but rather an accidental coincidence. [...] the claim that the inhibition of PP2A induces the hyperphosphorylation of MAP tau and interferes with the function of microtubules is highly speculative.

Relationship between intelligence and spectral characteristics of brain biophoton emission: Correlation does not automatically imply causation Vahid Salari,a,b István Bókkon,c,d Roohollah Ghobadi,b,e,f Felix Scholkmann,g,h and Jack A. Tuszynski Proc Natl Acad Sci U S A. 113(38): E5540–E5541. doi: 10.1073/pnas.1612646113

Work in progress... stay tuned. :) complex complexity. Dionisio

Despite enormous efforts, any correlation between “intelligence” and cognitive or physiological/anatomical properties of animal brains is still poorly understood because intelligence depends on multiple factors in parallel and not a single determinant [...]

Relationship between intelligence and spectral characteristics of brain biophoton emission: Correlation does not automatically imply causation Vahid Salari,a,b István Bókkon,c,d Roohollah Ghobadi,b,e,f Felix Scholkmann,g,h and Jack A. Tuszynski Proc Natl Acad Sci U S A. 113(38): E5540–E5541. doi: 10.1073/pnas.1612646113

complex complexity. Dionisio

If optical communication along myelinated axons is indeed a reality, this would reveal a whole new aspect of the brain, with potential impacts on many fundamental questions in neuroscience.

Possible existence of optical communication channels in the brain Sourabh Kumar,1 Kristine Boone,1 Jack Tuszy?ski,2,3 Paul Barclay,1,4 and Christoph Simon Sci Rep. 6: 36508. doi: 10.1038/srep36508

complex complexity. Dionisio

[...] many fundamental questions in neuroscience are still open [...] The human brain is a dynamic physical system of unparalleled complexity. [...] many fundamental questions are still unanswered, including the processes underlying memory formation, the working principle of anesthesia, and–most fundamentally–the generation of conscious experience.

Possible existence of optical communication channels in the brain Sourabh Kumar,1 Kristine Boone,1 Jack Tuszy?ski,2,3 Paul Barclay,1,4 and Christoph Simon Sci Rep. 6: 36508. doi: 10.1038/srep36508

complex complexity. Dionisio

Cis-regulatory elements, such as promoters, enhancers and silencers, are involved in determining the spatio-temporal patterns of gene expression. [...] it could be hypothesized that the binding site in ICR3 likely represents a holder platform for a Fox pioneer factor inducing both early specific neurogenic activation and later expression maintenance.

An Intronic cis-Regulatory Element Is Crucial for the Alpha Tubulin Pl-Tuba1a Gene Activation in the Ciliary Band and Animal Pole Neurogenic Domains during Sea Urchin Development Salvatore Costa,#1 Aldo Nicosia,#2 Angela Cuttitta,2 Fabrizio Gianguzza,1 and Maria Antonietta Ragusa PLoS One. 12(1): e0170969. doi: 10.1371/journal.pone.0170969

complex complexity. Dionisio

For many years it was thought that [...] This study, as well as recent studies [...] challenge this idea.

An anterior signaling center patterns and sizes the anterior neuroectoderm of the sea urchin embryo. Range RC, Wei Z Development. 143(9):1523-33. doi: 10.1242/dev.128165.

we've seen that happen before, haven't we? complex complexity. Dionisio

[...] sFRP1/5 and Dkk3 diffuse extracellularly in an anterior-to-posterior gradient and Wnt1 and Wnt8 in a posterior-to-anterior gradient and both gradients work in concert to restrict the ANE around the anterior pole.

An anterior signaling center patterns and sizes the anterior neuroectoderm of the sea urchin embryo. Range RC, Wei Z Development. 143(9):1523-33. doi: 10.1242/dev.128165.

how is such a spatiotemporal mechanism established and activated? complex complexity. Dionisio

The exact mechanism by which sFRP1/5 either promotes or antagonizes Fzl5/8-JNK signaling is unclear.

An anterior signaling center patterns and sizes the anterior neuroectoderm of the sea urchin embryo. Range RC, Wei Z Development. 143(9):1523-33. doi: 10.1242/dev.128165.

exact mechanism? Oops! they used the same 'tricky' word 'exact' that the Canadian biochemistry professor didn't notice in a question I asked a couple of years ago. Apparently that tricky word made my question dishonest. Should we say that the above quoted statement is also dishonest? :) complex complexity. Dionisio

[...] the signaling pathways that mediate ANE positioning depend on positive inputs from both primary poles of the embryo.

An anterior signaling center patterns and sizes the anterior neuroectoderm of the sea urchin embryo. Range RC, Wei Z Development. 143(9):1523-33. doi: 10.1242/dev.128165.

hmm... that seems like an 'AND' logic gate, doesn't it? complex complexity. Dionisio

Taken together, these studies make it tempting to speculate that signaling centers that are active around the opposite pole to that of high Wnt/?-catenin signaling along the primary axis might be an ancient developmental mechanism essential for eumetazoan (cnidarians and bilaterians) body axis specification and patterning.

An anterior signaling center patterns and sizes the anterior neuroectoderm of the sea urchin embryo. Range RC, Wei Z Development. 143(9):1523-33. doi: 10.1242/dev.128165.

tempting to speculate? hmm... complex complexity. Dionisio

[...] FoxQ2 initiates an anterior patterning center that implements correct size and positions of ANE structures. [...] the sea urchin embryo uses an ancient anterior patterning system that was present in the common ambulacrarian/chordate ancestor.

An anterior signaling center patterns and sizes the anterior neuroectoderm of the sea urchin embryo. Range RC, Wei Z Development. 143(9):1523-33. doi: 10.1242/dev.128165.

how does FoxQ2 initiate an anterior patterning center? how does the anterior patterning center implement correct size and positions of ANE structures? how did this "patterning system" appear in the common ambulacrarian/chordate ancestor? complex complexity. Dionisio

[...] researchers within systems biology reintroduce the quest for design principles through mathematical and computational modeling of biological ‘big data’. I have argued for a unifying role of general principles, exemplified through case studies in systems biology where researchers identify design principles. Design principles signify general dependency relations between biological structures and functions through formally defined constraints. General principles address a different type of question. Biologists may ask which network designs can possibly afford the type of robustness observed in biological systems, or why some logically possible phenotypic patterns are not realized in any real-world biological system.

Node-based differential network analysis in genomics Xiao-Fei Zhang, Le Ou-Yang, Hong Yanc DOI: 10.1016/j.compbiolchem.2017.03.010 Computational biology and chemistry

Did somebody say "design"? Complex complexity. Dionisio

[...] EMFs form a distinct subgroup of multifunctional proteins exhibiting characteristics that distinguish them from hubs, classical multifunctional proteins and the network in general and can pave the way towards a better understanding of protein moonlighting.

Extreme multifunctional proteins identified from a human protein interaction network Charles E. Chapple,1,2 Benoit Robisson,1,2 Lionel Spinelli,1,2,3,4,5 Céline Guien,1,2,* Emmanuelle Becker,1,2,† and Christine Bruna Nat Commun. 6: 7412. doi: 10.1038/ncomms8412

Complex complexity. Dionisio

Protein multifunctionality may be one of the ways a cell makes more with less. That ELMs (i) can bind competitively or sequentially to different interaction partners in a context-dependant manner, (ii) provide a large panoply of conditional regulatory types through interactions19 and (iii) are more numerous in EMFs, provides a possible molecular explanation of the functional versatility of these proteins. This clearly calls for further studies.

Extreme multifunctional proteins identified from a human protein interaction network Charles E. Chapple,1,2 Benoit Robisson,1,2 Lionel Spinelli,1,2,3,4,5 Céline Guien,1,2,* Emmanuelle Becker,1,2,† and Christine Bruna Nat Commun. 6: 7412. doi: 10.1038/ncomms8412

Complex complexity. Dionisio

Revisiting generality in biology: systems biology and the quest for design principles Biology and Philosophy 30(5) DOI: 10.1007/s10539-015-9496-9 Sara Green Dionisio

Error in author's name @3450: The correct name is Sara Green Dionisio

one can easily tell they're struggling with the issue: Extracting Phenomena, Integrating Explanations, and Styling Representations: Some Frontiers for Philosophizing About Biology Nicholaos Jones Chapter · December 2017 DOI: 10.1007/978-3-319-47000-9_14 In book: Philosophy of Systems Biology, pp.147-156 Dionisio

A common reductionist assumption is that macro-scale behaviors can be described “bottom-up” if only sufficient details about lower-scale processes are available. The view that an “ideal” or “fundamental” physics would be sufficient to explain all macro-scale phenomena has been met with criticism from philosophers of biology. Specifically, scholars have pointed to the impossibility of deducing biological explanations from physical ones, and to the irreducible nature of distinctively biological processes such as gene regulation and evolution. This paper takes a step back in asking whether bottom-up modeling is feasible even when modeling simple physical systems across scales. By comparing examples of multi-scale modeling in physics and biology, we argue that the “tyranny of scales” problem presents a challenge to reductive explanations in both physics and biology. The problem refers to the scale-dependency of physical and biological behaviors that forces researchers to combine different models relying on different scale-specific mathematical strategies and boundary conditions. Analyzing the ways in which different models are combined in multi-scale modeling also has implications for the relation between physics and biology. Contrary to the assumption that physical science approaches provide reductive explanations in biology, we exemplify how inputs from physics often reveal the importance of macro-scale models and explanations. We illustrate this through an examination of the role of biomechanical modeling in developmental biology. In such contexts, the relation between models at different scales and from different disciplines is neither reductive nor completely autonomous, but interdependent.

Biology meets physics: Reductionism and multi-scale modeling of morphogenesis Sara Greena, Robert Batterman https://doi.org/10.1016/j.shpsc.2016.12.003 Studies in History and Philosophy of Science Part C: Studies in History and Philosophy of Biological and Biomedical Sciences Volume 61, February 2017, Pages 20–34

Complex complexity. Dionisio

It would be interesting to investigate whether decreased CDK1/Cyclin A coordinates this switch in attachment stability at the prometaphase to metaphase transition with the re-activation of PP1 and consequently with SAC silencing. This could explain how PP1 switches off the SAC despite elevated Cyclin B levels in early metaphase.

Protein Phosphatase 1 inactivates Mps1 to ensure efficient Spindle Assembly Checkpoint silencing Margarida Moura,1,2,† Mariana Osswald,1,2,† Nelson Leça,1,2 João Barbosa,1,2 António J Pereira,1,2 Helder Maiato,1,2,3 Claudio E Sunkel,1,2,4,* and Carlos Condi eLife. 2017; 6: e25366. doi: 10.7554/eLife.25366

Complex complexity Dionisio

Despite the rekindled interest in this century-old idea, the concept of cell assembly still remains ill-defined and its operational principle is poorly understood.

Theory of Connectivity: Nature and Nurture of Cell Assemblies and Cognitive Computation. Li M1, Liu J2, Tsien JZ Front Neural Circuits. 10:34. doi: 10.3389/fncir.2016.00034.

Complex complexity. Dionisio

Further testing of this power-of-two-based logic in additional neural circuits and animal species will be highly desirable, and exploring its applications in general artificial intelligence systems can also be informative. Collectively, such efforts will likely lead to a better understanding of how the brain’s logic is organized in specific circuits and how various other rules and properties might be integrated [...]

Brain Computation Is Organized via Power-of-Two-Based Permutation Logic Kun Xie,1,2,† Grace E. Fox,1,† Jun Liu,1,2,† Cheng Lyu,3,4,† Jason C. Lee,1,† Hui Kuang,1,† Stephanie Jacobs,1 Meng Li,1,2 Tianming Liu,3 Sen Song,5 and Joe Z. Tsien Front Syst Neurosci. 10: 95. doi: 10.3389/fnsys.2016.00095

Unfortunately this otherwise good paper does contain some text that is archaic pseudoscientific hogwash. Work in progress... stay tuned. Complex complexity. Dionisio

Perhaps it will be best approached by studying in simpler organisms (drosophila larvae) in which structural connectivity and functional imaging can be better analyzed [...] [...] further testing in the koniocortex and motor cortex, which have six-layered cortices, will be necessary. It will also be crucial to examine whether and how this logic operates [...] [...] it will be of considerable interest to examine how environmental and emotional contexts (including habituation vs. novelty) might affect cell-assembly response patterns in neural circuits.

Brain Computation Is Organized via Power-of-Two-Based Permutation Logic Kun Xie,1,2,† Grace E. Fox,1,† Jun Liu,1,2,† Cheng Lyu,3,4,† Jason C. Lee,1,† Hui Kuang,1,† Stephanie Jacobs,1 Meng Li,1,2 Tianming Liu,3 Sen Song,5 and Joe Z. Tsien Front Syst Neurosci. 10: 95. doi: 10.3389/fnsys.2016.00095

Unfortunately this otherwise good paper does contain some text that is archaic pseudoscientific hogwash. Work in progress... stay tuned. Complex complexity. Dionisio

Extending the similar multi-categorical investigations to other modulatory neuron types (such as serotonin, adrenergic or cholinergic neurons) will be necessary and informative. It will be of great interest to examine how neural ontogeny and circuit development lead to such a remarkably deterministic blueprint [...] It is widely believed that functional selectivity reflects the underlying structural connectivity. Although the specific-to-general coding patterns suggest their underlying wiring logic, the direct evidence for such wiring patterns awaits future demonstration.

Brain Computation Is Organized via Power-of-Two-Based Permutation Logic Kun Xie,1,2,† Grace E. Fox,1,† Jun Liu,1,2,† Cheng Lyu,3,4,† Jason C. Lee,1,† Hui Kuang,1,† Stephanie Jacobs,1 Meng Li,1,2 Tianming Liu,3 Sen Song,5 and Joe Z. Tsien Front Syst Neurosci. 10: 95. doi: 10.3389/fnsys.2016.00095

Work in progress... stay tuned. Complex complexity. Dionisio

[...] it has long been recognized that there is a need to establish the basic computational frameworks that may underlie the brain’s functions [...] The human brain is estimated to have approximately 86 billion neurons [...] and each neuron has tens of thousands of synapses [...] leading to over one hundred trillion synaptic connections. On top of this astronomical complexity, one needs to map each connection or neuron to a given stimulus, yet possible numbers of stimuli that can be used are infinite given the complex, ever-changing nature of the world we live in. Adding yet another layer of complexity to this seemingly hopeless situation are the well-known variations in the number of neurons, axonal/dendritic branches and synapses—not only over the course of development and aging, but also across individual brains and animal species.

Brain Computation Is Organized via Power-of-Two-Based Permutation Logic Kun Xie,1,2,† Grace E. Fox,1,† Jun Liu,1,2,† Cheng Lyu,3,4,† Jason C. Lee,1,† Hui Kuang,1,† Stephanie Jacobs,1 Meng Li,1,2 Tianming Liu,3 Sen Song,5 and Joe Z. Tsien Front Syst Neurosci. 10: 95. doi: 10.3389/fnsys.2016.00095

Complex complexity. Dionisio

This same paper has been referenced @523 & 1412-1413: Rethinking gene regulatory networks in light of alternative splicing, intrinsically disordered protein domains, and post-translational modifications Karl J. Niklas, Sarah E. Bondos, A. Keith Dunker and Stuart A. Newman Front. Cell Dev. Biol., http://dx.doi.org/10.3389/fcell.2015.00008 http://journal.frontiersin.org/article/10.3389/fcell.2015.00008/full#h1 Dionisio

Two approaches have been shown to decrease inter-sister kinetochore distances in old oocytes: first, increasing the oocyte levels of Mps1 to strengthen the SAC during MI exit and secondly, restoring the levels of securin to enhance separase inhibition in MII oocytes. [...] restoring securin levels or overexpressing Mps1 partially reverses the inter-sister kinetochore distance and decreases the frequency of premature sister chromatid separation (PSCS). These approaches both improve cohesion but they target the same pathway so are unlikely to be additive. However, combining one of these approaches with increasing Sgo2 to increase protection of centromeric cohesin may provide a highly effective combinatorial approach to improving the fidelity of chromosome number of oocytes in cases of advanced maternal age.

Maternal age-dependent APC/C-mediated decrease in securin causes premature sister chromatid separation in meiosis II Ibtissem Nabti, Rosanna Grimes, Hema Sarna, Petros Marangos & John Carroll Nature Communications 8, Article number: 15346 (2017) doi:10.1038/ncomms15346 https://www.nature.com/articles/ncomms15346

Had we stayed in Eden, none of this would have been an issue. Complex complexity. Dionisio

Sister chromatid attachment during meiosis II (MII) is maintained by securin-mediated inhibition of separase. In maternal ageing, oocytes show increased inter-sister kinetochore distance and premature sister chromatid separation (PSCS), suggesting aberrant separase activity. [...] maternal ageing compromises the oocyte SAC–APC/C axis leading to a decrease in securin that ultimately causes sister chromatid cohesion loss. Manipulating this axis and/or increasing securin may provide novel therapeutic approaches to alleviating the risk of oocyte aneuploidy in maternal ageing.

Maternal age-dependent APC/C-mediated decrease in securin causes premature sister chromatid separation in meiosis II Ibtissem Nabti, Rosanna Grimes, Hema Sarna, Petros Marangos & John Carroll Nature Communications 8, Article number: 15346 (2017) doi:10.1038/ncomms15346 https://www.nature.com/articles/ncomms15346

Had we stayed in Eden, none of this would have been an issue. Complex complexity. Dionisio

As several major BRAIN initiatives are just now getting under way, perhaps this is the right time to ponder the question: Imagine if all the molecular and cellular parts were made available, what is the basic design principle that evolution and development should employ in constructing brains? [...] one can at least take a page from what architects or product-design engineers have routinely done - ask what the basic function of the structure or product is, then try to come up with the corresponding design blueprint to achieve it.

A postulate on the brain’s basic wiring logic Joe Z Tsien Trends Neurosci. 38(11): 669–671. doi: 10.1016/j.tins.2015.09.002

Did somebody say 'design'? :) Complex complexity. Dionisio

Alzheimer's disease (AD) is the most common age-related dementia. Pathognomonic accumulation of cerebral ?-amyloid plaques likely results from imbalanced production and removal of amyloid-? (A?) peptides. In AD, innate immune cells lose their ability to restrict cerebral A? accumulation. At least in principle, mononuclear phagocytes can be enlisted to clear A?/?-amyloid from the brain. While the classical focus has been on dampening neuroinflammation in the context of AD, we hypothesize that rebalancing cerebral innate immunity by inhibiting actions of key anti-inflammatory cytokines returns the brain to a physiological state. Recent experiments demonstrating beneficial effects of blocking anti-inflammatory cytokine signaling in preclinical mouse models provide supportive evidence. This concept represents an important step toward innate immune-targeted therapy to combat AD.

Innate Immunity Fights Alzheimer's Disease Marie-Victoire Guillot-Sestier, Kevin R. Doty, Terrence Town https://doi.org/10.1016/j.tins.2015.08.008 Trends in Neuroscience - Cell Press Volume 38, Issue 11, Pages 674–681

Had we stayed in Eden, none of this would have been an issue. We made the wrong choice. Too late now. Complex complexity. Dionisio

Some problems in neuroscience are nearly solved. For others, solutions are decades away. The current pace of advances in methods forces us to take stock, to ask where we are going, and what we should research next.

The unsolved problems of neuroscience Ralph Adolphs https://doi.org/10.1016/j.tics.2015.01.007 Trends in Cognitive Sciences Volume 19, Issue 4, Pages 173-175

Complex complexity. Dionisio

There is currently no molecular explanation for how differences in sibling cell size could affect cell fate [...] Whether animal cells produce sibling cells that are equal or unequal in size seems to be tightly controlled during development. It is currently not clear how Klp10A regulates the size of centrosomes, or what molecular mechanisms regulate spindle asymmetry in germline stem cells and other systems. In the future it may be possible to develop tools that allow us to artificially change the relative sizes of sibling cells in order to investigate how this affects animal development.

Cell division: Sibling cell size matters Clemens Cabernard DOI: http://dx.doi.org/10.7554/eLife.24038 eLife 2017;6:e24038

Work in progress… stay tuned. Complex complexity. Dionisio

Cell division is a highly regulated and tightly choreographed process. It ensures that the DNA, organelles and other components in a cell are correctly distributed between the two "sibling" cells that are produced during the cell division process. A motor protein called Klp10A ensures that germline stem cells in male fruit flies divide to produce two sibling cells that are equal in size.

Cell division: Sibling cell size matters Clemens Cabernard DOI: http://dx.doi.org/10.7554/eLife.24038 eLife 2017;6:e24038

Did somebody say "tightly choreographed process"? Whose choreography? Complex complexity. Dionisio

Gametes are generated through a specialized cell division called meiosis, in which ploidy is reduced by half because two consecutive rounds of chromosome segregation, meiosis I and meiosis II, occur without intervening DNA replication. Cdc14 also regulates the meiosis I to meiosis II transition, though its mode of action has remained unclear. Unique, yet poorly understood, controls allow a second round of spindle formation, but prevent a second round of DNA replication. Cdc14 is required to re-license SPB duplication between meiosis I and meiosis II and that its retention in the nucleolus during early meiosis is required to allow SPB separation during meiosis I. The significance of the asymmetric localization of Cdc14 at the SPB during anaphase I therefore remains unexplained. Understanding how this is regulated to ensure step-by-step release of cohesion, spindle elongation and spindle disassembly at meiosis I is an important priority for the future.

Cdc14 phosphatase directs centrosome re-duplication at the meiosis I to meiosis II transition in budding yeast Colette Fox, Juan Zou, Juri Rappsilber and Adele L. Marston Wellcome Open Res. 2: 2. doi: 10.12688/wellcomeopenres.10507.1

Work in progress... stay tuned. Complex complexity. Dionisio

1 Modeling Asymmetric Cell Division in Caulobacter crescentus Using a Boolean Logic Approach . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Ismael Sanchez-Osorio, Carlos A. Hernandez-Mart?nez, and Agustino Mart?nez-Antonio 2 Spatiotemporal Models of the Asymmetric Division Cycle of Caulobacter crescentus . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 Kartik Subramanian and John J. Tyson 3 Intrinsic and Extrinsic Determinants Linking Spindle Pole Fate, Spindle Polarity, and Asymmetric Cell Division in the Budding Yeast S. cerevisiae . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49 Marco Geymonat and Marisa Segal 4 Wnt Signaling Polarizes C. elegans Asymmetric Cell Divisions During Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83 Arielle Koonyee Lam and Bryan T. Phillips 5 Asymmetric Cell Division in the One-Cell C. elegans Embryo: Multiple Steps to Generate Cell Size Asymmetry . . . . . . . . . . . . . . 115 Anne Pacquelet 6 Size Matters: How C. elegans Asymmetric Divisions Regulate Apoptosis . . . . . . . . . . . . . . . . . . . . . . . . . . 141 Jerome Teuliere and Gian Garriga 7 The Midbody and its Remnant in Cell Polarization and Asymmetric Cell Division . . . . . . . . . . . . . . . . . . . . . . . . . . 165 Christian Pohl 8 Drosophila melanogaster Neuroblasts: A Model for Asymmetric Stem Cell Divisions . . . . . . . . . . . . . . . . . . . . . . . . 183 Emmanuel Gallaud, Tri Pham, and Clemens Cabernard 9 Asymmetric Divisions in Oogenesis . . . . . . . . . . . . . . . . . . . . . . . . . 211 Szczepan M. Bilinski, Jacek Z. Kubiak, and Malgorzata Kloc 10 Asymmetric Localization and Distribution of Factors Determining Cell Fate During Early Development of Xenopus laevis . . . . . . . . . 229 Radek Sindelka, Monika Sidova, Pavel Abaffy, and Mikael Kubista 11 Asymmetries in Cell Division, Cell Size, and Furrowing in the Xenopus laevis Embryo . . . . . . . . . . . . . . . . . . . . . . . . . . 243 Jean-Pierre Tassan, Martin Wühr, Guillaume Hatte, and Jacek Kubiak 12 Asymmetric and Unequal Cell Divisions in Ascidian Embryos . . . . 261 Takefumi Negishi and Hiroki Nishida 13 Asymmetries and Symmetries in the Mouse Oocyte and Zygote . . . 285 Agathe Chaigne, Marie-Emilie Terret, and Marie-Helene Verlhac 14 Symmetry Does not Come for Free: Cellular Mechanisms to Achieve a Symmetric Cell Division . . . . . . . . . . . . . . . . . . . . . . . 301 Damian Dudka and Patrick Meraldi 15 A Comparative Perspective on Wnt/?-Catenin Signalling in Cell Fate Determination . . . . . . . . . . . . . . . . . . . . . . . . . . . 323 Clare L. Garcin and Shukry J. Habib 16 Extracellular Regulation of the Mitotic Spindle and Fate Determinants Driving Asymmetric Cell Division . . . . . . . . . . . . . . 351 Prestina Smith, Mark Azzam, and Lindsay Hinck 17 Regulation of Asymmetric Cell Division in Mammalian Neural Stem and Cancer Precursor Cells . . . . . . . . . . . . . . . . . . . . . . . . . . 375 Mathieu Daynac and Claudia K. Petritsch 18 Molecular Programs Underlying Asymmetric Stem Cell Division and Their Disruption in Malignancy . . . . . . . . . . . . . . . . . . . . . . . . 401 Subhas Mukherjee and Daniel J. Brat

Asymmetric Cell Division in Development, Differentiation and Cancer Editors: Jean-Pierre Tassan, Jacek Z. Kubiak ISBN: 978-3-319-53149-6 (Print) 978-3-319-53150-2 Book Results and Problems in Cell Differentiation Volume 61 2017

Complex complexity. Dionisio

[...] there is a need for a machinery that assures the delivery of genetic material into the elongating cell [...] [...] the mechanism of the movement of chromosomes remains unknown.

Unique Function of the Bacterial Chromosome Segregation Machinery in Apically Growing Streptomyces - Targeting the Chromosome to New Hyphal Tubes and its Anchorage at the Tips Agnieszka Kois-Ostrowska, Agnieszka Strzalka, Natalia Lipietta, Emma Tilley, Jolanta Zakrzewska-Czerwi?ska, Paul Herron, Dagmara Jakimowicz PLoS Genet 12(12):e1006488. doi:10.1371/journal.pgen.1006488

Did somebody say "there is a need"? Whose "need"? Complex complexity. Dionisio

@3427-3430 adjust the citation:

Unique Function of the Bacterial Chromosome Segregation Machinery in Apically Growing Streptomyces - Targeting the Chromosome to New Hyphal Tubes and its Anchorage at the Tips Agnieszka Kois-Ostrowska, Agnieszka Strzalka, Natalia Lipietta, Emma Tilley, Jolanta Zakrzewska-Czerwi?ska, Paul Herron, Dagmara Jakimowicz PLoS Genet 12(12):e1006488. doi:10.1371/journal.pgen.1006488

Dionisio

It is tempting to speculate that the role of ParB complexes at the chromosomes along the hyphae is to facilitate targeting of chromosomes to the newly forming branches by interacting with ParA. This would represent a new function of ParA and polarisome complexes during germination and formation of new branches.

Unique Function of the Bacterial Chromosome Segregation Machinery in Apically Growing Streptomyces - Targeting the Chromosome to New Hyphal Tubes and its Anchorage at the Tips Agnieszka Kois-Ostrowska, Agnieszka Strzalka, Natalia Lipietta, Emma Tilley, Jolanta Zakrzewska-Czerwi?ska, Paul Herron, Dagmara Jakimowicz PLoS Genet 12(12):e1006488. doi:10.1371/journal.pgen.1006488

Did somebody say "tempting to speculate" ? That seems like an honest statement. Complex complexity. Dionisio

Until now, it was believed that the function of the polar complex was to maintain the rigidity of the extending tip and to establish the cell wall synthesis machinery [...] We have revealed an additional function, which is to provide anchorage for the oriC of the apical chromosome.

Unique Function of the Bacterial Chromosome Segregation Machinery in Apically Growing Streptomyces - Targeting the Chromosome to New Hyphal Tubes and its Anchorage at the Tips Agnieszka Kois-Ostrowska, Agnieszka Strzalka, Natalia Lipietta, Emma Tilley, Jolanta Zakrzewska-Czerwi?ska, Paul Herron, Dagmara Jakimowicz

Did somebody say "it was believed"? Belief-based science? Shouldn't it be evidence-based instead? Did somebody say "additional function"? Complex complexity. Dionisio

[...] in vegetative hyphae every copy of the chromosome is complexed with ParB, whereas ParA, through interaction with the apical protein complex (polarisome), tightly anchors only one chromosome at the hyphal tip. The anchor is maintained during replication, when ParA captures one of the daughter oriCs. During spore germination and branching, ParA targets one of the multiple chromosomal copies to the new hyphal tip, enabling efficient elongation of hyphal tube. [...] our studies reveal a novel role for ParAB proteins during hyphal tip establishment and extension.

Unique Function of the Bacterial Chromosome Segregation Machinery in Apically Growing Streptomyces - Targeting the Chromosome to New Hyphal Tubes and its Anchorage at the Tips Agnieszka Kois-Ostrowska, Agnieszka Strzalka, Natalia Lipietta, Emma Tilley, Jolanta Zakrzewska-Czerwi?ska, Paul Herron, Dagmara Jakimowicz

Complex complexity. Dionisio

[...] the requirement for active chromosome segregation is unclear in the absence of canonical cell division during vegetative growth except in the process of branch formation. The mechanism by which chromosomes are targeted to new hyphae in streptomycete vegetative growth has remained unknown until now.

Unique Function of the Bacterial Chromosome Segregation Machinery in Apically Growing Streptomyces - Targeting the Chromosome to New Hyphal Tubes and its Anchorage at the Tips Agnieszka Kois-Ostrowska, Agnieszka Strzalka, Natalia Lipietta, Emma Tilley, Jolanta Zakrzewska-Czerwi?ska, Paul Herron, Dagmara Jakimowicz

Complex complexity. Dionisio

The coordination of chromosome segregation with cell growth is fundamental to the proliferation of any organism. In most unicellular bacteria, chromosome segregation is strictly coordinated with cell division and involves ParA that moves the ParB nucleoprotein complexes bi- or unidirectionally toward the cell pole(s). However, the chromosome organization in multiploid, apically extending and branching Streptomyces hyphae challenges the known mechanisms of bacterial chromosome segregation.

Unique Function of the Bacterial Chromosome Segregation Machinery in Apically Growing Streptomyces - Targeting the Chromosome to New Hyphal Tubes and its Anchorage at the Tips Agnieszka Kois-Ostrowska, Agnieszka Strzalka, Natalia Lipietta, Emma Tilley, Jolanta Zakrzewska-Czerwi?ska, Paul Herron, Dagmara Jakimowicz

Did somebody say "strictly coordinated"? Complex complexity. Dionisio

[...] Spo0M interacts with a molecular complex of proteins involved in cell division. There are still several open questions related to the functions of Spo0M in B. subtilis [...] [...] Spo0M is not only a regulator of sporulation but also plays an important role during the vegetative growth of the bacterium. An improved understanding of the multifunctional role of Spo0M will allow a better understanding of the different cell processes in which Spo0M participate and how this processes are related.

Analysis of Spo0M function in Bacillus subtilis Luz Adriana Vega-Cabrera1, Adan Guerrero2, Jose Luis Rodriguez-Mejia, Maria Luisa Tabche, Christopher D. Wood, Rosa-Maria Gutierrez-Rios, Enrique Merino, Liliana Pardo-Lopez DOI: 10.1371/journal.pone.0172737 PLoS ONE 12(2):e0172737

Work in progress... stay tuned. Complex complexity. Dionisio

Spo0M has been previously reported as a regulator of sporulation in Bacillus subtilis; however, little is known about the mechanisms through which it participates in sporulation, and there is no information to date that relates this protein to other processes in the bacterium. [...] Spo0M function is not necessarily restricted to sporulation [...] [...] Spo0M interacts with cytoskeletal proteins involved in cell division [...] Spo0M expression is not restricted to the transition phase or sporulation; rather, its expression begins during the early stages of growth and Spo0M localization in B. subtilis depends on the bacterial life cycle and could be related to an additional proposed function. Our work paves the way for re-evaluation of the role of Spo0M in bacterial cell.

Analysis of Spo0M function in Bacillus subtilis Luz Adriana Vega-Cabrera1, Adan Guerrero2, Jose Luis Rodriguez-Mejia, Maria Luisa Tabche, Christopher D. Wood, Rosa-Maria Gutierrez-Rios, Enrique Merino, Liliana Pardo-Lopez DOI: 10.1371/journal.pone.0172737 PLoS ONE 12(2):e0172737

Did somebody say "re-evaluation of the role"? Complex complexity. Dionisio

The gram-negative bacterium Caulobacter crescentus is a powerful model organism for studies of bacterial cell cycle regulation. Although the major regulators and their connections in Caulobacter have been identified, it still is a challenge to properly understand the dynamics of its circuitry which accounts for both cell cycle progression and arrest. [...] the key decision module in Caulobacter is built from a limit cycle oscillator which controls the DNA replication program. The effect of an induced cell cycle arrest is demonstrated to be a key feature to classify the underlying dynamics.

Core-oscillator model of Caulobacter crescentus Yves Vandecan, Emanuele Biondi, and Ralf Blossey Phys. Rev. E 93, 062413 DOI: 10.1103/PhysRevE.93.062413

Complex complexity. Dionisio

On the one hand, what we currently know about the regulatory network that controls the cell cycle in C. crescentus is the fact that it directs a robust and complex process, able to buffer perturbations on the network without propagating dysfunction. On the other hand, the relatively long cascade of kinases and proteolytic proteins makes the network sensitive enough to respond to multiple environmental conditions.

Dynamical Modeling of the Cell Cycle and Cell Fate Emergence in Caulobacter crescentus César Quiñones-Valles, Ismael Sánchez-Osorio, Agustino Martínez-Antonio DOI: 10.1371/journal.pone.0111116 PLoS ONE 9(11):e111116

Complex complexity. Dionisio

The division of Caulobacter crescentus, a model organism for studying cell cycle and differentiation in bacteria, generates two cell types: swarmer and stalked. To complete its cycle, C. crescentus must first differentiate from the swarmer to the stalked phenotype. An important regulator involved in this process is CtrA, which operates in a gene regulatory network and coordinates many of the interactions associated to the generation of cellular asymmetry. The entire network is shown to be operating close to the critical regime, which means that it is robust enough to perturbations on dynamics of the network, but adaptable to environmental changes.

Dynamical Modeling of the Cell Cycle and Cell Fate Emergence in Caulobacter crescentus César Quiñones-Valles, Ismael Sánchez-Osorio, Agustino Martínez-Antonio DOI: 10.1371/journal.pone.0111116 PLoS ONE 9(11):e111116

Complex complexity. Dionisio

Although the MICAL family members have clearly emerged as essential regulators of actin dynamics in many cellular functions, several important questions need to be addressed.

Emerging roles of MICAL family proteins – from actin oxidation to membrane trafficking during cytokinesis Stéphane Frémont, Guillaume Romet-Lemonne, Anne Houdusse, Arnaud Echard J Cell Sci 130: 1509-1517; doi: 10.1242/jcs.202028

Work in progress... stay tuned. Complex complexity. Dionisio

Future studies are needed to better understand the differential roles of each Rab-binding site in determining the localization and functions of MICAL proteins in cells. In addition to the factors that determine the localization of MICALs, another key question is to understand how their enzymatic activity is activated to control F-actin disassembly at the right time and place.

Emerging roles of MICAL family proteins – from actin oxidation to membrane trafficking during cytokinesis Stéphane Frémont, Guillaume Romet-Lemonne, Anne Houdusse, Arnaud Echard J Cell Sci 130: 1509-1517; doi: 10.1242/jcs.202028

Complex complexity. Dionisio

Recently, two independent studies including ours solved the structure of thisMICAL1 domain by X-ray crystallography (Frémont et al., 2017; Rai et al., 2016). Surprisingly, the structure consists of a curved sheet of three helices, exposing two opposite flat surfaces and thus differs from most three-helix folds, which usually form compact bundles.

Emerging roles of MICAL family proteins – from actin oxidation to membrane trafficking during cytokinesis Stéphane Frémont, Guillaume Romet-Lemonne, Anne Houdusse, Arnaud Echard J Cell Sci 130: 1509-1517; doi: 10.1242/jcs.202028

Did somebody say “Surprisingly”? Complex complexity. Dionisio

It should be pointed out that approximately half of the MICAL1-depleted cells undergo abscission with normal timing, suggesting that additional as-yet-unknown mechanisms must exist in order to clear F-actin from intercellular bridges in the absence of MICAL1 (Frémont et al., 2017).

Emerging roles of MICAL family proteins – from actin oxidation to membrane trafficking during cytokinesis Stéphane Frémont, Guillaume Romet-Lemonne, Anne Houdusse, Arnaud Echard J Cell Sci 130: 1509-1517; doi: 10.1242/jcs.202028

Complex complexity. Dionisio

Surprisingly, we found that MICAL1 induces rapid depolymerization from both ends of the filaments with no sign of severing [...]

Emerging roles of MICAL family proteins – from actin oxidation to membrane trafficking during cytokinesis Stéphane Frémont, Guillaume Romet-Lemonne, Anne Houdusse, Arnaud Echard J Cell Sci 130: 1509-1517; doi: 10.1242/jcs.202028

Did somebody say “Surprisingly”? Complex complexity. Dionisio

[...] MsrB1 has a regulatory role as a MICAL1 antagonist in orchestrating actin dynamics and macrophage function [...] Whether SelR and MsrBs also counteract MICAL1 function during cytokinesis is an open question that should be addressed in future studies.

Emerging roles of MICAL family proteins – from actin oxidation to membrane trafficking during cytokinesis Stéphane Frémont, Guillaume Romet-Lemonne, Anne Houdusse, Arnaud Echard J Cell Sci 130: 1509-1517; doi: 10.1242/jcs.202028

Did somebody say "orchestrating"? Complex complexity. Dionisio

Knowing the precise mechanism of how MICAL proteins act on the actin cytoskeleton and how their activities are fine-tuned in space and time are essential for understanding the physiological functions of MICALs in normal cells, as well as in the context of disease (Wilson et al., 2016).

Emerging roles of MICAL family proteins – from actin oxidation to membrane trafficking during cytokinesis Stéphane Frémont, Guillaume Romet-Lemonne, Anne Houdusse, Arnaud Echard J Cell Sci 130: 1509-1517; doi: 10.1242/jcs.202028

Did somebody say "fine-tuned in space and time"? Complex complexity. Dionisio

Faithful cell division is crucial for the maintenance of genomic integrity, development and tissue homeostasis. At the end of cell division, cytokinesis drives the physical separation of the two daughter cells. [...] the mechanisms that remove F-actin in the intercellular bridge are not fully understood. Recently, we revealed an unexpected role for oxidoreduction in triggering local actin depolymerization during cytokinesis [...]

Emerging roles of MICAL family proteins – from actin oxidation to membrane trafficking during cytokinesis Stéphane Frémont, Guillaume Romet-Lemonne, Anne Houdusse, Arnaud Echard J Cell Sci 130: 1509-1517; doi: 10.1242/jcs.202028

Did somebody say “unexpected”? Why? Did they expect something else or nothing at all? Complex complexity. Dionisio

[...] microtubules and actin filaments must be locally disassembled for successful abscission. However, the mechanism that actively removes actin during abscission is poorly understood.

Emerging roles of MICAL family proteins – from actin oxidation to membrane trafficking during cytokinesis Stéphane Frémont, Guillaume Romet-Lemonne, Anne Houdusse, Arnaud Echard J Cell Sci 130: 1509-1517; doi: 10.1242/jcs.202028

Complex complexity. Dionisio

Cytokinetic abscission is the terminal step of cell division, leading to the physical separation of the two daughter cells. The exact mechanism mediating the final scission of the intercellular bridge connecting the dividing cells is not fully understood, but requires the local constriction of endosomal sorting complex required for transport (ESCRT)-III-dependent helices, as well as remodelling of lipids and the cytoskeleton at the site of abscission.

Emerging roles of MICAL family proteins – from actin oxidation to membrane trafficking during cytokinesis Stéphane Frémont, Guillaume Romet-Lemonne, Anne Houdusse, Arnaud Echard J Cell Sci 130: 1509-1517; doi: 10.1242/jcs.202028

Complex complexity. Dionisio

Cytokinesis is the terminal step of cell division and leads to the physical separation of daughter cells. [...] MICAL1 binding to Rab35 not only localizes MICAL1 in late cytokinetic bridges, but also activates monooxygenase activity. Oxidoreduction is one of the most fundamental processes in living organisms and plays a pivotal role in metabolic reactions. [...] this study highlights the critical role of controlled actin oxidation in cytoskeleton dynamics and reveals an unexpected role of oxidoreduction in cell division.

Oxidation of F-actin controls the terminal steps of cytokinesis Stéphane Frémont, Hussein Hammich, Jian Bai, Hugo Wioland, Kerstin Klinkert, Murielle Rocancourt, Carlos Kikuti, David Stroebel, Guillaume Romet-Lemonne, Olena Pylypenko, Anne Houdusse & Arnaud Echard Nature Communications 8, Article number: 14528 doi:10.1038/ncomms14528

Did somebody say “unexpected”? Why? Did they expect something else or nothing at all? Complex complexity. Dionisio

#3409 error: Obviously it's "Why?" not "wy?" Dionisio

Cytokinetic abscission, the terminal step of cell division, crucially depends on the local constriction of ESCRT-III helices after cytoskeleton disassembly. While the microtubules of the intercellular bridge are cut by the ESCRT-associated enzyme Spastin, the mechanism that clears F-actin at the abscission site is unknown. Our work reveals an unexpected role for oxidoreduction in triggering local actin depolymerization to control a fundamental step of cell division.

Oxidation of F-actin controls the terminal steps of cytokinesis Stéphane Frémont, Hussein Hammich, Jian Bai, Hugo Wioland, Kerstin Klinkert, Murielle Rocancourt, Carlos Kikuti, David Stroebel, Guillaume Romet-Lemonne, Olena Pylypenko, Anne Houdusse & Arnaud Echard Nature Communications 8, Article number: 14528 doi:10.1038/ncomms14528

Did somebody say "unexpected"? Wy? Did they expect something else or nothing at all? Complex complexity. Dionisio

[...] the MEN pathway must act through a so far unidentified target to influence meiotic plaque formation.

The mitotic exit network [MEN] regulates spindle pole body selection during sporulation of Saccharomyces cerevisiae (MEN role in meiotic SPB inheritance) Christian Renicke, Ann-Katrin Allmann, Anne Pia Lutz, Thomas Heimerl and Christof Taxis Genetics Volume 206 Issue 1 DOI: 10.1534/genetics.116.194522

Work in progress... stay tuned. Complex complexity. Dionisio

We cannot fully explain the phenotypic differences of the two mutants.

The mitotic exit network [MEN] regulates spindle pole body selection during sporulation of Saccharomyces cerevisiae (MEN role in meiotic SPB inheritance) Christian Renicke, Ann-Katrin Allmann, Anne Pia Lutz, Thomas Heimerl and Christof Taxis Genetics Volume 206 Issue 1 DOI: 10.1534/genetics.116.194522

Is there anything they can fully explain? Complex complexity. Dionisio

Surprisingly, we found a positive effect of Nud1 depletion on spore numbers conversely to that of the nud1-2 allele (Gordon et al. 2006), pointing to an inhibitory function of Nud1 on MP formation.

The mitotic exit network [MEN] regulates spindle pole body selection during sporulation of Saccharomyces cerevisiae (MEN role in meiotic SPB inheritance) Christian Renicke, Ann-Katrin Allmann, Anne Pia Lutz, Thomas Heimerl and Christof Taxis Genetics Volume 206 Issue 1 DOI: 10.1534/genetics.116.194522

Did somebody say “Surprisingly”? Why? (see comment @3401) Complex complexity. Dionisio

An interesting[*] question is the intrinsic activation mechanism of the MEN. The high conservation of Hippo signaling provokes[**] the question if a similar activation mechanism is in place in budding yeast meiosis.

The mitotic exit network [MEN] regulates spindle pole body selection during sporulation of Saccharomyces cerevisiae (MEN role in meiotic SPB inheritance) Christian Renicke, Ann-Katrin Allmann, Anne Pia Lutz, Thomas Heimerl and Christof Taxis Genetics Volume 206 Issue 1 DOI: 10.1534/genetics.116.194522

(*) there are many interesting questions in Biology (**) many things in Biology provoke questions Complex complexity. Dionisio

Surprisingly, Mob1? or Dbf2? Dbf20? mutants had a much weaker sporulation defect than the triple mutant. Thus, the coactivator Mob1 and/or the kinases Dbf2/20 might form sporulation-specific complexes with yet unknown binding partners.

The mitotic exit network [MEN] regulates spindle pole body selection during sporulation of Saccharomyces cerevisiae (MEN role in meiotic SPB inheritance) Christian Renicke, Ann-Katrin Allmann, Anne Pia Lutz, Thomas Heimerl and Christof Taxis Genetics Volume 206 Issue 1 DOI: 10.1534/genetics.116.194522

Did somebody say "Surprisingly"? Why? (see comment @3401) Complex complexity. Dionisio

In mitosis, the MEN is required for establishment of spindle polarity [...] During the developmental program of sporulation, a rewiring of the MEN takes place.

The mitotic exit network [MEN] regulates spindle pole body selection during sporulation of Saccharomyces cerevisiae (MEN role in meiotic SPB inheritance) Christian Renicke, Ann-Katrin Allmann, Anne Pia Lutz, Thomas Heimerl and Christof Taxis Genetics Volume 206 Issue 1 DOI: 10.1534/genetics.116.194522

Did somebody say "rewiring"? Complex complexity. Dionisio

The decision how many and which SPBs and their associated genomes will be incorporated into spores takes place at the onset of meiosis II by formation of meiotic plaques at selected SPBs [...]

The mitotic exit network [MEN] regulates spindle pole body selection during sporulation of Saccharomyces cerevisiae (MEN role in meiotic SPB inheritance) Christian Renicke, Ann-Katrin Allmann, Anne Pia Lutz, Thomas Heimerl and Christof Taxis Genetics Volume 206 Issue 1 DOI: 10.1534/genetics.116.194522

Did somebody say "decision"? Who decides? Complex complexity. Dionisio

***** --- oOo --- ***** The words "surprisingly", "unexpectedly", "strikingly" sometimes could be justified because they may point to a flaw in the experiment or to a mistake in its sequence of steps. However, we could assume that by the time the paper was printed out it had gone through a number of reviews that could have detected any mistakes in the experiment. That's why it's valid to ask about the reasons for those words to be used. ***** --- oOo --- ***** Dionisio

Surprisingly, in contrast to the nud1-2 allele, depletion of Nud1 induced higher spore numbers per ascus accompanied by a modest increase of unsporulated cells, whereas the sporulation efficiency was not significantly increased [...]

The mitotic exit network regulates spindle pole body selection during sporulation of Saccharomyces cerevisiae (MEN role in meiotic SPB inheritance) Christian Renicke, Ann-Katrin Allmann, Anne Pia Lutz, Thomas Heimerl and Christof Taxis Genetics Volume 206 Issue 1 DOI: 10.1534/genetics.116.194522

Did somebody say "Surprisingly"? Why? Did they expect something else or nothing at all? :) Complex complexity. Dionisio

How meiotic cells discriminate between the different SPBs and generate a signal for MP formation is still an open question. [...] MP grows rapidly due to a positive feedback mechanism until saturation is reached.

The mitotic exit network regulates spindle pole body selection during sporulation of Saccharomyces cerevisiae (MEN role in meiotic SPB inheritance) Christian Renicke, Ann-Katrin Allmann, Anne Pia Lutz, Thomas Heimerl and Christof Taxis Genetics Volume 206 Issue 1 DOI: 10.1534/genetics.116.194522

Complex complexity. Dionisio

Differential inheritance of centrosomes or corresponding structures can be observed in many organisms ranging from simple, unicellular fungi to mammals [...] During gametogenesis of S. cerevisiae, which is called sporulation, the situation is even more complex due to the higher number of genomes that must be faithfully distributed. In this developmental program, spore formation is coupled to meiotic divisions resulting in the formation of four haploid genomes encapsulated by spore walls and contained within the remnants of the former mother cell, then called an ascus [...]

The mitotic exit network regulates spindle pole body selection during sporulation of Saccharomyces cerevisiae Christian Renicke, Ann-Katrin Allmann, Anne Pia Lutz, Thomas Heimerl and Christof Taxis Genetics Volume 206 Issue 1 DOI: 10.1534/genetics.116.194522

Did somebody say "program"? Complex complexity. Dionisio

The budding yeast Polo-like kinase Cdc5 regulates multiple mitotic events including mitotic entry, chromosome segregation, mitotic exit, and cytokinesis [...] Whether Bfa1 retains Cdc5 at the dSPB in late anaphase to promote cytokinesis will be an interesting future study. Studying the roles of Cdc5 at each of its SPB populations will be important to explain the timing of the functions of this very complex protein during the cell cycle.

The budding yeast Polo-like kinase localizes to distinct populations at centrosomes during mitosis Vladimir V. Botchkarev Jr., Mikael V. Garabedian, Brenda Lemos, Eric Paulissen, and James E. Haber DOI: 10.1091/mbc.E16-05-0324 Molecular biology of the cell

Complex complexity. Dionisio

Depending on their assembly state, septin-based structures provide dynamic platforms from which the action of a significant number of protein kinases can be directed both spatially and temporally. [...] these kinases also regulate septin structure and organization, establishing an extremely complex feedback system which is yet to be fully understood. [...] there are still many mechanistic aspects of the control of septin-associated protein kinases that remain to be delineated. [...] this area of cell biology and biochemistry remains a fertile area for exploring the role of cellular structures in regulating signaling enzymes, and vice versa.

Septin-Associated Protein Kinases in the Yeast Saccharomyces cerevisiae Adam M.Perez, Gregory C. Finnigan, Françoise M. Roelants and Jeremy Thorner Front. Cell Dev. Biol. Emerging Functions of Septins DOI: 10.3389/fcell.2016.00119

Work in progress... stay tuned. Complex complexity. Dionisio

The actions of several septin-associated protein kinases also seem to regulate septin organization. Perhaps phosphorylation of Shs1 by Cdks and Gin4 is redundant with additional mechanisms that regulate septin assembly, but the precise consequence of these phosphorylation events on septin structure and/or function remains unclear.

Septin-Associated Protein Kinases in the Yeast Saccharomyces cerevisiae Adam M.Perez, Gregory C. Finnigan, Françoise M. Roelants and Jeremy Thorner Front. Cell Dev. Biol. Emerging Functions of Septins DOI: 10.3389/fcell.2016.00119

Complex complexity. Dionisio

The mechanisms responsible for the cell cycle-coupled ejection of Gin4 and the recruitment of Fpk1 are not known [...] [...] by the spatio-temporal control that Gin4 exerts on Fpk1 activity, it is clear that the septins at the bud neck are critical for protein kinase-mediated regulation of localized PM remodeling.

Septin-Associated Protein Kinases in the Yeast Saccharomyces cerevisiae Adam M.Perez, Gregory C. Finnigan, Françoise M. Roelants and Jeremy Thorner Front. Cell Dev. Biol. Emerging Functions of Septins DOI: 10.3389/fcell.2016.00119

Complex complexity. Dionisio

The dynamic relocation of the protein kinases of the MEN cascade to the split septin collar provides an elegant solution to help ensure that cell division only occurs after successful chromosome segregation. However, the mechanisms that promote recruitment of these kinases to the septins are unknown. Moreover, the SPOC protein kinase Kin4 also localizes to the septin rings late in anaphase, yet its function at the bud neck is not understood.

Septin-Associated Protein Kinases in the Yeast Saccharomyces cerevisiae Adam M.Perez, Gregory C. Finnigan, Françoise M. Roelants and Jeremy Thorner Front. Cell Dev. Biol. Emerging Functions of Septins DOI: 10.3389/fcell.2016.00119

Did somebody say "elegant solution"? Complex complexity. Dionisio

[...] the protein target (s) at each location that carry the phospho-epitopes to which the polo boxes bind have not been well defined. [...] the septin collar is the passageway through which any and all components segregated between a mother and daughter cell must pass and, hence, is a cellular structure ideally situated to monitor such cell cycle events.

Septin-Associated Protein Kinases in the Yeast Saccharomyces cerevisiae Adam M.Perez, Gregory C. Finnigan, Françoise M. Roelants and Jeremy Thorner Front. Cell Dev. Biol. Emerging Functions of Septins DOI: 10.3389/fcell.2016.00119

Complex complexity. Dionisio

[...] we highlight key regulatory pathways that use the septin cytoskeleton as a signaling platform to direct other orchestrated events required for successful passage through the cell cycle.

Septin-Associated Protein Kinases in the Yeast Saccharomyces cerevisiae Adam M.Perez, Gregory C. Finnigan, Françoise M. Roelants and Jeremy Thorner Front. Cell Dev. Biol. Emerging Functions of Septins DOI: 10.3389/fcell.2016.00119

Did somebody say "orchestrated"? Complex complexity. Dionisio

Hsl7 is a substrate of Hsl1 (Cid et al., 2001), and Hsl1 is also extensively autophosphorylated (Barral et al., 1999), but the functional consequences of these modifications remain to be determined.

Septin-Associated Protein Kinases in the Yeast Saccharomyces cerevisiae Adam M.Perez, Gregory C. Finnigan, Françoise M. Roelants and Jeremy Thorner Front. Cell Dev. Biol. Emerging Functions of Septins DOI: 10.3389/fcell.2016.00119

Complex complexity. Dionisio

[...] it is still not completely clear how many of these enzymes contribute directly to installing post-translational modifications on septins and/or septin-associated proteins that drive the observed dynamic changes in septin structure during cell cycle progression and how many of these enzymes are recruited to septin structures as “readers” of the status of septin assembly to phosphorylate other substrates and thereby drive subsequent downstream events.

Septin-Associated Protein Kinases in the Yeast Saccharomyces cerevisiae Adam M.Perez, Gregory C. Finnigan, Françoise M. Roelants and Jeremy Thorner Front. Cell Dev. Biol. Emerging Functions of Septins DOI: 10.3389/fcell.2016.00119

Complex complexity. Dionisio

Virtually all recognized checkpoint mechanisms involve regulation by reversible protein phosphorylation mediated by protein kinases and phosphoprotein phosphatases [...]

Septin-Associated Protein Kinases in the Yeast Saccharomyces cerevisiae Adam M.Perez, Gregory C. Finnigan, Françoise M. Roelants and Jeremy Thorner Front. Cell Dev. Biol. Emerging Functions of Septins DOI: 10.3389/fcell.2016.00119

Complex complexity. Dionisio

Septins are a family of eukaryotic GTP-binding proteins that associate into linear rods, which, in turn, polymerize end-on-end into filaments, and further assemble into other, more elaborate super-structures at discrete subcellular locations. Hence, septin-based ensembles are considered elements of the cytoskeleton. [...] septin structures represent a regulatory node at the intersection of many signaling pathways. In addition, and importantly, the activities of certain septin-associated protein kinases also regulate the state of organization of the septins themselves, creating a complex feedback loop.

Septin-Associated Protein Kinases in the Yeast Saccharomyces cerevisiae Adam M.Perez, Gregory C. Finnigan, Françoise M. Roelants and Jeremy Thorner Front. Cell Dev. Biol. Emerging Functions of Septins DOI: 10.3389/fcell.2016.00119

Complex complexity. Dionisio

[...] the molecular mechanism of competition between tropomyosins and ?-actinin for actin filament binding needs to be elucidated. Tropomyosins are well-established regulators of myosin II activity in muscle sarcomeres. [...] actin filaments decorated by different tropomyosin isoforms display distinct functional properties. [...] filament severing by ADF/cofilins is greatly enhanced by their co-factors, including coronin, and Aip1 in cells [35], adding more complexity to the system. The molecular mechanism underlying tropomyosin isoform segregation along actin filaments remains to be elucidated. [...] tropomyosins decorate the two structurally identical grooves along an actin filament, and thus their segregation cannot be solely determined by head-to-tail associations (i.e., some coordination must exist between the two tropomyosin-binding grooves when filament segments decorated by only one tropomyosin isoform exist). [...] the mechanisms by which different tropomyosin isoforms are targeted to their specific cellular destinations remain to be elucidated. [...] these formins may provide the link between actin filament nucleation and incorporation of specific tropomyosin isoforms into the different regions of the stress fiber network.

Tropomyosin Isoforms Specify Functionally Distinct Actin Filament Populations In Vitro. Gateva G, Kremneva E, Reindl T, Kotila T, Kogan K, Gressin L, Gunning PW, Manstein DJ, Michelot A, Lappalainen P Curr Biol. 27(5):705-713. doi: 10.1016/j.cub.2017.01.018.

Work in progress… stay tuned. Complex complexity. Dionisio

Actin filaments assemble into a variety of networks to provide force for diverse cellular processes [...] Tropomyosins are coiled-coil dimers that form head-to-tail polymers along actin filaments and regulate interactions of other proteins [...] [...] tropomyosin isoforms segregate to different actin filaments and specify functional properties of distinct actin filament populations.

Tropomyosin Isoforms Specify Functionally Distinct Actin Filament Populations In Vitro. Gateva G, Kremneva E, Reindl T, Kotila T, Kogan K, Gressin L, Gunning PW, Manstein DJ, Michelot A, Lappalainen P Curr Biol. 27(5):705-713. doi: 10.1016/j.cub.2017.01.018.

Complex complexity. Dionisio

The septins are a conserved family of GTP-binding proteins present in all eukaryotic cells except plants. The septins are regulators of spatial compartmentalization in yeast and act as key players in cytokinesis. Structure determination, the evaluation of the role of posttranslational modifications of the septins and the uncovering of so far unknown septin related processes in the living cell will represent the challenges for septin biologists for the next decade.

Septin Organization and Functions in Budding Yeast Oliver Glomb and Thomas Gronemeyer Front Cell Dev Biol. 4: 123. doi: 10.3389/fcell.2016.00123

Work in progress... stay tuned. Complex complexity. Dionisio

Cytokinesis is essential for the survival of all organisms. It requires concerted functions of cell signaling, force production, exocytosis, and extracellular matrix remodeling. Due to the conservation in core components and mechanisms between fungal and animal cells, the budding yeast Saccharomyces cerevisiae has served as an attractive model for studying this fundamental process.

Mechanics and regulation of cytokinesis in budding yeast Yogini P. Bhavsar-Jog, Erfei Bi DOI: 10.1016/j.semcdb.2016.12.010 Seminars in Cell and Developmental Biology

Complex complexity. Dionisio

Understanding the mechanisms that allow some cells but not others to escape the SPoC-mediated anaphase arrest will be an important next step in understanding the MEN and checkpoint control of the cell cycle.

LTE1 promotes exit from mitosis by multiple mechanisms Jill E. Falk, Ian W. Campbell, Kelsey Joyce, Jenna Whalen, Anupama Seshan, and Angelika Amon Mol Biol Cell. 27(25): 3991–4001. doi: 10.1091/mbc.E16-08-0563

Work in progress... stay tuned. Complex complexity. Dionisio

Another potential example of a situation where what seems like a bug could turn out a practical feature --using software development jargon.

This observation could have been dismissed as a leakiness of the SPoC, that is, as being the result of suboptimal regulatory mechanisms. However, the observation that the checkpoint arrest is irreversible in FEAR network mutants raises the possibility that there is perhaps purpose to this leakiness.

LTE1 promotes exit from mitosis by multiple mechanisms Jill E. Falk, Ian W. Campbell, Kelsey Joyce, Jenna Whalen, Anupama Seshan, and Angelika Amon Mol Biol Cell. 27(25): 3991–4001. doi: 10.1091/mbc.E16-08-0563

Complex complexity. Dionisio

[...] both an in-depth biochemical analysis of Lte1 and further examination of how Lte1’s GEF domains activate the MEN are critical to elucidate the function of Lte1. [...] an additional layer of control, the so-called spindle position checkpoint, becomes important. This regulatory mechanism buys the cell time during anaphase so that it can thread the anaphase spindle into the bud.

LTE1 promotes exit from mitosis by multiple mechanisms Jill E. Falk, Ian W. Campbell, Kelsey Joyce, Jenna Whalen, Anupama Seshan, and Angelika Amon Mol Biol Cell. 27(25): 3991–4001. doi: 10.1091/mbc.E16-08-0563

An additional layer of control? Another one? A regulatory mechanism that buys time purposely? Huh? Complex complexity. Dionisio

Polarized cell division is a defining characteristic of development and one mechanism by which cells produce progeny with distinct cell fates [...] Because these asymmetric cell divisions rely on the unequal distribution of fate determinants within the cell, it is critical that the mitotic spindle and hence the plane of cell division are correctly placed with respect to these spatially restricted developmental cues. Evidence suggests that feedback mechanisms that sense spindle position are in place to ensure that this occurs. [...] control of the MEN [mitotic exit network] by spindle position is exerted by both negative and positive regulatory elements that control the pathway’s GTPase activity.

LTE1 promotes exit from mitosis by multiple mechanisms Jill E. Falk, Ian W. Campbell, Kelsey Joyce, Jenna Whalen, Anupama Seshan, and Angelika Amon Mol Biol Cell. 27(25): 3991–4001. doi: 10.1091/mbc.E16-08-0563

How did we get those "sensing feedback mechanisms" to begin with? Complex complexity. Dionisio

[...] local satisfaction of checkpoints seems to be sufficient for global checkpoint silencing in binucleated cells. [...] misbalanced checkpoint integrity in binucleated cells might be a driver for genome instability and cancer development.

A FRET-based study reveals site-specific regulation of spindle position checkpoint proteins at yeast centrosomes Yuliya Gryaznova, Ayse Koca Caydasi, Gabriele Malengo, Victor Sourjik and Gislene Pereira eLife. 5: e14029. doi: 10.7554/eLife.14029

Had we stayed in Eden none of this would have been an issue. Like Sinatra, we preferred to do things our way. Too late now. Human history is messed up. The good news is that the ultimate remedy for the malady has been revealed and graciously offered to all. Now it's up to each of us to accept it and enjoy it. Complex complexity. Dionisio

[...] cell polarity associated factors play a critical role in SPOC silencing and mitotic exit [...] The molecular characterization of these factors, which were undermined in the last decade, will be critical to shed light onto the mechanisms controlling mitotic exit and/or SPOC silencing.

A FRET-based study reveals site-specific regulation of spindle position checkpoint proteins at yeast centrosomes Yuliya Gryaznova, Ayse Koca Caydasi, Gabriele Malengo, Victor Sourjik and Gislene Pereira eLife. 5: e14029. doi: 10.7554/eLife.14029

Work in progress... stay tuned. Complex complexity. Dionisio

[...] cells do not require an intact cytoplasmic microtubule cytoskeleton to establish and/or maintain Bfa1-Bub2 asymmetry. How cell polarity determinants control Bfa1 asymmetry is unclear.

A FRET-based study reveals site-specific regulation of spindle position checkpoint proteins at yeast centrosomes Yuliya Gryaznova, Ayse Koca Caydasi, Gabriele Malengo, Victor Sourjik and Gislene Pereira eLife. 5: e14029. doi: 10.7554/eLife.14029

Complex complexity. Dionisio

The Bfa1-Bub2 complex is recruited preferentially to the dSPB (asymmetric binding) in cells progressing normally through the cell cycle. How this asymmetry is established is still unclear.

A FRET-based study reveals site-specific regulation of spindle position checkpoint proteins at yeast centrosomes Yuliya Gryaznova, Ayse Koca Caydasi, Gabriele Malengo, Victor Sourjik and Gislene Pereira eLife. 5: e14029. doi: 10.7554/eLife.14029

Complex complexity. Dionisio

[...] Spc72 acts as a scaffold protein that coordinates the regulation of the checkpoint effector Bfa1 by both Kin4 and Cdc5 kinases in cells with mis-aligned spindle. [...] further biochemical and biophysical studies will be necessary to evaluate the affinity of Bfa1 towards Nud1 and Spc72, and to establish whether the same Bfa1 molecule can bind simultaneously to Nud1 and Spc72.

A FRET-based study reveals site-specific regulation of spindle position checkpoint proteins at yeast centrosomes Yuliya Gryaznova, Ayse Koca Caydasi, Gabriele Malengo, Victor Sourjik and Gislene Pereira eLife. 5: e14029. doi: 10.7554/eLife.14029

Complex complexity. Dionisio

Spindle pole bodies (SPBs) not only facilitate microtubule nucleation but also provide a scaffolding platform for binding of the mitotic exit network (MEN) and the spindle position checkpoint (SPOC) proteins. Our findings unraveled a novel molecular rearrangement of SPOC proteins at SPBs that is essential for SPOC function. [...] the SPOC is switched off as soon as one spindle enters the bud.

A FRET-based study reveals site-specific regulation of spindle position checkpoint proteins at yeast centrosomes Yuliya Gryaznova, Ayse Koca Caydasi, Gabriele Malengo, Victor Sourjik and Gislene Pereira eLife. 5: e14029. doi: 10.7554/eLife.14029

Complex complexity. Dionisio

A cell must duplicate its genetic material and then separate the two copies before it divides. This process is carefully controlled so that each new cell receives an identical set of chromosomes after cell division. The spindle position checkpoint (SPOC) is a spindle pole body (SPB, equivalent of mammalian centrosome) associated surveillance mechanism that halts mitotic exit upon spindle mis-orientation.

A FRET-based study reveals site-specific regulation of spindle position checkpoint proteins at yeast centrosomes Yuliya Gryaznova, Ayse Koca Caydasi, Gabriele Malengo, Victor Sourjik and Gislene Pereira eLife. 5: e14029. doi: 10.7554/eLife.14029

Complex complexity. Dionisio

Whether the cell requires an intelligent sensor to detect spindle orientation defects, or solely relies on compartmentalization for the SPOC function remains to be clarified.

Temporal and compartment-specific signals coordinate mitotic exit with spindle position Ayse Koca Caydasi, Anton Khmelinskii, Rafael Duenas-Sanchez, Bahtiyar Kurtulmus, Michael Knop and Gislene Pereiraa Nat Commun. 8: 14129. doi: 10.1038/ncomms14129

Did somebody say "intelligent"? Complex complexity. Dionisio

[...] FEAR, MEN, SPOC and daughter cell-associated factors regulate mitotic exit in space and time through an intricate combination of independent pathways that apply control at the level of compartmentalization (Lte1, Ste20) and timing (FEAR).

Temporal and compartment-specific signals coordinate mitotic exit with spindle position Ayse Koca Caydasi, Anton Khmelinskii, Rafael Duenas-Sanchez, Bahtiyar Kurtulmus, Michael Knop and Gislene Pereiraa Nat Commun. 8: 14129. doi: 10.1038/ncomms14129

Did somebody say "regulate"? Did somebody say "control"? Complex complexity. Dionisio

@3367: Did somebody say "orchestrate"? :) Dionisio

[...] a comprehensive understanding of how cells decide when to exit mitosis is still lacking.

Temporal and compartment-specific signals coordinate mitotic exit with spindle position Ayse Koca Caydasi, Anton Khmelinskii, Rafael Duenas-Sanchez, Bahtiyar Kurtulmus, Michael Knop and Gislene Pereiraa Nat Commun. 8: 14129. doi: 10.1038/ncomms14129

Did somebody say that "cells decide"? Complex complexity. Dionisio

The spatiotemporal control of mitotic exit is crucial for faithful chromosome segregation during mitosis. How the SPOC operates at a molecular level remains unclear. [...] mitotic signalling pathways orchestrate chromosome segregation in time and space.

Temporal and compartment-specific signals coordinate mitotic exit with spindle position Ayse Koca Caydasi, Anton Khmelinskii, Rafael Duenas-Sanchez, Bahtiyar Kurtulmus, Michael Knop and Gislene Pereiraa Nat Commun. 8: 14129. doi: 10.1038/ncomms14129

Complex complexity. Dionisio

Further investigation is needed to better understand the molecular basis and importance of these cell-to-cell differences. The analysis of cells with multiple centrosomes analogous to what has been described here could address this question.

Spatial signals link exit from mitosis to spindle position Jill Elaine Falk, Dai Tsuchiya, Jolien Verdaasdonk, Soni Lacefield, Kerry Bloom, and Angelika Amon eLife. 5: e14036. doi: 10.7554/eLife.14036

Complex complexity. Dionisio

Asymmetric cell division is a common characteristic of development and is seen in diverse cell types ranging from Drosophila neuroblasts to mammalian oocytes. In order to produce viable progeny with distinct cell fates, asymmetrically dividing cells must coordinate nuclear position with the site of cytokinesis.

Spatial signals link exit from mitosis to spindle position Jill Elaine Falk, Dai Tsuchiya, Jolien Verdaasdonk, Soni Lacefield, Kerry Bloom, and Angelika Amon eLife. 5: e14036. doi: 10.7554/eLife.14036

Did somebody say "coordinate"? Complex complexity. Dionisio

[...] exit from mitosis is triggered by a correctly positioned spindle rather than inhibited by improper spindle position.

Spatial signals link exit from mitosis to spindle position Jill Elaine Falk, Dai Tsuchiya, Jolien Verdaasdonk, Soni Lacefield, Kerry Bloom, and Angelika Amon eLife. 5: e14036. doi: 10.7554/eLife.14036

Complex complexity. Dionisio

Stem cells are characterized by their ability to asymmetrically divide, generating another self-renewing stem cell and a differentiating daughter cell. They reside within the local niche microenvironment, which, together with systemic signals, regulates intrinsic stem cell function. Stem cells are finely regulated [...] Despite what is already known, much remains to be studied about how systemic, extrinsic, and intrinsic factors coordinate to regulate stem cell function. [...] many questions still remain unanswered.

Regulation of Stem Cells in Their Niche Li Ming Gooi & Jay Gopalakrishnan Curr Stem Cell Rep 2:282–289 DOI 10.1007/s40778-016-0048-2

Complex complexity. Dionisio

During mitosis, cells must accurately segregate their genome in order to produce healthy daughter cells. While the molecular functions of Kin4 and Tem1 are well defined, the function of Ltel has remained unclear.

Mechanisms underlying spatial control of exit from mitosis Jill E Falk MIT Thesis

Complex complexity. Dionisio

How the information on centrosomal orientation is communicated to the spectrosome, where Par-1 and Cyclin A localize, remains to be determined. A major outstanding question in understanding the COC is how it senses the location of the centrosomewith respect to the hub cells. It awaits future investigation to understand how the association of the centrosome with the hub-GSC interface is mechanistically sensed, and how such information is integrated with the activity of COC component(s) on the spectrosome. [...] the COC is a checkpoint mechanism that is distinct from the SAC and monitors correct centrosome orientation specifically in GSCs. We speculate that a similar mechanism might be in place in other systems that rely on asymmetric cell division.

The centrosome orientation checkpoint is germline stem cell specific and operates prior to the spindle assembly checkpoint in Drosophila testis Zsolt G. Venkei and Yukiko M. Yamashita DOI: 10.1242/dev.117044 Development

Note that this paper was previously referenced @112 & @164 but both quoted mainly the abstract while this new reference quotes the conclusions. This paper is old in practical terms, but perhaps still at least partially valid. Perhaps some of the outstanding questions in this paper have been resolved since it got published. Complex complexity. Dionisio

Neuroblasts are neural stem cells that divide asymmetrically to produce one self-renewing neuroblast and one daughter cell that divides once more to generate two neurons or glial cells. Asymmetric inheritance of determinants of cell fate requires the apically localized protein Partner of Inscuteable (Pins), which interacts with the Par complex through the adaptor protein Inscuteable (Insc). Pins also interacts with Discs large (Dlg) and Mushroom body defect (Mud), both of which also interact with the spindle pole. Thus, Pins orients cell divisions by ensuring that one spindle pole localizes to the apical side of the neuroblast. [...] Hippo signaling influences spindle orientation through the Wts-mediated phosphorylation of the Pins-interacting proteins Cno and Mud.

Hippo signaling for spindle orientation Annalisa M. VanHook Sci. Signal. Vol. 8, Issue 402, pp. ec331 DOI: 10.1126/scisignal.aad8102

Complex complexity. Dionisio

Stem cells possess the extraordinary capacity of self-renewal and differentiation to various cell types, thus to form original tissues and organs. Stem cell heterogeneity including genetic and nongenetic mechanisms refers to biological differences amongst normal and stem cells originated within the same tissue. Cell differentiation hierarchy and stochasticity in gene expression and signaling pathways may result in phenotypic differences of stem cells. The maintenance of stemness and activation of differentiation potential are fundamentally orchestrated by microenvironmental stem cell niche-related cellular and humoral signals.

Heterogeneity of Stem Cells: A Brief Overview. M?zes G, Sipos F Methods Mol Biol. 1516:1-12. doi: 10.1007/7651_2016_345.

Did somebody say "orchestrated"? Complex complexity. Dionisio

[...] the origin of adult stem cells in some mature tissues is still to be elucidated. The big hurdle is the fact that the tissue microenvironment is very complex and reproducing the in vivo conditions required for stem cell differentiation is very difficult.

Adult Stem Cell Responses to Nanostimuli Penelope M. Tsimbouri Journal of Functional Biomaterials 6, 598-622; doi:10.3390/jfb6030598 http://www.mdpi.com/journal/jfb

Complex complexity. Dionisio

Adult or mesenchymal stem cells (MSCs) have been found in different tissues in the body, residing in stem cell microenvironments called “stem cell niches”. They play different roles but their main activity is to maintain tissue homeostasis and repair throughout the lifetime of an organism. Their ability to differentiate into different cell types makes them an ideal tool to study tissue development and to use them in cell-based therapies. This differentiation process is subject to both internal and external forces at the nanoscale level [...]

Adult Stem Cell Responses to Nanostimuli Penelope M. Tsimbouri Journal of Functional Biomaterials 6, 598-622; doi:10.3390/jfb6030598 www.mdpi.com/journal/jfb

Complex complexity. Dionisio

The human cerebral cortex is dramatically larger compared with that of other mammals [...] [...] the role of these proteins [that localize to the mitotic spindle poles] in the interphase centrosome is not clear. The centrosome consists of a pair of centrioles surrounded by pericentriolar material, which nucleates microtubules that allow the centrosome to serve as the major microtubule-organizing center in mammalian cells [...]

Microcephaly Proteins Wdr62 and Aspm Define a Mother Centriole Complex Regulating Centriole Biogenesis, Apical Complex, and Cell Fate Divya Jayaraman, Andrew Kodani, Dilenny M. Gonzalez, Joseph D. Mancias, Ganeshwaran H. Mochida, Cristiana Vagnoni, Jeffrey Johnson, Nevan Krogan, J. Wade Harper, Jeremy F. Reiter, Timothy W. Yu, Byoung-il Bae and Christopher A. Walsh DOI: 10.1016/j.neuron.2016.09.056 Neuron 92, 1–16

Complex complexity. Dionisio

The role of the MR in cell fate specification remains elusive [...] [...] the biological significance of asymmetric MR inheritance is not well understood beyond correlative relationships [...]

Evaluation of the Asymmetric Division of Drosophila Male Germline Stem Cells Mayu Inaba and Yukiko M. Yamashita DOI: 10.1007/978-1-4939-4017-2_3 Germline Stem Cells, Methods in Molecular Biology, vol. 1463,

Complex complexity. Dionisio

These studies suggest the presence of intricate mechanisms to asymmetrically segregate cellular components, possibly contributing to ACD. Yet, such asymmetries associated with ACD have only begun to be revealed and it remains unclear how critical these asymmetries are in determining asymmetric cell fates.

Evaluation of the Asymmetric Division of Drosophila Male Germline Stem Cells Mayu Inaba and Yukiko M. Yamashita DOI: 10.1007/978-1-4939-4017-2_3 Germline Stem Cells, Methods in Molecular Biology, vol. 1463,

Complex complexity. Dionisio

Asymmetric cell division (ACD) is utilized in many stem cell systems to produce two daughter cells with different cell fates. Despite the fundamental importance of ACD during development and tissue homeostasis, the nature of ACD is far from being fully understood. Step-by-step observation of events during ACD allows us to understand processes that lead to ACD.

Evaluation of the Asymmetric Division of Drosophila Male Germline Stem Cells Mayu Inaba and Yukiko M. Yamashita DOI: 10.1007/978-1-4939-4017-2_3 Germline Stem Cells, Methods in Molecular Biology, vol. 1463,

Complex complexity. Dionisio

[...] ACD is achieved by fine-tuned symmetries and asymmetries [...] [...] multiple aspects of ACDs (e.g. asymmetric segregation of fate determinants, spindle orientation, daughter cell size asymmetry) are carefully calibrated processes to achieve successful ACD unique to individual systems.

Klp10A, a stem cell centrosome-enriched kinesin, balances asymmetries in Drosophila male germline stem cell division Cuie Chen, Mayu Inaba, Zsolt G Venkei, Yukiko M Yamashita DOI: 10.7554/eLife.04960 eLife Sciences

Complex complexity. Dionisio

Asymmetric cell division (ACD) is a key process that balances stem cell self-renewal and differentiation by producing one stem cell and one differentiating cell [...] [...] the essence of successful cell division is the precise replication and segregation of cellular contents, such as chromosomes and essential organelles. It has been underexplored how cells may achieve productive ACD without interfering with the basic requirement of cell divisions.

Klp10A, a stem cell centrosome-enriched kinesin, balances asymmetries in Drosophila male germline stem cell division Cuie Chen, Mayu Inaba, Zsolt G Venkei, Yukiko M Yamashita DOI: 10.7554/eLife.04960 eLife Sciences

Complex complexity. Dionisio

Asymmetric stem cell division is often accompanied by stereotypical inheritance of the mother and daughter centrosomes. However, it remains unknown whether and how stem cell centrosomes are uniquely regulated and how this regulation may contribute to stem cell fate. [...] klp10A functions to counteract undesirable asymmetries that may result as a by-product of achieving asymmetries essential for successful stem cell divisions.

Klp10A, a stem cell centrosome-enriched kinesin, balances asymmetries in Drosophila male germline stem cell division Cuie Chen, Mayu Inaba, Zsolt G Venkei, Yukiko M Yamashita DOI: 10.7554/eLife.04960 eLife Sciences

Complex complexity. Dionisio

Asymmetric cell division during embryogenesis contributes to cell diversity by generating daughter cells that adopt distinct developmental fates. Two cellular processes-asymmetric fate allocation and orientation of the cell division plane-are coupled by a single factor in the first example, but these processes are regulated independently in the third example. Thus, various modes of asymmetric cell division operate even at the early developmental stages in this single type of organism.

Asymmetric and Unequal Cell Divisions in Ascidian Embryos. Negishi T, Nishida H. Results and problems in cell differentiation DOI: 10.1007/978-3-319-53150-2_12 Asymmetric Cell Division in Development, Differentiation and Cancer, pp.261-284

Complex complexity. Dionisio

[...] the direct function of DNA methylation at specific sites remains unclear.

DNA methylation: an epigenetic mark of cellular memory Mirang Kim and Joseph Costello Experimental & Molecular Medicine (2017) 49, e322; doi:10.1038/emm.2017.10

Complex complexity. Dionisio

DNA methylation is a stable epigenetic mark that can be inherited through multiple cell divisions. During development and cell differentiation, DNA methylation is dynamic, but some DNA methylation patterns may be retained as a form of epigenetic memory. DNA methylation can be a useful molecular marker for cancer diagnosis and drug treatment.

DNA methylation: an epigenetic mark of cellular memory Mirang Kim and Joseph Costello Experimental & Molecular Medicine (2017) 49, e322; doi:10.1038/emm.2017.10

Complex complexity. Dionisio

The understanding of mechanisms including asymmetric furrowing and its role during development and possibly in pathological processes still needs further investigation.

Asymmetries in Cell Division, Cell Size, and Furrowing in the Xenopus laevis Embryo Jean-Pierre Tassan, Martin W€uhr, Guillaume Hatte, and Jacek Kubiak DOI: 10.1007/978-3-319-53150-2_11 Results and problems in cell differentiation Asymmetric Cell Division in Development, Differentiation and Cancer, pp.243-260

Complex complexity. Dionisio

The cell-size asymmetry and the asymmetric distribution of cell fate determinants have been shown to be coupled in diverse model organisms. However, it is not clear to what extent the two asymmetries are really linked and/or co-dependent.

Asymmetries in Cell Division, Cell Size, and Furrowing in the Xenopus laevis Embryo Jean-Pierre Tassan, Martin W€uhr, Guillaume Hatte, and Jacek Kubiak DOI: 10.1007/978-3-319-53150-2_11 Results and problems in cell differentiation

Complex complexity. Dionisio

Asymmetric cell divisions produce two daughter cells with distinct fate. During embryogenesis, this mechanism is fundamental to build tissues and organs because it generates cell diversity. In adults, it remains crucial to maintain stem cells.

Asymmetries in Cell Division, Cell Size, and Furrowing in the Xenopus laevis Embryo Jean-Pierre Tassan, Martin W€uhr, Guillaume Hatte, and Jacek Kubiak DOI: 10.1007/978-3-319-53150-2_11 Results and problems in cell differentiation

Complex complexity. Dionisio

The complexities of studying proliferation in vivo are illustrated here with a focus on the gastrointestinal tract. Some of these methods can help elucidate the role of the stem cells and their relationship to label retaining cells.

Quantification of epithelial cell proliferation, cell dynamics, and cell kinetics in vivo Robert A. Goodlad DOI: 10.1002/wdev.274 Developmental Biology

Complex complexity. Dionisio

[...] many intracellular and extracellular factors function to achieve asymmetric cell divisions. [...] exquisite orientation control can be ensured by checkpoint mechanisms that function to dictate coordinated progression through the cell division cycle. [...] asymmetric cell division is the outcome of many interlinked biological processes, which include setting up, modulating and reinforcing asymmetries using cell intrinsic and extrinsic mechanisms. [...] combinatory use of those modular mechanisms likely allows distinct stem cell populations to adopt carefully tailored mechanisms of asymmetric cell divisions.

The ins(ide) and outs(ide) of asymmetric stem cell division Cuie Chen, Jaclyn M Fingerhut, Yukiko M Yamashita DOI: 10.1016/j.ceb.2016.06.001 Current opinion in cell biology 43:1-6

Work in progress... stay tuned. Complex complexity. Dionisio

[...] recent studies have illuminated the importance of intricate mechanisms that modulate and reinforce both cell-extrinsic and cell-intrinsic asymmetries in order to achieve a bipolar outcome following stem cell division. [...] ‘fate modulators’ of many forms have proven to be crucial in achieving an asymmetric outcome following cell division. Centrosomes have emerged as another organelle capable of modulating cell fate. [...] significant gaps exist in our understanding of how the intracellular machineries that orient the cell division are linked to the asymmetries provided by the extracellular environment.

The ins(ide) and outs(ide) of asymmetric stem cell division Cuie Chen, Jaclyn M Fingerhut, Yukiko M Yamashita DOI: 10.1016/j.ceb.2016.06.001 Current opinion in cell biology 43:1-6

Complex complexity. Dionisio

Asymmetric stem cell division is generally dictated by unequally distributed cell-extrinsic and/or cell-intrinsic fate determinants [...] [...] spindle orientation plays a key role in achieving an asymmetric outcome after stem cell division by aligning the cell division plane with pre-established cell-extrinsic or cell-intrinsic asymmetries [...] In the most simplistic view, cell-extrinsic or cell-intrinsic fate determinants in combination with spindle orientation should suffice to explain asymmetric stem cell divisions [...]

The ins(ide) and outs(ide) of asymmetric stem cell division Cuie Chen, Jaclyn M Fingerhut, Yukiko M Yamashita DOI: 10.1016/j.ceb.2016.06.001 Current opinion in cell biology 43:1-6

Complex complexity. Dionisio

Many adult stem cells divide asymmetrically, generating one stem cell (self-renewal) and one differentiating cell. Balancing self-renewal and differentiation is critical for sustaining tissue homeostasis throughout the life of an organism. Failure to execute asymmetric stem cell division can have profound impacts on tissue homeostasis, resulting in tissue degeneration or hyperplasia/tumorigenic overgrowth. Recent studies have expanded our understanding of both the extracellular and intracellular mechanisms that regulate, reinforce and ensure an asymmetric outcome following stem cell division. In this review, we discuss newly discovered aspects of asymmetric stem cell division that, in concert with well-established mechanisms, contribute to balancing self-renewal and differentiation.

The ins(ide) and outs(ide) of asymmetric stem cell division Cuie Chen, Jaclyn M Fingerhut, Yukiko M Yamashita DOI: 10.1016/j.ceb.2016.06.001 Current opinion in cell biology 43:1-6 https://www.researchgate.net/profile/Yukiko_Yamashita/publication/304066561_The_inside_and_outside_of_asymmetric_stem_cell_division/links/578db17308ae59aa66815ead/The-inside-and-outside-of-asymmetric-stem-cell-division.pdf

Complex complexity. Dionisio

The coordination of cell proliferation and differentiation is central to the development and maintenance of tissues, while its dysregulation underlies the transition to diseased states. By combining lineage tracing with transcriptional profiling and marker-based assays, statistical methods are delivering insights into the dynamics of stem cells and their developmental precursors. These studies have provided evidence for molecular heterogeneity and fate priming, and have revealed a role for stochasticity in stem cell fate, refocusing the search for regulatory mechanisms.

Tracing cellular dynamics in tissue development, maintenance and disease Steffen Rulands, Benjamin D Simons DOI: 10.1016/j.ceb.2016.07.001 Current opinion in cell biology 43:38-45

Complex complexity. Dionisio

Stem cells are essential for both tissue maintenance and injury repair, but many aspects of stem cell biology remain incompletely understood. Recent advances in live imaging technology have allowed the direct visualization and tracking of a wide variety of tissue-resident stem cells in their native environments over time. Results from these studies have helped to resolve long-standing debates about stem cell regulation and function while also revealing previously unanticipated phenomena that raise new questions for future work.

Live imaging of stem cells: answering old questions and raising new ones Sangbum Park, Valentina Greco, Katie Cockburn Differentiation and disease Current Opinion in Cell Biology Vol.43:30–37, doi:10.1016/j.ceb.2016.07.004

They ain’t seen nothin’ yet. Work in progress… stay tuned. Complex complexity. Dionisio

Functional information vs. classical information: Two mistakes https://uncommondescent.com/intelligent-design/functional-information-vs-classical-information-two-mistakes/#comment-631068 Dionisio

[...] the individual contribution of membranous protrusions or extracellular vesicles to cell fate patterning remains unclear [...] Advances in this area will rely on determining how these structures are formed, how ligands are targeted to them, and how they actively drive movement, to manipulate each specific mechanism.

Control of signaling molecule range during developmental patterning Scott G. Wilcockson, Catherine Sutcliffe, Hilary L. Ashe Cellular and Molecular Life Sciences June 2017, Volume 74, Issue 11, pp 1937–1956 DOI: 10.1007/s00018-016-2433-5

Work in progress... stay tuned. Complex complexity. Dionisio

Tissue patterning, through the concerted activity of a small number of signaling pathways, is critical to embryonic development. While patterning can involve signaling between neighbouring cells, in other contexts signals act over greater distances by traversing complex cellular landscapes to instruct the fate of distant cells.

Control of signaling molecule range during developmental patterning Scott G. Wilcockson, Catherine Sutcliffe, Hilary L. Ashe Cellular and Molecular Life Sciences June 2017, Volume 74, Issue 11, pp 1937–1956 DOI: 10.1007/s00018-016-2433-5

Complex complexity. Dionisio

Stem cells undergo extensive metabolic rewiring during reprogramming, proliferation and differentiation, and numerous studies have demonstrated a significant role of metabolism in controlling stem cell fates. Recent applications of metabolomics, the study of concentrations and fluxes of small molecules in cells, have advanced efforts to characterize and maturate stem cell fates, assess drug toxicity in stem cell tissue models, identify biomarkers, and study the effects of environment on metabolic pathways in stem cells and their progeny. Looking to the future, combining metabolomics with other -omics approaches will provide a deeper understanding of the complex regulatory mechanisms of stem cells.

Advances in applications of metabolomics in pluripotent stem cell research Vijesh J Bhute, Xiaoping Bao, Sean P Palecek Current Opinion in Chemical Engineering Volume 15, Pages 36–43 DOI: 10.1016/j.coche.2016.11.007

Did somebody say "rewiring"? Did somebody say "reprogramming"? Did somebody say "complex regulatory mechanisms"? Complex complexity. Dionisio

At the molecular level, circadian oscillations rely on a transcription–translation feedback loop driven by a core clock mechanism. [...] our understanding of how young cellular clocks maintain robust circadian outputs, and how this robustness is lost during ageing, remain largely unknown. [...] the intricate molecular oscillator is built with the capacity to respond to multiple environmental and metabolic time cues, such as the light/dark cycle, feeding/fasting rhythm, body temperature fluctuations and daily surges of hormones. [...] extracellular stiffness and intracellular tension signalling provide a key pathway to regulate the activity of circadian clocks in mammary epithelia.

Cellular mechano-environment regulates the mammary circadian clock Nan Yang, Jack Williams, Vanja Pekovic-Vaughan, Pengbo Wang, Safiah Olabi, James McConnell, Nicole Gossan, Alun Hughes, Julia Cheung, Charles H. Streuli & Qing-Jun Meng Nature Communications 8, Article number: 14287 (2017) doi:10.1038/ncomms14287

Complex complexity. Dionisio

[...] the breast epithelial clock is regulated by the mechano-chemical stiffness of the cellular microenvironment in primary cell culture. [...] the mammary clock is controlled by the periductal extracellular matrix in vivo, which contributes to a dampened circadian rhythm during ageing. Mechanistically, the tension sensing cell-matrix adhesion molecule, vinculin, and the Rho/ROCK pathway, which transduces signals provided by extracellular stiffness into cells, regulate the activity of the core circadian clock complex. [...] genetic perturbation, or age-associated disruption of self-sustained clocks, compromises the self-renewal capacity of mammary epithelia. [...] circadian clocks are mechano-sensitive, providing a potential mechanism to explain how ageing influences their amplitude and function.

Cellular mechano-environment regulates the mammary circadian clock Nan Yang, Jack Williams, Vanja Pekovic-Vaughan, Pengbo Wang, Safiah Olabi, James McConnell, Nicole Gossan, Alun Hughes, Julia Cheung, Charles H. Streuli & Qing-Jun Meng Nature Communications 8, Article number: 14287 (2017) doi:10.1038/ncomms14287

Complex complexity. Dionisio

Circadian clocks drive ?24?h rhythms in tissue physiology. They rely on transcriptional/translational feedback loops driven by interacting networks of clock complexes. However, little is known about how cell-intrinsic circadian clocks sense and respond to their microenvironment.

Cellular mechano-environment regulates the mammary circadian clock Nan Yang, Jack Williams, Vanja Pekovic-Vaughan, Pengbo Wang, Safiah Olabi, James McConnell, Nicole Gossan, Alun Hughes, Julia Cheung, Charles H. Streuli & Qing-Jun Meng Nature Communications 8, Article number: 14287 (2017) doi:10.1038/ncomms14287

Complex complexity. Dionisio

[...] the timing of the response to hypertonicity and mechanism by which TonEBP promotes transcription of select target genes such as IL6 and NOS2 is unique in NP cells. [...] the responses are finely tuned in a context and cell-type dependent fashion to promote homeostatic maintenance of NP health. [...] dysregulation of TonEBP could also potentially promote inflammation.

RNA Sequencing Reveals a Role of TonEBP Transcription Factor in Regulation of Pro-inflammatory Genes in Response to Hyperosmolarity in Healthy Nucleus Pulposus Cells A HOMEOSTATIC RESPONSE?* Zariel I. Johnson, Irving M. Shapiro and Makarand V. Risbud doi: 10.1074/jbc.M116.757732 The Journal of Biological Chemistry 291, 26686-26697.

Complex complexity. Dionisio

NP cells reside in a hypertonic environment within the disc, the severity of which fluctuates with daily activity (6). The transcription factor TonEBP plays a pro-survival role in the NP under hypertonic conditions via regulation of canonical osmotic response genes (3, 17) while also regulating matrix synthesis and tissue hydration genes [...]

RNA Sequencing Reveals a Role of TonEBP Transcription Factor in Regulation of Pro-inflammatory Genes in Response to Hyperosmolarity in Healthy Nucleus Pulposus Cells A HOMEOSTATIC RESPONSE?* Zariel I. Johnson, Irving M. Shapiro and Makarand V. Risbud doi: 10.1074/jbc.M116.757732 The Journal of Biological Chemistry 291, 26686-26697.

Complex complexity. Dionisio

The intervertebral disc is well suited to fulfill its mechanical role in the human spine, where it permits flexion and rotation, and absorbs compressive loads (1). The matrix-rich nucleus pulposus (NP) at the center of the disc gives the tissue its ability to resist compression through high osmotic swelling pressure (2–4), loss of which correlates with degeneration and back pain (5). Importantly, tonicity of the extracellular environment fluctuates widely with diurnal cycle - water is forced out of the disc during the day when the spine is loaded and imbibed during the unloaded phase at night [...] [...] little is known regarding broader functions of TonEBP in the hypertonic niche of the NP.

RNA Sequencing Reveals a Role of TonEBP Transcription Factor in Regulation of Pro-inflammatory Genes in Response to Hyperosmolarity in Healthy Nucleus Pulposus Cells A HOMEOSTATIC RESPONSE?* Zariel I. Johnson, Irving M. Shapiro and Makarand V. Risbud doi: 10.1074/jbc.M116.757732 The Journal of Biological Chemistry 291, 26686-26697.

Complex complexity. Dionisio

Although TonEBP maintains transcription of genes traditionally considered pro-inflammatory, it is important to note that some of these genes also serve anabolic and pro-survival roles. Therefore, in NP cells, this phenomenon may reflect a physiological adaptation to diurnal osmotic loading of the intervertebral disc.

RNA Sequencing Reveals a Role of TonEBP Transcription Factor in Regulation of Pro-inflammatory Genes in Response to Hyperosmolarity in Healthy Nucleus Pulposus Cells A HOMEOSTATIC RESPONSE?* Zariel I. Johnson, Irving M. Shapiro and Makarand V. Risbud doi: 10.1074/jbc.M116.757732 The Journal of Biological Chemistry 291, 26686-26697.

Complex complexity. Dionisio

Transcription factor tonicity-responsive enhancer-binding protein (TonEBP/NFAT5) is critical for osmo-adaptation and extracellular matrix homeostasis of nucleus pulposus (NP) cells in their hypertonic tissue niche. Recent studies implicate TonEBP signaling in inflammatory disease and rheumatoid arthritis pathogenesis. However, broader functions of TonEBP in the disc remain unknown.

RNA Sequencing Reveals a Role of TonEBP Transcription Factor in Regulation of Pro-inflammatory Genes in Response to Hyperosmolarity in Healthy Nucleus Pulposus Cells A HOMEOSTATIC RESPONSE?* Zariel I. Johnson, Irving M. Shapiro and Makarand V. Risbud doi: 10.1074/jbc.M116.757732 The Journal of Biological Chemistry 291, 26686-26697.

Complex complexity. Dionisio

Immune cells constantly patrol the body via the bloodstream and migrate into multiple tissues where they face variable and sometimes demanding environmental conditions. Nutrient and oxygen availability can vary during homeostasis, and especially during the course of an immune response, creating a demand for immune cells that are highly metabolically dynamic. [...] immune cells have developed different metabolic programmes to supply them with cellular energy and biomolecules, enabling them to cope with changing and challenging metabolic conditions. [...] cellular metabolism affects immune cell function and differentiation [...] [...] disease-specific metabolic configurations might provide an explanation for the dysfunctional immune responses seen in rheumatic diseases.

Metabolic regulation of inflammation Timo Gaber, Cindy Strehl & Frank Buttgereit Nature Reviews Rheumatology 13, 267–279 doi:10.1038/nrrheum.2017.37

Did somebody say "developed"? How? Did somebody say "programmes"? Hmm... cool! :) Complex complexity. Dionisio

At this point, research into immunometabolism in OA is still in its infancy;[...] An improved understanding of physiologic and pathophysiologic regulators of cartilage and synovial metabolism is also likely to provide new insights into the aetiology and pathophysiology of OA. When combined with proteomics, lipidomics and bioinformatics, metabolomics will help to reveal the pathways, proteins and metabolites that drive inflammatory processes in synovial joints, hopefully also revealing new therapeutic targets. Future research should also focus on delineating the role of metabolism in macrophages that infiltrate the synovium in OA and in FLS in OA.

The role of metabolism in the pathogenesis of osteoarthritis Ali Mobasheri, Margaret P. Rayman, Oreste Gualillo, Jérémie Sellam, Peter van der Kraan & Ursula Fearon Nature Reviews Rheumatology 13, 302–311 doi:10.1038/nrrheum.2017.50

Work in progress... stay tuned. Complex complexity. Dionisio

The pathogenesis of OA involves metabolic alterations in articular cartilage, subchondral bone and synovium. These changes influence metabolic pathways in chondrocytes, synoviocytes and bone cells and their interactions with the immune system via inflammatory mediators. A deeper mechanistic understanding of these complex metabolic pathways is therefore likely to provide insight into potential novel therapeutic strategies for treating OA and other inflammatory diseases of joints.

The role of metabolism in the pathogenesis of osteoarthritis Ali Mobasheri, Margaret P. Rayman, Oreste Gualillo, Jérémie Sellam, Peter van der Kraan & Ursula Fearon Nature Reviews Rheumatology 13, 302–311 doi:10.1038/nrrheum.2017.50

Complex complexity. Dionisio

Evidence suggests that six major metabolic pathways are involved in immunometabolism, including glycolysis, the tricarboxylic acid (TCA) cycle, the pentose phosphate pathway (PPP), fatty acid oxidation, fatty acid synthesis and amino acid metabolism3. Changes in the levels of metabolites in these pathways act as important metabolic switches with the capacity to shape the ways in which immune cells respond to their environment.

The role of metabolism in the pathogenesis of osteoarthritis Ali Mobasheri, Margaret P. Rayman, Oreste Gualillo, Jérémie Sellam, Peter van der Kraan & Ursula Fearon Nature Reviews Rheumatology 13, 302–311 doi:10.1038/nrrheum.2017.50

Had we stayed in Eden none of this would have been an issue. Oh well, too late now. Complex complexity. Dionisio

Metabolism is important for cartilage and synovial joint function. Under adverse microenvironmental conditions, mammalian cells undergo a switch in cell metabolism from a resting regulatory state to a highly metabolically activate state to maintain energy homeostasis. This phenomenon also leads to an increase in metabolic intermediates for the biosynthesis of inflammatory and degradative proteins, which in turn activate key transcription factors and inflammatory signalling pathways involved in catabolic processes, and the persistent perpetuation of drivers of pathogenesis.

The role of metabolism in the pathogenesis of osteoarthritis Ali Mobasheri, Margaret P. Rayman, Oreste Gualillo, Jérémie Sellam, Peter van der Kraan & Ursula Fearon Nature Reviews Rheumatology 13, 302–311 doi:10.1038/nrrheum.2017.50

Complex complexity. Dionisio

A molecular clock regulated by age and inflammatory cytokines is present in intervertebral disc (IVD) tissues, and targeted deletion of ARNTL (encoding aryl hydrocarbon receptor nuclear translocator-like protein 1, also known as BMAL1) in mice results in IVD degeneration, according to a new study by Qing-Jun Meng and colleagues.

Catching the rhythm of disc degeneration Dario Ummarino Nature Reviews Rheumatology 12, 561 doi:10.1038/nrrheum.2016.141

OK, let's see... a molecular clock is used to regulate some processes in the biological systems, but the clock is regulated using cytokines and other things, which themselves are regulated by other mechanisms which are regulated by... and so on and so on... it seems like the expression "bottom-up research" of a "top-down design" comes to mind, doesn't it? Complex complexity. Dionisio

Progressive degeneration of the IVD tissue, partly caused by increased catabolism driven by inflammatory/catabolic cytokines, is a major contributing factor in LBP. [...] the physiology of IVD is under strong influence by a diurnal rhythm associated with the rest/activity cycles, that is, daily cycles of loading (activity phase) and low-load recovery (resting phase). [...] disruptions to circadian rhythms during ageing or in shift workers may be a contributing factor for the increased susceptibility to degenerative IVD diseases and low back pain.

The intervertebral disc contains intrinsic circadian clocks that are regulated by age and cytokines and linked to degeneration Michal Dudek, Nan Yang, Jayalath PD Ruckshanthi, Jack Williams, Elzbieta Borysiewicz, Ping Wang, Antony Adamson, Jian Li, John F Bateman, Michael R White, Raymond P Boot-Handford, Judith A Hoyland, Qing-Jun Meng Annals of the Rheumatic Diseases 76(3):annrheumdis-2016-209428 August 3, 2016 (http://dx.doi.org/10.1136/annrheumdis-2016-209428).

Complex complexity. Dionisio

The circadian clocks are internal timing mechanisms which drive ?24-hour rhythms in physiology and behaviour. [...] disruptions to circadian rhythms may be a risk factor for degenerative IVD disease and low back pain. At the molecular level, the circadian clock consists of a network of transcriptional activators (Clock, Bmal1) and repressors (Per1/2 and Cry1/2) organised in a negative feedback loop. This core oscillator generates 24-hour rhythms in the expression of its core components and a myriad of clock-controlled genes.

The intervertebral disc contains intrinsic circadian clocks that are regulated by age and cytokines and linked to degeneration Michal Dudek, Nan Yang, Jayalath PD Ruckshanthi, Jack Williams, Elzbieta Borysiewicz, Ping Wang, Antony Adamson, Jian Li, John F Bateman, Michael R White, Raymond P Boot-Handford, Judith A Hoyland, Qing-Jun Meng Annals of the Rheumatic Diseases 76(3):annrheumdis-2016-209428 August 3, 2016 (http://dx.doi.org/10.1136/annrheumdis-2016-209428).

Complex complexity. Dionisio

[…] cell autonomous circadian clocks and clock genes regulate adult neural stem cells […]

Circadian Clock Genes Are Essential for Normal Adult Neurogenesis, Differentiation, and Fate Determination Astha Malik, Roman V. Kondratov, Roudabeh J. Jamasbi, Michael E. Geusz DOI: 10.1371/journal.pone.0139655 PLoS ONE

Is that accurate? Do genes regulate anything? They are used by the biological systems but they don't do anything by themselves. Do they? Complex complexity. Dionisio

[...] cell autonomous circadian clocks and clock genes regulate adult neural stem cells [...]

Circadian Clock Genes Are Essential for Normal Adult Neurogenesis, Differentiation, and Fate Determination Astha Malik, Roman V. Kondratov, Roudabeh J. Jamasbi, Michael E. Geusz DOI: 10.1371/journal.pone.0139655 PLoS ONE

Is that accurate? Do clocks regulate us? Or we use clocks --among other things-- to regulate our activities? Do the clocks within the microprocessors regulate the microprocessors or are used by the designer of the microprocessors to regulate their operations? IOW, the recurrent impulses produced by the clocks are used for coordination, synchronization, activation, deactivation, etc. Complex complexity. Dionisio

Adult neurogenesis creates new neurons and glia from stem cells in the human brain throughout life. It is best understood in the dentate gyrus (DG) of the hippocampus and the subventricular zone (SVZ). Circadian rhythms have been identified in the hippocampus, but the role of any endogenous circadian oscillator cells in hippocampal neurogenesis and their importance in learning or memory remains unclear. Any study of stem cell regulation by intrinsic circadian timing within the DG is complicated by modulation from circadian clocks elsewhere in the brain.

Circadian Clock Genes Are Essential for Normal Adult Neurogenesis, Differentiation, and Fate Determination Astha Malik, Roman V. Kondratov, Roudabeh J. Jamasbi, Michael E. Geusz DOI: 10.1371/journal.pone.0139655 PLoS ONE

Complex complexity. Dionisio

The timing of caffeic acid treatment with cisplatin determines sensitization or resistance of ovarian carcinoma cell lines R. Sirota, D. Gibson, R. Kohen Redox Biology 11 170–175

Complex complexity. Dionisio

Internal processes of the body may selectively favor persistence of CSC clocks that have optimal phase relationships with daily rhythms in nutrient availability, cytokines, hormones, and suppressive or mitogenic components oscillating in the blood. Similarly, various organs of animals oscillate with their own preferred circadian phase relative to the master neural clock in the hypothalamus.

Evaluating Circadian Oscillators In Cancer Stem Cells. Michael E. Geusz Vishal P. Sharma Ashapurna Sarma Astha Malik http://openaccesspub.org/jesr/article/173

Complex complexity. Dionisio

The relationship between circadian rhythms and cancer is generally thought to be one of mutual exclusion. Cells can receive circadian timing from other clocks within the body or they can produce their own rhythmic signal through interacting transcriptional and translational molecular loops. Both sources of timing information have their value.

Evaluating Circadian Oscillators In Cancer Stem Cells. Michael E. Geusz Vishal P. Sharma Ashapurna Sarma Astha Malik http://openaccesspub.org/jesr/article/173

Complex complexity. Dionisio

Although circadian clocks are found in most cell types of the body, the suprachiasmatic nucleus (SCN) in the hypothalamus synchronizes clocks within and outside the brain. The SCN receives retinal light information that it uses to bring the peripheral clocks into a preferred phase relationship with the environmental cycle.

Circadian Rhythms in Doxorubicin Nuclear Uptake and Clock Control of C6 Glioma Cells Ashapurna Sarma, Vishal P. Sharma, Michael E. Geusz DOI: 10.4236/jct.2016.78059 Journal of Cancer Therapy, 7, 558-572

Complex complexity. Dionisio

The numerous circadian rhythms of the body impact tumor growth and offer opportunities for maximizing anticancer treatments through drug delivery at an identified optimal time of day. This therapeutic approach would benefit from greater understanding of circadian cancer cell properties such as period, amplitude, and, most importantly, phase relative to rhythms in the rest of the body.

Circadian Rhythms in Doxorubicin Nuclear Uptake and Clock Control of C6 Glioma Cells Ashapurna Sarma, Vishal P. Sharma, Michael E. Geusz DOI: 10.4236/jct.2016.78059 Journal of Cancer Therapy, 7, 558-572

Complex complexity. Dionisio

Alterations of drug efficacy by the circadian clock are a concern when assessing drug therapies. Circadian rhythms persist in some cancer cells and are repressed in others. A better understanding of circadian activities generated within cancer cells could indicate therapeutic approaches that selectively disrupt rhythms and deprive cells of any benefits provided by circadian timing. Another option is to induce expression of the core clock gene Per2 to suppress cancer cell proliferation.

Circadian Rhythms in Doxorubicin Nuclear Uptake and Clock Control of C6 Glioma Cells Ashapurna Sarma, Vishal P. Sharma, Michael E. Geusz DOI: 10.4236/jct.2016.78059 Journal of Cancer Therapy, 7, 558-572

Complex complexity. Dionisio

Circadian clocks can control the cell division cycle at several checkpoints, most notably through p21 regulation by the core clock protein BMAL1 [...] [...] the circadian clock is compensated to maintain a more constant period as temperature changes [...] [...] the phase of the cell cycle can provide an estimate of circadian phase in some cancer cell types and may be useful for predicting when curcumin is most effective [...] [...] it will be necessary to predict the circadian phase of the cancer cells within the tumor. Additional studies are needed to determine whether human tumors with a functioning circadian clock are entrained by the body’s daily rhythms in cortisol, melatonin or other signals, resulting in a predictable maximum in PER2 expression for timing delivery of curcumin or similar drugs. However, any daily rhythms in curcumin’s absorption and degradation also need to be considered.

The circadian clock modulates anti-cancer properties of curcumin Ashapurna Sarma, Vishal P. Sharma, Arindam B. Sarkar, M. Chandra Sekar, Karunakar Samuel and Michael E. Geusz DOI: 10.1186/s12885-016-2789-9 BMC Cancer 16(1):759

Complex complexity. Dionisio

Curcumin is a promising phytochemical for treating several cancers. This ingredient of the spice turmeric has been used to treat several ailments for thousands of years because of its anti-inflammatory, anti-microbial, and wound-healing properties. It arrests tumor cell proliferation by inhibiting multiple signal transduction pathways, interfering with the cell cycle, and inducing apoptosis. Relative to most agents currently used to target cancer cells, curcumin is reported to have low toxicity towards normal cells [...]

The circadian clock modulates anti-cancer properties of curcumin Ashapurna Sarma, Vishal P. Sharma, Arindam B. Sarkar, M. Chandra Sekar, Karunakar Samuel and Michael E. Geusz DOI: 10.1186/s12885-016-2789-9 BMC Cancer 16(1):759

Had we stayed in Eden, none of this would have been an issue. Complex complexity. Dionisio

[...] a better comprehension of the intricate crosstalk among stem cell metabolism, epigenetics and circadian rhythms is desirable and could lead to effective strategies for manipulating stem cell fate and regenerative potential.

Metaboloepigenetics: The Emerging Network in Stem Cell Homeostasis Regulation Daniele Avitabile, Alessandra Magenta, Andrea Lauri, Elisa Gambini, Gabriella Spaltro and Maria Cristina Vinci DOI: 10.2174/1574888X11666151203223839 Current Stem Cell Research & Therapy

Work in progress... stay tuned. Complex complexity. Dionisio

It is overtly clear that metabolism and epigenetics play a central role in the regulation of stem cell functions. The circadian clock in turn synchronizes metabolism and epigenetics processes in order to maximize the cellular functions and adaptive responses with the minimum expenditure of energy. Since metabolic and epigenetic processes display circadian regulation, it is logical to speculate that each cell of our body is not identical to itself at different times of the day.

Metaboloepigenetics: The Emerging Network in Stem Cell Homeostasis Regulation Daniele Avitabile, Alessandra Magenta, Andrea Lauri, Elisa Gambini, Gabriella Spaltro and Maria Cristina Vinci DOI: 10.2174/1574888X11666151203223839 Current Stem Cell Research & Therapy

Complex complexity. Dionisio

[...] the role of circadian rhythms in the regulation of stem cell functioning and related molecular mechanisms represents an emerging and relatively new topic in the field of stem cell biology.

Metaboloepigenetics: The Emerging Network in Stem Cell Homeostasis Regulation Daniele Avitabile, Alessandra Magenta, Andrea Lauri, Elisa Gambini, Gabriella Spaltro and Maria Cristina Vinci DOI: 10.2174/1574888X11666151203223839 Current Stem Cell Research & Therapy

Did somebody say "an emerging and relatively new topic"? Another "new topic" in biology? Really? Didn't we have enough topics already? :) Complex complexity. Dionisio

[...] different metabolic pathways are circadian regulated and the misalignment of circadian cycles correlates with increased susceptibility to pathologic conditions [...] The molecular clock also has a central role in mediating the metabolic adaptation in response to environmental stress. The global epigenetic activity of the cell oscillates with circadian periodicity and emerging evidence implicates that some clock regulators are crucial to integrate epigenetics and metabolism.

Metaboloepigenetics: The Emerging Network in Stem Cell Homeostasis Regulation Daniele Avitabile, Alessandra Magenta, Andrea Lauri, Elisa Gambini, Gabriella Spaltro and Maria Cristina Vinci DOI: 10.2174/1574888X11666151203223839 Current Stem Cell Research & Therapy

Complex complexity. Dionisio

Despite the fact that each peripheral organ possesses its own independent and self-sustaining clock, their global activity is tightly coordinated within the SNC master clock. The majority of cyclically accumulating transcripts encode polypeptides with tissue-specific functions, supporting the notion that different organs must fulfil different temporally controlled tasks [...] Such physiological resonance is regulated at the cellular level by a highly conserved molecular mechanism based on a complex transcriptional/translational feedback loop (TTFL) [...]

Metaboloepigenetics: The Emerging Network in Stem Cell Homeostasis Regulation Daniele Avitabile, Alessandra Magenta, Andrea Lauri, Elisa Gambini, Gabriella Spaltro and Maria Cristina Vinci DOI: 10.2174/1574888X11666151203223839 Current Stem Cell Research & Therapy

Did somebody say "complex TTFL"? Complex complexity. Dionisio

Circadian rhythms are regulated by the master circadian clock, which is made up of a group of ~20,000 specialized neurons localized in the suprachiasmatic nucleus (SCN) of the hypothalamus. The light/dark cycle stimuli are transduced into neurohormonal signals by SCN neurons regulating the activity of tissue-specific molecular clocks present in the peripheral organs, including the heart, liver and skin [...]

Metaboloepigenetics: The Emerging Network in Stem Cell Homeostasis Regulation Daniele Avitabile, Alessandra Magenta, Andrea Lauri, Elisa Gambini, Gabriella Spaltro and Maria Cristina Vinci DOI: 10.2174/1574888X11666151203223839 Current Stem Cell Research & Therapy

Complex complexity. Dionisio

The term circadian comes from the Latin circa, meaning "around" and diem meaning "day". Circadian rhythms are a particular kind of biological process that is characterized by endogenous and entrainable oscillations lasting about 24 hours (h). In mammals, several biological processes are circadian regulated including sleep-wake cycles, hormone secretion, cardiovascular function, body temperature, and energy metabolism.

Metaboloepigenetics: The Emerging Network in Stem Cell Homeostasis Regulation Daniele Avitabile, Alessandra Magenta, Andrea Lauri, Elisa Gambini, Gabriella Spaltro and Maria Cristina Vinci DOI: 10.2174/1574888X11666151203223839 Current Stem Cell Research & Therapy

Complex complexity. Dionisio

Fine-tuned regulation of gene transcription is required for the maintenance of normal and dynamic functions in all cells of our body. Emerging evidence highlights an intimate interplay between metabolism, epigenetics and the circadian cycle in gene activity regulation, which enables cells to respond to environmental changes and physiological demands in a timely manner.

Metaboloepigenetics: The Emerging Network in Stem Cell Homeostasis Regulation Daniele Avitabile, Alessandra Magenta, Andrea Lauri, Elisa Gambini, Gabriella Spaltro and Maria Cristina Vinci DOI: 10.2174/1574888X11666151203223839 Current Stem Cell Research & Therapy

Did somebody say "fine-tuned regulation"? huh? say what? :) Did somebody say "intimate interplay"? Oh la la... :) Complex complexity. Dionisio

Epigenetics harbours all regulatory information that, beyond nucleotide sequences, allows cells to “make decisions” throughout their lifetime in response to the external environment. The information can be transitory or relatively stable, and is even transmittable either to daughter cells or to the next generations through the germ line. Recent discoveries shed light on numerous connections between metabolites and epigenetic chromatin-modifying enzymes, providing a link between the metabolic state of the cell and epigenetics, and ultimately between metabolism, gene expression and cell fate.

Metaboloepigenetics: The Emerging Network in Stem Cell Homeostasis Regulation Daniele Avitabile, Alessandra Magenta, Andrea Lauri, Elisa Gambini, Gabriella Spaltro and Maria Cristina Vinci DOI: 10.2174/1574888X11666151203223839 Current Stem Cell Research & Therapy

Did somebody say “make decisions”? Do cells do things like that? Wow! Cool! :) Complex complexity. Dionisio

Adult neurogenesis produces new neurons from neural stem progenitor cells (NSPCs). This neural plasticity provides interneurons for the mammalian hippocampus, olfactory bulb (OB), and other brain structures throughout life. NSPCs follow a defined progression in cell differentiation [...] [...] circadian pacemakers may regulate NSPC differentiation. [...] circadian gene expression rhythms have been identified in the hippocampus [4] and OB [5], possibly serving to optimize timing of neurogenesis [3] by providing more responsive cells when they are most needed for fine discrimination of sensory information [6]. Circadian rhythms appear in neurospheres before mature neurons are present, indicating that NSPCs, which are very prominent in neurospheres, also have functional circadian clocks. It is likely that neurospheres are composed of many individual circadian oscillator cells as well as non-clock cells that are unable to sustain a circadian rhythm without input of timing information from other cells.

Development of Circadian Oscillators in Neurosphere Cultures during Adult Neurogenesis Astha Malik, Roudabeh J. Jamasbi, Roman V. Kondratov, Michael E. Geusz DOI: 10.1371/journal.pone.0122937 PLoS ONE 10(3): e0122937

Did somebody say "fine discrimination of sensory information"? Do cells do things like that? Wow! Cool! :) Complex complexity. Dionisio

KF, Apparently this kind of discussion threads make some folks anxious. I wonder why? Perhaps they dislike serious science? It's heartbreaking to see folks who don't see beyond the tip of their noses. They can't point to any of the many specific issues highlighted through this and other discussion threads. Instead they simply bark up the wrong trees. What else is new? Poor things. We should show compassion to them. Dionisio

Type 2 diabetes (T2D) is a disease of pandemic proportions, one defined by a complex aetiological mix of genetic, epigenetic, environmental, and lifestyle risk factors. Whilst the last decade of T2D genetic research has identified more than 100 loci showing strong statistical association with disease susceptibility, our inability to capitalise upon these signals reflects, in part, a lack of appropriate human cell models for study. This article aims to reinforce the importance of investigating T2D signals in cell models reflecting appropriate species, genomic context, developmental time point, and tissue type.

Genome-edited human stem cell-derived beta cells: a powerful tool for drilling down on type 2 diabetes GWAS biology Nicola L. Beera, and Anna L. Gloyn Version 1. F1000Res. 5: F1000 Faculty Rev-1711. doi: 10.12688/f1000research.8682.1

Had we remained in Eden none of that would have been a problem. Too late now. Work in progress… stay tuned. Complex complexity. Dionisio

KF: "TA, in the span of only a few minutes you have suggested mental ill-health twice relating to supporters of ID in this blog. In addition, above you suggested mercenary interest. In fact, it should be obvious that D has taken time to document issues in the technical literature that point to substantiation of the design inference thesis, in effect creating an informal bibliography. He has also taken time to draw comparisons with the least disreputable of the penumbra of attack sites. I suggest you need to take time out. KF" I'm not the one posting 3000+ comments to a UD thread. Particularly when the pointers to scientific papers provide no specific support to the creationist position. But good luck to him/her. I hope it keeps him/her happy. timothya

TA, in the span of only a few minutes you have suggested mental ill-health twice relating to supporters of ID in this blog. In addition, above you suggested mercenary interest. In fact, it should be obvious that D has taken time to document issues in the technical literature that point to substantiation of the design inference thesis, in effect creating an informal bibliography. He has also taken time to draw comparisons with the least disreputable of the penumbra of attack sites. I suggest you need to take time out. KF kairosfocus

Do you get paid for this, or is it just an obsessive interest of yours? timothya

Pancreatic beta cell failure is the central event leading to diabetes. Beta cells share many phenotypic traits with neurons, and proper beta cell function relies on the activation of several neuron-like transcription programs. Regulation of gene expression by alternative splicing plays a pivotal role in brain, where it affects neuronal development, function, and disease. The role of alternative splicing in beta cells remains unclear [...] [...] beta cells share common splicing regulators and programs with neurons. These splicing regulators play key roles in insulin release and beta cell survival, and their dysfunction may contribute to the loss of functional beta cell mass in diabetes.

Neuron-enriched RNA-binding Proteins Regulate Pancreatic Beta Cell Function and Survival. Juan-Mateu J, Rech TH, Villate O, Lizarraga-Mollinedo E, Wendt A, Turatsinze JV, Brondani LA, Nardelli TR, Nogueira TC, Esguerra JL, Alvelos MI Marchetti P, Eliasson L, Eizirik DL J Biol Chem. 292(8):3466-3480. doi: 10.1074/jbc.M116.748335

Complex complexity. Dionisio

[...] the development of new tools and the refinement of existing technology will allow us to tackle some of these open questions in a variety of model systems and thus to assemble more and more pieces of the puzzle.

Where does axon guidance lead us? Stoeckli E F1000Res. 6:78. doi: 10.12688/f1000research.10126.1.

Work in progress... stay tuned. Complex complexity. Dionisio

We can follow molecules in isolated cells in vitro with sophisticated high-resolution imaging methods. We can also image neuronal activity in vivo in actively behaving animals. But there is a huge gap in between that needs to be closed before we understand formation and function of neural circuits.

Where does axon guidance lead us? Stoeckli E F1000Res. 6:78. doi: 10.12688/f1000research.10126.1.

Work in progress... stay tuned. Complex complexity. Dionisio

The analysis of single-gene knockouts is not sufficient to understand the dynamic role of a protein during neural circuit formation. Eventually, we will have to study neural circuit formation at the protein level. This remains a challenge because tools are not yet available to visualize protein function in vivo.

Where does axon guidance lead us? Stoeckli E F1000Res. 6:78. doi: 10.12688/f1000research.10126.1.

Work in progress... stay tuned. Complex complexity. Dionisio

[...] we will need not only to test molecules and mechanisms identified in simple circuits in complex brain circuits but also to conceptually and experimentally integrate different signaling pathways to understand the behavior of growth cones and axons during neural circuit formation.

Where does axon guidance lead us? Stoeckli E F1000Res. 6:78. doi: 10.12688/f1000research.10126.1.

Work in progress... stay tuned. Complex complexity. Dionisio

Are they missing so much because of their reductionist bottom-up approach? Or because they are not open-minded? Or because they don't think out of wrongly preconceived boxes? Or is it all of the above? Any hope they could correct the problem? Or is it because the complex complexity of the biological systems? Dionisio

We have identified roles for individual molecules during different developmental processes contributing to the formation of neural circuits, but it is still unclear how binding partners or the downstream signaling (or both) change over time.

Where does axon guidance lead us? Stoeckli E F1000Res. 6:78. doi: 10.12688/f1000research.10126.1.

Work in progress... stay tuned. Complex complexity. Dionisio

[...] temporal changes in signaling are poorly understood.

Where does axon guidance lead us? Stoeckli E F1000Res. 6:78. doi: 10.12688/f1000research.10126.1.

Work in progress... stay tuned. Complex complexity. Dionisio

While we start to understand individual signaling pathways, we do not have a clear idea how they interfere with each other.

Where does axon guidance lead us? Stoeckli E F1000Res. 6:78. doi: 10.12688/f1000research.10126.1.

Work in progress... stay tuned. Complex complexity. Dionisio

[...] we will need to understand how the interactions of guidance receptors with their ligands trigger specific intracellular signals and how they are translated into changes in growth cone behavior.

Where does axon guidance lead us? Stoeckli E F1000Res. 6:78. doi: 10.12688/f1000research.10126.1.

Work in progress... stay tuned. Complex complexity. Dionisio

[...] we still need to learn much more about axon guidance mechanisms before we can explain how neural circuits form. This is even true for simple circuits, such as those formed by spinal cord interneurons!

Where does axon guidance lead us? Stoeckli E F1000Res. 6:78. doi: 10.12688/f1000research.10126.1.

Work in progress... stay tuned. Complex complexity. Dionisio

[...] the switch from attraction to repulsion has to be timed very precisely. [axons] have to be equipped with receptors for the detection of guidance cues for the longitudinal axis. [...] how is this precise timing of responsiveness achieved? [...] the focus in axon guidance research today is on the characterization of regulatory mechanisms. The interaction between receptors can result in silencing or enhancement of a response. More recently, many more of these receptor interactions in the plane of the growth cone membrane have been identified as important regulators of growth cone behavior [...]

Where does axon guidance lead us? Stoeckli E F1000Res. 6:78. doi: 10.12688/f1000research.10126.1.

Complex complexity. Dionisio

Do we know everything about axonal navigation of the midline? Actually, far from it. Despite the identification of all of these molecules, we still do not fully understand how axons cross the midline and why they turn rostrally. This is not only because additional guidance cues for the navigation of the spinal cord midline were identified but also because the regulation of the different receptors is not clear.

Where does axon guidance lead us? Stoeckli E F1000Res. 6:78. doi: 10.12688/f1000research.10126.1.

Complex complexity. Dionisio

Clearly, we need to understand the formation and function of neural networks [...] [...] neural circuit formation is a multi-step process starting with cell differentiation and migration, involving axon guidance and synaptogenesis, and ending with synaptic maturation or pruning, a process that is not fundamentally different from the one ensuring synaptic plasticity in the adult nervous system. Therefore, we still struggle to understand the molecular mechanisms of neural circuit formation.

Where does axon guidance lead us? Stoeckli E F1000Res. 6:78. doi: 10.12688/f1000research.10126.1.

Complex complexity. Dionisio

Recent developments in the field of axon guidance suggest that the regulation of surface expression of guidance receptors comprises transcriptional, translational, and post-translational mechanisms, such as trafficking of vesicles with specific cargos, protein-protein interactions, and specific proteolysis of guidance receptors. Not only axon guidance molecules but also the regulatory mechanisms that control their spatial and temporal expression are involved in synaptogenesis and synaptic plasticity. Therefore, it is not surprising that genes associated with axon guidance are frequently found in genetic and genomic studies of neurodevelopmental disorders.

Where does axon guidance lead us? Stoeckli E F1000Res. 6:78. doi: 10.12688/f1000research.10126.1.

Complex complexity. Dionisio

During neural circuit formation, axons need to navigate to their target cells in a complex, constantly changing environment. Although we most likely have identified most axon guidance cues and their receptors, we still cannot explain the molecular background of pathfinding for any subpopulation of axons. We lack mechanistic insight into the regulation of interactions between guidance receptors and their ligands.

Where does axon guidance lead us? Stoeckli E F1000Res. 6:78. doi: 10.12688/f1000research.10126.1.

Complex complexity. Dionisio

The Slit axon guidance molecules and their receptors, known as Robo (Roundabout), form one of the most crucial ligand-receptor pairings among the classic axon guidance signaling pathways by serving as a repellent to allow precise axon pathfinding and neuronal migration during development [...] It will be interesting to study how Slit-Robo1 signalling regulates Schwann cell migration into the nerve bridge during peripheral nerve regeneration. It will be interesting to study the dynamic expression pattern of Slit1-3 and Robo1-2 in injured mouse peripheral nerves and their role in peripheral nerve regeneration.

Expression patterns of Slit and Robo family members in adult mouse spinal cord and peripheral nervous system Lauren Carr, David B. Parkinson and Xin-peng Dun PLoS One. 12(2): e0172736. doi: 10.1371/journal.pone.0172736

Complex complexity. Dionisio

The secreted glycoproteins, Slit1-3, are classic axon guidance molecules that act as repulsive cues through their well characterised receptors Robo1-2 to allow precise axon pathfinding and neuronal migration. Our work gives important new data on the expression patterns of Slit and Robo family members within the peripheral nervous system that may relate both to nerve homeostasis and the reaction of the peripheral nerves to injury.

Expression patterns of Slit and Robo family members in adult mouse spinal cord and peripheral nervous system Lauren Carr, David B. Parkinson and Xin-peng Dun PLoS One. 12(2): e0172736. doi: 10.1371/journal.pone.0172736

Complex complexity. Dionisio

[...] it remains unclear if the commissural populations that provide this connectivity utilize midline crossing mechanisms similar to spinal commissural populations that cross at the ventral midline. [...] DCNs do not utilize floor plate-derived axon guidance cues and do not require Robo3 for midline crossing. it will be interesting to consider if such populations indeed contribute to the DCN population. [...] other approaches are required to test the role of midline glia in coordinating dorsal commissure formation. [...] further characterization of the nature and connectivity of DCNs will contribute significantly to our understanding of the spinal circuitry of pain.

Sensory and spinal inhibitory dorsal midline crossing is independent of Robo3 John D. Comer, Fong Cheng Pan, Spencer G. Willet, Parthiv Haldipur, Kathleen J. Millen, Christopher V. E. Wright and Julia A. Kaltschmidt Front Neural Circuits. 9: 36. doi: 10.3389/fncir.2015.00036

Complex complexity. Dionisio

[...] the molecular and genetic identities of DCNs remain unclear, and our understanding of the development of this bilateral connectivity remains limited. [...] little is known regarding this critical developmental process at the dorsal midline. Whether similar mechanisms regulate crossing at the dorsal midline, however, remains unclear. [...] DCNs require Robo1/Robo2 and Slit signaling to traverse the midline; however, they cross the midline independently of Robo3.

Sensory and spinal inhibitory dorsal midline crossing is independent of Robo3 John D. Comer, Fong Cheng Pan, Spencer G. Willet, Parthiv Haldipur, Kathleen J. Millen, Christopher V. E. Wright and Julia A. Kaltschmidt Front Neural Circuits. 9: 36. doi: 10.3389/fncir.2015.00036

Complex complexity. Dionisio

Bilateral neuronal communication is present at all levels of the central nervous system (CNS) and underlies a diverse array of neuronal functions, including the coordination of motor activity [...] [...] less is known regarding the origins and molecular identities of dorsally-crossing commissural neurons (DCNs) or the guidance cues that control dorsal midline crossing.

Sensory and spinal inhibitory dorsal midline crossing is independent of Robo3 John D. Comer, Fong Cheng Pan, Spencer G. Willet, Parthiv Haldipur, Kathleen J. Millen, Christopher V. E. Wright and Julia A. Kaltschmidt Front Neural Circuits. 9: 36. doi: 10.3389/fncir.2015.00036

Complex complexity. Dionisio

[...] little is known of the genetic and molecular properties of dorsally-crossing neurons or of the mechanisms that regulate dorsal midline crossing. The dorsally-crossing commissural neuron population we describe suggests a substrate circuitry for pain processing in the dorsal spinal cord.

Sensory and spinal inhibitory dorsal midline crossing is independent of Robo3 John D. Comer, Fong Cheng Pan, Spencer G. Willet, Parthiv Haldipur, Kathleen J. Millen, Christopher V. E. Wright and Julia A. Kaltschmidt Front Neural Circuits. 9: 36. doi: 10.3389/fncir.2015.00036

Complex complexity. Dionisio

It is thus likely that a distinct pathway directs the dorsal migration. Additional studies are warranted to unveil the identity of these molecules.

Netrin1/DCC signaling promotes neuronal migration in the dorsal spinal cord Junge HJ, Yung AR, Goodrich LV, Chen Z Neural Dev. 11(1):19. DOI: 10.1186/s13064-016-0074-x

Work in progress... stay tuned. Complex complexity. Dionisio

Neuronal migration is one of the early and critical steps of neural development. It is a complex cellular process involving many classes of molecules, including extracelluar ligands and transmembrane receptors, intracellular signaling molecules, cytoskeletal and motor proteins, and transcriptional factors [...] Within the developing spinal cord, the molecular mechanism underlying the migration of neuroprogenitors and differentiated neurons is mostly uncharacterized. [...] Netrin1/DCC signaling also attracts the migration of the dorsal spinal cord progenitors and neurons [...]

Netrin1/DCC signaling promotes neuronal migration in the dorsal spinal cord Junge HJ, Yung AR, Goodrich LV, Chen Z Neural Dev. 11(1):19. DOI: 10.1186/s13064-016-0074-x

Complex complexity. Dionisio

Given the importance of the migration in building the spinal cord circuitry, it is critical to identify the molecular mechanisms that regulate the radial and tangential migration of spinal cord neurons. Whether Netrin1 can also attract the lateral and ventral migration of spinal cord neurons remains unknown. [...] the Netrin1 ligand functions through DCC and ROBO3 receptors to promote the migration of the dorsal spinal cord neurons.

Netrin1/DCC signaling promotes neuronal migration in the dorsal spinal cord Junge HJ, Yung AR, Goodrich LV, Chen Z Neural Dev. 11(1):19. DOI: 10.1186/s13064-016-0074-x

Complex complexity. Dionisio

Newborn neurons often migrate before undergoing final differentiation, extending neurites, and forming synaptic connections. Therefore, neuronal migration is crucial for establishing neural circuitry during development. In the developing spinal cord, neuroprogenitors first undergo radial migration within the ventricular zone. Differentiated neurons continue to migrate tangentially before reaching the final positions. The molecular pathways that regulate these migration processes remain largely unknown. [...] during earlier development of dorsal interneurons including commissural neurons, these molecules play an important role in promoting cell migration.

Netrin1/DCC signaling promotes neuronal migration in the dorsal spinal cord Junge HJ, Yung AR, Goodrich LV, Chen Z Neural Dev. 11(1):19. DOI: 10.1186/s13064-016-0074-x

Complex complexity. Dionisio

Error detected: The paper referenced @3263 was referenced @2516-2518 a few months ago. Dionisio

The nerve growth cone is bi-directionally attracted and repelled by the same cue molecules depending on the situations, while other non-neural chemotactic cells usually show uni-directional attraction or repulsion toward their specific cue molecules. However, how the growth cone differs from other non-neural cells remains unclear. [...] the balance between activator and inhibitor underlies the multi-phasic bi-directional turning response of the growth cone.

Multi-phasic bi-directional chemotactic responses of the growth cone. Naoki H, Nishiyama M, Togashi K, Igarashi Y, Hong K, Ishii S Sci Rep. 6:36256. doi: 10.1038/srep36256

Complex complexity. Dionisio

Netrin1 has been proposed to act from the floor plate (FP) as a long-range diffusible chemoattractant for commissural axons in the embryonic spinal cord. However, netrin1 mRNA and protein are also present in neural progenitors within the ventricular zone (VZ), raising the question of which source of netrin1 promotes ventrally directed axon growth. [...] the FP is not the source of netrin1 directing axons to the ventral midline, while local VZ-supplied netrin1 is required for this step. [...] rather than being present in a gradient, netrin1 protein accumulates on the pial surface adjacent to the path of commissural axon extension. [...] netrin1 does not act as a long-range secreted chemoattractant for commissural spinal axons but instead promotes ventrally directed axon outgrowth by haptotaxis, i.e., directed growth along an adhesive surface.

Netrin1 Produced by Neural Progenitors, Not Floor Plate Cells, Is Required for Axon Guidance in the Spinal Cord Supraja G. Varadarajan, Jennifer H. Kong, Keith D. Phan, Tzu-Jen Kao, S. Carmen Panaitof, Julie Cardin, Holger Eltzschig, Artur Kania, Bennett G. Novitch, Samantha J. Butler DOI: http://dx.doi.org/10.1016/j.neuron.2017.03.007

Complex complexity. Dionisio

The last few years has seen in quiet revolution in ESCRT cell biology. The new functions discovered or confirmed outnumber the classical function several times over. It is now hard to think of any example of “reverse” topology membrane budding and scission in eukaryotes (or in some Archaea) that does not involve the ESCRTs. Many of the most interesting discoveries are being made by cell and developmental biologists who are new to the ESCRT field—more evidence that the ESCRTs have gone mainstream in cell biology. It is hard to know how much farther the field can go in finding new functions. The frontier questions now may not be so much what do the ESCRTs do or why, but rather how they do what they do.

ESCRTs are everywhere. Hurley JH EMBO J. ;34(19):2398-407. doi: 10.15252/embj.201592484.

Complex complexity. Dionisio

The ESCRT proteins are an ancient system that buds membranes and severs membrane necks from their inner face. Three "classical" functions of the ESCRTs have dominated research into these proteins since their discovery in 2001: the biogenesis of multivesicular bodies in endolysosomal sorting; the budding of HIV-1 and other viruses from the plasma membrane of infected cells; and the membrane abscission step in cytokinesis. The past few years have seen an explosion of novel functions: the biogenesis of microvesicles and exosomes; plasma membrane wound repair; neuron pruning; extraction of defective nuclear pore complexes; nuclear envelope reformation; plus-stranded RNA virus replication compartment formation; and micro- and macroautophagy. Most, and perhaps all, of the functions involve the conserved membrane-neck-directed activities of the ESCRTs, revealing a remarkably widespread role for this machinery through a broad swath of cell biology.

ESCRTs are everywhere. Hurley JH EMBO J. ;34(19):2398-407. doi: 10.15252/embj.201592484.

Complex complexity. Dionisio

The endosomal sorting complex required for transport (ESCRT), originally identified for its role in endosomal protein sorting and biogenesis of multivesicular endosomes (MVEs), has proven to be a versatile machinery for involution and scission of narrow membrane invaginations filled with cytosol. Budding of enveloped viruses and cytokinetic abscission were early described functions for the ESCRT machinery, and recently a number of new ESCRT functions have emerged. These include cytokinetic abscission checkpoint control, plasma membrane repair, exovesicle release, quality control of nuclear pore complexes, neuron pruning, and sealing of the newly formed nuclear envelope.

Novel ESCRT functions in cell biology: spiraling out of control? Campsteijn C, Vietri M, Stenmark H Curr Opin Cell Biol. 41:1-8. doi: 10.1016/j.ceb.2016.03.008

Complex complexity. Dionisio

Complex molecular machineries bud, scission and repair cellular membranes. Components of the multi-subunit endosomal sorting complex required for transport (ESCRT) machinery are enlisted when multivesicular bodies are generated, extracellular vesicles are formed, the plasma membrane needs to be repaired, enveloped viruses bud out of host cells, defective nuclear pores have to be cleared, the nuclear envelope must be resealed after mitosis and for final midbody abscission during cytokinesis. While some ESCRT components are only required for specific processes, the assembly of ESCRT-III polymers on target membranes and the action of the AAA-ATPase Vps4 are mandatory for every process. [...] we speculate how ESCRT-III and Vps4 might function together and highlight how the characterization of their precise spatiotemporal organization will improve our understanding of ESCRT-mediated membrane budding and scission in vivo.

ESCRT-III and Vps4: a dynamic multipurpose tool for membrane budding and scission. Alonso Y Adell M, Migliano SM, Teis D FEBS J. 283(18):3288-302. doi: 10.1111/febs.13688.

Complex complexity. Dionisio

Our knowledge on mechanisms that drive cargo sorting into EVs and uptake by recipient cells is limited. There is an urgent need for assays that monitor cargo delivery to target cells that are amenable to high throughput screening. The fast and accurate detection of aggregate induction in recipient cells will help to characterize general cellular pathways involved in aggregation and dissemination of protein aggregates.

Prions on the run: How extracellular vesicles serve as delivery vehicles for self-templating protein aggregates Shu Liu, André Hossinger, Sarah Göbbels & Ina M. Vorberg? Journal Prion Volume 11, Issue 2 Pages 98-112 http://dx.doi.org/10.1080/19336896.2017.1306162

Complex complexity. Dionisio

Many, if not all cells, release a repertoire of vesicles in the extracellular milieu. Secreted vesicles shed from the plasma membrane or produced by the endosomal system are collectively termed extracellular vesicles (EVs).? EVs are important mediators of intercellular communication and transfer proteins, RNAs and other cellular components between cells, thereby modulating diverse cellular processes in acceptor cells. As biomolecules incorporated into exosomes reflect the physiological state of their donor cells, they are also intensely surveyed as biomarker sources.

Prions on the run: How extracellular vesicles serve as delivery vehicles for self-templating protein aggregates Shu Liu, André Hossinger, Sarah Göbbels & Ina M. Vorberg? Journal Prion Volume 11, Issue 2 Pages 98-112 http://dx.doi.org/10.1080/19336896.2017.1306162

Complex complexity. Dionisio

Extracellular vesicles (EVs) are actively secreted, membrane-bound communication vehicles that exchange biomolecules between cells. EVs also serve as dissemination vehicles for pathogens, including prions, proteinaceous infectious agents that cause transmissible spongiform encephalopathies (TSEs) in mammals. Our knowledge of how protein aggregates are sorted into EVs and how these vesicles adhere to and fuse with target cells is limited.

Prions on the run: How extracellular vesicles serve as delivery vehicles for self-templating protein aggregates Shu Liu, André Hossinger, Sarah Göbbels & Ina M. Vorberg? Journal Prion Volume 11, Issue 2 Pages 98-112 http://dx.doi.org/10.1080/19336896.2017.1306162

Complex complexity. Dionisio

These studies have also provided a considerable surprise. Whether resection remains defective in all these RING-less models remains to be seen [...] Definitive evidence for or against cancer protection denoted by BRCA1-BARD1 Ub ligase activity awaits further investigation.

The BRCA1 Ubiquitin ligase function sets a new trend for remodelling in DNA repair Ruth M. Densham & Joanna R. Morris Journal Nucleus Volume 8, Issue 2 Pages 116-125 http://dx.doi.org/10.1080/19491034.2016.1267092

[#3223 addendum] Did somebody say "surprise"? Work in progress... stay tuned. Complex complexity. Dionisio

Proline is an amino acid with a unique cyclic structure that facilitates the folding of many proteins, but also impedes the rate of peptide bond formation by the ribosome. As a ribosome substrate, proline reacts markedly slower when compared with other amino acids both as a donor and as an acceptor of the nascent peptide. Furthermore, synthesis of peptides with consecutive proline residues triggers ribosome stalling. Here, we report crystal structures of the eukaryotic ribosome bound to analogs of mono- and diprolyl-tRNAs. These structures provide a high-resolution insight into unique properties of proline as a ribosome substrate. They show that the cyclic structure of proline residue prevents proline positioning in the amino acid binding pocket and affects the nascent peptide chain position in the ribosomal peptide exit tunnel. These observations extend current knowledge of the protein synthesis mechanism. They also revise an old dogma that amino acids bind the ribosomal active site in a uniform way by showing that proline has a binding mode distinct from other amino acids.

Molecular insights into protein synthesis with proline residues. Melnikov S, Mailliot J, Rigger L, Neuner S, Shin BS, Yusupova G, Dever TE, Micura R, Yusupov M EMBO Rep. 17(12):1776-1784. DOI: 10.15252/embr.201642943

Did somebody say "observations extend current knowledge"? Did somebody say "revise an old dogma"? Complex complexity. Dionisio

Biocontainment comprises any strategy applied to ensure that harmful organisms are confined to controlled laboratory conditions and not allowed to escape into the environment. Genetically engineered microorganisms (GEMs), regardless of the nature of the modification and how it was established, have potential human or ecological impact if accidentally leaked or voluntarily released into a natural setting. Although all evidence to date is that GEMs are unable to compete in the environment, the power of synthetic biology to rewrite life requires a pre-emptive strategy to tackle possible unknown risks. Physical containment barriers have proven effective but a number of strategies have been developed to further strengthen biocontainment. Research on complex genetic circuits, lethal genes, alternative nucleic acids, genome recoding and synthetic auxotrophies aim to design more effective routes towards biocontainment.

Synthetic biology approaches to biological containment: pre-emptively tackling potential risks. Torres L, Krüger A, Csibra E, Gianni E, Pinheiro VB Essays Biochem. 60(4):393-410. DOI: 10.1042/EBC20160013

Complex complexity. Dionisio

Genetic code expansion and reprogramming enable the site-specific incorporation of diverse designer amino acids into proteins produced in cells and animals.

Expanding and reprogramming the genetic code of cells and animals. Chin JW Annu Rev Biochem. 83:379-408. doi: 10.1146/annurev-biochem-060713-035737.

Did somebody say "reprogramming"? Did somebody say "designer"? Complex complexity. Dionisio

Orthogonal protein translation with noncanonical amino acids (ncAAs) has become a standard method in biosciences. Whereas much effort is made to broaden the chemical space of ncAAs, only few attempts on their systematic low-cost in situ production are reported until now. The main aim is to engineer cells with newly designed biosynthetic pathways coupled with orthogonal aminoacyl-tRNA synthetase/tRNA pairs (o-pairs). These should provide cost-effective solutions to industrially relevant bio-production problems, such as peptide/protein production beyond the canonical set of natural molecules and to expand the arsenal of chemistries available for living cells. Therefore, coupling genetic code expansion (GCE) with metabolic engineering is the basic prerequisite to transform orthogonal translation from a standard technique in academic research to industrial biotechnology.

Coupling genetic code expansion and metabolic engineering for synthetic cells. Völler JS, Budisa N Curr Opin Biotechnol. 48:1-7. doi: 10.1016/j.copbio.2017.02.002

Complex complexity. Dionisio

Genetic code expansion (GCE) has become a central topic of synthetic biology. GCE relies on engineered aminoacyl-tRNA synthetases (aaRSs) and a cognate tRNA species to allow codon reassignment by co-translational insertion of non-canonical amino acids (ncAAs) into proteins. Introduction of such amino acids increases the chemical diversity of recombinant proteins endowing them with novel properties. Such proteins serve in sophisticated biochemical and biophysical studies both in vitro and in vivo, they may become unique biomaterials or therapeutic agents, and they afford metabolic dependence of genetically modified organisms for biocontainment purposes.

Pyrrolysyl-tRNA synthetase, an aminoacyl-tRNA synthetase for genetic code expansion. Crnkovi? A, Suzuki T, Söll D, Reynolds NM Croat Chem Acta. 89(2):163-174. doi: 10.5562/cca2825

Complex complexity. Dionisio

Phosphorylation of many aminoacyl tRNA synthetases (AARSs) has been recognized for decades, but the contribution of post-translational modification to their primary role in tRNA charging and decryption of genetic code remains unclear. In contrast, phosphorylation is essential for performance of diverse noncanonical functions of AARSs unrelated to protein synthesis. Phosphorylation of glutamyl-prolyl tRNA synthetase (EPRS) has been investigated extensively in our laboratory for more than a decade, and has served as an archetype for studies of other AARSs. EPRS is a constituent of the IFN-?-activated inhibitor of translation (GAIT) complex that directs transcript-selective translational control in myeloid cells. Stimulus-dependent phosphorylation of EPRS is essential for its release from the parental multi-aminoacyl tRNA synthetase complex (MSC), for binding to other GAIT complex proteins, and for regulating the binding to target mRNAs. Importantly, phosphorylation is the common driving force for the context- and stimulus-dependent release, and non-canonical activity, of other AARSs residing in the MSC, for example, lysyl tRNA synthetase (KARS).

Experimental approaches for investigation of aminoacyl tRNA synthetase phosphorylation. Arif A, Jia J, Halawani D, Fox PL Methods. 113:72-82. doi: 10.1016/j.ymeth.2016.10.004

Complex complexity. Dionisio

[...] understanding the function of aminoacyl-tRNA synthetases appeared to be a task much more complicated than previously anticipated due to the numerous secondary, noncanonical functions that are performed by this family of enzymes. Association and dissociation of the components of the MARS seems to be an important checkpoint for many cellular pathways. The recent finding that splice-variant synthetases may fulfill functions independently of their primary role in translation, also unexpectedly expands the sphere of influence of this family of enzymes [...]

Aminoacyl-tRNA Synthetase Complexes in Evolution Svitlana Havrylenko and Marc Mirande Int J Mol Sci. 16(3): 6571–6594. doi: 10.3390/ijms16036571

Did somebody say "unexpectedly"? Work in progress... stay tuned. Complex complexity. Dionisio

The knowledge of the protein interfaces involved in the different facets of their activity is of fundamental importance [...] [...] an intricate interaction network makes it more difficult to design molecules capable of inhibiting a single pathway. It is not known whether the same surface area of LysRS is involved in the interaction with p38 and with all these secondary partners. It remains to be established whether association of LysRS with the native, full-length scaffold protein will reveal a similar interaction pattern.

Aminoacyl-tRNA Synthetase Complexes in Evolution Svitlana Havrylenko and Marc Mirande Int J Mol Sci. 16(3): 6571–6594. doi: 10.3390/ijms16036571

Work in progress... stay tuned. Complex complexity. Dionisio

Decoding of genetic information is an essential step for all living organisms. The process of translation of the genetic message contained in mRNA into proteins is a universal mechanism conserved, with minor modifications, in the three branches of the tree of life, from bacteria, archaea, and to eukaryotes. A family of enzymes, the aminoacyl-tRNA synthetases, is responsible for pairing a specific amino acid to a cognate tRNA, thus establishing a univocal relationship between a triplet of nucleotides, the anticodon, and an elementary piece of proteins.

Aminoacyl-tRNA Synthetase Complexes in Evolution Svitlana Havrylenko and Marc Mirande Int J Mol Sci. 16(3): 6571–6594. doi: 10.3390/ijms16036571

Complex complexity. Dionisio

Aminoacyl-tRNA synthetases are essential enzymes for interpreting the genetic code. They are responsible for the proper pairing of codons on mRNA with amino acids. In addition to this canonical, translational function, they are also involved in the control of many cellular pathways essential for the maintenance of cellular homeostasis. Association of several of these enzymes within supramolecular assemblies is a key feature of organization of the translation apparatus in eukaryotes. It could be a means to control their oscillation between translational functions, when associated within a multi-aminoacyl-tRNA synthetase complex (MARS), and nontranslational functions, after dissociation from the MARS and association with other partners.

Aminoacyl-tRNA Synthetase Complexes in Evolution Svitlana Havrylenko and Marc Mirande Int J Mol Sci. 16(3): 6571–6594. doi: 10.3390/ijms16036571

Complex complexity. Dionisio

Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. They are a family of twenty enzymes, one for each amino acid. By coupling an amino acid to a specific RNA triplet, the anticodon, they are responsible for interpretation of the genetic code. In addition to this translational, canonical role, several aminoacyl-tRNA synthetases also fulfill nontranslational, moonlighting functions. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. Because the balance between their alternative functions rests on the assembly and disassembly of this supramolecular entity, it is essential to get precise insight into the structural organization of this complex. The high-resolution 3D-structure of the native particle, with a molecular weight of about 1.5 MDa, is not yet known. Low-resolution structures of the multi-aminoacyl-tRNA synthetase complex, as determined by cryo-EM or SAXS, have been reported. High-resolution data have been reported for individual enzymes of the complex, or for small subcomplexes. This review aims to present a critical view of our present knowledge of the aminoacyl-tRNA synthetase complex in 3D. These preliminary data shed some light on the mechanisms responsible for the balance between the translational and nontranslational functions of some of its components.

The Aminoacyl-tRNA Synthetase Complex. Mirande M Subcell Biochem. 83:505-522. doi: 10.1007/978-3-319-46503-6_18.

Complex complexity. Dionisio

Re this comment by Dionisio: "Recent advances in genetic engineering allow the creation of synthetic organisms that incorporate noncanonical, or even unnatural, amino acids into the proteome." The infamous tryptophan food supplement disaster of 1989 demonstrated that the inaccurate unpredictably GMO technology can introduce new, toxic, "unnatural amino acids" into the human organism. The GE technology is still inaccurate and unpredictable in 2017. The GMO technology has virtually zero longterm safety studies. Lots of good data by independent scientsts, rather than the official junk data created by corporate-funded scientists, shows serious risks. Politics is the real dominant factor behind the GE technology. Not real science. One of the earliest GMO cases (a public experiment) that has preambled the long history of ignoring and suppressing the real dangers of GMO foods was the tryptophan supplement disaster of 1989 where the FDA ignored the warnings of their own scientists about the real risks of GMOs, simply to protect the business interests of the GMO industry, which they've been colluding with for decades - see http://www.supplements-and-health.com/l-tryptophan.html The government-biotech industrial complex has the average person believing that they're protecting their health. Yet, lying about real facts, denying real facts, or minimizing or ignoring real facts is not protecting or helping the public, it's deceiving the public. Jiy Jay

Aminoacylation reaction is the first step of protein biosynthesis. The catalytic reorganization at the active site of aminoacyl tRNA synthetases (aaRSs) is driven by the loop motions. There remain lacunae of understanding concerning the catalytic loop dynamics in aaRSs. We analyzed the functional loop dynamics in seryl tRNA synthetase from Methanopyrus kandleri (mkSerRS) and histidyl tRNA synthetases from Thermus thermophilus (ttHisRS), respectively, using molecular dynamics. Results confirm that the motif 2 loop and other active site loops are flexible spots within the catalytic domain. Catalytic residues of the loops form a network of interaction with the substrates to form a reactive state. The loops undergo transitions between closed state and open state and the relaxation of the constituent residues occurs in femtosecond to nanosecond time scale. Order parameters are higher for constituent catalytic residues which form a specific network of interaction with the substrates to form a reactive state compared to the Gly residues within the loop. The development of interaction is supported from mutation studies where the catalytic domain with mutated loop exhibits unfavorable binding energy with the substrates. During the open-close motion of the loops, the catalytic residues make relaxation by ultrafast librational motion as well as fast diffusive motion and subsequently relax rather slowly via slower diffusive motion. The Gly residues act as a hinge to facilitate the loop closing and opening by their faster relaxation behavior. The role of bound water is analyzed by comparing implicit solvent-based and explicit solvent-based simulations. Loops fail to form catalytically competent geometry in absence of water. The present result, for the first time reveals the nature of the active site loop dynamics in aaRS and their influence on catalysis.

Dynamics of the active site loops in catalyzing aminoacylation reaction in seryl and histidyl tRNA synthetases. Dutta S, Kundu S, Saha A, Nandi N J Biomol Struct Dyn. 1-15. doi: 10.1080/07391102.2017.1301272.

Complex complexity. Dionisio

A full exploration of the possibilities enabled by genetic code engineering requires an understanding of the key molecular biological and biochemical mechanisms underlying the modifications.

Efforts and Challenges in Engineering the Genetic Code. Lin X, Yu AC, Chan TF Life (Basel). 7(1). pii: E12. doi: 10.3390/life7010012.

Complex complexity. Dionisio

This year marks the 48th anniversary of Francis Crick's seminal work on the origin of the genetic code, in which he first proposed the "frozen accident" hypothesis to describe evolutionary selection against changes to the genetic code that cause devastating global proteome modification. However, numerous efforts have demonstrated the viability of both natural and artificial genetic code variations. Recent advances in genetic engineering allow the creation of synthetic organisms that incorporate noncanonical, or even unnatural, amino acids into the proteome. Currently, successful genetic code engineering is mainly achieved by creating orthogonal aminoacyl-tRNA/synthetase pairs to repurpose stop and rare codons or to induce quadruplet codons. In this review, we summarize the current progress in genetic code engineering and discuss the challenges, current understanding, and future perspectives regarding genetic code modification.

Efforts and Challenges in Engineering the Genetic Code. Lin X, Yu AC, Chan TF Life (Basel). 7(1). pii: E12. doi: 10.3390/life7010012.

Complex complexity. Dionisio

Aminoacyl tRNA synthetase-interacting multifunctional protein 1 (AIMP1) has been reported to have antitumor effects in various tumor models. However, mechanisms by which AIMP1 ameliorates tumorigenesis are not well understood. As NK cells are a major cell type involved in antitumor activities and AIMP1 is known to activate professional APCs, we determined whether AIMP1 induced NK cell activation directly or via these APCs. AIMP1 induced the expression of surface activation markers on murine NK cells in total splenocytes, although AIMP1 did not directly induce these activation markers of NK cells. The inductive effect of AIMP1 on NK cell activation disappeared in macrophage-depleted splenocytes, indicating that macrophages were required for the AIMP1-induced activation of NK cells. Furthermore, coculture experiments showed that AIMP1 activated NK cells in the presence of isolated macrophages, but failed to activate NK cells when cultured alone or with dendritic cells or B cells. Although AIMP1 significantly promoted TNF-? production by macrophages, the secreted TNF-? partially affected the NK cell activation. Transwell cocultivation analysis revealed that direct contact between macrophages and NK cells was required for the AIMP1-induced NK cell activation. In addition, AIMP1 significantly enhanced cytotoxicity of NK cells against Yac-1 cells. Furthermore, the in vivo administration of AIMP1 also induced NK cell activation systemically with a macrophage-dependent manner. Importantly, AIMP1 dramatically reduced the lung metastasis of melanoma cells, which was mediated by NK cells. Taken together, our results show that AIMP1 induces antitumor responses by NK cell activation mainly via macrophages.

Aminoacyl tRNA Synthetase--Interacting Multifunctional Protein 1 Activates NK Cells via Macrophages In Vitro and In Vivo. Kim MS, Song JH, Cohen EP, Cho D, Kim TS J Immunol. pii: 1601558. doi: 10.4049/jimmunol.1601558

Complex complexity. Dionisio

[...] the complexity of recombinant AMP expression including a functional PTM machinery and SPI/SCS-based ncAA incorporation (cf. Figure ?Figure11) presents a challenging task for bioprocess and production strain engineering. [...] AMP production could benefit from well-balanced expression and activity levels of precursor and PTM machinery genes. [...] combination of PTM enzymes from different AMPs offers additional diversity for the generation of novel AMPs [...]

Prospects of In vivo Incorporation of Non-canonical Amino Acids for the Chemical Diversification of Antimicrobial Peptides. Baumann T1, Nickling JH1, Bartholomae M2, Buivydas A2, Kuipers OP2, Budisa N1 Front Microbiol. 8:124. doi: 10.3389/fmicb.2017.00124.

Reprogrammable biological devices? Complex complexity. Dionisio

The incorporation of non-canonical amino acids (ncAA) is an elegant way for the chemical diversification of recombinantly produced antimicrobial peptides (AMPs). Residue- and site-specific installation methods in several bacterial production hosts hold great promise for the generation of new-to-nature AMPs, and can contribute to tackle the ongoing emergence of antibiotic resistance in pathogens. Especially from a pharmacological point of view, desirable improvements span pH and protease resistance, solubility, oral availability and circulation half-life.

Prospects of In vivo Incorporation of Non-canonical Amino Acids for the Chemical Diversification of Antimicrobial Peptides. Baumann T1, Nickling JH1, Bartholomae M2, Buivydas A2, Kuipers OP2, Budisa N1 Front Microbiol. 8:124. doi: 10.3389/fmicb.2017.00124.

Reprogrammable biological cells? Complex complexity. Dionisio

Genetic code engineering that enables reassignment of genetic codons to non-canonical amino acids (ncAAs) is a powerful strategy for enhancing ribosomally synthesized peptides and proteins with functions not commonly found in Nature. Reprogrammed cells or proteins equipped with synthetic structures are currently usually considered as useful tools for academic research or small applications. However, this engineering can even have practical importance when applications such as bioremediation (in open systems) biocatalysts or peptide-based drugs (closed systems) are considered50. For future bioengineering purposes, our system and its improved versions will doubtlessly provide a manifold of opportunities to design various novel ribosomally synthesized compounds.

Towards Biocontained Cell Factories: An Evolutionarily Adapted Escherichia coli Strain Produces a New-to-nature Bioactive Lantibiotic Containing Thienopyrrole-Alanine. Kuthning A1, Durkin P2, Oehm S2, Hoesl MG2, Budisa N2, Süssmuth RD Sci Rep. 6:33447. doi: 10.1038/srep33447.

Did somebody say "Reprogrammed"? Did somebody say "engineering"? Did somebody say "design"? Complex complexity. Dionisio

We present here, to our knowledge, the first example of Arg analog incorporation into membrane-bound receptors, and as such, these results describe an incisive approach to dissecting chemical interactions in a broad and therapeutically relevant family of membrane proteins. Interestingly, an H-bond network adjacent to the ligand binding site has been proposed for the structurally related glycine receptor (32), suggesting that stabilization of ligand binding by such H-bond networks could be a conserved feature of ligand recognition by pLGICs.

Unique Contributions of an Arginine Side Chain to Ligand Recognition in a Glutamate-gated Chloride Channel. Lynagh T, Komnatnyy VV, Pless SA J Biol Chem. 292(9):3940-3946. doi: 10.1074/jbc.M116.772939.

Complex complexity. Dionisio

Neurotransmitter receptors are vital signaling proteins that are embedded in the cell membrane and trigger intracellular changes in response to extracellular chemical signals. The two classical receptor types are metabotropic, G-protein-coupled receptors (GPCRs) that act over seconds or minutes via intracellular second messengers (1), and ionotropic, ligand-gated ion channels (LGICs)2 that mediate ion flux across the membrane on the millisecond timescale (2). The rapid chemo-electric signaling of LGICs is perfectly suited to the nervous system, where activation of sodium channels and chloride channels mediates excitatory and inhibitory signals, respectively (2). The first step in the process of activation is the recognition of a specific ligand, which in the case of the animal nervous system is very often the neurotransmitter glutamate (3).

Unique Contributions of an Arginine Side Chain to Ligand Recognition in a Glutamate-gated Chloride Channel. Lynagh T, Komnatnyy VV, Pless SA J Biol Chem. 292(9):3940-3946. doi: 10.1074/jbc.M116.772939.

Complex complexity. Dionisio

Glutamate recognition by neurotransmitter receptors often relies on Arg residues in the binding site, leading to the assumption that charge-charge interactions underlie ligand recognition. However, assessing the precise chemical contribution of Arg side chains to protein function and pharmacology has proven to be exceedingly difficult in such large and complex proteins. [...] Arg contributes crucially to ligand sensitivity via a hydrogen bond network, where Arg interacts both with agonist and with a conserved Thr side chain within the receptor. Together, the data provide a new explanation for the reliance of neurotransmitter receptors on Arg side chains and highlight the exceptional capacity of unnatural amino acid incorporation for increasing our understanding of ligand recognition.

Unique Contributions of an Arginine Side Chain to Ligand Recognition in a Glutamate-gated Chloride Channel. Lynagh T, Komnatnyy VV, Pless SA J Biol Chem. 292(9):3940-3946. doi: 10.1074/jbc.M116.772939.

Complex complexity. Dionisio

Error @3230: A large portion of the text got repeated by mistake. Dionisio

The methods for establishing synthetic lifeforms with rewritten genetic codes comprising non-canonical amino acids (NCAA) in addition to canonical amino acids (CAA) include proteome-wide replacement of CAA, insertion through suppression of nonsense codon, and insertion via the pyrrolysine and selenocysteine pathways. The sharing of the same protein alphabet by all living species suggests that the alphabet determined by the standard code predated the earliest divergence of organisms. [...]?synthetic lifeforms employing rewritten genetic codes can be produced by a number of different methods. These methods will widen the scope of synthetic life research, bringing unique insights into protein chemistry and biology as well as a wide range of applications. Building the rewritten genetic codes and the novel protein alphabets ushered in by them, optimizing their uses and preventing all possibilities of misuse, will represent a momentous development that advances science, medicine and biotechnology. The sharing of the same protein alphabet by all living species suggests that the alphabet determined by the standard code predated the earliest divergence of organisms. [...]?synthetic lifeforms employing rewritten genetic codes can be produced by a number of different methods. These methods will widen the scope of synthetic life research, bringing unique insights into protein chemistry and biology as well as a wide range of applications. Building the rewritten genetic codes and the novel protein alphabets ushered in by them, optimizing their uses and preventing all possibilities of misuse, will represent a momentous development that advances science, medicine and biotechnology.

Future of the Genetic Code. Xue H, Wong JT Life (Basel). 7(1). pii: E10. doi: 10.3390/life7010010

Complex complexity. Dionisio

Genetic code expansion via amber stop suppression provides a powerful tool for introducing non-proteinogenic functionalities into proteins for a broad range of applications. Here, we report the implementation of a versatile platform for the development of engineered aminoacyl-tRNA synthetases with enhanced efficiency in mediating ncAA incorporation via amber stop codon suppression. This system integrates a white/blue colony screen with a plate-based colorimetric assay, thereby combining high-throughput capabilities with reliable and quantitative measurement of AARS-dependent ncAA incorporation efficiency. This two-tier functional screening system wassuccessfully applied to obtain a pyrrolysyl-tRNA synthetase variant (CrtK-RS(4.1)) with significantly improved efficiency (+250-370%) toward mediating the incorporation of N?-crotonyl-lysine and other lysine analogs of relevance for the study of protein post-translational modifications, into a target protein. Interestingly, the beneficial mutations accumulated by CrtK-RS(4.1) were found to localize within the non-catalytic N-terminal domain of the enzyme, and could be transferred to another PylRS variant improving its ability to incorporate its corresponding ncAA substrate. This work introduces and validates an efficient platform for the improvement of AARSs that could be readily extended to other members of this enzyme family and/or other target non-canonical amino acids. ?

Two-tier Screening Platform for Directed Evolution of Aminoacyl-tRNA Synthetases with Enhanced Stop Codon Suppression Efficiency. Owens AE1, Grasso KT, Ziegler CA, Fasan R2. Chembiochem. doi: 10.1002/cbic.201700039.

adjusting biological programmable devices? Cool! Complex complexity. Dionisio

The amino acid acridon-2-ylalanine (Acd) can be a valuable probe of protein dynamics, either alone or as part of a Förster resonance energy transfer (FRET) or photo-induced electron transfer (eT) probe pair. We have previously reported the genetic incorporation of Acd by an aminoacyl tRNA synthetase (RS). However, this RS, developed from a library of permissive RSs, also incorporates N-phenyl-aminophenylalanine (Npf), a trace byproduct of one Acd synthetic route. We have performed negative selections in the presence of Npf and analyzed the selectivity of the resulting AcdRSs by in vivo protein expression and detailed kinetic analyses of the purified RSs. We find that selection conferred a ?50-fold increase in selectivity for Acd over Npf, eliminating incorporation of Npf contaminants, and allowing one to use a high yielding Acd synthetic route for improved overall expression of Acd-containing proteins. More generally, our report also provides a cautionary tale on the use of permissive RSs, as well as a strategy for improving selectivity for the target amino acid. ?

Improving target amino acid selectivity in a permissive aminoacyl tRNA synthetase through counter-selection. Sungwienwong I1, Hostetler ZM2, Blizzard RJ3, Porter JJ3, Driggers CM4, Mbengi LZ4, Villegas JA1, Speight LC1, Saven JG1, Perona JJ5, Kohli RM2, Mehl RA3, Petersson EJ1 Org Biomol Chem. doi: 10.1039/c7ob00582b

papers referenced @ 3227 & @3228 show that they are dealing with programmable devices. Complex complexity. Dionisio

Transcriptional control can be used to program cells to label proteins with non-canonical amino acids by regulating the expression of orthogonal aminoacyl tRNA synthetases (aaRSs). However, we cannot yet program cells to control labeling in response to aaRS and ligand binding. To identify aaRSs whose activities can be regulated by interactions with ligands, we used a combinatorial approach to discover fragmented variants of Escherichia coli methionyl tRNA synthetase (MetRS) that require fusion to associating proteins for maximal activity. We found that these split proteins could be leveraged to create ligand-dependent MetRS using two approaches. When a pair of MetRS fragments was fused to FKBP12 and the FKBP-rapamycin binding domain of mTOR, and mutations were introduced that direct substrate specificity towards azidonorleucine (Anl), Anl metabolic labeling was significantly enhanced in growth medium containing rapamycin, which stabilizes the FKBP12-mTOR complex. In addition, fusion of MetRS fragments to the termini of the ligand-binding domain of the estrogen receptor yielded proteins whose Anl metabolic labeling was significantly enhanced when 4-hydroxytamoxifen was added to the growth medium. These findings suggest that split MetRS can be fused to a range of ligand-binding proteins to create aaRS whose metabolic labeling activities depend upon post-translational interactions with ligands. ?

Programming post-translational control over the metabolic labeling of cellular proteins with a non-canonical amino acid. Thomas EE, Pandey N, Knudsen SE, Ball ZT, Silberg JJ ACS Synth Biol. doi: 10.1021/acssynbio.7b00100.

Complex complexity. Dionisio

Off topic (just for a break): Out of touch with physical reality? http://www.msn.com/en-us/money/companies/mark-zuckerberg-just-signed-the-death-warrant-for-the-smartphone/ar-BBA0LDN?li=BBmkt5R&ocid=spartanntp Dionisio

The 20 aminoacyl tRNA synthetases (aaRSs) couple each amino acid to their cognate tRNAs. [...] 19 aaRSs expanded by acquiring novel noncatalytic appended domains, which are absent from bacteria and many lower eukaryotes but confer extracellular and nuclear functions in higher organisms. AlaRS is the single exception, with an appended C-terminal domain (C-Ala) that is conserved from prokaryotes to humans but with a wide sequence divergence. In human cells, C-Ala is also a splice variant of AlaRS. Crystal structures of two forms of human C-Ala, and small-angle X-ray scattering of AlaRS, showed that the large sequence divergence of human C-Ala reshaped C-Ala in a way that changed the global architecture of AlaRS. This reshaping removes the role of C-Ala in prokaryotes for docking tRNA and instead repurposes it to form a dimer interface presenting a DNA-binding groove. This groove cannot form with the bacterial ortholog. Direct DNA binding by human C-Ala, but not by bacterial C-Ala, was demonstrated. Thus, instead of acquiring a novel appended domain like other human aaRSs, which engendered novel functions, a new AlaRS architecture was created by diversifying a preexisting appended domain.

Two crystal structures reveal design for repurposing the C-Ala domain of human AlaRS Litao Sun, Youngzee Song, David Blocquel, Xiang-Lei Yang and Paul Schimmel PNAS vol. 113 no. 50 14300–14305 doi: 10.1073/pnas.1617316113

Complex complexity. Dionisio

Here we present an exception that supports the rule that the 20 human tRNA synthetases acquired new architectures to expand their functions during evolution. The new features are associated with novel, appended domains that are absent in prokaryotes and retained by their many splice variants. Alanyl-tRNA synthetase (AlaRS) is the single example that has a prototypical appended domain—C-Ala—even in prokaryotes, which is spliced out in humans. X-ray structural, small-angle X-ray scattering, and functional analysis showed that human C-Ala lost its prokaryotic tRNA functional role and instead was reshaped into a nuclear DNA-binding protein. Thus, we report another paradigm for tRNA synthetase acquisition of a novel function, namely, repurposing a preexisting domain rather than addition of a new one.

Two crystal structures reveal design for repurposing the C-Ala domain of human AlaRS Litao Sun, Youngzee Song, David Blocquel, Xiang-Lei Yang and Paul Schimmel PNAS vol. 113 no. 50 14300–14305 doi: 10.1073/pnas.1617316113

Did somebody say "design for repurposing"? Complex complexity. Dionisio

Several functions have been attributed to BRCA1 that contribute to genome integrity but which of these, if any, require this enzymatic function was unclear. The BRCA1 protein plays several roles in genome stability: including check-point promotion, DNA cross-link repair, replication fork stability and DNA double-strand break (DSB) repair.

The BRCA1 Ubiquitin ligase function sets a new trend for remodelling in DNA repair Ruth M. Densham & Joanna R. Morris? Journal Nucleus Volume 8, Issue 2 Pages 116-125 http://dx.doi.org/10.1080/19491034.2016.1267092

Complex complexity. Dionisio

It remains to be determined whether H3K18 interacts directly with 53BP1, and if so, what is the domain involved. Further research will shed light into the SIRT7-mediated regulation of 53BP1 recruitment to DNA damage sites, which might involve both epigenetic regulation and protein-protein functional interactions. [...] sirtuins can act at different levels on the DDR, but our knowledge of how their relative contributions are regulated in vivo is in its infancy.

Sirtuins and DNA damage repair: SIRT7 comes to play Berta N. Vazquez, Joshua K. Thackray & Lourdes Serrano? Journal Nucleus Volume 8, Issue 2 Pages 107-115 http://dx.doi.org/10.1080/19491034.2016.1264552

Work in progress… stay tuned. Complex complexity. Dionisio

Whether the acetylation wave precedes the deacetylation one or vice versa is not clear, and this warrants further investigation at high temporal and spatial resolution in living cells. Similarly, the functional implications of pan-nuclear acetylation signals also need further investigation.

Sirtuins and DNA damage repair: SIRT7 comes to play Berta N. Vazquez, Joshua K. Thackray & Lourdes Serrano? Journal Nucleus Volume 8, Issue 2 Pages 107-115 http://dx.doi.org/10.1080/19491034.2016.1264552

Work in progress... stay tuned. Complex complexity. Dionisio

Aging is characterized by a cumulative loss of genome integrity, which involves chromatin reorganization, transcriptional dysregulation and the accumulation of DNA damage. Sirtuins participate in the protection against these aging processes by promoting genome homeostasis in response to cellular stress.

Sirtuins and DNA damage repair: SIRT7 comes to play Berta N. Vazquez, Joshua K. Thackray & Lourdes Serrano? Journal Nucleus Volume 8, Issue 2 Pages 107-115 http://dx.doi.org/10.1080/19491034.2016.1264552

Complex complexity. Dionisio

Perhaps even more challenging will be to reveal how DDT defects and fork topology alterations brought about by defective repriming negatively influence sister chromatid cohesion [...] [...] understanding the connections between DDT defects, fork topology, replication stress and sister chromatid cohesion perturbations appears both timely and highly relevant. With the continued pursuit of understanding replication stress, cohesion mechanisms, and how these two processes influence genome integrity, new insights are hopefully forthcoming.

Priming for tolerance and cohesion at replication forks Dana Branzei? & Barnabas Szakal Journal Nucleus Volume 7, Issue 1 Pages 8-12 http://dx.doi.org/10.1080/19491034.2016.1149663

Work in progress... stay tuned. Complex complexity. Dionisio

[...] future studies will be needed to interrogate the relationship between fork reversal and DDT. Examination of these predictions will likely bring forward a better understanding on the coordination of DDT with fork movement and remodeling, and will likely provide new handles to investigate the integration of these events within known DNA damage response circuits.

Priming for tolerance and cohesion at replication forks Dana Branzei? & Barnabas Szakal Journal Nucleus Volume 7, Issue 1 Pages 8-12 http://dx.doi.org/10.1080/19491034.2016.1149663

Did somebody say "coordination"? Did somebody say "circuits"? Complex complexity. Dionisio

DNA damage stalls replication forks causing exposure of single stranded (ss) DNA, which in turn triggers activation of DNA damage tolerance (DDT) pathways that promote damage-bypass. Two modes of DDT have been described in all eukaryotic species.? Judging from the different implications that the two DDT modes have on genome integrity, an interesting question is whether cells are able to preferentially use error-free pathways first, while postponing error-prone pathways as last resort options. Recent findings suggest that this may be indeed the case. The underlying mechanism behind this preference remains largely mysterious, [...]

Priming for tolerance and cohesion at replication forks Dana Branzei? & Barnabas Szakal Journal Nucleus Volume 7, Issue 1 Pages 8-12 http://dx.doi.org/10.1080/19491034.2016.1149663

Did somebody imply that cells may have preferences? Complex complexity. Dionisio

Genome replication, required for the propagation of all living cells and organisms, is a prodigious task made possible by the complex and timely interplay between replication factors, DNA repair activities, and other DNA metabolism pathways that ensure correct chromosome structure establishment.

Priming for tolerance and cohesion at replication forks Dana Branzei? & Barnabas Szakal Journal Nucleus Volume 7, Issue 1 Pages 8-12 http://dx.doi.org/10.1080/19491034.2016.1149663

Complex complexity. Dionisio

Precise positioning of nucleosomes around regulatory sites is achieved by the action of chromatin remodelers, which use the energy of ATP to slide, evict or change the composition of nucleosomes. Chromatin remodelers act to bind nucleosomes, disrupt histone-DNA interactions and translocate the DNA around the histone core to reposition nucleosomes. Identification of the loss of histone-DNA contacts during chromatin remodeling by RSC in vivo has implications for the regulation of transcriptional initiation. [...] the mechanisms of BRM/BRG1 action are difficult to study because combinations of subunits give rise to numerous distinct complexes. Our paradigm of understanding remodeler action through identification of alternate nucleosome structures presents a new way to understand remodeler function that can override the combinatorial complexity of remodelers in metazoans.

Nucleosome dynamics during chromatin remodeling in vivo Srinivas Ramachandran & Steven Henikoff? Journal Nucleus Volume 7, Issue 1 Pages 20-26 http://dx.doi.org/10.1080/19491034.2016.1149666

Complex complexity. Dionisio

[...] lamin A binds to chromatin and restricts its motion. Consequently, it dampens chromatin dynamics, which allows chromosomes to remain localized, each in its chromosome territory, during interphase [...] We are confident that future progress and implementation of such interdisciplinary approaches will enable the identification of new nuclear processes that take place in living cells.

Exploring chromatin organization mechanisms through its dynamic properties Irena Bronshtein, Itamar Kanter, Eldad Kepten, Moshe Lindner, Shirly Berezin, Yaron Shav-Tal & Yuval Garini Journal Nucleus Volume 7, Issue 1 Pages 27-33 http://dx.doi.org/10.1080/19491034.2016.1139272

Complex complexity. Dionisio

The organization of the genome in the nucleus is believed to be crucial for different cellular functions. It is known that chromosomes fold into distinct territories, but little is known about the mechanisms that maintain these territories. [...] chromatin motion is mediated by lamin A [...] [...] constrained chromatin mobility allows to maintain chromosome territories. [...] the discovery of this function of nucleoplasmic lamin A proteins sheds light on the maintenance mechanism of chromosome territories in the interphase nucleus, which ensures the proper function of the genome.

Exploring chromatin organization mechanisms through its dynamic properties Irena Bronshtein, Itamar Kanter, Eldad Kepten, Moshe Lindner, Shirly Berezin, Yaron Shav-Tal & Yuval Garini Journal Nucleus Volume 7, Issue 1 Pages 27-33 http://dx.doi.org/10.1080/19491034.2016.1139272

Complex complexity. Dionisio

[...] although a large fraction of TAD structure is invariant between cell types, a subset of TADs are variable. We speculate that the observed differences in TAD organization between cell types are a biologically significant representation of cell-type specific gene expression. [...] we suggest that the alterations in 3D chromatin organization during differentiation may be more significant than previously reported [...]

Topologically Associating Domains: An invariant framework or a dynamic scaffold? Caelin Cubeñas-Potts & Victor G Corces? Journal Nucleus Volume 6, - Issue 6 Pages 430-434 http://dx.doi.org/10.1080/19491034.2015.1096467

Complex complexity. Dionisio

[...] the intricate 3D organization that occurs within a single chromosome has become evident. [...] chromatin interactions occur in a non-random manner along the chromosome arm, separated into regions of highly interacting chromatin named topologically associating domains (TADs).? [...] TADs are composed of multiple regions of local chromatin interaction enrichment, which have been named subTADs and contact domains.? [...] the observed cell-type specific TADs are functionally significant, likely representing novel regulatory element interactions leading to novel gene expression patterns.?

Topologically Associating Domains: An invariant framework or a dynamic scaffold? Caelin Cubeñas-Potts & Victor G Corces Journal Nucleus Volume 6, - Issue 6 Pages 430-434 http://dx.doi.org/10.1080/19491034.2015.1096467

Complex complexity. Now I recall gpuccio mentioned these TADs long before I had read about them. I think I started to understand why he seems so "obsessed" with this exciting stuff. :) I have to admit that back then I didn't quite get why all that hype, but finally I realized that the dottore italiano was definitely ahead of the crowd on this important topic. Dionisio

Metazoan genomes are organized into regions of topologically associating domains (TADs). TADs are demarcated by border elements, which are enriched for active genes and high occupancy architectural protein binding sites. [...] the subset of variable TADs observed after differentiation are representative of cell-type specific gene expression and are biologically significant.

Topologically Associating Domains: An invariant framework or a dynamic scaffold? Caelin Cubeñas-Potts & Victor G Corces Journal Nucleus Volume 6, - Issue 6 Pages 430-434 http://dx.doi.org/10.1080/19491034.2015.1096467

Complex complexity. Dionisio

Continued examination of the factors found at TAD boundaries will yield important insights into the biophysical properties of TADs and their boundaries, as well as into chromatin folding and overall genome organization that supports biological control.

The connection between BRG1, CTCF and topoisomerases at TAD boundaries A. Rasim Barutcu, Jane B. Lian, Janet L. Stein, Gary S. Stein & Anthony N. Imbalzano? Journal Nucleus Volume 8, Issue 2 Pages 150-155 http://dx.doi.org/10.1080/19491034.2016.1276145

Work in progress... stay tuned. Complex complexity. Dionisio

Our recent data indicating that BRG1, and hence the mammalian SWI/SNF chromatin remodeling enzyme, binds to TAD boundaries and promotes boundary strength adds a novel biochemical activity, ATP-dependent chromatin remodeling, to the complex structure that regulates TAD formation and function.

The connection between BRG1, CTCF and topoisomerases at TAD boundaries A. Rasim Barutcu, Jane B. Lian, Janet L. Stein, Gary S. Stein & Anthony N. Imbalzano? Journal Nucleus Volume 8, Issue 2 Pages 150-155 http://dx.doi.org/10.1080/19491034.2016.1276145

Complex complexity getting more complex? Dionisio

Although a relationship between TAD boundaries and the binding of insulators has been demonstrated, the effects of enzymes that modify or remodel chromatin are largely unknown. [...] the boundary is not defined by the exact boundary sequence or length, but instead depends either on the supercoiling or the overall composition of the factors present at the boundary.

The connection between BRG1, CTCF and topoisomerases at TAD boundaries A. Rasim Barutcu, Jane B. Lian, Janet L. Stein, Gary S. Stein & Anthony N. Imbalzano? Journal Nucleus Volume 8, Issue 2 Pages 150-155 http://dx.doi.org/10.1080/19491034.2016.1276145

Hmm... that's an interesting description of a boundary, isn't it? Complex complexity. Dionisio

[...] the dynamic folding of the chromatin is fundamental in regulating gene expression and DNA replication. The genome is folded in a hierarchical manner into chromosome territories, genomic compartments, and topologically associating domains (TADs), in which specific long-range looping interactions occur.? Each of these structures can be dynamically regulated during development, and perturbations in these folding units are associated with multiple diseases and cancer.

The connection between BRG1, CTCF and topoisomerases at TAD boundaries A. Rasim Barutcu, Jane B. Lian, Janet L. Stein, Gary S. Stein & Anthony N. Imbalzano? Journal Nucleus Volume 8, Issue 2 Pages 150-155 http://dx.doi.org/10.1080/19491034.2016.1276145

Complex complexity. Dionisio

The eukaryotic genome is partitioned into topologically associating domains (TADs). Despite recent advances characterizing TADs and TAD boundaries, the organization of these structures is an important dimension of genome architecture and function that is not well understood. [...] BRG1 may contribute to the regulation of the structural and functional properties of chromatin at TAD boundaries by affecting the function or the recruitment of CTCF and DNA topoisomerase complexes.

The connection between BRG1, CTCF and topoisomerases at TAD boundaries A. Rasim Barutcu, Jane B. Lian, Janet L. Stein, Gary S. Stein & Anthony N. Imbalzano? Journal Nucleus Volume 8, Issue 2 Pages 150-155 http://dx.doi.org/10.1080/19491034.2016.1276145

Complex complexity. Dionisio

Further studies are also needed to examine whether the exclusion of reader-containing protein complexes from mitotic chromatin depends on collaboration between phosphorylation sites. It will be interesting to investigate whether protein accumulation on microtubules is a mechanism to avert premature reassociation of histone readers with chromatin or to ensure equal distribution of important factors between daughter cells during mitosis.

Epigenetic countermarks in mitotic chromosome condensation Karel H. M. van Wely?, Carmen Mora Gallardo, Kendra R. Vann & Tatiana G. Kutateladze? Journal Nucleus Volume 8, Issue 2 Pages 144-149 http://dx.doi.org/10.1080/19491034.2016.1276144

Are they* there yet? Work in progress... stay tuned. Complex complexity. (*) note that a popularized version of this question refers to "we", but in this case it's about "them" (the scientific researchers) who are trying hard to climb the steep mountain of knowledge and reach the big "eureka!" summit. Also, some of us believe we know -- in general terms -- the end of the whole story, because the Author has graciously revealed it, therefore we could claim being already there (singing Hallelujah!). Dionisio

Over the past decade substantial progress has been made in our understanding of the physiologic importance of mitotic chromatin condensation, however many questions remain. [...] the precise role of histone H3 phosphorylation sites in chromatin condensation remains unclear [...] [...] we do not fully understand the antagonistic or cooperative effects and functional crosstalk involving phosphorylation and other histone PTMs.

Epigenetic countermarks in mitotic chromosome condensation Karel H. M. van Wely?, Carmen Mora Gallardo, Kendra R. Vann & Tatiana G. Kutateladze? Journal Nucleus Volume 8, Issue 2 http://dx.doi.org/10.1080/19491034.2016.1276144

Did somebody say "many questions remain"? Did somebody say "functional crosstalk"? Work in progress... stay tuned. Complex complexity. Dionisio

A rapid increase in chromatin compaction during mitosis, known as chromosome condensation, is essential for the faithful distribution of identical genetic material between daughter cells. Chromosome condensation involves the recruitment of condensin complexes to chromatin [...] and is characterized by a pattern of posttranslational modifications (PTMs) in histones.

Epigenetic countermarks in mitotic chromosome condensation Karel H. M. van Wely?, Carmen Mora Gallardo, Kendra R. Vann & Tatiana G. Kutateladze? Journal Nucleus Volume 8, Issue 2 http://dx.doi.org/10.1080/19491034.2016.1276144

Complex complexity. Dionisio

Mitosis in metazoans is characterized by abundant phosphorylation of histone H3 and involves the recruitment of condensin complexes to chromatin. The relationship between the 2 phenomena and their respective contributions to chromosome condensation in vivo remain poorly understood.

Epigenetic countermarks in mitotic chromosome condensation Karel H. M. van Wely?, Carmen Mora Gallardo, Kendra R. Vann & Tatiana G. Kutateladze? Journal Nucleus Volume 8, Issue 2 http://dx.doi.org/10.1080/19491034.2016.1276144

Complex complexity. Dionisio

[...] phosphorylation of the intramolecular interaction site in the PRD is one of the major mechanisms that activates the ESCRT function of ALIX. The MVB sorting of membrane receptors, the retroviral budding, and the cytokinetic abscission are three classical ESCRT-mediated processes that critically involve ALIX function [...]

Phosphorylation-Dependent Activation of the ESCRT Function of ALIX in Cytokinetic Abscission and Retroviral Budding. Sun S, Sun L, Zhou X, Wu C, Wang R, Lin SH, Kuang J Dev Cell. 2016 Feb 8;36(3):331-43. doi: 10.1016/j.devcel.2016.01.001.

Complex complexity. Dionisio

The involvement of NAIP with cell cycle progression will be investigated in future studies. In conclusion, we document a previously unknown localization of NAIP along the entire cytokinetic process whose dynamics exhibits a distinct behaviour (Fig. 1c); the molecular dissection of this novel profile may lead to a better understanding of the final steps of cell division. Future studies might include the investigation of NAIP post-translational modifications and protein variants expression and their relationship with cytokinesis as well as establishing which NAIP protein motifs are required for these putative roles along with the interaction between NAIP with the well established cytokinesis regulators.

Neuronal apoptosis inhibitory protein (NAIP) localizes to the cytokinetic machinery during cell division. Abadía-Molina F, Morón-Calvente V, Baird SD, Shamim F, Martín F, MacKenzie A Sci Rep. 7:39981. doi: 10.1038/srep39981.

Complex complexity. Dionisio

Cytokinesis is the final step in the cell cycle, by which dividing cells physically separate into two cells following mitotic sister chromatid segregation. Soon after anaphase is initiated, the mitotic spindle reorganizes in an array of antiparallel microtubules to form the central spindle at the cell equator; at the same time, the actomyosin contractile ring organizes along the cleavage furrow in the cell cortex beneath the plasma membrane. These two processes, formation of the central spindle and organization of the contractile ring, define the division plane; subsequently, activation of the contractile ring gradually constricts the dividing cell.

Neuronal apoptosis inhibitory protein (NAIP) localizes to the cytokinetic machinery during cell division. Abadía-Molina F, Morón-Calvente V, Baird SD, Shamim F, Martín F, MacKenzie A Sci Rep. 7:39981. doi: 10.1038/srep39981.

Complex complexity. Dionisio

The size of adult brains is the resultant of a delicate balance between neural progenitor proliferation, differentiation and neurite outgrowth, which occur during both embryogenesis and post-natally. A multitude of cell surface receptors and their downstream signaling harmoniously orchestrate these processes to allow proper brain development. The endolysosomal system is crucial for this orchestration, not only by regulating cell surface expression and degradation of the receptors, but also by organising signaling hubs inside endosomes. Alix plays a major role in determining the size of the brain by controlling neural progenitor survival at the start of neurogenesis and later on, by regulating post-natal dendrite development.

Alix is required during development for normal growth of the mouse brain. Laporte MH, Chatellard C, Vauchez V, Hemming FJ, Deloulme JC, Vossier F, Blot B, Fraboulet S, Sadoul R Sci Rep. 7:44767. doi: 10.1038/srep44767.

Did somebody say "orchestrate"? Did somebody say "orchestration"? Did somebody say "organising"? Complex complexity. Dionisio

It remains to be established whether one monomeric molecule of ALG-2 has a capacity to bridge two binding partners or only a homodimer can bridge them due to steric restrictions. It would be intriguing to see whether Pocket 4 accepts a new type of motif that has not been determined yet. Identification of novel interacting proteins and elucidation of functional roles should provide more lines of evidence that dimeric ALG-2 bridges proteins to expand the interacting network and contributes to regulation of Ca2+-dependent membrane trafficking.

Multifaceted Roles of ALG-2 in Ca(2+)-Regulated Membrane Trafficking. Maki M, Takahara T, Shibata H Int J Mol Sci. 17(9). pii: E1401. doi: 10.3390/ijms17091401.

Complex complexity. Dionisio

The molecular mechanisms and the biological functions of clathrin independent endocytosis (CIE) remain largely elusive. The plasma membrane of all eukaryotic cells undergoes constant renewal through repeated cycles of endocytosis and exocytosis. During endocytosis, cell surface proteins and lipids are internalized forming vesicular carriers which then merge with early endosomes, a process central to the regulation of nutrient uptake, cell surface receptor signaling, plasma membrane remodeling, cellular mobility and synaptic vesicle recycling1. Most of these processes rely on clathrin-mediated endocytosis (CME) based on the clathrin machinery for shaping endocytic vesicles. However alternative pathways, collectively referred to as clathrin-independent endocytosis (CIE), also occur at the plasma membrane, although the molecular mechanisms leading to membrane bending and fission, as well as the biological significance of these pathways have yet to be clarified2. Further work will be required to define whether endophilin binding to Alix is also mandatory for these endocytic processes. [...] it is unclear how CIE or CME of surface-activated receptors affects the propagation of intracellular signals.

ALG-2 interacting protein-X (Alix) is essential for clathrin-independent endocytosis and signaling. Mercier V, Laporte MH, Destaing O, Blot B, Blouin CM, Pernet-Gallay K, Chatellard C, Saoudi Y, Albiges-Rizo C, Lamaze C, Fraboulet S, Petiot A, Sadoul R Sci Rep. 6:26986. doi: 10.1038/srep26986.

Complex complexity. Dionisio

[...] CK2 acts as a negative regulator of centriole duplication and is required for proper cell cycle progression and cytokinesis. [...] identifying substrates and specific amino acid residues targeted by CK2 will help in understanding how CK2 regulates centrosome duplication, in particular, how protein kinase CK2 influences ZYG-1 levels at centrosomes in C. elegans embryos. [...] it remains unclear how CK2 function is linked to centrosome assembly.

Casein kinase II is required for proper cell division and acts as a negative regulator of centrosome duplication in Caenorhabditis elegans embryos. Medley JC, Kabara MM, Stubenvoll MD, DeMeyer LE, Song MH Biol Open. 6(1):17-28. doi: 10.1242/bio.022418.

Complex complexity. Dionisio

Control of proper centrosome number is crucial for the fidelity of cell division [...] In animal cells, centrosomes organize microtubules to direct the formation of bipolar mitotic spindles that contribute to accurate segregation of genomic content. Centrosomes comprise two orthogonally arranged centrioles surrounded by a dense network of proteins termed pericentriolar material (PCM). Centrioles must duplicate exactly once per cell cycle to provide daughter cells with the correct number of centrosomes.

Casein kinase II is required for proper cell division and acts as a negative regulator of centrosome duplication in Caenorhabditis elegans embryos. Medley JC, Kabara MM, Stubenvoll MD, DeMeyer LE, Song MH Biol Open. 6(1):17-28. doi: 10.1242/bio.022418.

Complex complexity. Dionisio

Centrosomes are the primary microtubule-organizing centers that orchestrate microtubule dynamics during the cell cycle. The correct number of centrosomes is pivotal for establishing bipolar mitotic spindles that ensure accurate segregation of chromosomes. Thus, centrioles must duplicate once per cell cycle, one daughter per mother centriole, the process of which requires highly coordinated actions among core factors and modulators. Protein phosphorylation is shown to regulate the stability, localization and activity of centrosome proteins. [...] CK2 functions in cell division and negatively regulates centrosome duplication in a kinase-dependent manner.

Casein kinase II is required for proper cell division and acts as a negative regulator of centrosome duplication in Caenorhabditis elegans embryos. Medley JC, Kabara MM, Stubenvoll MD, DeMeyer LE, Song MH Biol Open. 6(1):17-28. doi: 10.1242/bio.022418.

Did somebody say "orchestrate"? Did somebody say "highly coordinated actions"? Complex complexity. Dionisio

The multivesicular body (MVB) pathway sorts ubiquitinated membrane cargo to intraluminal vesicles (ILVs) within the endosome, en route to the lysosomal lumen. The pathway involves the sequential action of conserved protein complexes [endosomal sorting complexes required for transport (ESCRTs)], culminating in the activation by ESCRT-II of ESCRT-III, a membrane-sculpting complex. Although this linear pathway of ESCRT activation is widely accepted, a study by Luzio and colleagues in a recent issue of the Biochemical Journal suggests that there is greater complexity in ESCRT-III activation, at least for some MVB cargoes. They show that ubiquitin-dependent sorting of major histocompatibility complex (MHC) class I to the MVB requires the central ESCRT-III complex but does not involve either ESCRT-II or functional links between ESCRT-II and ESCRT-III. Instead, they propose that MHC class I utilizes histidine-domain protein tyrosine phosphatase (HD-PTP), a non-canonical ESCRT interactor, to promote ESCRT-III activation.

ESCRT-III on endosomes: new functions, new activation pathway. Woodman P Biochem J. 473(2):e5-8. doi: 10.1042/BJ20151115.

Complex complexity. Dionisio

Endosomal sorting complexes required for transport (ESCRTs) execute membrane remodeling and scission [...] Our model positions Doa4 and Bro1 at both the beginning and the end of ESCRT-III function in the ILV budding pathway of yeast (Figure 8), but several questions remain. [...] how Doa4 and Bro1 regulate ESCRT-III complex stability is unknown. Future studies may reveal whether ESCRT-III is also regulated at endosomes in mammalian cells either by ALIX or by UBPY, the apparent functional ortholog of Doa4.

Regulation of yeast ESCRT-III membrane scission activity by the Doa4 ubiquitin hydrolase. Johnson N, West M, Odorizzi G Mol Biol Cell. 28(5):661-672. doi: 10.1091/mbc.E16-11-0761.

Complex complexity. Dionisio

ESCRT-III executes membrane scission during the budding of intralumenal vesicles (ILVs) at endosomes. The scission mechanism is unknown but appears to be linked to the cycle of assembly and disassembly of ESCRT-III complexes at membranes. Regulating this cycle is therefore expected to be important for determining the timing of ESCRT-III-mediated membrane scission.

Regulation of yeast ESCRT-III membrane scission activity by the Doa4 ubiquitin hydrolase. Johnson N, West M, Odorizzi G Mol Biol Cell. 28(5):661-672. doi: 10.1091/mbc.E16-11-0761.

Complex complexity. Dionisio

[...] MKLP1 is likely to have the same inhibitory activity as Borealin. This raises the important question of what could be the signal that triggers the release of CHMP4C from MKLP1 and its assembly into the spiral filaments that promote abscission. [...] we speculate that other signals probably exist in addition to the gradual degradation and inactivation of the CPC. [...] future studies will be necessary to integrate all these factors into a comprehensive mechanistic model for ESCRT-mediated abscission.

Coordinated regulation of the ESCRT-III component CHMP4C by the chromosomal passenger complex and centralspindlin during cytokinesis Luisa Capalbo, Ioanna Mela, Maria Alba Abad, A. Arockia Jeyaprakash, J. Michael Edwardson, and Pier Paolo D'Avino Open Biol. 6(10): 160248. doi: 10.1098/rsob.160248

Work in progress... stay tuned. Complex complexity. Dionisio

CHMP4C plays an active role in membrane deformation during abscission and that its activity and localization are finely regulated by both the CPC and centralspindlin. Some questions, however, remain unanswered. [...] future investigations are required to fully understand the role of different phosphatases in CHMP4C regulation.

Coordinated regulation of the ESCRT-III component CHMP4C by the chromosomal passenger complex and centralspindlin during cytokinesis Luisa Capalbo, Ioanna Mela, Maria Alba Abad, A. Arockia Jeyaprakash, J. Michael Edwardson, and Pier Paolo D'Avino Open Biol. 6(10): 160248. doi: 10.1098/rsob.160248

Complex complexity. Dionisio

[...] the CPC and centralspindlin cooperate to regulate the activity and localization of CHMP4C during cytokinesis. [...] the molecular details are still missing, and our study provides novel crucial insights into this process. [...] a ‘relay’ mechanism between the CPC and centralspindlin could control the translocation of CHMP4C from the midbody arms to the Flemming body at the end of cytokinesis [...]

Coordinated regulation of the ESCRT-III component CHMP4C by the chromosomal passenger complex and centralspindlin during cytokinesis Luisa Capalbo, Ioanna Mela, Maria Alba Abad, A. Arockia Jeyaprakash, J. Michael Edwardson, and Pier Paolo D'Avino Open Biol. 6(10): 160248. doi: 10.1098/rsob.160248

Complex complexity. Dionisio

Cytokinesis is a rapid and robust process that ensures the faithful segregation of genomic and cytoplasmic contents into the two nascent daughter cells at the end of cell division. Cytokinesis progresses through a series of sequential steps orchestrated by several proteins and protein complexes in a very precise order.

Coordinated regulation of the ESCRT-III component CHMP4C by the chromosomal passenger complex and centralspindlin during cytokinesis Luisa Capalbo, Ioanna Mela, Maria Alba Abad, A. Arockia Jeyaprakash, J. Michael Edwardson, and Pier Paolo D'Avino Open Biol. 6(10): 160248. doi: 10.1098/rsob.160248

Did somebody say "orchestrated"? Complex complexity. Dionisio

The chromosomal passenger complex (CPC)—composed of Aurora B kinase, Borealin, Survivin and INCENP—surveys the fidelity of genome segregation throughout cell division. The CPC has been proposed to prevent polyploidy by controlling the final separation (known as abscission) of the two daughter cells via regulation of the ESCRT-III CHMP4C component. The molecular details are, however, still unclear. [...] gradual dephosphorylation of CHMP4C triggers a ‘relay’ mechanism between the CPC and centralspindlin that regulates the timely distribution and activation of CHMP4C for the execution of abscission.

Coordinated regulation of the ESCRT-III component CHMP4C by the chromosomal passenger complex and centralspindlin during cytokinesis Luisa Capalbo, Ioanna Mela, Maria Alba Abad, A. Arockia Jeyaprakash, J. Michael Edwardson, and Pier Paolo D'Avino Open Biol. 6(10): 160248. doi: 10.1098/rsob.160248

Complex complexity. Dionisio

[...] ESCRT-III recruitment during cytokinetic abscission remains poorly understood. [...] it remains unresolved to what extent other CHMP4 paralogs, such as the Aurora B–dependent abscission checkpoint regulator CHMP4C, rely on similar recruitment mechanisms [...] [...] the mechanism of recruitment of CHMP4B by ALIX or ESCRT-I during cytokinetic abscission has not been established. Collectively, our work resolves the molecular dependencies underlying CHMP4B recruitment during cytokinetic abscission and identifies ALIX as a novel abscission checkpoint signaling node. It will therefore be important to further dissect the molecular interplay between these ALIX functionalities, CHMP4 paralogs, and ANCHR as well as their regulation by Aurora B and ULK3 (Caballe et al., 2015) in the abscission checkpoint signaling [...]

ALIX and ESCRT-I/II function as parallel ESCRT-III recruiters in cytokinetic abscission Liliane Christ, Eva M. Wenzel, Knut Liestøl, Camilla Raiborg, Coen Campsteijn and Harald Stenmark J Cell Biol. 212(5): 499–513. doi: 10.1083/jcb.201507009

Complex complexity. Dionisio

Cytokinetic abscission, the final stage of cell division where the two daughter cells are separated, is mediated by the endosomal sorting complex required for transport (ESCRT) machinery. The ESCRT-III subunit CHMP4B is a key effector in abscission, whereas its paralogue, CHMP4C, is a component in the abscission checkpoint that delays abscission until chromatin is cleared from the intercellular bridge. How recruitment of these components is mediated during cytokinesis remains poorly understood [...]

ALIX and ESCRT-I/II function as parallel ESCRT-III recruiters in cytokinetic abscission Liliane Christ, Eva M. Wenzel, Knut Liestøl, Camilla Raiborg, Coen Campsteijn and Harald Stenmark J Cell Biol. 212(5): 499–513. doi: 10.1083/jcb.201507009

Complex complexity. Dionisio

Over the past 140 years, eukaryotic cell division has been extensively studied and is now understood to be an elaborate, tightly regulated set of events that culminates in the formation of two distinct daughter cells. Our overall understanding of the regulation of abscission still remains elementary [...] [...] the relationship between Aurora B–mediated phosphorylation of CHMP4C and its ability to bind ALIX must now be further explored.

Burning cellular bridges: Two pathways to the big breakup E.B. Frankel and Anjon Audhya J Cell Biol. 212(5): 491–493. doi: 10.1083/jcb.201602003

Work in progress... stay tuned. Complex complexity. Dionisio

During cytokinetic abscission, the endosomal sorting complex required for transport (ESCRT) proteins are recruited to the midbody and direct the severing of the intercellular bridge. [...] two separate but redundant pathways exist to recruit ESCRT-III proteins to the midbody.

Burning cellular bridges: Two pathways to the big breakup E.B. Frankel and Anjon Audhya J Cell Biol. 212(5): 491–493. doi: 10.1083/jcb.201602003

Complex complexity. Dionisio

How membrane removal orchestrated by the ESC RT machinery directly contributes to the timing of abscission and midbody internalization represents an important issue to be addressed in the future.

Membrane remodeling during embryonic abscission in Caenorhabditis elegans Julia König, E.B. Franke, Anjon Audhya and Thomas Müller-Reichert DOI: 10.1083/jcb.201607030 The Journal of Cell Biology

Did somebody say "orchestrated"? Complex complexity. Dionisio

[...] the precise role for the ESCRTs during abscission remains controversial. The specific roles of actin and myosin in executing the final step of cell cleavage are currently unclear. [...] DYN-1 plays a key role before abscission to clear excess membrane, which may otherwise interfere with generating a membrane topology conducive to abscission.

Membrane remodeling during embryonic abscission in Caenorhabditis elegans Julia König, E.B. Franke, Anjon Audhya and Thomas Müller-Reichert DOI: 10.1083/jcb.201607030 The Journal of Cell Biology

Complex complexity. Dionisio

[...] cytokinesis is initiated by signals from the anaphase spindle, triggering the assembly of an actomyosin ring that constricts the plasma membrane to generate a narrow intercellular bridge containing two bundles of antiparallel microtubules that overlap in the central zone called the midbody [...]

Membrane remodeling during embryonic abscission in Caenorhabditis elegans Julia König, E.B. Franke, Anjon Audhya and Thomas Müller-Reichert DOI: 10.1083/jcb.201607030 The Journal of Cell Biology

Complex complexity. Dionisio

Abscission is the final step of cytokinesis and results in the physical separation of two daughter cells. [...] membrane scission occurs on both sides of the midbody ring with random order and that completion of the scission process requires actomyosin-driven membrane remodeling, but not microtubules. Moreover, continuous membrane removal predominates during the late stages of cytokinesis, mediated by both dynamin and the ESC RT (endosomal sorting complex required for transport) machinery. Surprisingly, in the absence of ESC RT function in C. elegans, cytokinetic abscission is delayed but can be completed, suggesting the existence of parallel membrane-reorganizing pathways that cooperatively enable the efficient severing of cytoplasmic connections between dividing daughter cells.

Membrane remodeling during embryonic abscission in Caenorhabditis elegans Julia König, E.B. Franke, Anjon Audhya and Thomas Müller-Reichert DOI: 10.1083/jcb.201607030 The Journal of Cell Biology

Did somebody say "Surprisingly"? What's so surprising? Did they expect something else or nothing at all? :) Poor things. They ain't seen nothin' yet. Complex complexity. Dionisio

[...] further studies will be required to characterize the mechanism of interaction and to also determine whether L1 or L2 can affect the ability of VPS4 to interact with its cellular binding partners. Further studies will be needed to ascertain whether L1 and L2 are associated with VPS4 as part of a complex, and what specific role this may play in the infection process. [...] it is possible that VPS4 is also playing a role in ensuring the proper separation of L1 from L2 during virus infection. [...] there may be two distinct roles for the ESCRT machinery, one involving endosome maturation and the other potentially in aiding capsid uncoating.

The VPS4 component of the ESCRT machinery plays an essential role in HPV infectious entry and capsid disassembly. Broniarczyk J, Pim D, Massimi P, Bergant M, Go?dzicka-Józefiak A, Crump C, Banks L Sci Rep. 7:45159. doi: 10.1038/srep45159.

Complex complexity. Dionisio

The endosomal sorting complex required for transport (ESCRT) machinery is an assembly of protein subcomplexes (ESCRT I-III) that cooperate with the ATPase VPS4 to mediate scission of membrane necks from the inside. Cellular membrane scission processes mediated by ESCRT-III include biogenesis of multivesicular endosomes, budding of enveloped viruses, cytokinetic abscission, neuron pruning, plasma membrane wound repair, nuclear pore quality control, nuclear envelope reformation, and nuclear envelope repair.

Cellular Functions and Molecular Mechanisms of the ESCRT Membrane-Scission Machinery. Christ L, Raiborg C, Wenzel EM, Campsteijn C, Stenmark H Trends Biochem Sci. 42(1):42-56. doi: 10.1016/j.tibs.2016.08.016.

Complex complexity. Dionisio

Note the paper referenced @3172 was already referenced @3124-3127. Dionisio

The integrity of the nuclear envelope barrier relies on membrane remodeling by the ESCRTs, which seal nuclear envelope holes and contribute to the quality control of nuclear pore complexes (NPCs); whether these processes are mechanistically related remains poorly defined. [...] the ESCRT-II/III chimera, Chm7, is recruited to a nuclear envelope subdomain that expands upon inhibition of NPC assembly and is required for the formation of the storage of improperly assembled NPCs (SINC) compartment. Recruitment to sites of NPC assembly is mediated by its ESCRT-II domain and the LAP2-emerin-MAN1 (LEM) family of integral inner nuclear membrane proteins, Heh1 and Heh2. Interestingly, Chm7 is required for the viability of yeast strains where double membrane seals have been observed over defective NPCs; deletion of CHM7 in these strains leads to a loss of nuclear compartmentalization suggesting that the sealing of defective NPCs and nuclear envelope ruptures could proceed through similar mechanisms.

Chm7 and Heh1 collaborate to link nuclear pore complex quality control with nuclear envelope sealing. Webster BM, Thaller DJ, Jäger J, Ochmann SE, Borah S, Lusk CP DOI: 10.15252/embj.201694574 EMBO J. 35(22):2447-2467

Complex complexity. Dionisio

These are exciting times for ESCRT-biology — originally thought to be a key player in the biogenesis of MVBs, the repertoire of physiological and pathophysiological events that involve ESCRT proteins has expanded greatly. In many ways, this reflects the cell's exquisite ability to conserve and repurpose its machineries to accomplish a variety of functions — in this case, those functions that need a topologically equivalent membrane remodeling.

The ESCRT machinery: new roles at new holes Y Olmos and JG Carlton Curr Opin Cell Biol. 38: 1–11. doi: 10.1016/j.ceb.2015.12.001

Did somebody say "repurpose [...] to accomplish"? Do cells do things purposely? Whose purpose? Complex complexity. Dionisio

Cell division in eukaryotes involves extensive remodeling of the nuclear envelope (NE) to ensure proper segregation of nuclear and cytoplasmic contents. The mechanism by which annular fusion occurs has remained largely unknown [...] CHMP7 is unique amongst ESCRT-III subunits in that it contains an extended N-terminal domain of unknown function — whether this domain specifies a role in nuclear envelope functionality remains to be established. [...] ESCRT-III and Spastin work together to coordinate nuclear envelope sealing with disassembly of MTs during mitotic exit and highlight a conservation of the machineries that regulate mitotic membrane remodeling events [...]

The ESCRT machinery: new roles at new holes Y Olmos and JG Carlton Curr Opin Cell Biol. 38: 1–11. doi: 10.1016/j.ceb.2015.12.001

Complex complexity. Dionisio

[...] the exact mechanism by which ESCRT-III extracts membrane proteins and directs them to the proteasome (rather than the lysosome) is unknown. [...] additional components of this extraction machinery that direct ubiquitinated nucleoporins for ESCRT-III mediated extraction may exist. [...] it is unclear how vesicles in the inter-membrane space could then access the proteasome for degradation.

The ESCRT machinery: new roles at new holes Y Olmos and JG Carlton Curr Opin Cell Biol. 38: 1–11. doi: 10.1016/j.ceb.2015.12.001

Complex complexity. Dionisio

The Nuclear Pore Complex (NPC) is an ancient, conserved and long-lived structure that allows gated exchange between nucleoplasm and cytoplasm, allowing the establishment of proper nucleo-cytoplasmic compartmentalization [...] A recent epistasis screen uncovered an unexpected role for the core ESCRT-III complex in extracting defective NPCs, thus ascribing a surveillance role for this complex at the nuclear envelope [...]

The ESCRT machinery: new roles at new holes Y Olmos and JG Carlton Curr Opin Cell Biol. 38: 1–11. doi: 10.1016/j.ceb.2015.12.001

Did somebody say "unexpected role"? Why "unexpected"? Did they expect a different role or no role at all? That’s another indicator of lacking open-mindedness and not thinking out of wrongly preconceived boxes. Oh well, what else is new? :) Complex complexity. Dionisio

ESCRT: Endosomal Sorting Complex Required for Transport

The ESCRT machinery drives a diverse collection of membrane remodeling events, including multivesicular body biogenesis, release of enveloped retroviruses and both reformation of the nuclear envelope and cytokinetic abscission during mitotic exit. These events share the requirement for a topologically equivalent membrane remodeling for their completion and the cells deployment of the ESCRT machinery in these different contexts highlights its functionality as a transposable membrane-fission machinery.

The ESCRT machinery: new roles at new holes Y Olmos and JG Carlton Curr Opin Cell Biol. 38: 1–11. doi: 10.1016/j.ceb.2015.12.001

Complex complexity. Dionisio

Further quantitative data for lipid species in exosomes secreted from different cell lines and tissues are needed to understand the function of exosomal lipids and the variability of the lipid compositions of exosomes. [...] different mechanisms can be involved in the formation and secretion of exosomes in different cell lines and also for various types of exosomes secreted from a cell line.

Lipids in exosomes: Current knowledge and the way forward Tore Skotland, Kirsten Sandvig, Alicia Llorente Progress in Lipid Research Volume 66, Pages 30–41 DOI: 10.1016/j.plipres.2017.03.001

Work in progress... stay tuned. Complex complexity. Dionisio

Exosomes are considered as one of three main types of extracellular vesicles [...] Exosomes have a complex composition including proteins, nucleic acids, lipids and other metabolites [...] During recent years there has been much focus on exosomes. How are they made and secreted to the extracellular environment? What is their specific composition?

Lipids in exosomes: Current knowledge and the way forward Tore Skotland, Kirsten Sandvig, Alicia Llorente Progress in Lipid Research Volume 66, Pages 30–41 DOI: 10.1016/j.plipres.2017.03.001

Complex complexity. Dionisio

The biogenesis of exosomes can be regarded as a three-step process: ( a ) biogenesis of MVBs, ( b ) transport of MVBs to the plasma membrane, and ( c ) release of the intraluminal vesicles of the MVBs as a consequence of fusion of MVBs with the plasma membrane.

Lipids in exosomes: Current knowledge and the way forward Tore Skotland, Kirsten Sandvig, Alicia Llorente Progress in Lipid Research Volume 66, Pages 30–41 DOI: 10.1016/j.plipres.2017.03.001

Complex complexity. Dionisio

Lipids are essential components of exosomal membranes, and it is well-known that specific lipids are enriched in exosomes compared to their parent cells. Exosomes are small vesicles (40–150 nm in diameter) released from cells after fusion of the multivesicular bodies (MVBs) with the plasma membrane [...]

Lipids in exosomes: Current knowledge and the way forward Tore Skotland, Kirsten Sandvig, Alicia Llorente Progress in Lipid Research Volume 66, Pages 30–41 DOI: 10.1016/j.plipres.2017.03.001

Complex complexity. Dionisio

Extracellular vesicles (EVs) are a heterogeneous collection of membrane-bound carriers with complex cargoes including proteins, lipids, and nucleic acids. While the release of EVs was previously thought to be only a mechanism to discard nonfunctional cellular components, increasing evidence implicates EVs as key players in intercellular and even interorganismal communication. EVs confer stability and can direct their cargoes to specific cell types. EV cargoes also appear to act in a combinatorial manner to communicate directives to other cells.

Extracellular Vesicles: Unique Intercellular Delivery Vehicles. Maas SL, Breakefield XO, Weaver AM Trends Cell Biol. 27(3):172-188. doi: 10.1016/j.tcb.2016.11.003.

"[...] was previously thought to be only [...]" Why? Based on what evidences? That's another indicator of lacking open-mindedness and not thinking out of wrongly preconceived boxes. Oh well, what else is new? Scientists should test everything and hold what is good. BTW, did somebody say "communicate directives"? :) Complex complexity. Dionisio

EVs are also increasingly recognized as having a direct role in pathologies such as cancer and neurodegeneration. Accordingly, EVs have been the focus of intense investigation as biomarkers of disease, prognostic indicators, and even therapeutic tools. The rising attention to EV-resident RNAs as biomarkers stems from the fact that RNAs can be detected at extremely low quantities using a number of methods.

RNA in extracellular vesicles. Kim KM, Abdelmohsen K, Mustapic M, Kapogiannis D, Gorospe M Wiley Interdiscip Rev RNA. doi: 10.1002/wrna.1413

Complex complexity. Dionisio

Cells release a range of membrane-enclosed extracellular vesicles (EVs) into the environment. Among them, exosomes and microvesicles (collectively measuring 40-1000 nm in diameter) carry proteins, signaling lipids, and nucleic acids from donor cells to recipient cells, and thus have been proposed to serve as intercellular mediators of communication. EVs transport cellular materials in many physiologic processes, including differentiation, stem cell homeostasis, immune responses, and neuronal signaling.

RNA in extracellular vesicles. Kim KM, Abdelmohsen K, Mustapic M, Kapogiannis D, Gorospe M Wiley Interdiscip Rev RNA. doi: 10.1002/wrna.1413

Complex complexity. Dionisio

Whether certain signaling factors are indeed modulated by MVB-mediated trafficking requires further investigation. FGFR signaling is complex and requires multiple factors for signaling; further experiments are required to elucidate the specific factors involved in MVB formation.

The formation of multivesicular bodies in activated blastocysts is influenced by autophagy and FGF signaling in mice. Shin H, Bang S, Kim J, Jun JH, Song H, Lim HJ Sci Rep. 7:41986. doi: 10.1038/srep41986.

Work in progress… stay tuned. Complex complexity. Dionisio

Although the complexity of EVs naturally broadens their functional impact, at the same time, this makes study of their activity difficult. The dedicated studies necessary to address these complex questions, and indeed the future success of the EV field, fundamentally require improvements in characterization of EVs. A more accurate defining of EV surface membrane composition and EV cargoes through approaches such as proteomic analysis (70) coupled with RNA and/or DNA sequencing (71) may yield significant advances.

Extracellular vesicles: masters of intercellular communication and potential clinical interventions. Pitt JM, Kroemer G, Zitvogel L. J Clin Invest. 126(4):1139-43. doi: 10.1172/JCI87316

Work in progress... stay tuned. Complex complexity. Dionisio

[...] this means of intercellular crosstalk can transfer an extraordinarily detailed level of information that may be precisely targeted to a given recipient cell type [...]

Extracellular vesicles: masters of intercellular communication and potential clinical interventions. Pitt JM, Kroemer G, Zitvogel L. J Clin Invest. 126(4):1139-43. doi: 10.1172/JCI87316

"[...] intercellular crosstalk can transfer an extraordinarily detailed level of information that may be precisely targeted to a given recipient [...]" Wow! Complex complexity. Dionisio

The complex degree of signaling mediated by EVs is utilized by many body systems under both physiological and pathophysiological conditions.

Extracellular vesicles: masters of intercellular communication and potential clinical interventions. Pitt JM, Kroemer G, Zitvogel L. J Clin Invest. 126(4):1139-43. doi: 10.1172/JCI87316

Did somebody say "complex degree of signaling"? Complex complexity. Dionisio

[...] it seems remarkable that EV signaling often remains a less considered mode of crosstalk and regulation between cells.

Extracellular vesicles: masters of intercellular communication and potential clinical interventions. Pitt JM, Kroemer G, Zitvogel L. J Clin Invest. 126(4):1139-43. doi: 10.1172/JCI87316

Scientists should be open-minded and think out of wrongly preconceived boxes. Test everything and hold what is good. Dionisio

Cell-cell communication is an essential component in mammalian development and preservation of homeostasis, ensuring fast and efficient responses to alterations or threats within the environment surrounding host cells. Beyond classical signaling through cell-cell contact and soluble factors, such as cytokines, inflammatory mediators, metabolites, and hormones, such intercellular communication also occurs through cellular release of extracellular vesicles (EVs). This mode of communication has the potential to deliver a particularly diverse array of messages to EV-accepting cells at a level beyond that of soluble factor signaling, since EVs may carry a number of bioactive molecules, surface receptors, and genetic information (e.g., protein-coding mRNAs and regulatory microRNAs [miRNAs])

Extracellular vesicles: masters of intercellular communication and potential clinical interventions. Pitt JM, Kroemer G, Zitvogel L. J Clin Invest. 126(4):1139-43. doi: 10.1172/JCI87316

Did somebody say "messages"? Complex complexity. Dionisio

RE: paper referenced @3152: Did somebody say "cell-cell crosstalk"? Do cells talk? Did somebody say "complex instructions"? Huh? say what? :) Dionisio

Intercellular signaling via extracellular vesicles (EVs) is an underappreciated modality of cell-cell crosstalk that enables cells to convey packages of complex instructions to specific recipient cells. EVs transmit these instructions through their cargoes of multiple proteins, nucleic acids, and specialized lipids, which are derived from their cells of origin and allow for combinatorial effects upon recipient cells.

Extracellular vesicles: masters of intercellular communication and potential clinical interventions. Pitt JM, Kroemer G, Zitvogel L. J Clin Invest. 126(4):1139-43. doi: 10.1172/JCI87316

Complex complexity. Dionisio

Further dissection of the NE-localization signal sequence in AtJAT1/AtABCG16 protein will provide a new avenue to develop pharmaceutical agents targeting the nuclear entry of small molecules in humans.

Transporter-Mediated Nuclear Entry of Jasmonoyl-Isoleucine Is Essential for Jasmonate Signaling Qingqing Li, Jian Zheng, Shuaizhang Li, Guanrong Huang, Stephen J. Skilling, Lijian Wang, Ling Li, Mengya Li, Lixing Yuan, Pei Liu DOI: 10.1016/j.molp.2017.01.010 Molecular Plant ·

Work in progress... stay tuned. Complex complexity. Dionisio

[...] plants have to constantly adapt to the changing environments by coordinating the fluctuating growth–defense dynamics through timely activation and deactivation of JA signaling. The reciprocal antagonistic crosstalk of JA and gibberellin (GA) signaling is involved in orchestrating the tradeoff between growth and defense [...]

Transporter-Mediated Nuclear Entry of Jasmonoyl-Isoleucine Is Essential for Jasmonate Signaling Qingqing Li, Jian Zheng, Shuaizhang Li, Guanrong Huang, Stephen J. Skilling, Lijian Wang, Ling Li, Mengya Li, Lixing Yuan, Pei Liu DOI: 10.1016/j.molp.2017.01.010 Molecular Plant ·

Did somebody say "coordinating"? Did somebody say "orchestrating"? Complex complexity. Dionisio

To control gene expression by directly responding to hormone concentrations, both animal and plant cells have exploited comparable mechanisms to sense small-molecule hormones in nucleus. Whether nuclear entry of these hormones is actively transported or passively diffused, as conventionally postulated, through the nuclear pore complex, remains enigmatic. [...] transporter-mediated nuclear entry of small hormone molecules is a new mechanism to regulate nuclear hormone signaling.

Transporter-Mediated Nuclear Entry of Jasmonoyl-Isoleucine Is Essential for Jasmonate Signaling Qingqing Li, Jian Zheng, Shuaizhang Li, Guanrong Huang, Stephen J. Skilling, Lijian Wang, Ling Li, Mengya Li, Lixing Yuan, Pei Liu DOI: 10.1016/j.molp.2017.01.010 Molecular Plant ·

Complex complexity. Dionisio

Tescalcin (TESC, also known as calcineurin-homologous protein 3, CHP3) is a 24-kDa EF-hand Ca2+-binding protein that has recently emerged as a regulator of cell differentiation and growth. The expression level of tescalcin changes dramatically during development and upon signal-induced cell differentiation. [...] tescalcin is not only subjected to up- or down-regulation, but also has an active role in pathways that drive cell growth and differentiation programs. [...] tescalcin can directly interact with and regulate the activities of the Na+/H+ exchanger NHE1, subunit 4 of the COP9 signalosome (CSN4) and protein kinase glycogen-synthase kinase 3 (GSK3). In hematopoetic precursor cells, tescalcin has been shown to couple activation of the extracellular signal-regulated kinase (ERK) cascade to the expression of transcription factors that control cell differentiation.

Emerging roles of the single EF-hand Ca2+ sensor tescalcin in the regulation of gene expression, cell growth and differentiation Ksenia G. Kolobynina, Valeria V. Solovyova, Konstantin Levay, Albert A. Rizvanov, Vladlen Z. Slepak J Cell Sci doi: 10.1242/jcs.191486

Complex complexity. Dionisio

It is not yet known how organoids are able to trigger and refine these self-assembly events, which means that this exciting field will probably yield further surprises.

From morphogen to morphogenesis and back Darren Gilmour, Martina Rembold & Maria Leptin doi:10.1038/nature21348 Nature Vol 541

Did somebody say "surprises"? Why? Will they expect something else? Complex complexity. Dionisio

Future mechanistic investigations into how tissue shaping is encoded genetically and how, conversely, tissue shaping feeds back into gene expression to control cell fate will therefore [...] increase our understanding of embryonic development [...]

From morphogen to morphogenesis and back Darren Gilmour, Martina Rembold & Maria Leptin doi:10.1038/nature21348 Nature Vol 541

Did somebody say "control"? Complex complexity. Dionisio

[...] embryos are not simple patchworks of autonomously developing tissues; rather, they are integrated systems in which the final shape emerges from physical interactions between domains.

From morphogen to morphogenesis and back Darren Gilmour, Martina Rembold & Maria Leptin doi:10.1038/nature21348 Nature Vol 541

Did somebody say "integrated systems"? Complex complexity. Dionisio

[...] the subdivision of embryos into distinct domains is a hallmark of all developmental programs.

From morphogen to morphogenesis and back Darren Gilmour, Martina Rembold & Maria Leptin doi:10.1038/nature21348 Nature Vol 541

Did somebody say "programs"? Complex complexity. Dionisio

Direct links between these two levels of shape control — gene expression and the universal cell-shaping apparatus — are provided by interacting proteins that ‘plug in’ to generate tissue-specific patterns of actomyosin localization and resultant shape changes.

From morphogen to morphogenesis and back Darren Gilmour, Martina Rembold & Maria Leptin doi:10.1038/nature21348 Nature Vol 541

Did somebody say "levels of [...] control"? Complex complexity. Dionisio

[...] the generation of shape itself is achieved through a more standard set of cellular machinery.

From morphogen to morphogenesis and back Darren Gilmour, Martina Rembold & Maria Leptin doi:10.1038/nature21348 Nature Vol 541

Did somebody say "machinery"? Complex complexity. Dionisio

[...] the processes that shape tissues are controlled in space and time by specific programs of gene regulation [...]

From morphogen to morphogenesis and back Darren Gilmour, Martina Rembold & Maria Leptin doi:10.1038/nature21348 Nature Vol 541

Did somebody say "specific programs"? Complex complexity. Dionisio

The connection of patterning systems and universal cellular effectors through the expression of specific mediator proteins seems to be a widely used strategy for the genetic regulation of tissue-folding events.

From morphogen to morphogenesis and back Darren Gilmour, Martina Rembold & Maria Leptin doi:10.1038/nature21348 Nature Vol 541

Did somebody say "strategy"? Complex complexity. Dionisio

[...] shape, at the local level, emerges from the interaction of tissue-specific genetic inputs and the self-organizing behaviour of core intracellular machines.

From morphogen to morphogenesis and back Darren Gilmour, Martina Rembold & Maria Leptin doi:10.1038/nature21348 Nature Vol 541

Did somebody say "behavior of [...] machines"? Complex complexity. Dionisio

[...] we still know surprisingly little about how the various levels of shape control are integrated during morphogenesis.

From morphogen to morphogenesis and back Darren Gilmour, Martina Rembold & Maria Leptin doi:10.1038/nature21348 Nature Vol 541

Did somebody refer to "integrated levels of control"? Complex complexity. Dionisio

[...] the first step in morphogenesis is the subdivision of the embryo into discrete regions by a cascade of ‘patterning’ genes4. Only then is each domain converted to the corresponding region of the body through a bespoke morphogenetic program, [...]

From morphogen to morphogenesis and back Darren Gilmour, Martina Rembold & Maria Leptin doi:10.1038/nature21348 Nature Vol 541

Did somebody say "bespoke [...] program"? Complex complexity. Dionisio

The complex 3D form of tissues, organs and organisms emerges from the coordinated behaviour of cell groups through mechanisms that are collectively termed morphogenesis (the generation of shape).

From morphogen to morphogenesis and back Darren Gilmour, Martina Rembold & Maria Leptin doi:10.1038/nature21348 Nature Vol 541

Complex complexity. Dionisio

A long-term aim of the life sciences is to understand how organismal shape is encoded by the genome. An important challenge is to identify mechanistic links between the genes that control cell-fate decisions and the cellular machines that generate shape, therefore closing the gap between genotype and phenotype. The logic and mechanisms that integrate these different levels of shape control are beginning to be described, and recently discovered mechanisms of cross-talk and feedback are beginning to explain the remarkable robustness of organ assembly. The ‘full-circle’ understanding of morphogenesis that is emerging, besides solving a key puzzle in biology, provides a mechanistic framework for future approaches to tissue engineering.

From morphogen to morphogenesis and back Darren Gilmour, Martina Rembold & Maria Leptin doi:10.1038/nature21348 Nature Vol 541

Complex complexity. Dionisio

Torsin ATPases (Torsins) belong to the widespread AAA+ (ATPases associated with a variety of cellular activities) family of ATPases, which share structural similarity but have diverse cellular functions. Torsins are outliers in this family because they lack many characteristics of typical AAA+ proteins, and they are the only members of the AAA+ family located in the endoplasmic reticulum and contiguous perinuclear space. While it is clear that Torsins have essential roles in many, if not all metazoans, their precise cellular functions remain elusive.

Torsins: not your typical AAA+ ATPases April E. Rose, Rebecca S. H. Brown & Christian Schlieker http://dx.doi.org/10.3109/10409238.2015.1091804 Pages 532-549 Taylor & Francis Online

Complex complexity. Dionisio

[...] Torsin participates in a pathway distinct from the canonical ERAD pathway. Whether such spatially confined ubiquitylated species result indirectly from Torsin dysfunction—for example, resulting from perturbed trafficking or assembly of NPC components—or represents a failure to remove misassembled or unfolded proteins from the NE remains to be established. This cell line and the identification of nups as a defining component of the blebs will enable directed approaches toward defining the precise function of Torsin ATPases and their cofactors in NE/NPC homeostasis.

Dissecting Torsin/cofactor function at the nuclear envelope: a genetic study. Laudermilch E, Tsai PL, Graham M, Turner E, Zhao C, Schlieker C DOI: 10.1091/mbc.E16-07-0511 Mol Biol Cell. 27(25):3964-3971.

Complex complexity. Dionisio

The human genome encodes four Torsin ATPases, the functions of which are poorly understood. These findings suggest a functional link between the Torsin/cofactor system and NE/nuclear pore complex biogenesis or homeostasis and establish a Torsin-deficient cell line as a valuable experimental platform with which to decipher Torsin function.

Dissecting Torsin/cofactor function at the nuclear envelope: a genetic study. Laudermilch E, Tsai PL, Graham M, Turner E, Zhao C, Schlieker C DOI: 10.1091/mbc.E16-07-0511 Mol Biol Cell. 27(25):3964-3971.

Complex complexity. Dionisio

[...] LEM2 plays a specific, initiating role in coordinating membrane remodeling events, particularly during nuclear assembly, in addition to the other roles it plays as a NE resident during interphase [...] It will therefore be of great interest to determine whether additional LEM-domain family members, which are present at the nascent NE (44, 45), also serve as ESCRT recruitment factors in human cells. [...] further biochemical studies will be required to elucidate how the dynamic interplay between LEM2, CHMP7, and lipids regulates the recruitment and activity of the ESCRT pathway at the nascent NE. Studies of these and related activities in the future will benefit from the facile S. pombe genetic system for investigating how the ESCRT pathway senses and seals breaches of the envelope—a nuclear membrane integrity pathway that is conserved from yeast to human.

LEM2 recruits CHMP7 for ESCRT-mediated nuclear envelope closure in fission yeast and human cells. Gu M, LaJoie D, Chen OS, von Appen A, Ladinsky MS, Redd MJ, Nikolova L, Bjorkman PJ, Sundquist WI, Ullman KS, Frost A Proc Natl Acad Sci U S A. 114(11):E2166-E2175. doi: 10.1073/pnas.1613916114.

Complex complexity. Dionisio

Chromosome inheritance depends on assembly of a mitotic spindle, which pulls chromosomes toward opposite sides of the duplicating cell. Spindle assembly begins when two microtubule-organizing centers (MTOCs) nucleate polymerization of antiparallel arrays of microtubules to capture daughter chromosomes. Despite functional conservation throughout Eukarya, the mechanisms by which spindle microtubules breach the NE to gain access to metaphase chromosomes vary markedly (3–6). In vertebrates and other organisms that have an “open mitosis,” the NE disassembles completely, so that nucleoplasmic identity is lost. Certain protists and fungi, by contrast, maintain NE integrity throughout a “closed mitosis” (3, 5).

LEM2 recruits CHMP7 for ESCRT-mediated nuclear envelope closure in fission yeast and human cells. Gu M, LaJoie D, Chen OS, von Appen A, Ladinsky MS, Redd MJ, Nikolova L, Bjorkman PJ, Sundquist WI, Ullman KS, Frost A Proc Natl Acad Sci U S A. 114(11):E2166-E2175. doi: 10.1073/pnas.1613916114.

Complex complexity. Dionisio

Eukaryotic genomes are secluded within the nucleus, an organelle with a boundary that comprises the double-membraned nuclear envelope (NE) (1). The inner and outer bilayers of the NE are perforated by annular channels that contain nuclear pore complexes (NPCs), each a massive assembly that regulates the trafficking of macromolecules like mRNA and proteins between the cytoplasm and nucleoplasm.

LEM2 recruits CHMP7 for ESCRT-mediated nuclear envelope closure in fission yeast and human cells. Gu M, LaJoie D, Chen OS, von Appen A, Ladinsky MS, Redd MJ, Nikolova L, Bjorkman PJ, Sundquist WI, Ullman KS, Frost A Proc Natl Acad Sci U S A. 114(11):E2166-E2175. doi: 10.1073/pnas.1613916114.

Complex complexity. Dionisio

Endosomal sorting complexes required for transport III (ESCRT-III) proteins have been implicated in sealing the nuclear envelope in mammals, spindle pole body dynamics in fission yeast, and surveillance of defective nuclear pore complexes in budding yeast. Lem2p/LEM2 is a conserved nuclear site-specific adaptor that recruits Cmp7p/CHMP7 and downstream ESCRT factors to the nuclear envelope.

LEM2 recruits CHMP7 for ESCRT-mediated nuclear envelope closure in fission yeast and human cells. Gu M, LaJoie D, Chen OS, von Appen A, Ladinsky MS, Redd MJ, Nikolova L, Bjorkman PJ, Sundquist WI, Ullman KS, Frost A Proc Natl Acad Sci U S A. 114(11):E2166-E2175. doi: 10.1073/pnas.1613916114.

Complex complexity. Dionisio

There is a particular lack of clarity regarding the fundamental mechanism of de novo NPC assembly. This requires remarkable spatiotemporal control over hundreds of proteins that converge at a NE domain competent for NPC assembly; what defines a biogenesis site remains unclear [...]

Chm7 and Heh1 collaborate to link nuclear pore complex quality control with nuclear envelope sealing. Webster BM, Thaller DJ, Jäger J, Ochmann SE, Borah S, Lusk CP DOI: 10.15252/embj.201694574 EMBO J. 2016 Nov 15;35(22):2447-2467.

Complex complexity. Dionisio

Understanding the molecular mechanisms that drive the membrane remodeling necessary for NE homeostasis is a critical goal for the field, particularly with the ever growing links between disruptions in nuclear compartmentalization and human disease [...]

Chm7 and Heh1 collaborate to link nuclear pore complex quality control with nuclear envelope sealing. Webster BM, Thaller DJ, Jäger J, Ochmann SE, Borah S, Lusk CP DOI: 10.15252/embj.201694574 EMBO J. 2016 Nov 15;35(22):2447-2467.

Complex complexity. Dionisio

[...] the nuclear envelope (NE) in multicellular eukaryotes undergoes a dramatic breakdown and reformation during cell division [...] [...] the two membranes of the NE undergo extensive remodeling during interphase [...]

Chm7 and Heh1 collaborate to link nuclear pore complex quality control with nuclear envelope sealing. Webster BM, Thaller DJ, Jäger J, Ochmann SE, Borah S, Lusk CP DOI: 10.15252/embj.201694574 EMBO J. 2016 Nov 15;35(22):2447-2467.

Complex complexity. Dionisio

The integrity of the nuclear envelope barrier relies on membrane remodeling by the ESCRTs, which seal nuclear envelope holes and contribute to the quality control of nuclear pore complexes (NPCs); whether these processes are mechanistically related remains poorly defined.

Chm7 and Heh1 collaborate to link nuclear pore complex quality control with nuclear envelope sealing. Webster BM, Thaller DJ, Jäger J, Ochmann SE, Borah S, Lusk CP DOI: 10.15252/embj.201694574 EMBO J. 2016 Nov 15;35(22):2447-2467.

Complex complexity. Dionisio

Future studies will be required to elucidate the bypass mechanism, [...] [...] it is unclear why other components of the Sec63 complex, including temperature-sensitive sec63 alleles and sec72?, do not share the same ability to rescue mps3? or mps2?. [...] it is unclear why deletion of POM152 is unable to rescue mps3? during meiosis because the SPB is key to the formation of the meiosis I and II spindles [...]

Sec66-Dependent Regulation of Yeast Spindle-Pole Body Duplication Through Pom152 Santharam S. Katta,* Jingjing Chen,* Jennifer M. Gardner,* Jennifer M. Friederichs,* Sarah E. Smith,* Madelaine Gogol,* Jay R. Unruh,* Brian D. Slaughter,* and Sue L. Jaspersen Genetics. 201(4): 1479–1495. doi: 10.1534/genetics.115.178012

Complex complexity. Dionisio

ACCURATE transmission of genetic material to daughter cells during cell division requires two precise duplication events: DNA replication and centrosome duplication. In addition, the cell must increase the number of organelles and protein complexes such as ribosomes and nuclear pore complexes (NPCs) so that the daughter cells have material to continue cell growth, metabolism, transcription, translation, and other vital cellular processes. While much is known about the mechanism and regulation of DNA replication, less is known about how cells duplicate protein-based structures such as the centrosome once per cell cycle.

Sec66-Dependent Regulation of Yeast Spindle-Pole Body Duplication Through Pom152 Santharam S. Katta,* Jingjing Chen,* Jennifer M. Gardner,* Jennifer M. Friederichs,* Sarah E. Smith,* Madelaine Gogol,* Jay R. Unruh,* Brian D. Slaughter,* and Sue L. Jaspersen Genetics. 201(4): 1479–1495. doi: 10.1534/genetics.115.178012

Complex complexity. Dionisio

In closed mitotic systems such as Saccharomyces cerevisiae, the nuclear envelope (NE) does not break down during mitosis, so microtubule-organizing centers such as the spindle-pole body (SPB) must be inserted into the NE to facilitate bipolar spindle formation and chromosome segregation. The mechanism of SPB insertion has been linked to NE insertion of nuclear pore complexes (NPCs) through a series of genetic and physical interactions between NPCs and SPB components.

Sec66-Dependent Regulation of Yeast Spindle-Pole Body Duplication Through Pom152 Santharam S. Katta,* Jingjing Chen,* Jennifer M. Gardner,* Jennifer M. Friederichs,* Sarah E. Smith,* Madelaine Gogol,* Jay R. Unruh,* Brian D. Slaughter,* and Sue L. Jaspersen Genetics. 201(4): 1479–1495. doi: 10.1534/genetics.115.178012

Complex complexity. Dionisio

Fluorescence super-resolution microscopy techniques are very novel tools that are still in the early stages of development.

Advances in super-resolution imaging: applications in biology and medicine M. Baztán, P. Fernández-Robredo, S. Recalde, A. García-Layana and M. Hernández

Complex complexity. Dionisio

Today, the use of modern super-resolution fluorescence microscopes allows us to zoom into the intracellular structures of live cells [...] Super-resolution microscopy is the term commonly given to fluorescence microscopy techniques with resolutions that are not limited by the diffraction of light. The timescales and spatial scales of the processes and molecules associated with life span extremely broad ranges, covering many orders of magnitude Observing and understanding all of these components of life requires us to be, at best, passive witnesses of undisturbed processes, but also to demand hard observational data that can allow us to quantitatively measure and trace all of the players involved—ranging from small molecules up to the interactions of whole cells in cellular communities—with the highest specificity and precision.

From single molecules to life: microscopy at the nanoscale Bartosz Turkowyd, David Virant, Ulrike Endesfelder Analytical and Bioanalytical Chemistry Volume 408, Issue 25, pp 6885–6911 DOI: 10.1007/s00216-016-9781-8

Complex complexity. Dionisio

[...] our knowledge on the regulations of their [Rho GAPs] localizations and functions is still limited. Currently, it is unknown whether Rng10 directly binds to Rga7. In vitro binding assays using purified proteins/domains will be of great interest in future studies. Rng10 may help Rga7 localize to the plasma membrane through three mechanisms. Future experiments are needed to distinguish these possibilities. Further investigation is needed to shed light on the alternative localization pathway for Rga7. [...] Rng10 and Rga7 also have independent functions during cell division and polarized growth, which will be further investigated in the future. It will be interesting to elucidate how Rng10 interacts with Rga7.

Roles of the novel coiled-coil protein Rng10 in septum formation during fission yeast cytokinesis Yajun Liu, I-Ju Lee, Mingzhai Sun, Casey A. Lower, Kurt W. Runge, Jianjie Ma and Jian-Qiu Wu Molecular Biology of the Cell 27(16) DOI: 10.1091/mbc.E16-03-0156

Work in progress... stay tuned. Complex complexity. Dionisio

Cytokinesis segregates chromosomes, cytoplasm, and organelles into the two daughter cells during the cell-division cycle. Cytokinesis requires six coordinated events: 1. division-site selection, 2. actomyosin contractile-ring assembly, 3. ring constriction and the associated disassembly, 4. plasma-membrane deposition, 5. septum formation or extracellular matrix remodeling, and 6. daughter-cell separation or midbody abscission The later stages of cytokinesis are still poorly understood.

Roles of the novel coiled-coil protein Rng10 in septum formation during fission yeast cytokinesis Yajun Liu, I-Ju Lee, Mingzhai Sun, Casey A. Lower, Kurt W. Runge, Jianjie Ma and Jian-Qiu Wu Molecular Biology of the Cell 27(16) DOI: 10.1091/mbc.E16-03-0156

Work in progress... stay tuned. Complex complexity. Dionisio

Rho GAPs are important regulators of Rho GTPases, which are involved in various steps of cytokinesis and other processes. [...] Rng10 and Rga7 work together to regulate the accumulation and dynamics of glucan synthases for successful septum formation in cytokinesis. [...] cellular localization and function of the Rho-GAP Rga7 are regulated by a novel protein Rng10 during cytokinesis in fission yeast.

Roles of the novel coiled-coil protein Rng10 in septum formation during fission yeast cytokinesis Yajun Liu, I-Ju Lee, Mingzhai Sun, Casey A. Lower, Kurt W. Runge, Jianjie Ma and Jian-Qiu Wu Molecular Biology of the Cell 27(16) DOI: 10.1091/mbc.E16-03-0156

Complex complexity. Dionisio

Sbg1 is important for Bgs1 stability and trafficking. Further studies are needed to determine the Sbg1 regions/domains involved in binding with Bgs1. [...] our studies on Sbg1 in fission yeast will help us not only understand cytokinesis but also develop a novel drug target. Together, our data reveal a new mode of regulation for the essential ?-glucan synthase Bgs1 by the novel protein Sbg1.

Sbg1 Is a Novel Regulator for the Localization of the ?-Glucan Synthase Bgs1 in Fission Yeast Reshma Davidson, Josef A. Pontasch, Jian-Qiu Wu PLOS ONE DOI:10.1371/journal.pone.0167043

Did somebody say "new mode of regulation"? :) Another one? Complex complexity. Dionisio

[...] TON1a and PPB formation might take part in the coordination between cytoplasmic events and the nuclear cell cycle to ensure that cells divide at the right time and in the right orientation. [...] a possibility that will need to be tested is whether TON1a, in concert with the TTP protein complex of which it is an essential component (Spinner et al., 2013), is part of a mechanosensory system able to sense cytoskeletal changes through its association with microtubules and respond to such changes by modulating cell-cycle progression through binding and compartimentalization into the cytoplasm of CDKA;1.

Are division plane determination and cell-cycle progression coordinated? Silvia Costa DOI: 10.1111/nph.14261 New Phytologist

Complex complexity. Dionisio

[...] cross talk between STRIPAK and other conserved eukaryotic regulatory complexes occurs. [...] insights into the phosphorylation status of STRIPAK subunits will greatly increase our mechanistic understanding of phospho-signaling in eukaryotes. [...] the catalytic activity of STRIPAK subunit PP2Ac1 is required for fungal fruiting body formation. [...] PP2Ac1 mediates cross talk between STRIPAK and other key regulatory complexes involved in nutrient signaling, CWI, and cytokinesis [...] Such information may be useful for understanding cellular development in general in higher eukaryotes.

Catalytic Subunit 1 of Protein Phosphatase 2A Is a Subunit of the STRIPAK Complex and Governs Fungal Sexual Development Anna Beier, Ines Teichert, Christoph Krisp, Dirk A. Wolters and Ulrich Kück mBio. 7(3): e00870-16. doi: 10.1128/mBio.00870-16

Complex complexity. Dionisio

The striatin-interacting phosphatase and kinase (STRIPAK) complex is highly conserved from yeasts to humans and is an important regulator of numerous eukaryotic developmental processes, such as cellular signaling and cell development. [...] the detailed molecular mechanisms of single subunits are only partially understood. [...] PP2Ac1 activity connects STRIPAK with other signaling pathways and thus forms a large interconnected signaling network.

Catalytic Subunit 1 of Protein Phosphatase 2A Is a Subunit of the STRIPAK Complex and Governs Fungal Sexual Development Anna Beier, Ines Teichert, Christoph Krisp, Dirk A. Wolters and Ulrich Kück mBio. 7(3): e00870-16. doi: 10.1128/mBio.00870-16

Complex complexity. Dionisio

[...] the effects of Pgb2 on Arabidopsis somatic embryogenesis are influenced by its cellular localization. [...] Pgb2 function during Arabidopsis somatic embryogenesis is exercised only when the protein is present in the nucleus and cannot exclude the possibility this might be a universal mechanism in dicotyledonous plants.

Cellular localization of the Arabidopsis class 2 phytoglobin influences somatic embryogenesis ? Cara Godee; Mohamed M. Mira; Owen Wally; Robert D. Hill; Claudio Stasolla J Exp Bot (2017) 68 (5): 1013-1023. DOI: https://doi.org/10.1093/jxb/erx003

Complex complexity. Dionisio

Arabidopsis somatic embryogenesis consists of two distinct phases: an induction phase resulting in the formation of the embryogenic tissue from the adaxial side of the cotyledons of the zygotic embryo explants and an auxin-free development phase culminating with the formation of fully developed somatic embryos.

Cellular localization of the Arabidopsis class 2 phytoglobin influences somatic embryogenesis ? Cara Godee; Mohamed M. Mira; Owen Wally; Robert D. Hill; Claudio Stasolla J Exp Bot (2017) 68 (5): 1013-1023. DOI: https://doi.org/10.1093/jxb/erx003

Complex complexity. Dionisio

The embryogenic program can be recapitulated in vitro through manipulating the media and culture components that induce cells to reprogram their developmental fate and embark along an embryogenic pathway. The genetic basis of this reprogramming is largely unknown

Cellular localization of the Arabidopsis class 2 phytoglobin influences somatic embryogenesis ? Cara Godee; Mohamed M. Mira; Owen Wally; Robert D. Hill; Claudio Stasolla J Exp Bot (2017) 68 (5): 1013-1023. DOI: https://doi.org/10.1093/jxb/erx003

Did somebody say "program"? :) Complex complexity. Dionisio

Embryogenesis is a crucial event in the plant life cycle. It is initiated by the formation of the zygote, which through precise and conserved cell division and differentiation patterns, generates a mature embryo consisting of an embryonic axis separating the shoot and root apical meristems and one or more cotyledons [...]

Cellular localization of the Arabidopsis class 2 phytoglobin influences somatic embryogenesis ? Cara Godee; Mohamed M. Mira; Owen Wally; Robert D. Hill; Claudio Stasolla J Exp Bot (2017) 68 (5): 1013-1023. DOI: https://doi.org/10.1093/jxb/erx003

Complex complexity. Dionisio

Glycosaminoglycans (GAGs), such as chondroitin sulfate (CS) and dermatan sulfate (DS) from various vertebrate and invertebrate sources are known to be involved in diverse cellular mechanisms during repair and regenerative processes. [...] proper sulfation of GAGs is important for A. filiformis arm regeneration [...] [...] these molecules may participate in mechanisms controlling cell proliferation.

A potential role for chondroitin sulfate/dermatan sulfate in arm regeneration in Amphiura filiformis Rashmi Ramachandra; Ramesh B Namburi; Sam T Dupont; Olga Ortega-Martinez; Toin H van Kuppevelt; Ulf Lindahl; Dorothe Spillmann? Glycobiology (2017) 27 (5): 438-449. DOI: https://doi.org/10.1093/glycob/cwx010

Complex complexity. Dionisio

It remains to be determined if either: (i) CUX1 promotes DNA looping; or (ii) CUX1 is recruited to pre-existing DNA loops. Intriguingly, SATB1, a member of the CUT homeobox superclass, regulates gene expression by fostering DNA looping and TF recruitment (61). In future work, it will be key to test if CUX1 directly facilitates DNA looping and TF recruitment in a manner similar to SATB1.

The haploinsufficient tumor suppressor, CUX1, acts as an analog transcriptional regulator that controls target genes through distal enhancers that loop to target promoters ? Robert K. Arthur; Ningfei An; Saira Khan; Megan E. McNerney Nucleic Acids Res gkx218. DOI: https://doi.org/10.1093/nar/gkx218

Work in progress... stay tuned. Complex complexity. Dionisio

The CUX1 transcription factor is a conserved, essential, and ubiquitous protein recurrently mutated across cancer types. The genome-scale properties and targets of endogenous CUX1 DNA-binding have remained unknown, in any species, creating a substantial gap in our knowledge of CUX1 function.

The haploinsufficient tumor suppressor, CUX1, acts as an analog transcriptional regulator that controls target genes through distal enhancers that loop to target promoters ? Robert K. Arthur; Ningfei An; Saira Khan; Megan E. McNerney Nucleic Acids Res gkx218. DOI: https://doi.org/10.1093/nar/gkx218

Work in progress... stay tuned. Complex complexity. Dionisio

DNA recombination, repair and replication are three large and vibrant research fields where each ‘R’ could deserve a series of reviews in its own right. However, as the 3Rs are tightly interwoven processes, one R can often not be fully understood without including the others. With some 10%–20% of the predicted yeast genes remaining uncharacterized, we foresee the discovery of new 3R genes in the future. We also expect to see a continued shift from traditional random genetic yeast screens toward systematic genome-wide analyses taking advantage of the genomics and cellulomics tools available in yeast setting the stage for a systems biology approach to understanding the 3R interactions. [...] the yeast model system is expected to yield pioneering insights into 3R processes for many years to come.

Editorial: 3Rs tightly intertwined to maintain genome stability ? Michael Lisby; Uffe H. Mortensen FEMS Yeast Res (2017) 17 (1): fox003. DOI: https://doi.org/10.1093/femsyr/fox003

Work in progress... stay tuned. Complex complexity. Dionisio

The eukaryotic cell cycle is robustly designed, with interacting molecules organized within a definite topology that ensures temporal precision of its phase transitions. Its underlying dynamics are regulated by molecular switches, for which remarkable insights have been provided by genetic and molecular biology efforts. In a number of cases, this information has been made predictive, through computational models. These models have allowed for the identification of novel molecular mechanisms, later validated experimentally. Logical modeling represents one of the youngest approaches to address cell cycle regulation. We summarize the advances that this type of modeling has achieved to reproduce and predict cell cycle dynamics. Furthermore, we present the challenge that this type of modeling is now ready to tackle: its integration with intracellular networks, and its formalisms, to understand crosstalks underlying systems level properties, ultimate aim of multi-scale models. Specifically, we discuss and illustrate how such an integration may be realized, by integrating a minimal logical model of the cell cycle with a metabolic network.

Advances and challenges in logical modeling of cell cycle regulation: perspective for multi-scale, integrative yeast cell models. Barberis M, Todd RG, van der Zee L FEMS Yeast Res. 17(1). pii: fow103. doi: 10.1093/femsyr/fow103.

Did somebody say "robustly designed"? :) Complex complexity. Dionisio

The data presented in this study are consistent with the notion of two, genetically separable, states of the SIN; an ‘early’ state, which is dependent upon Plo1p for its establishment, and a ‘late’ state, which is dependent upon Etd1p and Spg1p. Future studies will investigate how the transition occurs.

Analysis of S. pombe SIN protein association to the SPB reveals two genetically separable states of the SIN. Wachowicz P, Chasapi A, Krapp A, Cano Del Rosario E, Schmitter D, Sage D, Unser M, Xenarios I, Rougemont J, Simanis V J Cell Sci. 128(4):741-54. doi: 10.1242/jcs.160150.

Work in progress... stay tuned. Complex complexity. Dionisio

Asymmetric events are of fundamental importance in biology. Asymmetry of centrosome behaviour and inheritance is also implicated in an increasing number of cellular and developmental processes [...] [...] a contractile actomyosin ring (CAR) is important for cytokinesis [...] and acts as a ‘guide’ for synthesis of the division septum [...] The position of the division plane is determined by signalling from the nucleus and the cell tips [...] The coordination of cytokinesis with other mitotic events is assured by a conserved network of protein kinases known as the septation initiation network (SIN).

Analysis of S. pombe SIN protein association to the SPB reveals two genetically separable states of the SIN. Wachowicz P, Chasapi A, Krapp A, Cano Del Rosario E, Schmitter D, Sage D, Unser M, Xenarios I, Rougemont J, Simanis V J Cell Sci. 128(4):741-54. doi: 10.1242/jcs.160150.

Complex complexity. Dionisio

The Schizosaccharomyces pombe septation initiation network (SIN) regulates cytokinesis, and asymmetric association of SIN proteins with the mitotic spindle pole bodies (SPBs) is important for its regulation. These data reveal that multiple regulatory mechanisms control the SIN in mitosis and lead us to propose a two-state model to describe the SIN.

Analysis of S. pombe SIN protein association to the SPB reveals two genetically separable states of the SIN. Wachowicz P, Chasapi A, Krapp A, Cano Del Rosario E, Schmitter D, Sage D, Unser M, Xenarios I, Rougemont J, Simanis V J Cell Sci. 128(4):741-54. doi: 10.1242/jcs.160150.

Complex complexity. Dionisio

We conclude that SIN activity is both necessary and sufficient to disperse type 1 nodes based on our previous observation that SIN-deficient cells do not disperse Cdr2p from nodes in mitosis and our present finding that hyperactivation of the SIN forces rapid dispersal of type 1 nodes in interphase and mitotic cells.

The septation initiation network controls the assembly of nodes containing Cdr2p for cytokinesis in fission yeast. Pu KM, Akamatsu M, Pollard TD J Cell Sci. 128(3):441-6. DOI: 10.1242/jcs.160077

Complex complexity. Dionisio

In the fission yeast Schizosaccharomyces pombe, cortical protein structures called interphase nodes help to prepare the cell for cytokinesis by positioning precursors of the cytokinetic contractile ring, and the septation initiation network (SIN) regulates the onset of cytokinesis and septum formation.

The septation initiation network controls the assembly of nodes containing Cdr2p for cytokinesis in fission yeast. Pu KM, Akamatsu M, Pollard TD J Cell Sci. 128(3):441-6. DOI: 10.1242/jcs.160077

Complex complexity. Dionisio

[...] the connection between the cell wall and the AR through the plasma membrane is emerging as an important condition for a successful cytokinesis and for the maintenance of cell integrity. [...] it is still unknown how this connection is accomplished [...] The characterization of new double conditional mutants, proteomics and high-resolution microscopy techniques will help to further characterize this connection.

Overview of fission yeast septation Pilar Pérez, Juan C. G. Cortés, Rebeca Martín-García, Juan C. Ribas DOI: 10.1111/cmi.12611 Cellular Microbiology Volume 18, Issue 9 Pages 1201–1207

Complex complexity. Dionisio

There are still a number of open questions on the septation process that need to be further addressed: the targets of the SIN that activate septation, the different functions of F-BAR proteins during septum formation, the role of Rho GTPases and other molecules that regulate cell wall synthesis, etc.

Overview of fission yeast septation Pilar Pérez, Juan C. G. Cortés, Rebeca Martín-García, Juan C. Ribas DOI: 10.1111/cmi.12611 Cellular Microbiology Volume 18, Issue 9 Pages 1201–1207

Complex complexity. Dionisio

Whether or how Rgf3 and Pxl1 functionally interact to transform the AR contraction into an activation signal for the biosynthetic enzymes that form the septum remains to be discovered. Whether and how the AR contractile force stimulates the cell wall machinery and how the cell wall maintains the AR and stimulates its contraction are currently major questions in fungal septation.

Overview of fission yeast septation Pilar Pérez, Juan C. G. Cortés, Rebeca Martín-García, Juan C. Ribas DOI: 10.1111/cmi.12611 Cellular Microbiology Volume 18, Issue 9 Pages 1201–1207

Complex complexity. Dionisio

Cytokinesis is the final stage of the eukaryotic cell cycle during which, after mitotic exit, the formation of a cleavage furrow separates the cell giving rise to two new cells. Cleavage furrow formation always requires the establishment and closure of a cytokinetic actomyosin ring (AR).

Overview of fission yeast septation Pilar Pérez, Juan C. G. Cortés, Rebeca Martín-García, Juan C. Ribas DOI: 10.1111/cmi.12611 Cellular Microbiology Volume 18, Issue 9 Pages 1201–1207

Complex complexity. Dionisio

Cytokinesis is the final process of the vegetative cycle, which divides a cell into two independent daughter cells once mitosis is completed. Here we review the current knowledge of the septation and separation processes in this fungus, as well as recent advances in understanding the functional interaction between the transmembrane enzymes that build the septum and the actomyosin ring proteins.

Overview of fission yeast septation Pilar Pérez, Juan C. G. Cortés, Rebeca Martín-García, Juan C. Ribas DOI: 10.1111/cmi.12611 Cellular Microbiology Volume 18, Issue 9 Pages 1201–1207

Complex complexity. Dionisio

Gradient formation of Pom1 is a key regulator of cell cycle and cell growth in fission yeast (Schizosaccharomyces pombe). A variety of models to explain Pom1 gradient formation have been proposed, a quantitative analysis and comparison of these models is, however, still missing. In this work we present four models from the literature and perform a quantitative comparison using published single-cell images of the gradient formation process. For the comparison of these partial differential equation (PDE) models we use state-of-the-art techniques for parameter estimation together with model selection. The model selection supports the hypothesis that buffering of the gradient is achieved via clustering. The selected model does, however, not ensure mass conservation, which might be considered as problematic.

Quantitative Comparison of Competing PDE Models for Pom1p Dynamics in Fission Yeast Hross, Sabrina , Fiedler, Anna , Theis, Fabian J. Hasenauer, Jan

Complex complexity. Dionisio

addendum to 2841:

[...] the cytoplasm of energy-depleted cells transitions from a fluid- to a solid-like state. [...] what is still unclear is how water is released from forming spores and re-enters into spores upon germination. Future studies will have to determine the molecular mechanisms and physical causes promoting the formation of a solid-like cytoplasm. Dissection of this important problem will require the use of sophisticated biophysical, biochemical, and genetic approaches.

A pH-driven transition of the cytoplasm from a fluid- to a solid-like state promotes entry into dormancy Matthias Christoph Munder, Daniel Midtvedt, Titus Franzmann, Elisabeth Nüske, Oliver Otto, Maik Herbig, Elke Ulbricht, Paul Müller, Anna Taubenberger, Shovamayee Maharana, Liliana Malinovska, Doris Richter, Jochen Guck, Vasily Zaburdaev, and Simon Alberti eLife. 5: e09347. doi: 10.7554/eLife.09347

Complex complexity. Dionisio

addendum to 2841:

Most organisms live in unpredictable environments, which can often lead to nutrient shortages and other conditions that limit their ability to grow. To survive in these harsh conditions, many organisms adopt a dormant state in which their metabolism slows down to conserve vital energy. When the environmental conditions improve, the organisms can return to their normal state and continue to grow.

A pH-driven transition of the cytoplasm from a fluid- to a solid-like state promotes entry into dormancy Matthias Christoph Munder, Daniel Midtvedt, Titus Franzmann, Elisabeth Nüske, Oliver Otto, Maik Herbig, Elke Ulbricht, Paul Müller, Anna Taubenberger, Shovamayee Maharana, Liliana Malinovska, Doris Richter, Jochen Guck, Vasily Zaburdaev, and Simon Alberti eLife. 5: e09347. doi: 10.7554/eLife.09347

Complex complexity. Dionisio

A long-term aim of the life sciences is to understand how organismal shape is encoded by the genome. An important challenge is to identify mechanistic links between the genes that control cell-fate decisions and the cellular machines that generate shape, therefore closing the gap between genotype and phenotype. The logic and mechanisms that integrate these different levels of shape control are beginning to be described, and recently discovered mechanisms of cross-talk and feedback are beginning to explain the remarkable robustness of organ assembly. The 'full-circle' understanding of morphogenesis that is emerging, besides solving a key puzzle in biology, provides a mechanistic framework for future approaches to tissue engineering.

From morphogen to morphogenesis and back. Gilmour D, Rembold M, Leptin M Nature. 541(7637):311-320. doi: 10.1038/nature21348.

Complex complexity. Dionisio

In humans, approximately 5 to 8 liters of air passes in and out of the lung per minute when resting. The air can vary in oxygen and CO2 concentration, may carry allergens, and confers different extents of mechanical stretch of the airway and gas-exchange surfaces. These signals are sensed, relayed, and processed into physiological outputs such as the control of pulmonary blood pressure, immune responses, and breathing rhythm, but the mechanism is unclear.

Pulmonary neuroendocrine cells function as airway sensors to control lung immune response. Branchfield K, Nantie L, Verheyden JM, Sui P, Wienhold MD, Sun X Science. 351(6274):707-10. doi: 10.1126/science.aad7969.

Complex complexity. Dionisio

The lung is constantly exposed to environmental atmospheric cues. How it senses and responds to these cues is poorly defined. Roundabout receptor (Robo) genes are expressed in pulmonary neuroendocrine cells (PNECs), a rare, innervated epithelial population.

Pulmonary neuroendocrine cells function as airway sensors to control lung immune response. Branchfield K, Nantie L, Verheyden JM, Sui P, Wienhold MD, Sun X Science. 351(6274):707-10. doi: 10.1126/science.aad7969.

Complex complexity. Dionisio

Despite the functional importance of NE cells and NEBs, their developmental course remains unclear, in part because of technical limitations in obtaining high-resolution images and quantitative analysis of the behavior of epithelial cells in the context of a 3D branching morphology. Given that NE cells are thought to be the cells of origin in highly malignant small-cell lung cancer, investigating the molecular mechanisms of NE cell migration may provide important clues toward the development of new therapeutic approaches to mitigate this malignancy [...]

Directed Migration of Pulmonary Neuroendocrine Cells toward Airway Branches Organizes the Stereotypic Location of Neuroepithelial Bodies. Noguchi M, Sumiyama K, Morimoto M Cell Rep. 13(12):2679-86. doi: 10.1016/j.celrep.2015.11.058

Work in progress… stay tuned. Complex complexity. Dionisio

The epithelium of the mammalian lung consists of various cell types that serve to support respiratory function [...] The distribution patterns of these cells are determined at the pseudoglandular stage [...] of the fetal lung, during which airway branching morphogenesis occurs and the terminal buds come to contain a population of multipotent epithelial progenitors [...] As the bronchial tree extends, descendants of the multipotent progenitor cells give rise to lineage-restricted progenitors that produce all of the differentiated cells. One such cell type, neuroendocrine (NE) cells, are bi-functional epithelial cells that are detected either as scattered solitary cells or as small clusters in the trachea to bronchioles but not the alveoli [...] These NE cell clusters are referred to as neuroepithelial bodies (NEBs), and multiple reports have shown that NEBs are frequently observed at bifurcation points of branching airways.

Directed Migration of Pulmonary Neuroendocrine Cells toward Airway Branches Organizes the Stereotypic Location of Neuroepithelial Bodies. Noguchi M, Sumiyama K, Morimoto M Cell Rep. 13(12):2679-86. doi: 10.1016/j.celrep.2015.11.058

Complex complexity. Dionisio

The airway epithelium consists of diverse cell types, including neuroendocrine (NE) cells. NE cells often localize at bifurcation points of airway tubes, forming small clusters called neuroepithelial bodies (NEBs). [...] NEBs localize at stereotypic positions in the bifurcation area irrespective of variations in size. Notch-Hes1 signaling contributes to the differentiation of solitary NE cells, regulating their number but not localization. [...] individual NE cells migrate distally to and cluster at bifurcation points, driving NEB formation. [...] NEB development is a multistep process involving differentiation of individual NE cells and their directional migration to organize NEBs.

Directed Migration of Pulmonary Neuroendocrine Cells toward Airway Branches Organizes the Stereotypic Location of Neuroepithelial Bodies. Noguchi M, Sumiyama K, Morimoto M Cell Rep. 13(12):2679-86. doi: 10.1016/j.celrep.2015.11.058

Complex complexity. Dionisio

DC hold a great promise for the therapy of human diseases. On the one hand, DC may enhance anti-tumour immunity when attempting to fight cancer. On the other hand, they may induce tolerance, which is essential in case of transplantation and autoimmunity. Nonetheless, here lies their main danger: the potential threat that the transferred cells may change once within the patients, and thus cause tolerance instead of immunity, and vice versa.

Dendritic cells as gatekeepers of tolerance Ari Waisman , Dominika Lukas, Björn E. Clausen, Nir Yogev Seminars in Immunopathology Volume 39, Issue 2, pp 153–163 DOI: 10.1007/s00281-016-0583-z

Complex complexity. Dionisio

Dendritic cells (DC) serve as unique sentinels of the immune system, continuously sampling their environment and exerting different properties that in turn determine immunological outcomes. Although DC do not serve as effector cells that fight against pathogens, they control adaptive immunity by providing essential signals that are mandatory for directing the desired immune response. Apart from antigen presentation, DC deliver co-stimulatory signals and produce cytokines, which are necessary for instructing appropriate effector or regulatory T cell responses.

Dendritic cells as gatekeepers of tolerance Ari Waisman , Dominika Lukas, Björn E. Clausen, Nir Yogev Seminars in Immunopathology Volume 39, Issue 2, pp 153–163 DOI: 10.1007/s00281-016-0583-z

Complex complexity. Dionisio

Dendritic cells (DC) are unique hematopoietic cells, linking innate and adaptive immune responses. In particular, they are considered as the most potent antigen presenting cells, governing both T cell immunity and tolerance. In view of their exceptional ability to present antigen and to interact with T cells, DC play distinct roles in shaping T cell development, differentiation and function. The outcome of the DC-T cell interaction is determined by the state of DC maturation, the type of DC subset, the cytokine microenvironment and the tissue location. Both regulatory Tcells (Tregs) and DC are indispensable for maintaining central and peripheral tolerance. Over the past decade, accumulating data indicate that DC critically contribute to Treg differentiation and homeostasis.

Dendritic cells as gatekeepers of tolerance Ari Waisman , Dominika Lukas, Björn E. Clausen, Nir Yogev Seminars in Immunopathology Volume 39, Issue 2, pp 153–163 DOI: 10.1007/s00281-016-0583-z

Complex complexity. Dionisio

Dendritic cells (DCs) play a central role in the control of the adaptive immune response. DCs drive the differentiation of effector T cells (Teffs) that fight off pathogens, but the dysregulated activity of Teffs can result in immunopathology and autoimmune disorders . Under certain scenarios, DCs show tolerogenic properties that allow them to limit autoimmune T cell responses. Although DCs with tolerogenic function have been identified, little is known about the molecular mechanisms that control them. Cytokines, pathogen-, and danger-associated molecular patterns (PAMPs, DAMPs) are known to have important effects on DC development and function. However, additional molecules are also involved in the regulation of DCs. DCs express receptors responsive to neurotransmitters released by sympathetic fibers that innervate tissues. [...] immune-based therapies have shown promising results for the treatment of cancer.

Dendritic cells in autoimmunity, infections, and cancer Francisco J. Quintana Semin Immunopathol 39:97–98 DOI 10.1007/s00281-016-0618-5

Complex complexity. Dionisio

Dendritic cells are of paramount importance bridging innate and adaptive immune responses. Depending on the context, after sensing environmental antigens, commensal microorganisms, pathogenic agents, or antigens from the diet, dendritic cells may drive either different effector adaptive immune responses or tolerance, avoiding tissue damage. Although the plasticity of the immune response and the capacity to regulate itself are considered essential to orchestrate appropriate physiological responses, it is known that the nervous system plays a relevant role controlling immune cell function. Dendritic cells present in the skin, the intestine, and lymphoid organs, besides expressing adrenergic receptors, can be reached by neurotransmitters released by sympathetic fibers innervating these tissues. These review focus on how neurotransmitters from the sympathetic nervous system can modulate dendritic cell function and how this may impact the immune response and immune-mediated disorders.

Neuroimmune interactions: dendritic cell modulation by the sympathetic nervous system Maisa C. Takenaka, Marcia G. Guereschi, Alexandre S. Basso Seminars in Immunopathology Volume 39, Issue 2, pp 165–176 DOI: 10.1007/s00281-016-0590-0

Complex complexity. Dionisio

Tissue macrophages and monocyte-derived macrophages are under continuous influence from environmental signals that define their activation status. Along these lines, macrophages integrate tissue and stress signals and are specifically programmed by these signals towards a spectrum of functions necessary to fulfill their duty within their particular microenvironment, be it homeostatic tissue function, response to inflammatory pathophysiology, or even resolution of an inflammation. Recent years have seen tremendous progress in our understanding how macrophages at different sites are transcriptionally and epigenetically programmed to execute their diverse tasks throughout the body. The identification of transcription factors guiding these reprogramming activities is currently a major topic in macrophage research. We summarize the most recent findings within the last 18 months concerning the identification of novel transcription factors associated with particular macrophage location or function. Furthermore, we extend the view of cellular programming of macrophages to additional levels of regulation, for example, by long non-coding RNAs. Clearly, in addition to transcription factors, there are many more “programmers” shaping the versatile functionality of these exciting innate immune cells.

New “programmers” in tissue macrophage activation Pflügers Archiv - European Journal of Physiology Volume 469, Issue 3, pp 375–383 Anna C. Aschenbrenner , Joachim L. Schultze DOI: 10.1007/s00424-017-1943-9

Did somebody say "programmed"? :) Complex complexity. Dionisio

Communication between the brain and gut is not one-way, but a bidirectional highway whereby reciprocal signals between the two organ systems are exchanged to coordinate function. The messengers of this complex dialogue include neural, metabolic, endocrine and immune mediators responsive to diverse environmental cues, including nutrients and components of the intestinal microbiota (microbiota–gut–brain axis). We are now starting to understand how perturbation of these systems affects transition between health and disease. The pathological repercussions of disordered gut–brain dialogue are probably especially pertinent in functional gastrointestinal diseases, including IBS and functional dyspepsia. New insights into these pathways might lead to novel treatment strategies in these common gastrointestinal diseases. In this Review, we consider the role of the immune system as the gatekeeper and master regulator of brain–gut and gut–brain communications. Although adaptive immunity (T cells in particular) participates in this process, there is an emerging role for cells of the innate immune compartment (including innate lymphoid cells and cells of the mononuclear phagocyte system). We will also consider how these key immune cells interact with the specific components of the enteric and central nervous systems, and rapidly respond to environmental variables, including the microbiota, to alter gut homeostasis.

The mucosal immune system: master regulator of bidirectional gut–brain communications Nick Powell, Marjorie M. Walker & Nicholas J. Talley Nature Reviews Gastroenterology & Hepatology 14, 143–159 doi:10.1038/nrgastro.2016.191

Complex complexity. Dionisio

Interactions between the nervous system and immune system are required for organ function and homeostasis. Evidence suggests that enteric neurons and intestinal immune cells share common regulatory mechanisms and can coordinate their responses to developmental challenges and environmental aggressions. These discoveries shed light on the physiology of system interactions and open novel perspectives for therapy designs that target underappreciated neurological–immunological commonalities. Here we highlight findings that address the importance of neuroimmune cell units (NICUs) in intestinal development, homeostasis and disease.

Neuroimmune regulation during intestinal development and homeostasis Henrique Veiga-Fernandes & Vassilis Pachnis Nature Immunology 18, 116–122 doi:10.1038/ni.3634

Complex complexity. Dionisio

The identification of this neural circuit and the demonstration that chemical inhibition of dopamine signaling in the nervous system can control immune pathways at the cell-non-autonomous level provide proof of concept for the use of neural interventions to control infections and conditions that involve aberrant immune functions.

Neural Inhibition of Dopaminergic Signaling Enhances Immunity in a Cell-Non-autonomous Manner Xiou Cao, Alejandro Aballay DOI: 10.1016/j.cub.2016.06.036 Current Biology, Volume 26, Issue 17, Page 2398

Complex complexity. Dionisio

The innate immune system is the front line of host defense against microbial infections, but its rapid and uncontrolled activation elicits microbicidal mechanisms that have deleterious effects [1 ; 2]. Increasing evidence indicates that the metazoan nervous system, which responds to stimuli originating from both the internal and the external environment, functions as a modulatory apparatus that controls not only microbial killing pathways but also cellular homeostatic mechanisms [3; 4 ; 5]. Here we report that dopamine signaling controls innate immune responses through a D1-like dopamine receptor, DOP-4, in Caenorhabditis elegans. Chlorpromazine inhibition of DOP-4 in the nervous system activates a microbicidal PMK-1/p38 mitogen-activated protein kinase signaling pathway that enhances host resistance against bacterial infections. The immune inhibitory function of dopamine originates in CEP neurons and requires active DOP-4 in downstream ASG neurons. Our findings indicate that dopamine signaling from the nervous system controls immunity in a cell-non-autonomous manner and identifies the dopaminergic system as a potential therapeutic target for not only infectious diseases but also a range of conditions that arise as a consequence of malfunctioning immune responses.

Neural Inhibition of Dopaminergic Signaling Enhances Immunity in a Cell-Non-autonomous Manner Xiou Cao, Alejandro Aballay http://dx.doi.org/10.1016/j.cub.2016.06.036 Current Biology, Volume 26, Issue 17, Page 2398

Complex complexity. Dionisio

Studies bridging neuroscience and immunology have identified neural pathways that regulate immunity and inflammation. Recent research using methodological advances in molecular genetics has improved our understanding of the neural control of immunity. Here we outline mechanistic insights, focusing on translational relevance and conceptual developments. We also summarize findings from recent clinical studies of bioelectronic neuromodulation in inflammatory and autoimmune diseases.

Neural regulation of immunity: molecular mechanisms and clinical translation Valentin A Pavlov & Kevin J Tracey Nature Neuroscience 20, 156–166 doi:10.1038/nn.4477

Complex complexity. Dionisio

Tissue-specific genetic targeting, novel sequencing approaches, and groundbreaking imaging tools revealed unappreciated functional and mechanistic consequences of neuroimmune interactions. [...] we can certainly anticipate that new tools will allow for the discovery of new anatomical and functional bases for neuro-immune units at an organismic level in health and disease.

Neuro-Immune Interactions at Barrier Surfaces. Veiga-Fernandes H, Mucida D Cell. 165(4):801-11. doi: 10.1016/j.cell.2016.04.041.

Work in progress... stay tuned. Complex complexity. Dionisio

The emergent evidence for micro-anatomical and functional neuro-immune units has not been fully complemented by mechanistic, physiological, and pathological insights. [...] a deeper understanding of the physiology of system interactions at the organism level is still lacking. [...] tissue-clearing and novel imaging techniques may pave the way for future understanding of organismic neuro-immune circuits [...]

Neuro-Immune Interactions at Barrier Surfaces. Veiga-Fernandes H, Mucida D Cell. 165(4):801-11. doi: 10.1016/j.cell.2016.04.041.

Complex complexity. Dionisio

[...] it remains unclear whether neuro-immune interactions might be also co-regulated by competition for commonly used resources. [...] whether consumption of neuromediators and neurotrophins in the HSC environment shape neuronal or immune cell fates remains to be explored. [...] how intricate and closely associated networks of neuronal, immune, and glia cells integrate endogenous and exogenous perturbations during physiology and disease conditions, regulating each other’s activity, constitutes a yet unresolved question.

Neuro-Immune Interactions at Barrier Surfaces. Veiga-Fernandes H, Mucida D Cell. 165(4):801-11. doi: 10.1016/j.cell.2016.04.041.

Complex complexity. Dionisio

The nervous system and immune system are the main body sensory interfaces that perceive, integrate, and respond to environmental challenges. Major pitfalls in the study of neuro-immune interactions include the use of static imaging analysis, which provides poor insight into spatio-temporal dynamics. [...] over the last decade, some of these technical obstacles have been partly surmounted, shedding light on novel aspects of barrier tissue physiology.

Neuro-Immune Interactions at Barrier Surfaces. Veiga-Fernandes H, Mucida D Cell. 165(4):801-11. doi: 10.1016/j.cell.2016.04.041.

Complex complexity. Dionisio

Multidirectional interactions between the nervous and immune systems have been documented in homeostasis and pathologies ranging from multiple sclerosis to autism, and from leukemia to acute and chronic inflammation. Recent studies have addressed this crosstalk using cell-specific targeting, novel sequencing, imaging, and analytical tools, shedding light on unappreciated mechanisms of neuro-immune regulation. This Review focuses on neuro-immune interactions at barrier surfaces-mostly the gut, but also including the skin and the airways, areas densely populated by neurons and immune cells that constantly sense and adapt to tissue-specific environmental challenges.

Neuro-Immune Interactions at Barrier Surfaces. Veiga-Fernandes H, Mucida D Cell. 165(4):801-11. doi: 10.1016/j.cell.2016.04.041.

Complex complexity. Dionisio

Defining the mechanisms by which ILC3 integrate environmental cues is critical to understand mucosal homeostasis. Glial-derived neurotrophic factors operate in an ILC3-intrinsic manner by activating the tyrosine kinase RET [...] [...] RET signals critically fine-tune innate IL-22 leading to efficient gut homeostasis and defence.

Glial-cell-derived neuroregulators control type 3 innate lymphoid cells and gut defence. Ibiza S, García-Cassani B, Ribeiro H, Carvalho T, Almeida L, Marques R, Misic AM, Bartow-McKenney C, Larson DM, Pavan WJ, Eberl G, Grice EA, Veiga-Fernandes H. Nature. 535(7612): 440–443. doi: 10.1038/nature18644

Complex complexity. [2861 should follow 3065-3067] Dionisio

[...] ILC3-intrinsic neurotrophic factor cues regulate gut defence and homeostasis. [...] cell-autonomous RET signals control ILC3 function and gut defence via direct regulation of Il22 downstream of STAT3 activation. [...] mucosal glial cells orchestrate innate IL-22 via neurotrophic factors, downstream of MYD88-dependent sensing of commensal products and alarmins.

Glial-cell-derived neuroregulators control type 3 innate lymphoid cells and gut defence. Ibiza S, García-Cassani B, Ribeiro H, Carvalho T, Almeida L, Marques R, Misic AM, Bartow-McKenney C, Larson DM, Pavan WJ, Eberl G, Grice EA, Veiga-Fernandes H. Nature. 535(7612): 440–443. doi: 10.1038/nature18644

Complex complexity. Dionisio

#2861 addendum:

Group 3 innate lymphoid cells (ILC3) are major regulators of inflammation and infection at mucosal barriers. ILC3 development has been considered to be programmed. Nevertheless, how ILC3 perceive, integrate and respond to local environmental signals remains unclear. [...] ILC3 sense their environment and control gut defence as part of a novel glial-ILC3-epithelial cell unit orchestrated by neurotrophic factors.

Glial-cell-derived neuroregulators control type 3 innate lymphoid cells and gut defence. Ibiza S, García-Cassani B, Ribeiro H, Carvalho T, Almeida L, Marques R, Misic AM, Bartow-McKenney C, Larson DM, Pavan WJ, Eberl G, Grice EA, Veiga-Fernandes H. Nature. 535(7612): 440–443. doi: 10.1038/nature18644

Did somebody say "programmed"? Complex complexity. Dionisio

Gene regulation happens to be one of the most important processes that take place in living cells [1, 2]. For instance, it includes controls over the transcription of messenger RNA (mRNA) and the eventual translation of mRNA into protein via gene regulatory networks (GRNs). Future work will focus on the inference of the structure of a (potentially larger) network by incorporating a general s-step missing values for s-consecutive time points, which may address more complex missing data scenarios.

Reverse engineering gene regulatory networks from measurement with missing values. Ogundijo OE, Elmas A, Wang X EURASIP J Bioinform Syst Biol. 2017(1):2. doi: 10.1186/s13637-016-0055-8.

Complex complexity. Dionisio

PBGA filters are proposed to elucidate the underlying gene regulatory network (GRN) from time series gene expression data that contain missing values. In our state-space model, we proposed a measurement model that incorporates the effect of the missing data points into the sequential algorithm. This approach produces a better inference of the model parameters and hence, more accurate prediction of the underlying GRN compared to when using the conventional Gaussian approximation (GA) filters ignoring the missing data points.

Reverse engineering gene regulatory networks from measurement with missing values. Ogundijo OE, Elmas A, Wang X EURASIP J Bioinform Syst Biol. 2017(1):2. doi: 10.1186/s13637-016-0055-8.

Complex complexity. Dionisio

The inference of an ensemble of networks, rather than a single network, provides an avenue to cope with the underdetermined nature of the GRN inference from transcriptional expression data.

TRaCE+: Ensemble inference of gene regulatory networks from transcriptional expression profiles of gene knock-out experiments. Ud-Dean SM, Heise S, Klamt S, Gunawan R BMC Bioinformatics. 17:252. doi: 10.1186/s12859-016-1137-z.

Complex complexity. Dionisio

The central dogma of molecular biology describes the process by which genetic information flows linearly from deoxyribonucleic acid (DNA) to ribonucleic acid (RNA) to proteins through the process of transcription and translation [1]. This dogma has guided research on the causes of cellular phenotype and diseases since its inception in 1956. However, such reductionist view has been continually challenged in the post-genomic era, during which we also saw the rise of systems biology and the use of networks to understand biology at all levels.

TRaCE+: Ensemble inference of gene regulatory networks from transcriptional expression profiles of gene knock-out experiments. Ud-Dean SM, Heise S, Klamt S, Gunawan R BMC Bioinformatics. 17:252. doi: 10.1186/s12859-016-1137-z.

Complex complexity. Dionisio

[...] the importance of the circadian timing of exercise and nutritional intake for muscular and osseous health has not been well elucidated. Further advanced evidence is required and it is expected to lead to a better understanding of the mutual interaction between the circadian clock and muscle/bone.

The Role of Circadian Rhythms in Muscular and Osseous Physiology and Their Regulation by Nutrition and Exercise Shinya Aoyama and Shigenobu Shibata Front Neurosci. 11: 63. doi: 10.3389/fnins.2017.00063

Complex complexity. Dionisio

[...] disturbances of circadian rhythms by social or environmental factors, such as shift work, may result in dysfunctions of skeletal muscle and bone. In epidemiological studies, the prevalence of metabolic syndrome, osteoporosis and bone fractures is increased in shift workers [...] [...] long term constant light exposure reduces muscle strength and bone mass [...] [...] the regulation of circadian rhythms in skeletal muscle and bone by external cues, such as feeding and exercise, are important for the maintenance of homeostasis in these tissues, since circadian rhythm in these tissues can be entrained or regulated by the feeding/fasting rhythm and the physical activity rhythm, including scheduled exercise. [...] exercise in the morning but not in the afternoon or evening increases fat oxidation over 24 h in healthy humans [...]

The Role of Circadian Rhythms in Muscular and Osseous Physiology and Their Regulation by Nutrition and Exercise Shinya Aoyama and Shigenobu Shibata Front Neurosci. 11: 63. doi: 10.3389/fnins.2017.00063

Complex complexity. Dionisio

Various physiological functions, including the sleep wake cycle, body temperature, hormone secretion, and locomotor activity, exhibit circadian rhythms. This time-dependent regulation is driven by an internal circadian clock. In mammals, the circadian clock is divided into two parts, the master clock in the suprachiasmatic nucleus (SCN) of the hypothalamus and peripheral clocks in the peripheral tissues, such as the liver, skeletal muscle and so on, as well as brain areas other than the SCN. The master clock in the SCN acts as a time keeper in the whole body; thus, it integrates and entrains the peripheral circadian clocks by regulating neural and endocrine pathways, such as the sympathetic nervous system and glucocorticoid signaling

The Role of Circadian Rhythms in Muscular and Osseous Physiology and Their Regulation by Nutrition and Exercise Shinya Aoyama and Shigenobu Shibata Front Neurosci. 11: 63. doi: 10.3389/fnins.2017.00063

Complex complexity. Dionisio

The mammalian circadian clock regulates the day and night cycles of various physiological functions. The circadian clock system consists of a central clock in the suprachiasmatic nucleus (SCN) of the hypothalamus and peripheral clocks in peripheral tissues. According to the results of circadian transcriptomic studies in several tissues, the majority of rhythmic genes are expressed in a tissue-specific manner and are influenced by tissue-specific circadian rhythms.

The Role of Circadian Rhythms in Muscular and Osseous Physiology and Their Regulation by Nutrition and Exercise Shinya Aoyama and Shigenobu Shibata Front Neurosci. 11: 63. doi: 10.3389/fnins.2017.00063

Complex complexity. Dionisio

Gene expression factory is formed by integration of transcription and RNA-processing machineries, which is mediated by mRNPs [...] Future research should be directed to identify diverse forms of SR-mRNPs in the nucleus as well as in the cytoplasm to understand multifunctionality of SR proteins. [...] it will be important to identify known and novel RBPs relevant to SR-regulated splicing. [...] it will be important to identify signaling pathways and critical signaling molecules relevant to SR protein regulation. It will be interesting to dissect the signaling pathways involved in SR protein modifications, including phosphorylation.

SR Proteins: Binders, Regulators, and Connectors of RNA Sunjoo Jeong Mol Cells. 40(1): 1–9. doi: 10.14348/molcells.2017.2319

Work in progress... stay tuned. Complex complexity. Dionisio

Gene expression regulation is highly connected process. Transcriptional regulation is interdependent on post-transcriptional processes both in the nucleus and cytoplasm (Maniatis and Reed, 2002). Regulatory proteins, such as RNA-binding proteins (RBPs), play important roles throughout the gene expression program, from the transcription to translation (Glisovic et al., 2008). One such important family of regulatory RBPs is the Serine–Arginine (SR) family of proteins.

SR Proteins: Binders, Regulators, and Connectors of RNA Sunjoo Jeong Mol Cells. 40(1): 1–9. doi: 10.14348/molcells.2017.2319

Complex complexity. Dionisio

Serine and arginine-rich (SR) proteins are RNA-binding proteins (RBPs) known as constitutive and alternative splicing regulators. As splicing is linked to transcriptional and post-transcriptional steps, SR proteins are implicated in the regulation of multiple aspects of the gene expression program. Recent global analyses of SR-RNA interaction maps have advanced our understanding of SR-regulated gene expression. Diverse SR proteins play partially overlapping but distinct roles in transcription-coupled splicing and mRNA processing in the nucleus. In addition, shuttling SR proteins act as adaptors for mRNA export and as regulators for translation in the cytoplasm.

SR Proteins: Binders, Regulators, and Connectors of RNA Sunjoo Jeong Mol Cells. 40(1): 1–9. doi: 10.14348/molcells.2017.2319

Complex complexity. Dionisio

[...] the diverse chemical modifications in nucleic acids provide essential or critical chemical-coding processes that exponentially expand the complexity of eukaryotic organisms. These modifications serve as another layer of information carrier, precisely regulating almost every aspect of cell physiology. These pathways provide new opportunities for chemical biologists to investigate the underlying mechanisms, manipulate the modification status to affect gene expression, and develop small molecules or other means to tune these pathways for fundamental research and therapeutic purposes in the future.

Nucleic Acid Modifications in Regulation of Gene Expression. Chen K, Zhao BS, He C Cell Chem Biol. 23(1):74-85. doi: 10.1016/j.chembiol.2015.11.007.

Complex complexity. Dionisio

Recent studies have uncovered this mRNA methylation as a new realm of biological regulation at the post-transcriptional level. As new modifications and new functions continue to emerge, these chemical marks on RNA may collectively provide additional tuning that affect biological outcomes at the post-transcriptional level. [...] a quantitative picture of how chemical modifications affect gene expression regulation and their effects in various human diseases will emerge. RNA modifications may very likely mirror histone modifications: multiple chemical marks on bio-macromolecules that dynamically controlled by multiple enzymes and proteins to enable synergistic regulation of the metabolism, processing and function of the target RNA.

Nucleic Acid Modifications in Regulation of Gene Expression. Chen K, Zhao BS, He C Cell Chem Biol. 23(1):74-85. doi: 10.1016/j.chembiol.2015.11.007.

Complex complexity. Dionisio

Unlike genomic DNA, RNA has more complicated post-transcriptional processing: RNA splicing significantly increase the complex of gene expression by alternatively joining exons and removing introns; RNA editing alters the nucleoside sequence of specific transcript, which may or may not change protein coding regions or potential splicing sites to further diversify the transcriptome; RNA chemical modifications, most of which do not affect nucleotide sequence, are much more diverse and functionally versatile, suggesting broader functional impacts

Nucleic Acid Modifications in Regulation of Gene Expression. Chen K, Zhao BS, He C Cell Chem Biol. 23(1):74-85. doi: 10.1016/j.chembiol.2015.11.007.

Complex complexity. Dionisio

[...] DNA methylation, as a bona fide epigenetic marker, is not only inheritable and dynamic, but also involved in diverse regulatory processes.

Nucleic Acid Modifications in Regulation of Gene Expression. Chen K, Zhao BS, He C Cell Chem Biol. 23(1):74-85. doi: 10.1016/j.chembiol.2015.11.007.

Complex complexity. Dionisio

[...] work in this field will yield additional layers of both chemical and biological complexity as we continue to uncover functional consequences of known nucleic acid modifications and discover new ones.

Nucleic Acid Modifications in Regulation of Gene Expression. Chen K, Zhao BS, He C Cell Chem Biol. 23(1):74-85. doi: 10.1016/j.chembiol.2015.11.007.

Complex complexity. Dionisio

RNA plays central roles in biology and novel functions and regulation mechanisms are constantly emerging. To accomplish some of their functions within the cell, RNA molecules undergo hundreds of chemical modifications from which N6-methyladenosine (m6A), inosine (I), pseudouridine (?) and 5-methylcytosine (5mC) have been described in eukaryotic mRNA. Interestingly, the m6A modification was shown to be reversible, adding novel layers of regulation of gene expression through what is now recognized as epitranscriptomics. The development of molecular mapping strategies coupled to next generation sequencing allowed the identification of thousand of modified transcripts in different tissues and under different physiological conditions such as viral infections. As intracellular parasites, viruses are confronted to cellular RNA modifying enzymes and, as a consequence, viral RNA can be chemically modified at some stages of the replication cycle.

Epitranscriptomic regulation of viral replication. Pereira-Montecinos C, Valiente-Echeverría F, Soto-Rifo R Biochim Biophys Acta. 1860(4):460-471. doi: 10.1016/j.bbagrm.2017.02.002.

Complex complexity. Dionisio

The first chemical modification to RNA was discovered nearly 60 years ago; to date, more than 100 chemically distinct modifications have been identified in cellular RNA. With the recent development of novel chemical and/or biochemical methods, dynamic modifications to RNA have been identified in the transcriptome, including N6-methyladenosine (m6A), inosine (I), 5-methylcytosine (m5C), pseudouridine (?), 5-hydroxymethylcytosine (hm5C), and N1-methyladenosine (m1A). Collectively, the multitude of RNA modifications are termed epitranscriptome, leading to the emerging field of epitranscriptomics.

Chemical Modifications to RNA: A New Layer of Gene Expression Regulation. Song J, Yi C ACS Chem Biol. 12(2):316-325. doi: 10.1021/acschembio.6b00960.

Complex complexity. Dionisio

[...] the primary challenges for cellular and molecular biologists to still explore. One of these challenges is to elucidate more fully the mechanisms involved in the specification of the corneal epithelium. A major challenge [...] will be to find an early molecular marker for corneal fate. [...] it will be interesting to compare the inducing potential of corneal epithelium versus that of the oral epithelium. It will be interesting to know the result of the interaction with a “naïve mesenchyme,” as it might differ from that which occurs when the CE is associated with an embryonic dermis. [...] there is a distinct shift in the clonal composition of the cornea during the course of development, which reflects a change in the localisation of the corneal stem cells as the organisms develop and age [...] These open questions, together with the increasing numbers of molecular tools available, make this an exciting time to study the development and renewal of corneal epithelium. A deeper understanding of these mechanisms will certainly aid us make significant advances in clinical applications.

The Vertebrate Corneal Epithelium: From Early Specification to Constant Renewal Danielle Dhouailly, David J. Pearton and Frederic Michon3 DEVELOPMENTAL DYNAMICS DOI: 10.1002/DVDY.24179

Complex complexity. Dionisio

Much of the recent focus has been directed towards understanding the early development of the cornea and its renewal mechanisms as a step towards applications in regenerative medicine. Much work, however, remains but the use of cellular, molecular, and genetic approaches will enable continued progress.

The Vertebrate Corneal Epithelium: From Early Specification to Constant Renewal Danielle Dhouailly, David J. Pearton and Frederic Michon3 DEVELOPMENTAL DYNAMICS DOI: 10.1002/DVDY.24179

Complex complexity. Dionisio

The cornea is an ectodermal/neural crest derivative formed through a cascade of molecular mechanisms to give rise to the specific optical features necessary for its refractory function. Moreover, during cornea formation and maturation, epithelial stem cells are sequestered to ensure a constant source for renewal in the adult. While the embryonic origin as well as the localization of stem cells for most other ectodermal organs has been studied in depth, in the case of the cornea these two major questions are still under debate.

The Vertebrate Corneal Epithelium: From Early Specification to Constant Renewal Danielle Dhouailly, David J. Pearton and Frederic Michon3 DEVELOPMENTAL DYNAMICS DOI: 10.1002/DVDY.24179

Complex complexity. Dionisio

The advent of next-generation sequencing techniques [...] should technically enable researchers to tie together the transcriptional networks, the chromatin regulators and the enhancer elements that are key in cortical development. [...] Pax6 is only one of many key TF for cortical development. Integrating the information garnered for each TF into a coherent model will indubitably be a major goal and hurdle in our understanding of cortical developmental processes. Major concerted efforts to determine the epigenetic marks present in different cell types at different time points, such as the large-scale project currently being carried out by ENCODE, are undeniably going to enable the community to begin understanding TF networks in the context of their epigenetic environment. Moreover, other efforts designed to systematically track down enhancers active in cortical tissue in development will also provide greatly needed resources for the neuroscience community

Transcriptional and epigenetic mechanisms of early cortical development – an examination of how Pax6 coordinates cortical development Athéna R. Ypsilanti and John L.R. Rubenstein J Comp Neurol. 524(3): 609–629. doi: 10.1002/cne.23866

Work in progress... stay tuned. Complex complexity. Dionisio

It will be important to determine the gene regulatory networks important for conferring appropriate patterning to the cortex as it develops. Currently, much work remains to understand the transcriptional network required to propagate patterning information from the VZ to the cortical plate, and an even more arduous enterprise will be required in identifying the cis-regulatory elements at play in this complex developmental process.

Transcriptional and epigenetic mechanisms of early cortical development – an examination of how Pax6 coordinates cortical development Athéna R. Ypsilanti and John L.R. Rubenstein J Comp Neurol. 524(3): 609–629. doi: 10.1002/cne.23866

Work in progress... stay tuned. Complex complexity. Dionisio

The mammalian cortex is a region with an exceedingly complicated cytoarchitecture. Distinct regions of the adult cortex execute discrete cortical functions (i.e. visual processing) that are central to cognition. Moreover, it is organized into six layers, which differ in their cellular constituents and connectivity. The cortex possesses two main categories of neurons: excitatory projection neurons, that extend their axons over long distances to cortical and subcortical targets; and inhibitory interneurons, which generally have short axons and regulate local circuits. Excitatory neurons are generated by cortical progenitors, whereas inhibitory neurons are generated by subcortical progenitors in the ganglionic eminences.

Transcriptional and epigenetic mechanisms of early cortical development – an examination of how Pax6 coordinates cortical development Athéna R. Ypsilanti and John L.R. Rubenstein J Comp Neurol. 524(3): 609–629. doi: 10.1002/cne.23866

Complex complexity. Dionisio

The development of the cortex is an elaborate process which integrates a plethora of finely tuned molecular processes ranging from carefully regulated gradients of transcription factors, dynamic changes in the chromatin landscape or formation of protein complexes to elicit and regulate transcription. Combined with cellular processes such as cell type specification, proliferation, differentiation and migration, all of these developmental processes result in the establishment of an adult mammalian cortex with its typical lamination and regional patterning.

Transcriptional and epigenetic mechanisms of early cortical development – an examination of how Pax6 coordinates cortical development Athéna R. Ypsilanti and John L.R. Rubenstein J Comp Neurol. 524(3): 609–629. doi: 10.1002/cne.23866

Complex complexity. Note: this interesting paper reference was graciously provided by gpuccio in another discussion thread: https://uncommondescent.com/intelligent-design/gp-on-the-origin-of-body-plans-oobp-challenge/#comment-628278 Dionisio

In conclusion, this study identifies a genetic requirement for Meis1 and Meis2 for early steps of mammalian eye development and reveals an apparent robustness of the gene regulatory mechanism whereby two independent "shadow enhancers" of similar molecular architecture maintain critical levels of a dosage-sensitive gene, Pax6, during lens induction. These results allow us to establish a genetic hierarchy during early vertebrate eye development and provide novel mechanistic insights into the regulatory logic of this process.

The Gene Regulatory Network of Lens Induction Is Wired through Meis-Dependent Shadow Enhancers of Pax6 Barbora Antosova, Jana Smolikova, Lucie Klimova, Jitka Lachova, Michaela Bendova,Iryna Kozmikova, Ondrej Machon and Zbynek Kozmik PLoS Genet. 12(12): e1006441. doi: 10.1371/journal.pgen.1006441

Complex complexity. Dionisio

[...] it is very likely that Meis1 and Meis2 fulfill the redundant function only in specific developmental stages and processes [...] while having many discrete functions in the embryo even within the eye development.

The Gene Regulatory Network of Lens Induction Is Wired through Meis-Dependent Shadow Enhancers of Pax6 Barbora Antosova, Jana Smolikova, Lucie Klimova, Jitka Lachova, Michaela Bendova,Iryna Kozmikova, Ondrej Machon and Zbynek Kozmik PLoS Genet. 12(12): e1006441. doi: 10.1371/journal.pgen.1006441

Complex complexity. Dionisio

GRNs provide a system level explanation of development in terms of the genomic regulatory code [...] While significant insights into the functional role of many transcription factors during the lens placode formation have been realised, much less is known about the upstream regulation of these critical factors and the intricate wiring of the GRN that controls the earliest stages of lens development.

The Gene Regulatory Network of Lens Induction Is Wired through Meis-Dependent Shadow Enhancers of Pax6 Barbora Antosova, Jana Smolikova, Lucie Klimova, Jitka Lachova, Michaela Bendova,Iryna Kozmikova, Ondrej Machon and Zbynek Kozmik PLoS Genet. 12(12): e1006441. doi: 10.1371/journal.pgen.1006441

Complex complexity. Dionisio

Remarkably, our data demonstrate the existence of two independent and partially redundant Meis-dependent enhancers, with similar molecular architecture, involved in the regulation of Pax6 expression during lens placode formation, thereby providing an unexpected level of robustness to the system.

The Gene Regulatory Network of Lens Induction Is Wired through Meis-Dependent Shadow Enhancers of Pax6 Barbora Antosova, Jana Smolikova, Lucie Klimova, Jitka Lachova, Michaela Bendova,Iryna Kozmikova, Ondrej Machon and Zbynek Kozmik PLoS Genet. 12(12): e1006441. doi: 10.1371/journal.pgen.1006441

Did somebody say "unexpected"? :) Complex complexity. Dionisio

While significant insights into the functional role of some transcription factors during lens formation have been accomplished, much less is known about the intricate wiring of the gene regulatory network (GRN) that controls the earliest stages of lens development.

The Gene Regulatory Network of Lens Induction Is Wired through Meis-Dependent Shadow Enhancers of Pax6 Barbora Antosova, Jana Smolikova, Lucie Klimova, Jitka Lachova, Michaela Bendova,Iryna Kozmikova, Ondrej Machon and Zbynek Kozmik PLoS Genet. 12(12): e1006441. doi: 10.1371/journal.pgen.1006441

Complex complexity. Dionisio

Lens induction is a classical developmental model allowing investigation of cell specification, spatiotemporal control of gene expression, as well as how transcription factors are integrated into highly complex gene regulatory networks (GRNs). Pax6 represents a key node in the gene regulatory network governing mammalian lens induction. Meis1 and Meis2 homeoproteins are considered as essential upstream regulators of Pax6 during lens morphogenesis based on their interaction with the ectoderm enhancer (EE) located upstream of Pax6 transcription start site.

The Gene Regulatory Network of Lens Induction Is Wired through Meis-Dependent Shadow Enhancers of Pax6 Barbora Antosova, Jana Smolikova, Lucie Klimova, Jitka Lachova, Michaela Bendova,Iryna Kozmikova, Ondrej Machon and Zbynek Kozmik PLoS Genet. 12(12): e1006441. doi: 10.1371/journal.pgen.1006441

Complex complexity. Dionisio

This chaos existing in naming method causes the difficulty of circRNA classification. A normative and widely accepted naming system is necessary.

Circles reshaping the RNA world: from waste to treasure. Liu J, Liu T, Wang X, He A Mol Cancer. 16(1):58. doi: 10.1186/s12943-017-0630-y.

Complex complexity. Dionisio

What will happen to miRNAs after their release in a inactive state from the cleaved circRNAs? What contributes do the interaction between circRNA, miRNA and their parental gene serves in the process of aging and functional organ degeneration? These questions are all worthy of further study. Maybe someday humans can unveil the mystery of aging by researching these promising RNAs.

Circles reshaping the RNA world: from waste to treasure. Liu J, Liu T, Wang X, He A Mol Cancer. 16(1):58. doi: 10.1186/s12943-017-0630-y.

Complex complexity. Dionisio

[...] the function of large amounts of circRNAs which have been detected inside animal cells still remains largely unknown and awaits further detailed study.

Circles reshaping the RNA world: from waste to treasure. Liu J, Liu T, Wang X, He A Mol Cancer. 16(1):58. doi: 10.1186/s12943-017-0630-y.

Complex complexity. Dionisio

Brain circRNAs are suggested to regulate synaptic function and go hand in hand with the development of nervous system, this important discovery adds further dimension to our understanding of the molecular pervasiveness and importance of circular RNAs.

Circles reshaping the RNA world: from waste to treasure. Liu J, Liu T, Wang X, He A Mol Cancer. 16(1):58. doi: 10.1186/s12943-017-0630-y.

Complex complexity. Dionisio

The regulating role of circRNAs is not isolated but through an enormous complicated network involving mRNAs, miRNAs and proteins. [...] most of the potential functions still remain unclear [...]

Circles reshaping the RNA world: from waste to treasure. Liu J, Liu T, Wang X, He A Mol Cancer. 16(1):58. doi: 10.1186/s12943-017-0630-y.

Complex complexity. Dionisio

Accumulating studies were performed to explore the expression profile of circRNAs in different cell types and diseases, the outcomes totally changed our view of ncRNAs, which was thought to be junk by-products in the process of gene transcription, and enriched our poor understanding of its underlying functions.

Circles reshaping the RNA world: from waste to treasure. Liu J, Liu T, Wang X, He A Mol Cancer. 16(1):58. doi: 10.1186/s12943-017-0630-y.

Complex complexity. Dionisio

Intense efforts are underway to elucidate the functions of circRNAs. [...] circRNAs are widely believed to influence mRNA metabolism on many levels (transcription, splicing, mRNA turnover, translation) [...] The ongoing efforts to elucidate circRNA function must include these considerations as they will illuminate more fully the rich and versatile impact of circRNAs in physiology and pathology.

Emerging roles and context of circular RNAs. Panda AC, Grammatikakis I, Munk R, Gorospe M, Abdelmohsen K. Wiley Interdiscip Rev RNA. 8(2). doi: 10.1002/wrna.1386.

Complex complexity. Dionisio

The biogenesis of circRNAs is not fully understood [...] [...] more than one type of circRNA containing exon(s), intron(s), or both can be produced from a single gene. It will be particularly important to establish more comprehensively whether subsets of circRNAs associate with polysomes and might be translated.

Emerging roles and context of circular RNAs. Panda AC, Grammatikakis I, Munk R, Gorospe M, Abdelmohsen K. Wiley Interdiscip Rev RNA. 8(2). doi: 10.1002/wrna.1386.

Complex complexity. Dionisio

Circular RNAs (circRNAs) comprise a family of noncoding RNAs (ncRNAs) that have drawn intense interest in the last few years. Although they were first discovered in 1979 by electron microscopy, they were thought to be byproducts of splicing and did not receive much attention due to their low abundance and lack of known functions.

Emerging roles and context of circular RNAs. Panda AC, Grammatikakis I, Munk R, Gorospe M, Abdelmohsen K. Wiley Interdiscip Rev RNA. 8(2). doi: 10.1002/wrna.1386.

Complex complexity. Dionisio

Circular RNAs (circRNAs) represent a large class of noncoding RNAs (ncRNAs) that have recently emerged as regulators of gene expression. They have been shown to suppress microRNAs, thereby increasing the translation and stability of the targets of such microRNAs. The ensuing changes in gene expression patterns elicited by circRNAs are proposed to drive key cellular processes, such as cell proliferation, differentiation, and survival, that govern health and disease.

Emerging roles and context of circular RNAs. Panda AC, Grammatikakis I, Munk R, Gorospe M, Abdelmohsen K. Wiley Interdiscip Rev RNA. 8(2). doi: 10.1002/wrna.1386.

Complex complexity. Dionisio

Determining the function, if any, of the thousands of circRNAs expressed across the tree of life will likely occupy researchers for years to come. The abundance of circRNA and the significant sequence overlap with mRNA or linear ncRNA transcribed from the same locus pose technical and conceptual challenges to studies of circRNA regulation and function that the field will have to address [...]

Circular RNA Expression: Its Potential Regulation and Function Julia Salzman Trends Genet. 32(5): 309–316. doi: 10.1016/j.tig.2016.03.002

Complex complexity. Dionisio

[...] circRNA from both protein-coding and noncoding genes are alternatively spliced through exon skipping and, in some cases, through intron inclusion, and regulated in a cell type-specific manner [...] [...] the processes underlying this regulation are not yet well understood [...]

Circular RNA Expression: Its Potential Regulation and Function Julia Salzman Trends Genet. 32(5): 309–316. doi: 10.1016/j.tig.2016.03.002

What else is new? Complex complexity. Dionisio

Given its prevalence and the fact that it was overlooked until very recently, circRNA warrants attention from essentially all molecular biologists.

Circular RNA Expression: Its Potential Regulation and Function Julia Salzman Trends Genet. 32(5): 309–316. doi: 10.1016/j.tig.2016.03.002

Did somebody say "overlooked until very recently"? :) Why did it take them that long to look at it? Complex complexity. Dionisio

[...] these discoveries suggest greater complexity, regulation, and function of complex eukaryotic gene expression, as well as begging many significant and fundamental questions about the role of circRNA in the cell. Much work remains to be done in this area, which is now very active.

Circular RNA Expression: Its Potential Regulation and Function Julia Salzman Trends Genet. 32(5): 309–316. doi: 10.1016/j.tig.2016.03.002

Complex complexity. Dionisio

[...] circRNA production has either been conserved over billions of years or else is a feature that has re-evolved multiple times; either implies a likely functional role for circRNAs in the cell.

Circular RNA Expression: Its Potential Regulation and Function Julia Salzman Trends Genet. 32(5): 309–316. doi: 10.1016/j.tig.2016.03.002

Did somebody say "re-evolved multiple times"? Is the term "re-evolved" associated with the word revolver? :) Complex complexity. Dionisio

In 2012, a statistical analysis of RNA-Seq data and subsequent biochemical analysis revealed a complete surprise: circRNA (see Glossary) molecules transcribed and spliced from exons in protein and noncoding genes are ubiquitous in the human and mouse genomes and, thus, are likely to be a pervasive and previously overlooked feature of eukaryotic gene expression and regulation [...]

Circular RNA Expression: Its Potential Regulation and Function Julia Salzman Trends Genet. 32(5): 309–316. doi: 10.1016/j.tig.2016.03.002

Did somebody say "revealed a complete surprise"? :) Why were they so surprised? What did they expect? Did somebody say "previously overlooked feature"? :) Why did they overlook it? Could it be because they are doing bottom-up reductionist reverse-engineering research? Complex complexity. Dionisio

In 2012, a new feature of eukaryotic gene expression emerged: ubiquitous expression of circular RNA (circRNA) from genes traditionally thought to express messenger or linear noncoding (nc)RNA only. CircRNAs are covalently closed, circular RNA molecules that typically comprise exonic sequences and are spliced at canonical splice sites. This feature of gene expression was first recognized in humans and mouse, but it quickly emerged that it was common across essentially all eukaryotes studied by molecular biologists. CircRNA abundance, and even which alternatively spliced circRNA isoforms are expressed, varies by cell type and can exceed the abundance of the traditional linear mRNA or ncRNA transcript. CircRNAs are enriched in the brain and increase in abundance during fetal development. Together, these features raise fundamental questions regarding the regulation of circRNA in cis and in trans, and its function.

Circular RNA Expression: Its Potential Regulation and Function Julia Salzman Trends Genet. 32(5): 309–316. doi: 10.1016/j.tig.2016.03.002

Complex complexity. Dionisio

Nucleus is the residence and place of work for a plethora of long noncoding RNAs. Here, we provide a summary of the functions and functional mechanisms of several relatively well studied examples of nuclear long noncoding RNAs (lncRNAs) in the nucleus, such as Xist, NEAT1, MALAT1 and TERRA. The recently identified novel EIciRNA is also highlighted. These nuclear lncRNAs play a variety of roles with diverse molecular mechanisms in animal cells. We also discuss insights and concerns about current and future studies of nuclear lnc RNAs.

Functions of long noncoding RNAs in the nucleus Bin Yu & Ge Shan? Journal Nucleus ? Volume 7, 2016 - Issue 2 DOI: 10.1080/19491034.2016.1179408

Complex complexity. Dionisio

Circadian clocks regulate rhythmic gene expression levels by means of mRNA oscillations that are mainly driven by post-transcriptional regulation. Major components of paraspeckles including the long noncoding RNA Neat1, which is the structural component, and its major protein partners, as well as the number of paraspeckles, follow a circadian pattern in pituitary cells. Paraspeckles are known to retain within the nucleus RNAs containing inverted repeats of Alu sequences.

Paraspeckles as rhythmic nuclear mRNA anchorages responsible for circadian gene expression Manon Torres, Denis Becquet, Marie-Pierre Blanchard, Séverine Guillen, Bénédicte Boyer, Mathias Moreno, Jean-Louis Franc & Anne-Marie François-Bellan? DOI: 10.1080/19491034.2016.1277304 Joournal Nucleus

Complex complexity. Dionisio

Future studies are needed to decipher the molecular and biological differences among these states and to determine what dynamically regulates the conformation of paraspeckles, including after cellular stimulations. The combination of live cell imaging and super-resolution microscopy in single cells may be able to address these questions.

Shedding light on paraspeckle structure by super-resolution microscopy Shi-Bin Hu, Run-Wen Yao, Ling-Ling Chen DOI: 10.1083/jcb.201609008 THe Journal of Cell Biology The Rockefeller University Press http://jcb.rupress.org/content/early/2016/09/14/jcb.201609008

Complex complexity. Dionisio

Improved imaging techniques will be needed to further delineate the detailed structure of paraspeckles and other cellular subcompartments enriched in RNAs and proteins in the future. [...] the Neat1_2 isoform is folded and binds to paraspeckle core proteins to first form paraspeckle-like units, which are bridged together by FUS proteins to form the ordered paraspeckle sphere. [...] how paraspekles sequester these AG-rich RNAs is unknown. [...] it will be of great interest to identify additional RNAs that are sequestered in paraspeckles and to dissect their exact localization.

Shedding light on paraspeckle structure by super-resolution microscopy Shi-Bin Hu, Run-Wen Yao, Ling-Ling Chen DOI: 10.1083/jcb.201609008 THe Journal of Cell Biology The Rockefeller University Press http://jcb.rupress.org/content/early/2016/09/14/jcb.201609008

Complex complexity. Dionisio

The mechanism involved in the circadian nuclear retention of Alu-containing egfp mRNA remains anyway to be determined. [...] post-transcriptional circadian regulation plays a major role in determining oscillations at the mRNA level. [...] circadian mRNA oscillations could be post-transcriptionally controlled through rhythmic nuclear retention by paraspeckle nuclear bodies.

Circadian RNA expression elicited by 3’-UTR IRAlu-paraspeckle associated elements Manon Torres, Denis Becquet, Marie-Pierre Blanchard, Severine Guillen, Benedicte Boyer, Mathias Moreno, Jean-Louis Franc, Anne-Marie Franc¸ois-Bellan DOI: 10.7554/eLife.14837 eLife Sciences

Complex complexity. Dionisio

[...] circadian rhythms are driven by an internal body clock and are essential for the organism to adapt to the daily cycle of light and dark. Circadian rhythms also take place inside individual cells – for example, the amount of a given protein in a cell often rises and falls over each 24-hour period. To generate these daily fluctuations, the processes used to make proteins based on the instructions encoded within a gene must be carefully controlled.

Circadian RNA expression elicited by 3’-UTR IRAlu-paraspeckle associated elements Manon Torres, Denis Becquet, Marie-Pierre Blanchard, Severine Guillen, Benedicte Boyer, Mathias Moreno, Jean-Louis Franc, Anne-Marie Franc¸ois-Bellan DOI: 10.7554/eLife.14837 eLife Sciences

Complex complexity. Dionisio

The circadian clock orchestrates daily rhythms in metabolism, physiology and behavior that allow organisms to anticipate regular changes in their environment, increasing their adaptation [...] [...] substantial regulation is achieved after transcription so that post-transcriptional controls are emerging as crucial modulators of circadian clocks [...] [...] post-transcriptional mechanisms including RNA splicing, polyadenylation, mRNA stability, mRNA cytoplasmic export and RNAs nuclear retention are essential layers for generation of gene expression rhythmicity [...]

Circadian RNA expression elicited by 3’-UTR IRAlu-paraspeckle associated elements Manon Torres, Denis Becquet, Marie-Pierre Blanchard, Severine Guillen, Benedicte Boyer, Mathias Moreno, Jean-Louis Franc, Anne-Marie Franc¸ois-Bellan DOI: 10.7554/eLife.14837 eLife Sciences

Did somebody say "orchestrates"? Complex complexity. Dionisio

Paraspeckles are nuclear bodies form around the long non-coding RNA, Neat1, and RNA-binding proteins. While their role is not fully understood, they are believed to control gene expression at a post-transcriptional level by means of the nuclear retention of mRNA containing in their 3’-UTR inverted repeats of Alu sequences (IRAlu). [...] paraspeckles, thanks to their circadian expression, control circadian gene expression at a post-transcriptional level.

Circadian RNA expression elicited by 3’-UTR IRAlu-paraspeckle associated elements Manon Torres, Denis Becquet, Marie-Pierre Blanchard, Severine Guillen, Benedicte Boyer, Mathias Moreno, Jean-Louis Franc, Anne-Marie Franc¸ois-Bellan DOI: 10.7554/eLife.14837 eLife Sciences

Complex complexity. Dionisio

[...] the knowledge concerning the presence of these modifications within the coding sequence of mRNAs is rather novel. [...] investigating the influence of these modifications on pivotal cellular processes, such as mRNA translation, will generate new research opportunities and will change our understanding of gene regulation.

Translating the epitranscriptome. Hoernes TP, Erlacher MD Wiley Interdiscip Rev RNA. 8(1). doi: 10.1002/wrna.1375

Complex complexity. Dionisio

Why is the interpretation of modified codons by the ribosome not universally conserved across different species? It might even be conceivable that within one species, the translational response might vary in different tissues.

Translating the epitranscriptome. Hoernes TP, Erlacher MD Wiley Interdiscip Rev RNA. 8(1). doi: 10.1002/wrna.1375

Complex complexity. Dionisio

mRNA modifications also modulate protein synthesis [...] It will be crucial to define which modified codons directly affect the ribosome as potential regulators of translation. [...] the mechanism behind this regulatory function will certainly reveal some exciting new insights in the decoding process of modified mRNA nucleotides.

Translating the epitranscriptome. Hoernes TP, Erlacher MD Wiley Interdiscip Rev RNA. 8(1). doi: 10.1002/wrna.1375

Complex complexity. Dionisio

In the last decade of RNA research [...] RNA modifications have re?gained much attention. [...] the RNA modification repertoire is constantly expanding and the significance of the RNA modifications involved in several cellular aspects is currently undisputed. The emerging roles of mRNA modifications are extremely diverse [...] RNA modifications have been unveiled in unexpected places in mRNAs, thereby additionally expanding the potential functional repertoire [...] It will be an exciting and challenging future task to distinguish between meaningful epitranscriptomal marks and silent bystander modifications that simply decorate nucleic acids.

Translating the epitranscriptome. Hoernes TP, Erlacher MD Wiley Interdiscip Rev RNA. 8(1). doi: 10.1002/wrna.1375

Complex complexity. Dionisio

Post-transcriptional modifications of RNA can be historically classified into two groups: edited RNA and modified RNA. The definition of edited or modified RNAs should not be taken too strictly, as these terms are often context-dependent. The modification and editing of mRNAs are essential processes that influence and regulate gene expression at the post-transcriptional level. mRNA modifications are involved in many aspects of mRNA processing, stability, folding and translation.

Translating the epitranscriptome. Hoernes TP, Erlacher MD Wiley Interdiscip Rev RNA. 8(1). doi: 10.1002/wrna.1375

Complex complexity. Dionisio

More than 100 different types of RNA modifications in almost every class of non?coding and coding RNAs have been reported. Considering the effort necessary to specifically introduce modifications, the functional role of these modifications during the ‘life cycle’ of a tRNA might not yet be revealed. [...] many questions concerning the role of rRNA modifications during protein synthesis or ribosome assembly remain unanswered.

Translating the epitranscriptome. Hoernes TP, Erlacher MD Wiley Interdiscip Rev RNA. 8(1). doi: 10.1002/wrna.1375

Complex complexity. Dionisio

Messenger RNA (mRNA) translation is a central process in every living organism. The regulation of translation is typically associated with the necessity of regulatory proteins and regulatory non?coding RNAs (ncRNAs). [...] equally important for the translation process are nucleotide modifications, which are present in all involved classes of RNA. Ribosomal RNAs (rRNAs), transfer RNAs (tRNAs) and mRNAs are co? or post?transcriptionally modified. [...] the precise function of many of these nucleotide derivatives remains enigmatic [...]

Translating the epitranscriptome. Hoernes TP, Erlacher MD Wiley Interdiscip Rev RNA. 8(1). doi: 10.1002/wrna.1375

Complex complexity. Dionisio

This is the post # 3001 in this thread. A total of over 7500 visits registered so far. Over 4500 visits were quiet -i.e. did not leave comments. In the 27 months since the OP was posted many discoveries have been published in research papers. The number of articles on the leading edge research topics keeps growing. The "Big Data" problem seems to get worse. With every new discovery the big picture seems more and more fascinating. Dionisio

[...] transcription and mRNA degradation machineries cross-talk to control the total mRNA concentration within a homeostatic range [...] [...] for both the ESR genes and the mitochondria-related genes, mRNA concentration correlated either positively or negatively with the GR. mRNA decay, but not transcription, was controlled by the GR in mitochondrial genes, whereas transcription, but not degradation, was modulated by the GR in ESR genes [...]

The cellular growth rate controls overall mRNA turnover, and modulates either transcription or degradation rates of particular gene regulons José García-Martínez; Lidia Delgado-Ramos; Guillermo Ayala; Vicent Pelechano; Daniel A. Medina; Fany Carrasco; Ramón González; Eduardo Andrés-León; Lars Steinmetz; Jonas Warringer; Sebastián Chávez; José E. Pérez-Ortín Nucleic Acids Res 44 (8): 3643-3658 DOI: https://doi.org/10.1093/nar/gkv1512

Complex complexity. Dionisio

The need for novel proteins in proliferation cells is enormous (1), which means that much, and probably the majority, of the transcription effort should be dedicated to translation-related RNAs [...] [...] a primary task for transcriptional machineries is the production of these RNA molecules at a rate that is directly related to the growth rate. [...] transcription of genes encoding ribosomal components and translation-related elements is directly dependent on the GR [...]

The cellular growth rate controls overall mRNA turnover, and modulates either transcription or degradation rates of particular gene regulons José García-Martínez; Lidia Delgado-Ramos; Guillermo Ayala; Vicent Pelechano; Daniel A. Medina; Fany Carrasco; Ramón González; Eduardo Andrés-León; Lars Steinmetz; Jonas Warringer; Sebastián Chávez; José E. Pérez-Ortín Nucleic Acids Res 44 (8): 3643-3658 DOI: https://doi.org/10.1093/nar/gkv1512

Complex complexity. Dionisio

The translation machinery includes the most abundant noncoding RNAs: rRNA and tRNAs. Thus the eukaryotic RNA polymerases (RNA pol) devoted to the synthesis of rRNA and tRNA (RNA pol I and III) must increase their transcription rates (TRs [...]) in parallel to the GR [...]

The cellular growth rate controls overall mRNA turnover, and modulates either transcription or degradation rates of particular gene regulons José García-Martínez; Lidia Delgado-Ramos; Guillermo Ayala; Vicent Pelechano; Daniel A. Medina; Fany Carrasco; Ramón González; Eduardo Andrés-León; Lars Steinmetz; Jonas Warringer; Sebastián Chávez; José E. Pérez-Ortín Nucleic Acids Res 44 (8): 3643-3658 DOI: https://doi.org/10.1093/nar/gkv1512

Complex complexity. Dionisio

The regulation of overall mRNA turnover keeps a constant ratio between mRNA decay and the dilution of [mRNA] caused by cellular growth. This regulation minimizes the indiscriminate transmission of mRNAs from mother to daughter cells, and favors the response capacity of the latter to physiological signals and environmental changes. [...] by uncoupling mRNA synthesis from decay, cells control the mRNA abundance of those gene regulons that characterize fast and slow growth.

The cellular growth rate controls overall mRNA turnover, and modulates either transcription or degradation rates of particular gene regulons José García-Martínez; Lidia Delgado-Ramos; Guillermo Ayala; Vicent Pelechano; Daniel A. Medina; Fany Carrasco; Ramón González; Eduardo Andrés-León; Lars Steinmetz; Jonas Warringer; Sebastián Chávez?; José E. Pérez-Ortín? Nucleic Acids Res 44 (8): 3643-3658 DOI: https://doi.org/10.1093/nar/gkv1512

Complex complexity. Dionisio

The cellular response to other environmental stresses also requires high and timely transcription of protective genes and down-regulation and later recovery of housekeeping genes, such as RP genes [...]. Our observation that cellular growth under various stresses requires Cbc1 and Cbc2 (Fig. S3), suggests that the multifunctional roles in gene expression of the mRNA cap-binding proteins are necessary to attain an adequate response to stress.

The mRNA cap-binding protein Cbc1 is required for high and timely expression of genes by promoting the accumulation of gene-specific activators at promoters Tianlu Li, Nikki De Clercq, Daniel A. Medina, Elena Garre, Per Sunnerhagen, José E. Pérez-Ortín, Paula Alepuza http://dx.doi.org/10.1016/j.bbagrm.2016.01.002 Biochimica et Biophysica Acta (BBA) – Gene Regulatory Mechanisms Volume 1859, Issue 2, Pages 405–419 DOI: 10.1016/j.bbagrm.2016.01.002

Complex complexity. Dionisio

[...] a connection between recruitment of gene-specific activators to chromatin and enhanced degradation has been established [...] [...] attenuation of the stress response has been connected to nuclear protein modification and degradation of such activators as Msn2 [...] [...] dephosphorylation occurs on chromatin-bound proteins [...] [...] Cbc1 has multifunctional roles during osmotic stress, and acts as a key factor coordinating different levels of gene expression.

The mRNA cap-binding protein Cbc1 is required for high and timely expression of genes by promoting the accumulation of gene-specific activators at promoters Tianlu Li, Nikki De Clercq, Daniel A. Medina, Elena Garre, Per Sunnerhagen, José E. Pérez-Ortín, Paula Alepuza http://dx.doi.org/10.1016/j.bbagrm.2016.01.002 Biochimica et Biophysica Acta (BBA) – Gene Regulatory Mechanisms Volume 1859, Issue 2, Pages 405–419 DOI: 10.1016/j.bbagrm.2016.01.002

Complex complexity. Dionisio

[...] Cbc1 connects RNA processing to all steps of transcription and also to signaling by accumulating signal-induced transcription activators at gene promoters. Further experiments should be performed to fully understand how Cbc1 mediates the accumulation of different specific activators at promoters.

The mRNA cap-binding protein Cbc1 is required for high and timely expression of genes by promoting the accumulation of gene-specific activators at promoters Tianlu Li, Nikki De Clercq, Daniel A. Medina, Elena Garre, Per Sunnerhagen, José E. Pérez-Ortín, Paula Alepuza http://dx.doi.org/10.1016/j.bbagrm.2016.01.002 Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms Volume 1859, Issue 2, Pages 405–419 DOI: 10.1016/j.bbagrm.2016.01.002

Complex complexity. Dionisio

RNAPII transcription is a complex process involving diverse, yet distinct stages, such as initiation, elongation and termination,which respond to intracellular signaling in such a dynamic manner that the mRNA being synthesized is simultaneously modified and imprinted for its subsequent life [...] Cross-talk between the factors involved in all these processes will determine the speed, intensity and length of transcription for each particular mRNA under each particular cellular condition [...] In this context, interaction between factors of different processes and the existence of factors with multifunctional roles will be necessary to achieve this complex coordination.

The mRNA cap-binding protein Cbc1 is required for high and timely expression of genes by promoting the accumulation of gene-specific activators at promoters Tianlu Li, Nikki De Clercq, Daniel A. Medina, Elena Garre, Per Sunnerhagen, José E. Pérez-Ortín, Paula Alepuza http://dx.doi.org/10.1016/j.bbagrm.2016.01.002 Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms Volume 1859, Issue 2, Pages 405–419 DOI: 10.1016/j.bbagrm.2016.01.002

Complex complexity. Dionisio

[...] the role of SMAR1 in memory T cell differentiation and maturation are not studied in detail and require further investigation. Since SMAR1 regulates genes that are essential for specific T cell lineage commitment, it is also important to examine whether SMAR1 plays a role in differentiation of Th9 or Th22 cells, a novel CD4+ T cells subsets. It would be interesting to study the regulation of SMAR1 in Treg cells that could be regulated by an IL-6:STAT3 or IL-2:STAT5 dependent mechanism as STAT3 and STAT5 are essential transcription factors required for Th17 and Treg differentiation, respectively. It would be also exciting to investigate whether SMAR1 play a role in the T follicular helper cell differentiation. Studies illuminating the role of lincRNAs in the regulation of SMAR1 in CD4+ T cell subtypes could also elucidate the signaling pathways and molecular mechanisms that regulate the lineage commitment of various subtypes of CD4+ T cells.

Chromatin Remodeling Protein SMAR1 Is a Critical Regulator of T Helper Cell Differentiation and Inflammatory Diseases Bhalchandra Mirlekar, Dipendra Gautam and Samit Chattopadhyay Front Immunol. 8: 72. doi: 10.3389/fimmu.2017.00072

Work in progress… stay tuned. Complex complexity. Dionisio

Various MAR-binding nuclear proteins are involved in crosstalk between genetic and epigenetic factors during differentiation of naïve T cells through chromatin changes. Studying “adaptor proteins” that bind to chromatin and define chromatin conformation provides us with cues to understand the mechanism of T cell differentiation. Further investigation into the possibilities of identifying novel molecular targets will be beneficial in modulating therapeutic interventions and immune responses.

Chromatin Remodeling Protein SMAR1 Is a Critical Regulator of T Helper Cell Differentiation and Inflammatory Diseases Bhalchandra Mirlekar, Dipendra Gautam and Samit Chattopadhyay Front Immunol. 8: 72. doi: 10.3389/fimmu.2017.00072

Complex complexity. Dionisio

Various subsets of T lymphocytes play a central role in vertebrate adaptive immune response. The Naïve T cells that are generated in the thymus mature into distinct subtype of T cells that differ greatly in their phenotypical and functional properties. Naive T cells when challenged with antigens undergo epigenetic alterations that affect expression of many genes involved in T cell-mediated immune responses. These changes ultimately lead to expression of cytokines that marks the functionality of T cells (1–4). Currently, the role of master regulators in the chromatin changes for lineage-specific differentiation of T cells is not well understood.

Chromatin Remodeling Protein SMAR1 Is a Critical Regulator of T Helper Cell Differentiation and Inflammatory Diseases Bhalchandra Mirlekar, Dipendra Gautam and Samit Chattopadhyay Front Immunol. 8: 72. doi: 10.3389/fimmu.2017.00072

Complex complexity. Dionisio

T cell differentiation from naïve T cells to specialized effector subsets of mature cells is determined by the iterative action of transcription factors. At each stage of specific T cell lineage differentiation, transcription factor interacts not only with nuclear proteins such as histone and histone modifiers but also with other factors that are bound to the chromatin and play a critical role in gene expression.

Chromatin Remodeling Protein SMAR1 Is a Critical Regulator of T Helper Cell Differentiation and Inflammatory Diseases Bhalchandra Mirlekar, Dipendra Gautam and Samit Chattopadhyay Front Immunol. 8: 72. doi: 10.3389/fimmu.2017.00072

Complex complexity. Dionisio

Many human complex diseases are characterized by dysregulation of immune and inflammatory activity. However, the repertoire of immune genes and cell subsets implicated in the pathogenesis of individual disease can vary dramatically. A key challenge is that these disease variants map predominantly to noncoding regions of the human genome, where they are predicted to alter regulatory function [...] Linking susceptibility variants to their respective causative genes and cell-specific regulatory elements thus remains a main priority in order to realize the potential of association studies to advance understanding of disease biology and etiology, leading to therapeutic advances.

Genetic Drivers of Epigenetic and Transcriptional Variation in Human Immune Cells. Chen L1, Ge B2, Casale FP3, Vasquez L4, Kwan T2, Garrido-Martín D5, Watt S4, Yan Y4, Kundu K1, Ecker S6, Datta A7, Richardson D7, Burden F8, Mead D4, Mann AL4, Fernandez JM9, Rowlston S8, Wilder SP10, Farrow S8, Shao X2, Lambourne JJ11, Redensek A2, Albers CA12, Amstislavskiy V13, Ashford S8, Berentsen K14, Bomba L4, Bourque G2, Bujold D2, Busche S2, Caron M2, Chen SH2, Cheung W2, Delaneau O15, Dermitzakis ET15, Elding H4, Colgiu I16, Bagger FO17, Flicek P7, Habibi E14, Iotchkova V18, Janssen-Megens E14, Kim B14, Lehrach H13, Lowy E7, Mandoli A14, Matarese F14, Maurano MT19, Morris JA2, Pancaldi V9, Pourfarzad F20, Rehnstrom K8, Rendon A21, Risch T13, Sharifi N14, Simon MM2, Sultan M13, Valencia A9, Walter K4, Wang SY14, Frontini M22, Antonarakis SE15, Clarke L7, Yaspo ML13, Beck S23, Guigo R24, Rico D25, Martens JH14, Ouwehand WH26, Kuijpers TW27, Paul DS28, Stunnenberg HG14, Stegle O3, Downes K8, Pastinen T29, Soranzo N Cell. 167(5):1398-1414.e24. doi: 10.1016/j.cell.2016.10.026.

Complex complexity. Dionisio

The extent and functional interpretation of transcriptional and epigenetic variability have not been systematically investigated genome-wide across multiple immune cell types in the general population. Our data further reveal potential molecular mechanisms of immune responses to environmental stimuli and provide a resource to enable future functional studies into the phenotypic plasticity of human immune cells in health and disease.

Genome-wide analysis of differential transcriptional and epigenetic variability across human immune cell types. Ecker S, Chen L, Pancaldi V, Bagger FO, Fernández JM, Carrillo de Santa Pau E, Juan D, Mann AL, Watt S, Casale FP, Sidiropoulos N, Rapin N, Merkel A; BLUEPRINT Consortium, Stunnenberg HG, Stegle O, Frontini M, Downes K, Pastinen T, Kuijpers TW, Rico D, Valencia A, Beck S, Soranzo N, Paul DS Genome Biol. 18(1):18. doi: 10.1186/s13059-017-1156-8.

Work in progress... stay tuned. Complex complexity. Dionisio

Phenotypic plasticity is fundamental to human immunity, allowing rapid cellular adaptation in response to changing environmental conditions [1]. Plasticity of immune cells can be influenced by the variability of cellular traits, including gene expression and DNA methylation. B and T cells utilize genetic recombination to generate a highly diverse repertoire of immunoglobulins and T-cell surface receptors, respectively. In addition, immune responses are driven by the variability of key signaling molecules and transcription factors not controlled by genetic factors [10, 11]. Epigenetic states, including DNA methylation, also contribute to plastic gene expression during cell fate commitment, thus enhancing fitness in response to external cues [12, 13].

Genome-wide analysis of differential transcriptional and epigenetic variability across human immune cell types. Ecker S, Chen L, Pancaldi V, Bagger FO, Fernández JM, Carrillo de Santa Pau E, Juan D, Mann AL, Watt S, Casale FP, Sidiropoulos N, Rapin N, Merkel A; BLUEPRINT Consortium, Stunnenberg HG, Stegle O, Frontini M, Downes K, Pastinen T, Kuijpers TW, Rico D, Valencia A, Beck S, Soranzo N, Paul DS Genome Biol. 18(1):18. doi: 10.1186/s13059-017-1156-8.

Complex complexity. Dionisio

[...] how can we integrate all of this knowledge to explain the regulation of the complex traits [?] The answer may be that we need to start thinking of biological systems instead of a collection of genes or components. Therefore, we need to do experiments using a systems-driven research and perhaps, in the future, change from “genomics prediction” to “systems (biology) prediction”.

The Importance of Endophenotypes to Evaluate the Relationship between Genotype and External Phenotype Marinus F. W. te Pas, Ole Madsen, Mario P. L. Calus and Mari A. Smits Int. J. Mol. Sci. 2017, 18(2), 472; doi:10.3390/ijms18020472

Complex complexity. Dionisio

[...] the biology underlying complex traits in livestock relates to the genotype and regulatory sequences of multiple genes, the effects of the environment resulting in modulation of the epigenome, the expression of the genes via diverse transcriptional mechanisms and post-transcriptional expression processes modulating the activity of the proteins and subsequently the metabolome.

The Importance of Endophenotypes to Evaluate the Relationship between Genotype and External Phenotype Marinus F. W. te Pas, Ole Madsen, Mario P. L. Calus and Mari A. Smits Int. J. Mol. Sci. 2017, 18(2), 472; doi:10.3390/ijms18020472

Complex complexity. Dionisio

The current status of the annotation of the functional genome probably is only a snapshot of it. The lack of good annotated functional genomes hampers the understanding of GWAS results and their use in “weighted” (i.e., using biological knowledge) genome prediction. Furthermore, it will facilitate the understanding and meaning of the biological processes underlying the complex (endo) phenotypes.

The Importance of Endophenotypes to Evaluate the Relationship between Genotype and External Phenotype Marinus F. W. te Pas, Ole Madsen, Mario P. L. Calus and Mari A. Smits Int. J. Mol. Sci. 2017, 18(2), 472; doi:10.3390/ijms18020472

Complex complexity. Dionisio

It is important to realize that many (differences in) phenotypes are caused by differences in gene expression rather than by variation in the coding sequences of the genes [57]. Variation in gene expression is regulated by a complex regulatory network called the functional genome. The functional genome consist of a number of different (epigenetic) regulatory components, including regulatory DNA sequences, DNA methylation, histone modifications and regulatory non-coding RNAs (ncRNA), together acting in a complex network regulating gene expression, which in turn determines the so-called expressed QTL (eQTL).

The Importance of Endophenotypes to Evaluate the Relationship between Genotype and External Phenotype Marinus F. W. te Pas, Ole Madsen, Mario P. L. Calus and Mari A. Smits Int. J. Mol. Sci. 2017, 18(2), 472; doi:10.3390/ijms18020472

Complex complexity. Dionisio

With the exception of a few Mendelian traits, almost all phenotypes (traits) in livestock science are quantitative or complex traits regulated by the expression of many genes. For most of the complex traits, differential expression of genes, rather than genomic variation in the gene coding sequences, is associated with the genotype of a trait. The expression profiles of the animal’s transcriptome, proteome and metabolome represent endophenotypes that influence/regulate the externally-observed phenotype. These expression profiles are generated by interactions between the animal’s genome and its environment that range from the cellular, up to the husbandry environment.

The Importance of Endophenotypes to Evaluate the Relationship between Genotype and External Phenotype Marinus F. W. te Pas, Ole Madsen, Mario P. L. Calus and Mari A. Smits Int. J. Mol. Sci. 2017, 18(2), 472; doi:10.3390/ijms18020472

Complex complexity. Dionisio

Due to the lack of annotation of the functional genome and ontologies of genes, our knowledge about the various biological systems that contribute to the development of external phenotypes is sparse. Furthermore, interaction with the animals’ microbiome, especially in the gut, greatly influences the external phenotype. We conclude that a detailed understanding of complex traits requires not only understanding of variation in the genome, but also its expression at all functional levels.

The Importance of Endophenotypes to Evaluate the Relationship between Genotype and External Phenotype Marinus F. W. te Pas, Ole Madsen, Mario P. L. Calus and Mari A. Smits Int. J. Mol. Sci. 2017, 18(2), 472; doi:10.3390/ijms18020472

Complex complexity. Dionisio

Understanding how our genome determines the distinct cell-types, tissues and organs that together make a functional human body is essential for better understanding of complex traits and susceptibility to disease. Deeper studies of this type will be of great functional value for interpreting the wave of epigenome wide associations studies (EWAS) to come [...] The role of DNA methylation in gene expression variation is not well understood [...] [...] methylation can be associated to gene expression in a positive or negative manner that is highly replicated across cell-types, but the effect sizes of these associations appear more cell-type specific than genetic effects on expression and DNA methylation. [...] future studies will need to further disentangle the positive and negative associations between DNA methylation and gene expression. [...] DNA methylation is extensively associated to alternative splicing across the genome, and many of these associations present cell-type specificity. [...] splicing can be dependent not only on factors occurring within the gene, but also on factors acting in both promoter proximal and distant regulatory regions. [...] characterizing the genetic causes of their inter-individual variation provides biological insights and mechanistic clues to the underlying pathophysiology of complex diseases and traits.

Tissue-Specific Effects of Genetic and Epigenetic Variation on Gene Regulation and Splicing Maria Gutierrez-Arcelus, Halit Ongen, Tuuli Lappalainen, Stephen B. Montgomery, Alfonso Buil, Alisa Yurovsky, Julien Bryois, Ismael Padioleau, Luciana Romano, Alexandra Planchon, Emilie Falconnet, Deborah Bielser, Maryline Gagnebin, Thomas Giger, Christelle Borel, Audrey Letourneau, Periklis Makrythanasis, Michel Guipponi, Corinne Gehrig, Stylianos E. Antonarakis and Emmanouil T. Dermitzakis doi: 10.1371/journal.pgen.1004958 PLoS Genet. 11(1): e1004958

Complex complexity. Dionisio

Understanding how genetic variation affects distinct cellular phenotypes, such as gene expression levels, alternative splicing and DNA methylation levels, is essential for better understanding of complex diseases and traits. Furthermore, how inter-individual variation of DNA methylation is associated to gene expression is just starting to be studied. [...] genome sequence variation has a broad effect on cellular phenotypes across cell-types [...] [...] epigenetic factors provide a secondary layer of variation that is more tissue-specific. [...] the details of how this tissue-specificity may vary across inter-relations of molecular traits, and where these are occurring, can yield further insights into gene regulation and cellular biology as a whole.

Tissue-Specific Effects of Genetic and Epigenetic Variation on Gene Regulation and Splicing Maria Gutierrez-Arcelus, Halit Ongen, Tuuli Lappalainen, Stephen B. Montgomery, Alfonso Buil, Alisa Yurovsky, Julien Bryois, Ismael Padioleau, Luciana Romano, Alexandra Planchon, Emilie Falconnet, Deborah Bielser, Maryline Gagnebin, Thomas Giger, Christelle Borel, Audrey Letourneau, Periklis Makrythanasis, Michel Guipponi, Corinne Gehrig, Stylianos E. Antonarakis and Emmanouil T. Dermitzakis doi: 10.1371/journal.pgen.1004958 PLoS Genet. 11(1): e1004958

Complex complexity. Dionisio

The circadian clock plays key roles in critical aspects of skeletal muscle physiology. Thus, it is imperative to dissect the precise underlying mechanisms involved in these multifaceted interactions.

Circadian clock regulation of skeletal muscle growth and repair. Chatterjee S, Ma K F1000Res. 5:1549. doi: 10.12688/f1000research.9076.1.

Work in progress... stay tuned. Complex complexity. Dionisio

[...] the clock machinery in skeletal muscle plays a significant role in orchestrating metabolic substrate metabolism. [...] whether clock functions as a temporal mechanism to adapt to feeding-fasting induced metabolic substrate switching remains to be studied. Future investigation into the molecular mechanisms linking clock and muscle metabolic substrate flux may yield novel targets for disease treatment including obesity and diabetes.

Circadian clock regulation of skeletal muscle growth and repair. Chatterjee S, Ma K F1000Res. 5:1549. doi: 10.12688/f1000research.9076.1.

Work in progress... stay tuned. Complex complexity. Dionisio

The complex interplays between central and peripheral clock systems function in concert to exert proper temporal control on various circadian physiological outputs. At the molecular level, an intricate transcriptional-translational network of circadian clock circuit that generates circadian rhythmicity has been well-defined, although novel modulators of the circadian clock loop continue to emerge.

Circadian clock regulation of skeletal muscle growth and repair. Chatterjee S, Ma K F1000Res. 5:1549. doi: 10.12688/f1000research.9076.1.

Complex complexity. Dionisio

The circadian clock system consists of a hierarchal organization. The central clock resides in the suprachiasmatic nuclei (SCN) of the hypothalamus and transmits timing signals from light inputs to drive peripheral tissue clocks. Nearly all tissue/cell types in the body possess cell-autonomous clock circuits that are entrained by central clock signals, but can be fully uncoupled through diet timing manipulations such as restricted feeding [...]

Circadian clock regulation of skeletal muscle growth and repair. Chatterjee S, Ma K F1000Res. 5:1549. doi: 10.12688/f1000research.9076.1.

Complex complexity. Dionisio

[...] the circadian clock, a transcriptional/translational feedback circuit that generates ~24-hour oscillations in behavior and physiology, is a key temporal regulatory mechanism involved in many important aspects of muscle physiology. [...] investigations into the underlying molecular pathways that transmit clock signals to the maintenance of skeletal muscle growth and function are only emerging. Studies of mechanisms underlying circadian clock function and regulation in skeletal muscle warrant continued efforts.

Circadian clock regulation of skeletal muscle growth and repair. Chatterjee S, Ma K F1000Res. 5:1549. doi: 10.12688/f1000research.9076.1.

Complex complexity. Dionisio

Much progress has been made on understanding how immune functions are regulated by biological clocks, but a number of questions remain. [...] it will be important to determine whether oscillations in immunity are driven by clock controlled changes in cellular metabolism. [...] it is not known whether environmental signals can entrain adaptive and innate immunity. [...] it is not known whether this feature of the oscillator is used to separate mutually incompatible programs in immune cells, [...] Addressing these questions will enhance our basic understanding of how the circadian clock optimizes immune functions to anticipate changes in the environment [...]

Immunity around the clock. Man K, Loudon A, Chawla A Science. 354(6315):999-1003. DOI: 10.1126/science.aah4966

Work in progress… stay tuned. Complex complexity. Dionisio

In mammals, the central circadian pacemaker is located in the suprachiasmatic nucleus (SCN), which entrains peripheral clocks found in nearly every cell of the body [...] The SCN oscillator has two distinct properties. First, it is the only part of the circadian system that has retinal innervation, allowing it to be entrained by the solar cycle. Second, unlike the peripheral clocks, which dampen over time, the interneuronal signaling pathways that establish communication between the SCN neurons endow it with an unlimited capacity to generate circadian outputs.

Immunity around the clock. Man K, Loudon A, Chawla A Science. 354(6315):999-1003. DOI: 10.1126/science.aah4966

Complex complexity. Dionisio

Virtually all life on Earth is exposed to regular 24-hour environmental cycles generated by the planet’s rotation. The sleep-wake cycle is perhaps the most obvious output of the circadian system, but numerous other physiological systems are under circadian control, including behavior and locomotor activity; body temperature; the cardiovascular, digestive, and endocrine systems; and metabolic and immune functions [...]

Immunity around the clock. Man K, Loudon A, Chawla A Science. 354(6315):999-1003. DOI: 10.1126/science.aah4966

Complex complexity. Dionisio

Immunity is a high-cost, high-benefit trait that defends against pathogens and noxious stimuli but whose overactivation can result in immunopathologies and sometimes even death. Because many immune parameters oscillate rhythmically with the time of day, the circadian clock has emerged as an important gatekeeper for reducing immunity-associated costs, which, in turn, enhances organismal fitness. This is mediated by interactions between extrinsic environmental cues and the intrinsic oscillators of immune cells, which together optimize immune responses throughout the circadian cycle. The elucidation of these clock-controlled immuno-modulatory mechanisms might uncover new approaches for treating infections and chronic inflammatory diseases.

Immunity around the clock. Man K, Loudon A, Chawla A Science. 354(6315):999-1003. DOI: 10.1126/science.aah4966

Work in progress… stay tuned. ???? Complex complexity. Dionisio

[...] this method is still far from satisfaction of practical application requirements. [...] there are two further researches for the causal relationship of the large-scale GRNs. On one hand, we are interested in investigating the overall topology identification by incorporating the power law distribution of the GRNs. On the other hand, using this sparse reconstruction approach to corroborate the actual gene networks obtained by biological experiments is part of our future work.

A Sparse Reconstruction Approach for Identifying Gene Regulatory Networks Using Steady-State Experiment Data. Zhang W, Zhou T PLoS One. 10(7):e0130979. doi: 10.1371/journal.pone.0130979.

Work in progress... stay tuned. :) Complex complexity. Dionisio

In biological sciences, a significant task is to reconstruct GRNs from experiment data and other a priori information, which is a fundamental problem in understanding cellular functions and behaviors [...] The present challenges in biological research are that the GRN is generally large-scaled and there are many restrictions on probing signals in biochemical experiments. These challenges make the problem of identifying a GRN much more difficult than other reverse engineering problems [...]

A Sparse Reconstruction Approach for Identifying Gene Regulatory Networks Using Steady-State Experiment Data. Zhang W, Zhou T PLoS One. 10(7):e0130979. doi: 10.1371/journal.pone.0130979.

Complex complexity. Dionisio

This research proposed an algorithm for reconstructing GRN with the main aim to solve cascade error problem. With regard to our experiment, even though MLR appears to be able to handle cascade errors, the identified limitations detected in MLR make us recommend that other regression technique shall be used to replace MLR with GRN inference, particularly when n ? p type of datasets is involved. Even though we have tried to eliminate some of the predictors using a systematic approach (as proposed in this work), that method requires more detailed study on how to combine prediction on separated subnetworks to represent the whole E. coli networks.

Multiple Linear Regression for Reconstruction of Gene Regulatory Networks in Solving Cascade Error Problems Faridah Hani Mohamed Salleh, 1 , * Suhaila Zainudin, 2 and Shereena M. Arif Adv Bioinformatics. 2017: 4827171. doi: 10.1155/2017/4827171

Complex complexity. Dionisio

Gene regulatory networks (GRNs) that explicitly characterize regulatory processes in cells are typically modeled by graphs, in which the nodes represent the genes and the edges reflect the regulatory or interaction relationship between genes [1]. Accurately inferring GRN is of great importance and also an essential task to understand the biological activity from signal emulsion to metabolic dynamics, prioritize potential drug targets of various diseases, devise effective therapeutics, and discover the novel pathways

Inference of Gene Regulatory Network Based on Local Bayesian Networks. Liu F1,2, Zhang SW1, Guo WF1, Wei ZG1, Chen L1 PLoS Comput Biol. ;12(8):e1005024. doi: 10.1371/journal.pcbi.1005024.

Complex complexity. Dionisio

Gene regulatory network (GRN) represents how some genes encode regulatory molecules such as transcription factors or microRNAs for regulating the expression of other genes. Accurate inference of GRN is an important task to understand the biological activity from signal emulsion to metabolic dynamics, prioritize potential drug targets of various diseases, devise effective therapeutics, and discover the novel pathways.

Inference of Gene Regulatory Network Based on Local Bayesian Networks. Liu F1,2, Zhang SW1, Guo WF1, Wei ZG1, Chen L1 PLoS Comput Biol. ;12(8):e1005024. doi: 10.1371/journal.pcbi.1005024.

Complex complexity. Dionisio

It included eight scientific sessions, three tutorials, four keynote presentations, three highlight talks, and a poster session that covered current research in bioinformatics, systems biology, computational biology, biotechnologies, and computational medicine. It was also an important educational and training venue for students and junior investigators in bioinformatics, systems biology, intelligent computing, and computational medicine. Four keynote speakers who are world-renowned leaders in bioinformatics, medical informatics, integrative genomics, systems biology and computational medicine delivered lectures on their cutting-edge research, provided insightful views for their research fields, and shared their perspectives on the future of these fields in the era of big data.

Intelligent biology and medicine in 2015: advancing interdisciplinary education, collaboration, and data science Kun Huang,#1 Yunlong Liu,#2,3 Yufei Huang,4 Lang Li,#2,3 Lee Cooper,5,6 Jianhua Ruan,corresponding author7 and Zhongming Zhao BMC Genomics. 17(Suppl 7): 524. doi: 10.1186/s12864-016-2893-x

Dionisio

In metazoans, during endoplasmic reticulum (ER) stress, the endoribonuclease (RNase) Inositol Requiring Enzyme 1a (Ire1?) initiates removal of a 26 nt region from the mRNA encoding the transcription factor Xbp1 via an non-canonical mechanism (atypically within the cytosol). This causes a transitional open reading frame-shift to produce a potent transcription factor, Xbp1s, that induces expression of numerous downstream genes in response to ER stress as part of the unfolded protein response (UPR) [1, 2]. In addition, spliceosome-independent cytoplasmic splicing, as a part of the unfolded protein response pathway, has been described in yeast [3] where HAC1p was found to be the sole splicing substrate of Ire1. The mechanism of Ire1?-mediated RNA-splicing is likely conserved in all eukaryotes as well [4].

Read-Split-Run: an improved bioinformatics pipeline for identification of genome-wide non-canonical spliced regions using RNA-Seq data. Bai Y1,2, Kinne J3, Donham B3, Jiang F3, Ding L4, Hassler JR5, Kaufman RJ BMC Genomics. 17 Suppl 7:503. doi: 10.1186/s12864-016-2896-7.

Complex complexity. Dionisio

Gene regulatory network (GRN), consisting of multiple regulators and their target molecules, plays critical roles in numerous biological processes by modulating the expression levels of RNAs and proteins [...]. While remarkable successes in dissecting single genes that are responsible for certain biological functions, behavior or diseases have been achieved over the past few decades, it has been increasingly recognized that elucidating gene functions and interactions in the context of networks becomes more and more important to gain novel insight into mechanisms, effects and interventions of molecular, cellular or organ-level biological processes [...]

A scalable algorithm for structure identification of complex gene regulatory network from temporal expression data. Gui S, Rice AP, Chen R, Wu L, Liu J, Miao H BMC Bioinformatics. 18(1):74. doi: 10.1186/s12859-017-1489-z.

Complex complexity. Dionisio

Gene regulatory interactions are of fundamental importance to various biological functions and processes. However, only a few previous computational studies have claimed success in revealing genome-wide regulatory landscapes from temporal gene expression data, especially for complex eukaryotes like human.

A scalable algorithm for structure identification of complex gene regulatory network from temporal expression data. Gui S, Rice AP, Chen R, Wu L, Liu J, Miao H BMC Bioinformatics. 18(1):74. doi: 10.1186/s12859-017-1489-z.

Complex complexity. Dionisio

[...] detailed studies on conditional Nfil3 deletion in mature ILC subsets need to be performed in order to fully address this question. [...] NFIL3 is a key regulator of the common-helper-like innate lymphoid precursor [...] [...] cytotoxic ILC development, notably NK cells, also rely on NFIL3 [...] [...] NFIL3 may be required for the early establishment of a common helper- and cytotoxic-ILC lineage progenitor [...] [...] NFIL3 can direct the development of a common cytotoxic and helper ILC precursor [...] Genetic fate-mapping studies, multiparametric reporter lines, and lineage-targeted strategies will be central to further elucidate the existence and the fate of such global innate lymphoid progenitor (GILP) to helper and cytotoxic ILCs [...]

NFIL3 orchestrates the emergence of common helper innate lymphoid cell precursors. Xu W1, Domingues RG2, Fonseca-Pereira D2, Ferreira M2, Ribeiro H2, Lopez-Lastra S1, Motomura Y3, Moreira-Santos L2, Bihl F4, Braud V4, Kee B5, Brady H6, Coles MC7, Vosshenrich C1, Kubo M8, Di Santo JP9, Veiga-Fernandes H10 Cell Rep. 10(12):2043-54. doi: 10.1016/j.celrep.2015.02.057.

Complex complexity. Dionisio

The relationship between ?LP and CHILP is unclear, but it is possible that NFIL3 may act by distinct mechanisms in different ILC precursors. A potent cell-intrinsic role for NFIL3 in the generation of all recognized ILC subsets, including NK cells [...] and ILC1, ILC2, and ILC3 [...] has recently been reported. [...] NFIL3 directly regulated Id2 in CHILP. [...] cytokine-dependent signals may promote stabilization and/or enhancement of NFIL3, which in turn orchestrates the emergence of CHILP via direct Id2 regulation. [...] NFIL3 may also play additional context-dependent roles at later stages of ILC differentiation and for maintenance of effector functions in mature ILC subsets.

NFIL3 orchestrates the emergence of common helper innate lymphoid cell precursors. Xu W1, Domingues RG2, Fonseca-Pereira D2, Ferreira M2, Ribeiro H2, Lopez-Lastra S1, Motomura Y3, Moreira-Santos L2, Bihl F4, Braud V4, Kee B5, Brady H6, Coles MC7, Vosshenrich C1, Kubo M8, Di Santo JP9, Veiga-Fernandes H10 Cell Rep. 10(12):2043-54. doi: 10.1016/j.celrep.2015.02.057.

Did somebody say "orchestrates"? :) Complex complexity. Dionisio

The development of multiple and distinct hematopoietic cell lineages relies on tightly controlled expression of transcription factors that promote lineage specification and commitment while suppressing alternative cell fates. [...] how the emergence of CHILP from CLP is regulated remains elusive. [...] it is not clear how Id2 expression is regulated in lymphoid progenitors (CLP) or how titration and reduction of E-protein activity allows for emergence of CHILP from these cells. [...] the molecular basis for the NFIL3 effect remained unclear. [...] NFIL3 is a critical regulator of the common-helper-like ILC progenitor (CHILP), while being dispensable for overall helper-like ILC fate and maintenance of discrete mature ILC subsets [...] [...] NFIL3 emerges as a central regulator of the common helper ILC precursor in early lymphopoiesis.

NFIL3 orchestrates the emergence of common helper innate lymphoid cell precursors. Xu W1, Domingues RG2, Fonseca-Pereira D2, Ferreira M2, Ribeiro H2, Lopez-Lastra S1, Motomura Y3, Moreira-Santos L2, Bihl F4, Braud V4, Kee B5, Brady H6, Coles MC7, Vosshenrich C1, Kubo M8, Di Santo JP9, Veiga-Fernandes H10 Cell Rep. 10(12):2043-54. doi: 10.1016/j.celrep.2015.02.057.

Complex complexity. Dionisio

#2953 addendum:

The immune system is composed by myriads of cell types and lymphoid organs that ensure immune surveillance and protective immunity. The adaptive immune system [...] consists of B and T lymphocytes that express recombining antigen-specific receptors. Naive T and B cells are activated by their cognate antigen in secondary lymphoid organs and undergo significant cell division and differentiation before exerting their effector function. In contrast, innate lymphocytes display rapid effector functions despite their set of limited germ-line-encoded receptors.

NFIL3 orchestrates the emergence of common helper innate lymphoid cell precursors. Xu W1, Domingues RG2, Fonseca-Pereira D2, Ferreira M2, Ribeiro H2, Lopez-Lastra S1, Motomura Y3, Moreira-Santos L2, Bihl F4, Braud V4, Kee B5, Brady H6, Coles MC7, Vosshenrich C1, Kubo M8, Di Santo JP9, Veiga-Fernandes H10 Cell Rep. 10(12):2043-54. doi: 10.1016/j.celrep.2015.02.057.

Complex complexity. Dionisio

In the developing brain, miR-9 influences gene expression, proliferation, neurogenesis, maturation, migration, and differentiation in a spatiotemporal pattern. There are also feedback loop mechanisms for Tlx, Foxg1, and Foxp1 with miR-9 that regulates cellular events within the developing vertebrate brain. Further studies are required to completely understand the role of miR-9 in vertebrate brain development. [...] miR-9 is necessary for the development of the embryonic brain.

Role of miRNA-9 in Brain Development. Radhakrishnan B, Alwin Prem Anand A J Exp Neurosci. 10:101-120. DOI: 10.4137/JEN.S32843

Complex complexity. Dionisio

MicroRNAs (miRNAs) are a class of small regulatory RNAs involved in gene regulation. The regulation is effected by either translational inhibition or transcriptional silencing. In vertebrates, the importance of miRNA in development was discovered from mice and zebrafish dicer knockouts. The miRNA-9 (miR-9) is one of the most highly expressed miRNAs in the early and adult vertebrate brain. It has diverse functions within the developing vertebrate brain. In vertebrate brain development, miR-9 is involved in regulating several region-specific genes in a spatiotemporal pattern.

Role of miRNA-9 in Brain Development. Radhakrishnan B, Alwin Prem Anand A J Exp Neurosci. 10:101-120. DOI: 10.4137/JEN.S32843

Complex complexity. Dionisio

Innate lymphoid cells (ILCs) are a family of effectors that originate from a common innate lymphoid cell progenitor. However, the transcriptional program that sets the identity of the ILC lineage remains elusive. NFIL3 is a critical regulator of the common helper-like innate lymphoid cell progenitor (CHILP).

NFIL3 orchestrates the emergence of common helper innate lymphoid cell precursors. Xu W1, Domingues RG2, Fonseca-Pereira D2, Ferreira M2, Ribeiro H2, Lopez-Lastra S1, Motomura Y3, Moreira-Santos L2, Bihl F4, Braud V4, Kee B5, Brady H6, Coles MC7, Vosshenrich C1, Kubo M8, Di Santo JP9, Veiga-Fernandes H10 Cell Rep. 10(12):2043-54. doi: 10.1016/j.celrep.2015.02.057.

Complex complexity. Dionisio

Even though NK cells are mainly known as killer cells of the innate immune system, there is more and more evidence that NK cells can shape the adaptive immune system by influencing T cells in different stages of their lifespan. More detailed insight into the detailed mechanisms of DC/NK interaction will be important to tailor T cell immunity in the context of vaccination or toleration. The absence of NK cells induces alterations in the early phase of T cell responses, including direct attack of T cells. The detailed mechanisms of this direct regulation are, however, still being defined. [...] more insights into the regulation of NK receptor ligand expression on activated T cells is required. [...] a more detailed molecular understanding about this shielding process is important. Such knowledge might also be useful to understand whether and how autoreactive T cells can be rendered targets for NK cell attack.

Recognition and Regulation of T Cells by NK Cells. Pallmer K, Oxenius A Front Immunol. 7:251. doi: 10.3389/fimmu.2016.00251

Complex complexity. Dionisio

Regulation of T cell responses by innate lymphoid cells (ILCs) is increasingly documented and studied. Direct or indirect crosstalk between ILCs and T cells early during and after T cell activation can affect their differentiation, polarization, and survival. Natural killer (NK) cells, presenting at a frequency of around 5% in the blood, belong to the family of group 1 innate lymphocytes (ILC1) and are functionally characterized by their cytotoxicity and their ability to produce cytokines, most prominently interferon ? (IFN?). NK cells belong to the innate immune system, and they can react to rapid changes in host cells without prior sensitization.

Recognition and Regulation of T Cells by NK Cells. Pallmer K, Oxenius A Front Immunol. 7:251. doi: 10.3389/fimmu.2016.00251

Complex complexity. Dionisio

[...] it will be important to further investigate the mechanisms by which ILCs prevent or promote T cell responses in various tissues. [...] it will be interesting to unravel whether ILCs can express inhibitory receptors and/or collaborate with Treg cells. [...] a better understanding of the regulation of cytokine expression by ILCs and their interaction with T cells will help to develop new strategies to treat inflammatory diseases in humans.

Maintenance of Immune Homeostasis through ILC/T Cell Interactions. von Burg N, Turchinovich G, Finke D Front Immunol. 6:416. doi: 10.3389/fimmu.2015.00416

Complex complexity. Dionisio

[...] several CD4+ TH cells are often clustering with the same APC, a fact that may increase local cytokine concentrations for optimal cell–cell interactions.

Maintenance of Immune Homeostasis through ILC/T Cell Interactions. von Burg N, Turchinovich G, Finke D Front Immunol. 6:416. doi: 10.3389/fimmu.2015.00416

Do those cells do things for a "purpose"? :) Complex complexity. Dionisio

Considering the fact that the number of ILCs in most tissues is rather low as compared to other immune cells, they appear to have a surprising in vivo impact on immune homeostasis. The localization of ILCs in relatively high density at Ag-entry sites and T cell areas as well as bystander effects on classical DCs might explain this effect.

Maintenance of Immune Homeostasis through ILC/T Cell Interactions. von Burg N, Turchinovich G, Finke D Front Immunol. 6:416. doi: 10.3389/fimmu.2015.00416

Did somebody say "surprising"? :) Complex complexity. Dionisio

Our understanding of immune homeostasis has been challenged by the notion that environmental factors, including commensal bacteria and nutritional components, as well as cholinergic and metabolic signals can regulate immune functions and pro-inflammatory processes. ILCs are important “early sentinel” cells, which connect innate and adaptive immunity by sensing environmental changes, such as infections and inflammation and by the release of immuno-regulatory cytokines.

Maintenance of Immune Homeostasis through ILC/T Cell Interactions. von Burg N, Turchinovich G, Finke D Front Immunol. 6:416. doi: 10.3389/fimmu.2015.00416

Complex complexity. Dionisio

Adaptive immune responses are tightly controlled by the selection of the T and B cell receptor repertoire and by transcriptional networks regulating commitment, expansion, and contraction of the responses. Upon cognate antigen (Ag)–peptide–major histocompatibility complex (MHC) recognition Ag-specific T helper (TH) cells proliferate and differentiate into effector TH cell subsets with distinguishable cytokine profiles. In the past 5 years, new subsets of innate immune cells have emerged as a first line of defense at mucosal barriers. Like conventional natural killer (cNK) cells, they belong to the lymphoid lineage and develop from common lymphoid progenitor (CLP) cells but unlike T and B cells, they lack rearranged Ag-receptors. Hence, they were termed innate lymphoid cells (ILCs).

Maintenance of Immune Homeostasis through ILC/T Cell Interactions. von Burg N, Turchinovich G, Finke D Front Immunol. 6:416. doi: 10.3389/fimmu.2015.00416

Complex complexity. Dionisio

Both ILC2s and ILC3s are able to process and present foreign antigens (Ags) via major histocompatibility complex class II, and to induce cognate CD4(+) T cell responses. In addition, Ag-stimulated T cells promote ILC activation and effector functions indicating a reciprocal interaction between the adaptive and innate immune system. A fundamental puzzle in ILC function is how ILC/T cell interactions promote host protection and prevent autoimmune diseases. Furthermore, the way in which microenvironmental and inflammatory signals determine the outcome of ILC/T cell immune responses in various tissues is not yet understood.

Maintenance of Immune Homeostasis through ILC/T Cell Interactions. von Burg N, Turchinovich G, Finke D Front Immunol. 6:416. doi: 10.3389/fimmu.2015.00416

Did somebody say "fundamental puzzle"? :) Complex complexity. Dionisio

Innate lymphoid cells (ILCs) have emerged as a new family of immune cells with crucial functions in innate and adaptive immunity. ILC subsets mirror the cytokine and transcriptional profile of CD4(+) T helper (TH) cell subsets. Hence, group 1 (ILC1), group 2 (ILC2), and group 3 (ILC3) ILCs can be distinguished by the production of TH1, TH2, and TH17-type cytokines, respectively. Cytokine release by ILCs not only shapes early innate immunity but can also orchestrate TH immune responses to microbial or allergen exposure.

Maintenance of Immune Homeostasis through ILC/T Cell Interactions. von Burg N, Turchinovich G, Finke D Front Immunol. 6:416. doi: 10.3389/fimmu.2015.00416

Did somebody say "orchestrate"? :) Complex complexity. Dionisio

The discovery of the ILCs in recent years together with a deeper understanding of their biology has led to a major paradigm shift in the study of immunity and hematopoiesis. Many of the transcription factors that programme TH cell differentiation are also conserved in the ILCs but the cues for switching them on, and when they can be replaced or substituted by another transcription factor are not completely understood. These aspects of ILC development form exciting research questions for future investigation.

Deciphering the transcriptional switches of innate lymphoid cell programming: the right factors at the right time. Lim AW, McKenzie AN Genes Immun. 16(3):177-86. doi: 10.1038/gene.2014.83.

Did somebody say “major paradigm shift”? Complex complexity. Dionisio

Transcriptional programming of immune cell fate and lineage specificity is essential for the commitment and development of the hematopoietic system. Innate lymphoid cells (ILCs) are increasingly recognised as an innate immune counterpart of adaptive TH cells. Natural killer cells, which are the cytotoxic ILCs, develop along a pathway distinct from the rest of the helper-like ILCs that are derived from a common progenitor to all helper-like innate lymphoid cells (CHILPs). PLZF? CHILPs give rise to lymphoid tissue inducer cells while PLZF+ CHILPs have multi-lineage potential and could give rise to ILCs 1, 2 and 3. Such lineage specificity is dictated by the controlled expression of T-bet, ROR?, ROR?t and AHR. In addition to the type of transcription factors, the developmental stages at which these factors are expressed are crucial in specifying the fate of the ILCs.

Deciphering the transcriptional switches of innate lymphoid cell programming: the right factors at the right time. Lim AW, McKenzie AN Genes Immun. 16(3):177-86. doi: 10.1038/gene.2014.83.

Did somebody say “programming”? Complex complexity. Dionisio

Surprisingly, we found that the loss of NFIL3 function in cells expressing ID2 did not significantly affect the subsequent development of ILC subsets. Collectively, our data establish a genome-wide transcriptional blueprint of the different ILC progenitors and uncover potentially important transcriptional regulators that are likely to reveal key insights into ILC development and interactions with other immune cells in the tissue.

Deciphering the Innate Lymphoid Cell Transcriptional Program. Seillet C, Mielke LA, Amann-Zalcenstein DB, Su S, Gao J, Almeida FF, Shi W, Ritchie ME, Naik SH, Huntington ND, Carotta S, Belz GT Cell Rep. 17(2):436-447. doi: 10.1016/j.celrep.2016.09.025.

Did somebody say "surprisingly"? Complex complexity. Dionisio

Innate lymphoid cells (ILCs) are enriched at mucosal surfaces and sense inflammatory signals to provide protection from mechanical and pathogenic insults through rapid secretion of cytokines. They develop initially from progenitors in the fetal liver [...] later, in the adult bone marrow (BM) [...] [...] exactly how the molecular cues of each of these factors are integrated and drive commitment remains unclear. Collectively, we define the transcriptional landscape of ILC precursors and provide insight into the interplay of transcription factors, particularly the hierarchical interactions, among Id2, Nfil3, and Tcf7 utilized by progenitor cells to generate ILC populations.

Deciphering the Innate Lymphoid Cell Transcriptional Program. Seillet C, Mielke LA, Amann-Zalcenstein DB, Su S, Gao J, Almeida FF, Shi W, Ritchie ME, Naik SH, Huntington ND, Carotta S, Belz GT Cell Rep. 17(2):436-447. doi: 10.1016/j.celrep.2016.09.025.

Complex complexity. Dionisio

Innate lymphoid cells (ILCs) are enriched at mucosal surfaces, where they provide immune surveillance. All ILC subsets develop from a common progenitor that gives rise to pre-committed progenitors for each of the ILC lineages. Currently, the temporal control of gene expression that guides the emergence of these progenitors is poorly understood. [...] the timing and order of expression of the transcription factors NFIL3, ID2, and TCF-1 was critical. [...] induction of ILC lineage commitment required only transient expression of NFIL3 prior to ID2 and TCF-1 expression. These findings highlight the importance of the temporal program that permits commitment of progenitors to the ILC lineage, and they expand our understanding of the core transcriptional program by identifying potential regulators of ILC development.

Deciphering the Innate Lymphoid Cell Transcriptional Program. Seillet C, Mielke LA, Amann-Zalcenstein DB, Su S, Gao J, Almeida FF, Shi W, Ritchie ME, Naik SH, Huntington ND, Carotta S, Belz GT Cell Rep. 17(2):436-447. doi: 10.1016/j.celrep.2016.09.025.

Complex complexity. Dionisio

Group 2 innate lymphoid cells (ILC2s) are a recently identified group of cells with the potent capability to produce Th2-type cytokines such as interleukin (IL)-5 and IL-13. Altogether, these new findings uncover iTregs as potent regulators of ILC2 activation and implicate their utility as a therapeutic approach for the treatment of ILC2-mediated allergic asthma and respiratory disease.

Regulatory T cells and type 2 innate lymphoid cell-dependent asthma J. L. Aron, O. Akbari DOI: 10.1111/all.13139View European Journal of Allergy and Clinical Immunology http://onlinelibrary.wiley.com/doi/10.1111/all.13139/full

This is a very interesting example of the translation of biology research discoveries to clinical applications in more effective precise personalized treatments. BTW, had we remained in Eden, none of this would have been an issue. Oh, well. Too late now. Complex complexity. Dionisio

Taken together, these observations reveal the potential for novel mechanisms of ILC2 and ILC3 cell activation under inflammatory conditions. In summary, this study provides a global, comprehensive, and detailed description of human heterogeneity in ILCs across patients, tissues, in non-pathological conditions, and within various pathological environments. Despite a homology with mice, our study highlights the uniqueness of human ILCs in terms of their composition, phenotypes, and heterogeneity.

Human Innate Lymphoid Cell Subsets Possess Tissue-Type Based Heterogeneity in Phenotype and Frequency Yannick Simoni'Correspondence information about the author Yannick SimoniEmail the author Yannick Simoni, Michael Fehlings, Henrik N. Kløverpris, Naomi McGovern, Si-Lin Koo, Chiew Yee Loh, Shawn Lim, Ayako Kurioka, Joannah R. Fergusson, Choong-Leong Tang, Ming Hian Kam, Koh Dennis, Tony Kiat Hon Lim, Alexander Chung Yaw Fui, Chan Weng Hoong, Jerry Kok Yen Chan, Maria Curotto de Lafaille, Sriram Narayanan, Sonia Baig, Muhammad Shabeer, Sue-Anne Ee Shiow Toh, Henry Kun Kiaang Tan, Rosslyn Anicete, Eng-Huat Tan, Angela Takano, Paul Klenerman, Alasdair Leslie, Daniel S.W. Tan, Iain Beehuat Tan, Florent Ginhoux, Evan W. Newell DOI: 10.1016/j.immuni.2016.11.005 Immunity, Volume 46, Issue 1, p148–161

Did somebody say "uniqueness of human [...]"? :) Complex complexity. Dionisio

Across all tissues studied, we were unable to clearly detect MHC II expression by ILCs. As compared to mice, this observation can be explained by different molecular mechanisms regulating MHCII expression in humans [...] [...] MHC II expression on ILCs is restricted to some specific inflammatory conditions.

Human Innate Lymphoid Cell Subsets Possess Tissue-Type Based Heterogeneity in Phenotype and Frequency Yannick Simoni'Correspondence information about the author Yannick SimoniEmail the author Yannick Simoni, Michael Fehlings, Henrik N. Kløverpris, Naomi McGovern, Si-Lin Koo, Chiew Yee Loh, Shawn Lim, Ayako Kurioka, Joannah R. Fergusson, Choong-Leong Tang, Ming Hian Kam, Koh Dennis, Tony Kiat Hon Lim, Alexander Chung Yaw Fui, Chan Weng Hoong, Jerry Kok Yen Chan, Maria Curotto de Lafaille, Sriram Narayanan, Sonia Baig, Muhammad Shabeer, Sue-Anne Ee Shiow Toh, Henry Kun Kiaang Tan, Rosslyn Anicete, Eng-Huat Tan, Angela Takano, Paul Klenerman, Alasdair Leslie, Daniel S.W. Tan, Iain Beehuat Tan, Florent Ginhoux, Evan W. Newell DOI: 10.1016/j.immuni.2016.11.005 Immunity, Volume 46, Issue 1, p148–161

Humans have different molecular regulatory mechanisms for equivalent genetic expression? Hmm... interesting. This may help: https://ghr.nlm.nih.gov/primer/genefamily/hla Complex complexity. Dionisio

[...] human tissues can be divided into two categories based on their overall ILC subsets composition. [...] ILC2 cells found in cord blood are functionally similar to ILC2 cells derived from adult blood when stimulated with IL-33. In contrast to non-mucosal and lung tissues, oral and gastrointestinal mucosal and skin tissues contained high frequencies of helper-type ILCs [...] [...] observations about helper type ILC phenotypes could be considered as additional targets for therapeutics approaches.

Human Innate Lymphoid Cell Subsets Possess Tissue-Type Based Heterogeneity in Phenotype and Frequency Yannick Simoni'Correspondence information about the author Yannick SimoniEmail the author Yannick Simoni, Michael Fehlings, Henrik N. Kløverpris, Naomi McGovern, Si-Lin Koo, Chiew Yee Loh, Shawn Lim, Ayako Kurioka, Joannah R. Fergusson, Choong-Leong Tang, Ming Hian Kam, Koh Dennis, Tony Kiat Hon Lim, Alexander Chung Yaw Fui, Chan Weng Hoong, Jerry Kok Yen Chan, Maria Curotto de Lafaille, Sriram Narayanan, Sonia Baig, Muhammad Shabeer, Sue-Anne Ee Shiow Toh, Henry Kun Kiaang Tan, Rosslyn Anicete, Eng-Huat Tan, Angela Takano, Paul Klenerman, Alasdair Leslie, Daniel S.W. Tan, Iain Beehuat Tan, Florent Ginhoux, Evan W. Newell DOI: 10.1016/j.immuni.2016.11.005 Immunity, Volume 46, Issue 1, p148–161

Complex complexity. Dionisio

[...] a large number of markers was required for this detailed and accurate characterization of putative ILC1 cells [...] [...] it might be possible that previous identifications of human ILC1 cells comprised cellular contaminations, which could not be excluded due to technical limitations.

Human Innate Lymphoid Cell Subsets Possess Tissue-Type Based Heterogeneity in Phenotype and Frequency Yannick Simoni'Correspondence information about the author Yannick SimoniEmail the author Yannick Simoni, Michael Fehlings, Henrik N. Kløverpris, Naomi McGovern, Si-Lin Koo, Chiew Yee Loh, Shawn Lim, Ayako Kurioka, Joannah R. Fergusson, Choong-Leong Tang, Ming Hian Kam, Koh Dennis, Tony Kiat Hon Lim, Alexander Chung Yaw Fui, Chan Weng Hoong, Jerry Kok Yen Chan, Maria Curotto de Lafaille, Sriram Narayanan, Sonia Baig, Muhammad Shabeer, Sue-Anne Ee Shiow Toh, Henry Kun Kiaang Tan, Rosslyn Anicete, Eng-Huat Tan, Angela Takano, Paul Klenerman, Alasdair Leslie, Daniel S.W. Tan, Iain Beehuat Tan, Florent Ginhoux, Evan W. Newell DOI: 10.1016/j.immuni.2016.11.005 Immunity, Volume 46, Issue 1, p148–161

Complex complexity. Dionisio

[...] helper-type ILCs can be subdivided into three main groups analogous to the main subsets of T helper lymphocytes. ILC1 cells can produce T helper-1 (Th1) cell signature cytokines (i.e., IFN-g) and express the transcription factor T-bet [...] ILC2 cells are capable of secreting Th2 cell-type cytokines and display aGATA3+ phenotype. ILC3 cells have been shown to be associated with interleukin-17 (IL-17) and IL-22 production, as well as RORgt transcription factor expression, characteristic of Th17 helper T cells [...] [...] similar to ILC2 cells, ILC3 cells express CD127 (IL-7R), which is crucial for their development and survival [...]

Human Innate Lymphoid Cell Subsets Possess Tissue-Type Based Heterogeneity in Phenotype and Frequency Yannick Simoni'Correspondence information about the author Yannick SimoniEmail the author Yannick Simoni, Michael Fehlings, Henrik N. Kløverpris, Naomi McGovern, Si-Lin Koo, Chiew Yee Loh, Shawn Lim, Ayako Kurioka, Joannah R. Fergusson, Choong-Leong Tang, Ming Hian Kam, Koh Dennis, Tony Kiat Hon Lim, Alexander Chung Yaw Fui, Chan Weng Hoong, Jerry Kok Yen Chan, Maria Curotto de Lafaille, Sriram Narayanan, Sonia Baig, Muhammad Shabeer, Sue-Anne Ee Shiow Toh, Henry Kun Kiaang Tan, Rosslyn Anicete, Eng-Huat Tan, Angela Takano, Paul Klenerman, Alasdair Leslie, Daniel S.W. Tan, Iain Beehuat Tan, Florent Ginhoux, Evan W. Newell DOI: 10.1016/j.immuni.2016.11.005 Immunity, Volume 46, Issue 1, p148–161

Complex complexity. Dionisio

[...] human ILCs are highly heterogeneous cell types between individuals and tissues. Innate lymphoid cells (ILCs) represent a heterogeneous population of innate immune cells in mice and humans that include classically defined natural killer (NK) cells as well as more recently described helper-type ILCs (ILC1, ILC2, and ILC3). In contrast to T- and B-lymphocytes, ILCs lack somatic rearrangement of antigen receptors (e.g., TCR,BCR), and can be activated by cytokines and/or through natural cytotoxicity receptors (e.g., NKp44) [...] In contrast to NK cells, helper-type ILCs do not possess efficient cytotoxic capacity [...]

Human Innate Lymphoid Cell Subsets Possess Tissue-Type Based Heterogeneity in Phenotype and Frequency Yannick Simoni'Correspondence information about the author Yannick SimoniEmail the author Yannick Simoni, Michael Fehlings, Henrik N. Kløverpris, Naomi McGovern, Si-Lin Koo, Chiew Yee Loh, Shawn Lim, Ayako Kurioka, Joannah R. Fergusson, Choong-Leong Tang, Ming Hian Kam, Koh Dennis, Tony Kiat Hon Lim, Alexander Chung Yaw Fui, Chan Weng Hoong, Jerry Kok Yen Chan, Maria Curotto de Lafaille, Sriram Narayanan, Sonia Baig, Muhammad Shabeer, Sue-Anne Ee Shiow Toh, Henry Kun Kiaang Tan, Rosslyn Anicete, Eng-Huat Tan, Angela Takano, Paul Klenerman, Alasdair Leslie, Daniel S.W. Tan, Iain Beehuat Tan, Florent Ginhoux, Evan W. Newell DOI: 10.1016/j.immuni.2016.11.005 Immunity, Volume 46, Issue 1, p148–161

Complex complexity. Dionisio

Integration of the accumulating knowledge on microbial community structure in different disease scenarios with the corresponding changes in the metabolome and its bioactivity may enable addressing fundamental questions regarding the molecular mechanisms by which the microbiome impacts physiology, pathophysiology and even its own community function

Microbiome-Modulated Metabolites at the Interface of Host Immunity Eran Blacher, Maayan Levy, Evgeny Tatirovsky and Eran Elinav DOI: 10.4049/jimmunol.1601247 J Immunol 2017; 198:572-580 http://www.jimmunol.org/content/198/2/572

Complex complexity. Dionisio

[...] the mechanisms through which commensal bacteria regulate host immunity remain unclear and merit future investigation. [...] further investigation is required to determine the repertoire, bio-geographical distribution, and bioactivity of metabolites in the gastrointestinal tract and how it may impact local and systemic inflammatory processes.

Microbiome-Modulated Metabolites at the Interface of Host Immunity Eran Blacher, Maayan Levy, Evgeny Tatirovsky and Eran Elinav DOI: 10.4049/jimmunol.1601247 J Immunol 2017; 198:572-580 http://www.jimmunol.org/content/198/2/572

Complex complexity. Dionisio

The gut microbiome is a microbial ecosystem that has diverse effects on physiological host functions, particularly immune development and activity. The molecular basis of host-microbiome interactions is only just beginning to be unraveled, and is mediated by both cell to cell interactions and the production, modification, and sensing of a large variety of bioactive small molecules, termed metabolites. Some microbiome-associated metabolites are bioactive and affect the host cellular processes [...] A number of metabolites impact mucosal and systemic immune maturation and function [...]

Microbiome-Modulated Metabolites at the Interface of Host Immunity Eran Blacher, Maayan Levy, Evgeny Tatirovsky and Eran Elinav DOI: 10.4049/jimmunol.1601247 J Immunol 2017; 198:572-580 http://www.jimmunol.org/content/198/2/572

Complex complexity. Dionisio

[...] little is known about the genes required for intestinal colonization and exploitation of nutrients by some of the pathogens that colonize the intestinal tract. Further studies in this area are necessary in order to fully clarify how certain pathogens are able to invade the intestinal tract and the mechanisms by which key members of the microbiota outcompete them.

Roles of the intestinal microbiota in pathogen protection Carles Ubeda, Ana Djukovic and Sandrine Isaac Clinical & Translational Immunology (2017) 6, e128; doi:10.1038/cti.2017.2

Work in progress... stay tuned. Complex complexity. Dionisio

[...] the microbiota can confer protection to pathogens through mechanisms that do not require the induction of the immune system. These mechanisms include the production of molecules that inhibit the growth of the pathogen or that interfere with their colonization capabilities. Further analysis of new subsets of metagenomic sequences, in combination with in vitro and in vivo experiments, should therefore expand our knowledge of bacterial derived molecules that can directly influence pathogen colonization capabilities. [...] a greater understanding of the biology of commensals and pathogens is required to identify novel mechanisms of protection.

Roles of the intestinal microbiota in pathogen protection Carles Ubeda, Ana Djukovic and Sandrine Isaac Clinical & Translational Immunology (2017) 6, e128; doi:10.1038/cti.2017.2

Work in progress... stay tuned. Complex complexity. Dionisio

The molecular mechanisms involved in the interaction between commensals and immune responses against pathogens are starting to be understood. [...] the type of diet consumed by the host can play an important role in the defense against infections, a field that requires further investigation.

Roles of the intestinal microbiota in pathogen protection Carles Ubeda, Ana Djukovic and Sandrine Isaac Clinical & Translational Immunology (2017) 6, e128; doi:10.1038/cti.2017.2

Work in progress... stay tuned. Complex complexity. Dionisio

Commensal microbes that colonize the gut can also have systemic effects on immunity, including the activation of neutrophils, induction of IgG responses and enhancement of myelopoiesis. The key commensal bacteria involved in the induction of the different components of the immune system are now starting to be identified, [...] [...] future research using mouse models may elucidate the impact of these novel cultivable bacterial species on the immune system and defense against infections.

Roles of the intestinal microbiota in pathogen protection Carles Ubeda, Ana Djukovic and Sandrine Isaac Clinical & Translational Immunology (2017) 6, e128; doi:10.1038/cti.2017.2

Work in progress... stay tuned. Complex complexity. Dionisio

Commensal microbes that inhabit the gastrointestinal tract are essential for the proper development and functionality of multiple immune cell types. [...] novel subtypes of ILCs have recently been discovered, although their role in defense against infections and how commensal microbes influence their functionality has yet to be defined. It is expected that novel interactions between the intestinal immune system, the microbiota and the pathogen will be discovered in the next few years.

Roles of the intestinal microbiota in pathogen protection Carles Ubeda, Ana Djukovic and Sandrine Isaac Clinical & Translational Immunology (2017) 6, e128; doi:10.1038/cti.2017.2

Complex complexity. Dionisio

Although the host has developed numerous strategies to avoid infections, some pathogens, such as Salmonella, are able to outcompete commensal microbes by exploiting host immune responses. [...] therapies based on the microbiota have started to be applied in the clinical setting with extremely high success. This is the case of fecal transplants utilized for treating C. difficile infections. Although such transplants seem to be very efficient in eliminating certain pathogens, they are not free of risk. Therefore, alternative approaches, including the administration of specific microbes or bacterial-derived molecules, are desirable in order to diminish the appearance of negative side effects. Administration of specific microbes has been proven to confer protection against infections. [...] administration of single or multiple bacteria could be an efficient method for conferring resistance against infections. As an alternative to the ‘probiotic’-based approach, direct administration of bacterial-derived products is proven to be effective in restricting intestinal colonization by pathogens. [...] inoculation of bacterial-derived products that activate certain components of the immune system has also been tested with success. [...] deficits in the immune response caused by antibiotic disruption of the microbiota can be restored by administration of bacterial products.

Roles of the intestinal microbiota in pathogen protection Carles Ubeda, Ana Djukovic and Sandrine Isaac Clinical & Translational Immunology (2017) 6, e128; doi:10.1038/cti.2017.2

Complex complexity. Dionisio

Microbiota induction of the adaptive arm of the immune system, including B cells and T cells, plays a central role in the defense against intestinal pathogens in the gastrointestinal tract. Within the intestinal tract, two major T-cell subsets with very different functions are greatly influenced by commensal microbes [...] [...] the intestinal microbiota influences B-cell development and antibody production.

Roles of the intestinal microbiota in pathogen protection Carles Ubeda, Ana Djukovic and Sandrine Isaac Clinical & Translational Immunology (2017) 6, e128; doi:10.1038/cti.2017.2

Complex complexity. Dionisio

Beneath the epithelium, several specialized innate immune cells are necessary to create an adequate response against intestinal pathogens. Within these cells, ILCs represent the most recently identified arm of the innate immune system, which is crucial for defense against intestinal pathogens. [...] the microbiota has an impact on both the relative abundance of different ILC types and their expression. [...] the three ILC types produce different cytokines and consequently have been implicated in protection against different pathogens. [...] different ILCs confer protection against different pathogens and the microbiota influences ILC functionality. The intestinal microbiota is also required for the proper development and functionality of myeloid cells. [...] contrary microbiota effects through induction of different innate immune cells (i.e. activation of pro-inflammatory neutrophils or regulatory monocytes) are required to counteract infections.

Roles of the intestinal microbiota in pathogen protection Carles Ubeda, Ana Djukovic and Sandrine Isaac Clinical & Translational Immunology (2017) 6, e128; doi:10.1038/cti.2017.2

Complex complexity. Dionisio

Underneath the mucus lies the intestinal epithelium, which is composed of different cell types [...] The intestinal epithelium constitutes the second barrier separating the intestinal microbial ecosystem from the largely sterile underlying tissue. This layer of cells not only constitutes a physical barrier but is also able to synthetize and secrete antimicrobial peptides, which are essential for inhibiting pathogen colonization and for restraining commensal microbes from coming into direct contact with the epithelium. In addition to antimicrobial peptide induction, specific commensal strains can confer resistance to infection by decreasing intestinal permeability to bacterial toxins.

Roles of the intestinal microbiota in pathogen protection Carles Ubeda, Ana Djukovic and Sandrine Isaac Clinical & Translational Immunology (2017) 6, e128; doi:10.1038/cti.2017.2

Complex complexity. Dionisio

The intestinal tract is home to hundreds of bacterial species, referred to collectively as the intestinal microbiota. [...] consumption of dietary nutrients by commensals can confer protection to infections, but certain pathogens exploit products derived from the microbiota metabolism to invade the gut. The layer of mucus that covers the intestinal tract epithelium can be considered the first line of host defense against pathogens.

Roles of the intestinal microbiota in pathogen protection Carles Ubeda, Ana Djukovic and Sandrine Isaac Clinical & Translational Immunology (2017) 6, e128; doi:10.1038/cti.2017.2

Complex complexity. Dionisio

Hundreds of commensal bacterial species inhabit the gastrointestinal tract. This diverse microbial ecosystem plays a crucial role in the prevention and resolution of infectious diseases.

Roles of the intestinal microbiota in pathogen protection Carles Ubeda, Ana Djukovic and Sandrine Isaac Clinical & Translational Immunology (2017) 6, e128; doi:10.1038/cti.2017.2

Complex complexity. Dionisio

[...] proper transcriptional regulation of the ILC- microbiota crosstalk may play critical roles in preservation of a healthy intestinal microenvironment, while preventing auto-inflammatory disorders, some of which involve aberrant ILC3 activity [...] [...] studies of ILC subsets in other tissues from both mice and humans, and in response to various environmental perturbations, have the potential to define new markers, regulatory regions, targets, and pathways perturbed across a wide range of diseases, with prospective for therapeutic intervention.

The Spectrum and Regulatory Landscape of Intestinal Innate Lymphoid Cells Are Shaped by the Microbiome Meital Gury-BenAri, Christoph A. Thaiss, Nicolas Serafini, Deborah R. Winter, Amir Giladi, David Lara-Astiaso, Maayan Levy, Tomer Meir Salame, Assaf Weiner, Eyal David, Hagit Shapiro, Mally Dori-Bachash, Meirav Pevsner-Fischer, Erika Lorenzo-Vivas, Hadas Keren-Shaul, Franziska Paul, Alon Harmelin, Gérard Eberl, Shalev Itzkovitz DOI: 10.1016/j.cell.2016.07.043 Cell, Volume 166, Issue 5, Pages 1231–1246.e13 2016 Elsevier Inc.

Work in progress... stay tuned. Complex complexity. Dionisio

[...] homeostatic commensal colonization may suppress the regulatory elements involved in ILC3 fate determination and the execution of the associated transcriptional program [...]

The Spectrum and Regulatory Landscape of Intestinal Innate Lymphoid Cells Are Shaped by the Microbiome Meital Gury-BenAri, Christoph A. Thaiss, Nicolas Serafini, Deborah R. Winter, Amir Giladi, David Lara-Astiaso, Maayan Levy, Tomer Meir Salame, Assaf Weiner, Eyal David, Hagit Shapiro, Mally Dori-Bachash, Meirav Pevsner-Fischer, Erika Lorenzo-Vivas, Hadas Keren-Shaul, Franziska Paul, Alon Harmelin, Gérard Eberl, Shalev Itzkovitz DOI: 10.1016/j.cell.2016.07.043 Cell, Volume 166, Issue 5, Pages 1231–1246.e13 2016 Elsevier Inc.

Did somebody say "program"? :) Complex complexity. Dionisio

[...] temporal and spatial dynamics of marker gene expression not captured by our analysis might constitute another layer of regulation that can be resolved by longitudinal application of the technologies presented here [...] [...] the responsiveness of ILCs to the microbiota is highly heterogeneous, even within the defined subsets. Integration of all three levels of genomic assessment—population transcriptomics, population epigenetics, and single-cell transcriptomics— point toward an unexpected phenomenon, namely, the acquisition of ILC3-like expression profiles across multiple subsets upon depletion of the microbiota.

The Spectrum and Regulatory Landscape of Intestinal Innate Lymphoid Cells Are Shaped by the Microbiome Meital Gury-BenAri, Christoph A. Thaiss, Nicolas Serafini, Deborah R. Winter, Amir Giladi, David Lara-Astiaso, Maayan Levy, Tomer Meir Salame, Assaf Weiner, Eyal David, Hagit Shapiro, Mally Dori-Bachash, Meirav Pevsner-Fischer, Erika Lorenzo-Vivas, Hadas Keren-Shaul, Franziska Paul, Alon Harmelin, Gérard Eberl, Shalev Itzkovitz DOI: 10.1016/j.cell.2016.07.043 Cell, Volume 166, Issue 5, Pages 1231–1246.e13 2016 Elsevier Inc.

Did somebody say "unexpected"? :) Complex complexity. Dionisio

[...] several fundamental questions of ILC physiology have remained unsolved. The mechanisms by which ILCs perform this integration task are poorly understood. [...] ILCs evaluate the state of microbial colonization by adjusting the enhancer landscape and the accessibility of transcription factor-binding sites within the chromatin architecture [...] [...] the elucidation of functional crosstalk between these pathways and ILC function will present an exciting area of future study. Elucidating the role of within-tissue distribution, cell-cell interactions, exposure to soluble mediators, and response to luminal metabolites on these transcriptional clusters awaits further study.

The Spectrum and Regulatory Landscape of Intestinal Innate Lymphoid Cells Are Shaped by the Microbiome Meital Gury-BenAri, Christoph A. Thaiss, Nicolas Serafini, Deborah R. Winter, Amir Giladi, David Lara-Astiaso, Maayan Levy, Tomer Meir Salame, Assaf Weiner, Eyal David, Hagit Shapiro, Mally Dori-Bachash, Meirav Pevsner-Fischer, Erika Lorenzo-Vivas, Hadas Keren-Shaul, Franziska Paul, Alon Harmelin, Gérard Eberl, Shalev Itzkovitz DOI: 10.1016/j.cell.2016.07.043 Cell, Volume 166, Issue 5, Pages 1231–1246.e13 2016 Elsevier Inc.

Complex complexity. Dionisio

Innate lymphoid cells (ILCs) are the most recently discovered arm of the innate immune system, consisting of cytotoxic cells (NK cells) and ‘‘helper-like’’ ILCs [...] [...] whether these findings represent general plasticity between ILC subsets and whether additional subsets exist that are lacking equivalent T cell counterparts remains unknown.

The Spectrum and Regulatory Landscape of Intestinal Innate Lymphoid Cells Are Shaped by the Microbiome Meital Gury-BenAri, Christoph A. Thaiss, Nicolas Serafini, Deborah R. Winter, Amir Giladi, David Lara-Astiaso, Maayan Levy, Tomer Meir Salame, Assaf Weiner, Eyal David, Hagit Shapiro, Mally Dori-Bachash, Meirav Pevsner-Fischer, Erika Lorenzo-Vivas, Hadas Keren-Shaul, Franziska Paul, Alon Harmelin, Gérard Eberl, Shalev Itzkovitz DOI: 10.1016/j.cell.2016.07.043 Cell, Volume 166, Issue 5, Pages 1231–1246.e13 2016 Elsevier Inc.

Complex complexity. Dionisio

Innate lymphoid cells (ILCs) are critical modulators of mucosal immunity, inflammation, and tissue homeostasis, but their full spectrum of cellular states and regulatory landscapes remains elusive. [...] ILCs differentially integrate signals from the microbial microenvironment to generate phenotypic and functional plasticity.

The Spectrum and Regulatory Landscape of Intestinal Innate Lymphoid Cells Are Shaped by the Microbiome Meital Gury-BenAri, Christoph A. Thaiss, Nicolas Serafini, Deborah R. Winter, Amir Giladi, David Lara-Astiaso, Maayan Levy, Tomer Meir Salame, Assaf Weiner, Eyal David, Hagit Shapiro, Mally Dori-Bachash, Meirav Pevsner-Fischer, Erika Lorenzo-Vivas, Hadas Keren-Shaul, Franziska Paul, Alon Harmelin, Gérard Eberl, Shalev Itzkovitz DOI: 10.1016/j.cell.2016.07.043 Cell, Volume 166, Issue 5, Pages 1231–1246.e13 2016 Elsevier Inc.

Complex complexity. Dionisio

This result reflected earlier findings that ILC and T cell subclasses produce similar sets of cytokines, but also revealed differences in how the two cell types control the activities of these key immune response genes. While the regulatory landscapes of ILCs are primed for a quick defense upon infection, those of T cells are minimally prepared when the pathogen invades. Only following infection are modifications in the landscape made that enable T cells to launch their attack. “ILCs and T cells appear very different, but in the end, the way they control key responses is amazingly similar,” said Han-Yu Shih, Ph.D., a post-doctoral fellow at NIAMS.

Rapid-response immune cells are fully prepared before invasion strikes https://www.nih.gov/news-events/news-releases/rapid-response-immune-cells-are-fully-prepared-before-invasion-strikes Shih et al., Developmental Acquisition of Regulomes Underlies Innate Lymphoid Cell Functionality, Cell (2016), http://dx.doi.org/10.1016/j.cell.2016.04.029

Did somebody say "amazingly"? :) Complex complexity. Dionisio

[...] each subclass of ILCs is associated with a distinct pattern of accessible regions. These patterns can be viewed as a type of barcode for each subclass. [...] ILCs acquire their barcodes in a stepwise manner over the course of cellular development. [...] the barcodes are in place in ILCs before they encounter infection. This open, accessible configuration surrounding the switches that control cytokine genes may be instrumental in enabling ILCs to rapidly launch an assault upon infection. [...] many of the DNA regions controlling cytokine genes in the mice’s T cells are inaccessible and silenced prior to exposure to a pathogen. But upon infection, T cells adopted barcodes similar to those of their ILC counterparts.

Rapid-response immune cells are fully prepared before invasion strikes https://www.nih.gov/news-events/news-releases/rapid-response-immune-cells-are-fully-prepared-before-invasion-strikes Shih et al., Developmental Acquisition of Regulomes Underlies Innate Lymphoid Cell Functionality, Cell (2016), http://dx.doi.org/10.1016/j.cell.2016.04.029

Complex complexity. Dionisio

Part of what makes each cell type unique is its distinctive pattern of DNA structure and regulatory factors. The combination of a stretch of DNA and a set of regulatory factors can be thought of as a switch — it helps determine whether a gene is turned off (inactive) or on (active). Inactive regions of DNA are twisted into tight coils, whereas active regions are open and accessible to the cellular machinery that reads the genetic information. The open portions of the genome include genes themselves, as well as many regions that contribute to the regulation of their activities (the switches). The areas of the genome and the factors that control whether or not the information is read, in total, are referred to as the cell’s regulome.

Rapid-response immune cells are fully prepared before invasion strikes https://www.nih.gov/news-events/news-releases/rapid-response-immune-cells-are-fully-prepared-before-invasion-strikes Shih et al., Developmental Acquisition of Regulomes Underlies Innate Lymphoid Cell Functionality, Cell (2016), http://dx.doi.org/10.1016/j.cell.2016.04.029

Complex complexity. Dionisio

[...] the development of immune cells, called innate lymphoid cells (ILCs), gradually prepares these cells for rapid response to infection. “ILCs are coming into the spotlight because they appear to have a critical role in defending the body’s barrier regions, such as the skin, lungs, and gut, where microbes must first pass to make their way into the body.” - John J. O’Shea, M.D., scientific director of NIAMS.

Rapid-response immune cells are fully prepared before invasion strikes https://www.nih.gov/news-events/news-releases/rapid-response-immune-cells-are-fully-prepared-before-invasion-strikes Shih et al., Developmental Acquisition of Regulomes Underlies Innate Lymphoid Cell Functionality, Cell (2016), http://dx.doi.org/10.1016/j.cell.2016.04.029

Complex complexity. Dionisio

Our immune system has two arms — innate and adaptive. ILCs are innate immune cells that respond quickly against pathogens at the first site of invasion. They release small molecules called cytokines that transmit signals to fight infection. The adaptive immune response kicks in more slowly to build an army of cells that can target specific offending pathogens. T cells, especially helper T cells, are a key part of the adaptive immune system. They produce different cytokines depending upon the type of pathogen they are trying to combat.

Rapid-response immune cells are fully prepared before invasion strikes https://www.nih.gov/news-events/news-releases/rapid-response-immune-cells-are-fully-prepared-before-invasion-strikes Shih et al., Developmental Acquisition of Regulomes Underlies Innate Lymphoid Cell Functionality, Cell (2016), http://dx.doi.org/10.1016/j.cell.2016.04.029

Complex complexity. Dionisio

The human microbiota plays an important role in the wellbeing of the human host, and participates actively in the development of a wide variety of diseases. From the structure to the function of the microbiota, future research should move microbiome investigations toward providing explanations of causality. [...] future advances will help to clarify the interactions between the microbiota and human development, and the potential roles of those microbiota involved in the mechanisms of various diseases [...] The crucial roles of the human microbiota should be investigated at a much deeper level [...]

The Human Microbiota in Health and Disease Baohong Wang, Mingfei Yao, Longxian Lv, Zongxin Ling, Lanjuan Li* Engineering 3 (2017) 71–82 https://www.researchgate.net/publication/314185613

Complex complexity. Dionisio

The metabolic disease is at the dawn of new knowledge. Anyone considering studying metabolic disease should take a deep look at gut microbiota diversity and immune responses. Therapeutic strategies, either pharmacological or nutritional, will most likely emerge over the course of the next decade or so.

Gut microbiota and immune crosstalk in metabolic disease Rémy Burcelin Mol Metab. 5(9): 771–781. doi: 10.1016/j.molmet.2016.05.016

Complex complexity. Dionisio

[...] confirmation of allele-specific binding events is necessary to confirm that a SNP does indeed impact transcription factor function and provides a mechanistic link between genetic variation and disease risk. [...] altered binding of T cell master regulators can predispose individuals to specific autoimmune and inflammatory conditions. This study establishes a scalable method that can be used to explore the impact of genetic variation on the function of other lineage-specifying transcriptional factors. These insights will identify molecular mechanisms that underlie the genetic basis of autoimmune diseases and suggest new therapies for their treatment.

Genetic variants alter T-bet binding and gene expression in mucosal inflammatory disease. Soderquest K, Hertweck A, Giambartolomei C, Henderson S, Mohamed R, Goldberg R, Perucha E, Franke L, Herrero J, Plagnol V, Jenner RG, Lord GM PLoS Genet. 13(2):e1006587. doi: 10.1371/journal.pgen.1006587.

Had we remained in Eden, none of this would have been an issue. Too late now. Work in progress... stay tuned. Complex complexity. Dionisio

The polarization of CD4+ T cells into distinct T helper cell lineages is essential for protective immunity against infection, but aberrant T cell polarization can cause autoimmunity. The transcription factor T-bet (TBX21) specifies the Th1 lineage and represses alternative T cell fates. Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) that may be causative for autoimmune diseases. [...] genetic polymorphisms may predispose individuals to mucosal autoimmune disease through alterations in T-bet binding. Other disease-associated variants may similarly act by modulating the binding of lineage-specifying transcription factors in a tissue-selective and disease-specific manner.

Genetic variants alter T-bet binding and gene expression in mucosal inflammatory disease. Soderquest K, Hertweck A, Giambartolomei C, Henderson S, Mohamed R, Goldberg R, Perucha E, Franke L, Herrero J, Plagnol V, Jenner RG, Lord GM PLoS Genet. 13(2):e1006587. doi: 10.1371/journal.pgen.1006587.

Had we remained in Eden, none of this would have been an issue. Too late now. Dionisio

[...] our identification of circulating and tissue-resident human ILCPs suggests a concept of ‘‘ILC-poiesis’’ in which ILC differentiation can occur ‘‘on demand’’ in any tissue and at any age. [...] ILCs are long-lived tissue-resident cells that do not recirculate under steady state and some inflammatory conditions [...] The discovery of a circulating ILCPs provides a mechanism to replenish tissue ILCs in response to steady-state losses and in the context of infection and inflammation.

Systemic Human ILC Precursors Provide a Substrate for Tissue ILC Differentiation. Lim AI, Li Y, Lopez-Lastra S, Stadhouders R, Paul F, Casrouge A, Serafini N, Puel A, Bustamante J, Surace L, Masse-Ranson G, David E, Strick-Marchand H, Le Bourhis L, Cocchi R, Topazio D, Graziano P, Muscarella LA, Rogge L, Norel X, Sallenave JM, Allez M, Graf T, Hendriks RW, Casanova JL, Amit I, Yssel H, Di Santo JP. Cell. 168(6):1086-1100.e10. doi: 10.1016/j.cell.2017.02.021.

Complex complexity. Dionisio

Regulation of TF expression dictates ILC fate as well as function. Signature TFs have been identified for ILC subsets that regulate their differentiation at the level of surface phenotype and effector outputs [...]

Systemic Human ILC Precursors Provide a Substrate for Tissue ILC Differentiation. Lim AI, Li Y, Lopez-Lastra S, Stadhouders R, Paul F, Casrouge A, Serafini N, Puel A, Bustamante J, Surace L, Masse-Ranson G, David E, Strick-Marchand H, Le Bourhis L, Cocchi R, Topazio D, Graziano P, Muscarella LA, Rogge L, Norel X, Sallenave JM, Allez M, Graf T, Hendriks RW, Casanova JL, Amit I, Yssel H, Di Santo JP. Cell. 168(6):1086-1100.e10. doi: 10.1016/j.cell.2017.02.021.

Complex complexity. Dionisio

It is therefore likely that each tissue harbors a unique ILCP ‘‘repertoire’’ conditioned by environmental signals. It is remarkable that other uni-potent ILCPs were rarely detected in this organ, suggesting that at this stage of fetal development, the microenvironment may deliver signals that strongly polarize ILCPs toward ILC3s. Notch-mediated signaling has been proposed to play a role in directing lymphoid cell fate decisions, promoting the development of T-lineage primed precursors, as well as modifying ILCPs homeostasis [...]

Systemic Human ILC Precursors Provide a Substrate for Tissue ILC Differentiation. Lim AI, Li Y, Lopez-Lastra S, Stadhouders R, Paul F, Casrouge A, Serafini N, Puel A, Bustamante J, Surace L, Masse-Ranson G, David E, Strick-Marchand H, Le Bourhis L, Cocchi R, Topazio D, Graziano P, Muscarella LA, Rogge L, Norel X, Sallenave JM, Allez M, Graf T, Hendriks RW, Casanova JL, Amit I, Yssel H, Di Santo JP. Cell. 168(6):1086-1100.e10. doi: 10.1016/j.cell.2017.02.021.

Complex complexity. Dionisio

[...] ILCPs resemble naive T cells that can differentiate to diverse T helper subsets under appropriate environmental signals. [...] human ILCPs have signature TFs in a poised state that contrasts with the situation in naive T cells where these loci are actively repressed [...] [...] ILCPs expand extensively in the presence of cytokines, whereas naïve T cell homeostasis is primarily maintained through cytokine driven survival [...] [...] ILCPs appear to have some properties in common with naïve T cells, although a number of important differences exist that are consistent with their designation as immature progenitors.

Systemic Human ILC Precursors Provide a Substrate for Tissue ILC Differentiation. Lim AI1, Li Y2, Lopez-Lastra S3, Stadhouders R4, Paul F5, Casrouge A2, Serafini N2, Puel A6, Bustamante J6, Surace L2, Masse-Ranson G2, David E5, Strick-Marchand H2, Le Bourhis L7, Cocchi R8, Topazio D8, Graziano P8, Muscarella LA8, Rogge L9, Norel X10, Sallenave JM11, Allez M12, Graf T4, Hendriks RW13, Casanova JL14, Amit I5, Yssel H15, Di Santo JP16. Cell. 168(6):1086-1100.e10. doi: 10.1016/j.cell.2017.02.021.

Complex complexity. Dionisio

Innate lymphoid cells (ILCs) are a novel family of lymphoid effector cells that serve essential roles in the early immune response, comprising both ‘‘cytotoxic’’ ILCs (natural killer [NK] cells) and ‘‘helper’’ ILCs. Our identification of systemically distributed ILCPs suggests a model whereby circulating and tissue ILCPs provide a cellular substrate for ILC differentiation in situ in response to local environmental signals.

Systemic Human ILC Precursors Provide a Substrate for Tissue ILC Differentiation. Lim AI1, Li Y2, Lopez-Lastra S3, Stadhouders R4, Paul F5, Casrouge A2, Serafini N2, Puel A6, Bustamante J6, Surace L2, Masse-Ranson G2, David E5, Strick-Marchand H2, Le Bourhis L7, Cocchi R8, Topazio D8, Graziano P8, Muscarella LA8, Rogge L9, Norel X10, Sallenave JM11, Allez M12, Graf T4, Hendriks RW13, Casanova JL14, Amit I5, Yssel H15, Di Santo JP16. Cell. 168(6):1086-1100.e10. doi: 10.1016/j.cell.2017.02.021.

Complex complexity. Dionisio

Innate lymphoid cells (ILCs) represent innate versions of T helper and cytotoxic T cells that differentiate from committed ILC precursors (ILCPs). How ILCPs give rise to mature tissue-resident ILCs remains unclear. [...] diverse ILC subsets are generated in situ from systemically distributed ILCPs in response to local environmental signals.

Systemic Human ILC Precursors Provide a Substrate for Tissue ILC Differentiation. Lim AI1, Li Y2, Lopez-Lastra S3, Stadhouders R4, Paul F5, Casrouge A2, Serafini N2, Puel A6, Bustamante J6, Surace L2, Masse-Ranson G2, David E5, Strick-Marchand H2, Le Bourhis L7, Cocchi R8, Topazio D8, Graziano P8, Muscarella LA8, Rogge L9, Norel X10, Sallenave JM11, Allez M12, Graf T4, Hendriks RW13, Casanova JL14, Amit I5, Yssel H15, Di Santo JP16. Cell. 168(6):1086-1100.e10. doi: 10.1016/j.cell.2017.02.021.

Complex complexity. Dionisio

the cross-regulation of ILCs and T cells, involving DCs as a central platform of information exchange, needs to be deciphered by using new mouse models that allow targeting each cell type individually. [...] a role for ILCs beyond immunity, such as in the regulation of fat metabolism, needs to be unravelled in order to understand the integration of the immune system in host physiology.

Innate lymphoid cells: A new paradigm in immunology Gérard Eberl, Marco Colonna, James P. Di Santo, Andrew N. J. McKenzie Science Vol. 348, Issue 6237, aaa6566 DOI: 10.1126/science.aaa6566

Complex complexity. Dionisio

Much remains to be uncovered on the activation and function of ILCs. ILCs promptly translate signals produced by infected or injured tissues into effector cytokines that activate and regulate local innate and adaptive effector functions. Signals produced by the tissues activating ILCs include cytokines, and possibly also stress ligands and microbial compounds.

Innate lymphoid cells: A new paradigm in immunology Gérard Eberl, Marco Colonna, James P. Di Santo, Andrew N. J. McKenzie Science Vol. 348, Issue 6237, aaa6566 DOI: 10.1126/science.aaa6566

Complex complexity. Dionisio

The multiple facets of ILC development, activation, and function need to be further explored before efficient manipulation of ILCs can be achieved in the clinic. The developmental pathways leading to the different types of ILCs appear to be relatively complex, and modulation of these pathways by the microenvironment remains poorly understood, with questions remaining about ILC subset plasticity and stability. It will also be insightful to explore the development of ILCs not only during ontogeny, but also during evolution, in order to assess whether “cytotoxic” ILCs (NK cells) and “helper” ILCs (ILC1s, ILC2s, and ILC3s) served as a blueprint for the appearance of CD8+ cytotoxic and CD4+ TH cells

Innate lymphoid cells: A new paradigm in immunology Gérard Eberl, Marco Colonna, James P. Di Santo, Andrew N. J. McKenzie Science Vol. 348, Issue 6237, aaa6566 DOI: 10.1126/science.aaa6566

Complex complexity. Dionisio

A logical next step will be the identification of molecules that allow manipulation of ILCs and the orchestration of the optimal immune response after vaccination and immunotherapy—or in contrast, to block detrimental responses. The combination of a prompt activation of ILCs with both effector and regulatory functions, with the expansion of antigen-specific B and T cells, should lead to new and powerful avenues in clinical immunology.

Innate lymphoid cells: A new paradigm in immunology Gérard Eberl, Marco Colonna, James P. Di Santo, Andrew N. J. McKenzie Science Vol. 348, Issue 6237, aaa6566 DOI: 10.1126/science.aaa6566

Complex complexity. Dionisio

Innate lymphoid cells (ILCs) are a growing family of immune cells that mirror the phenotypes and functions of T cells. However, in contrast to T cells, ILCs do not express acquired antigen receptors or undergo clonal selection and expansion when stimulated. Instead, ILCs react promptly to signals from infected or injured tissues and produce an array of secreted proteins termed cytokines that direct the developing immune response into one that is adapted to the original insult. The complex cross-talk between microenvironment, ILCs, and adaptive immunity remains to be fully deciphered. Only by understanding these complex regulatory networks can the power of ILCs be controlled or unleashed in order to regulate or enhance immune responses in disease prevention and therapy.

Innate lymphoid cells: A new paradigm in immunology Gérard Eberl, Marco Colonna, James P. Di Santo, Andrew N. J. McKenzie Science Vol. 348, Issue 6237, aaa6566 DOI: 10.1126/science.aaa6566

Complex complexity. Dionisio

[...] being able to better associate long-range enhancers with gene targets would enhance the power of our approach considerably. [...] the interaction of enhancers and promoters is confined in topologically associated domains. [...] exploration of the chromatin organization of enhancer marks as well as the use of new computational methods should facilitate the assignment of enhancers to their targets. [...] future studies should aim to refine and resolve the transcriptional networks by incorporating these additional approaches.

Epigenetic landscapes reveal transcription factors that regulate CD8+ T cell differentiation Bingfei Yu, Kai Zhang, J Justin Milner, Clara Toma, Runqiang Chen, James P Scott-Browne, Renata M Pereira, Shane Crotty, John T Chang, Matthew E Pipkin, Wei Wang & Ananda W Goldrath Nature Immunology doi:10.1038/ni.3706

Work in progress... stay tuned. Complex complexity. Dionisio

Global investigation of TF-binding motifs using new approaches, such as protein-binding microarrays, might be beneficial in broadening the database of known TF-binding motifs. TFs function with co-factors to regulate specific gene expression; co-binding analyses could be incorporated into these analyses to improve our network construction.

Epigenetic landscapes reveal transcription factors that regulate CD8+ T cell differentiation Bingfei Yu, Kai Zhang, J Justin Milner, Clara Toma, Runqiang Chen, James P Scott-Browne, Renata M Pereira, Shane Crotty, John T Chang, Matthew E Pipkin, Wei Wang & Ananda W Goldrath Nature Immunology doi:10.1038/ni.3706

Work in progress... stay tuned. Complex complexity. Dionisio

Treatment with dexamethasone increased the proportion of MP subset during differentiation, which demonstrated a previously unknown role for glucocorticoid hormones in modulating CD8+ T cell differentiation and a potential strategy for manipulating memory-cell differentiation.

Epigenetic landscapes reveal transcription factors that regulate CD8+ T cell differentiation Bingfei Yu, Kai Zhang, J Justin Milner, Clara Toma, Runqiang Chen, James P Scott-Browne, Renata M Pereira, Shane Crotty, John T Chang, Matthew E Pipkin, Wei Wang & Ananda W Goldrath Nature Immunology doi:10.1038/ni.3706

Work in progress... stay tuned. Complex complexity. Dionisio

How YY1 regulates differentiation of the TE subset and if YY1 controls chromatin interactions in the TE subset remain to be determined.

Epigenetic landscapes reveal transcription factors that regulate CD8+ T cell differentiation Bingfei Yu, Kai Zhang, J Justin Milner, Clara Toma, Runqiang Chen, James P Scott-Browne, Renata M Pereira, Shane Crotty, John T Chang, Matthew E Pipkin, Wei Wang & Ananda W Goldrath Nature Immunology doi:10.1038/ni.3706

Work in progress... stay tuned. Complex complexity. Dionisio

[...] it is essential to develop new methods that rank the potential importance of TFs on the basis of the quantity and quality of the TF-regulated genes. Future modifications of gene weights by gene ontology could facilitate identification of TFs important in specific functions or pathways.

Epigenetic landscapes reveal transcription factors that regulate CD8+ T cell differentiation Bingfei Yu, Kai Zhang, J Justin Milner, Clara Toma, Runqiang Chen, James P Scott-Browne, Renata M Pereira, Shane Crotty, John T Chang, Matthew E Pipkin, Wei Wang & Ananda W Goldrath Nature Immunology doi:10.1038/ni.3706

Work in progress... stay tuned. Complex complexity. Dionisio

[...] the identification of relevant TFs exclusively on the basis of gene-expression analysis provides only partial understanding of the TF networks involved. [...] gene expression alone could not fully explain the mechanisms behind cell-fate determination and supported the idea that the binding of TFs and gene expression should be considered together to facilitate the identification of important TFs. Differential TF binding can be achieved via numerous mechanisms, including variable chromatin state and accessibility, TF localization, the availability of co-factors, and post-translational modification of TFs.

Epigenetic landscapes reveal transcription factors that regulate CD8+ T cell differentiation Bingfei Yu, Kai Zhang, J Justin Milner, Clara Toma, Runqiang Chen, James P Scott-Browne, Renata M Pereira, Shane Crotty, John T Chang, Matthew E Pipkin, Wei Wang & Ananda W Goldrath Nature Immunology doi:10.1038/ni.3706

Work in progress... stay tuned. Complex complexity. Dionisio

This analysis suggested a previously unknown function for T-bet in maintaining the accumulation of MP cells, potentially through regulation of the anti-apoptotic protein Bcl-2 and additional targets. Studies of distinct targets will further elucidate nuanced functions of T-bet in driving effector and memory fates.

Epigenetic landscapes reveal transcription factors that regulate CD8+ T cell differentiation Bingfei Yu, Kai Zhang, J Justin Milner, Clara Toma, Runqiang Chen, James P Scott-Browne, Renata M Pereira, Shane Crotty, John T Chang, Matthew E Pipkin, Wei Wang & Ananda W Goldrath Nature Immunology doi:10.1038/ni.3706

Work in progress... stay tuned. Complex complexity. Dionisio

The function and differentiation state of immune cells are controlled by TFs that relay environmental cues through regulation of gene expression. Efficient transcriptional regulation requires interaction between TFs and chromatin remodelers to control the binding of TFs with high fidelity. Key information is encoded in regulatory elements that contain TF-binding sequences and are associated with specific histone modifications that influence the accessibility, structure and location of those elements.

Epigenetic landscapes reveal transcription factors that regulate CD8+ T cell differentiation Bingfei Yu, Kai Zhang, J Justin Milner, Clara Toma, Runqiang Chen, James P Scott-Browne, Renata M Pereira, Shane Crotty, John T Chang, Matthew E Pipkin, Wei Wang & Ananda W Goldrath Nature Immunology doi:10.1038/ni.3706

Complex complexity. Dionisio

In response to infection, naive CD8+ T cells differentiate into a heterogeneous population of pathogen-specific effector CD8+ T cells. While the majority of these T cells undergo apoptosis after resolution of the infection, a small fraction persists as memory cells and provide lasting protection against re-infection.

Epigenetic landscapes reveal transcription factors that regulate CD8+ T cell differentiation Bingfei Yu, Kai Zhang, J Justin Milner, Clara Toma, Runqiang Chen, James P Scott-Browne, Renata M Pereira, Shane Crotty, John T Chang, Matthew E Pipkin, Wei Wang & Ananda W Goldrath Nature Immunology doi:10.1038/ni.3706

Complex complexity. Dionisio

Dynamic changes in the expression of transcription factors (TFs) can influence the specification of distinct CD8+ T cell fates, but the observation of equivalent expression of TFs among differentially fated precursor cells suggests additional underlying mechanisms. Our data define the epigenetic landscape of differentiation intermediates and facilitate the identification of TFs with previously unappreciated roles in CD8+ T cell differentiation.

Epigenetic landscapes reveal transcription factors that regulate CD8+ T cell differentiation Bingfei Yu, Kai Zhang, J Justin Milner, Clara Toma, Runqiang Chen, James P Scott-Browne, Renata M Pereira, Shane Crotty, John T Chang, Matthew E Pipkin, Wei Wang & Ananda W Goldrath Nature Immunology doi:10.1038/ni.3706

Complex complexity. Dionisio

[...] as most transcription factors are used in both innate and adaptive lineages, unique combinations of factors could result in innate vs. adaptive lineage choice. Uncovering the factors and mechanisms that specify innate versus adaptive fates during early development is a fascinating and challenging new issue. The ongoing identification of early intermediate stages between lymphoid progenitors and ILCs should eventually allow these questions to be addressed.

A doppelgänger of T cell development Christelle Harly & Avinash Bhandoola Editorials: Cell Cycle Features http://dx.doi.org/10.1080/15384101.2015.1125244 Journal Cell Cycle ? Volume 15, 2016 – Issue 4

Complex complexity. Dionisio

Innate lymphoid cells (ILCs) were recently identified as the innate counterpart of adaptive T-cells, after the discovery of several ILC subsets with effector functions strikingly similar to T-cell subsets. Although our understanding of ILCs is still preliminary, it is becoming clear that transcriptional programs controlling ILC terminal differentiation and effector functions closely mirror those of conventional ?? T-cells [...]

A doppelgänger of T cell development Christelle Harly & Avinash Bhandoola Editorials: Cell Cycle Features http://dx.doi.org/10.1080/15384101.2015.1125244 Journal Cell Cycle ? Volume 15, 2016 - Issue 4

Did somebody say “programs”? ???? Complex complexity. Dionisio

CD8 T cell memory is characterized by rapid recall of effector function, increased proliferation, and reduced activation requirements. Despite the extensive functional characterization, the molecular mechanisms that facilitate these enhanced properties are not well characterized. [...] memory CD8 T cells display a preprogrammed chromatin accessibility profile and maintain a molecular history of cis-element usage, thereby reducing the steps necessary to revive effector functions.

Cutting Edge: Chromatin Accessibility Programs CD8 T Cell Memory. Scharer CD, Bally AP, Gandham B, Boss JM J Immunol. 198(6):2238-2243. doi: 10.4049/jimmunol.1602086

[Emphasis added] Did somebody say "preprogrammed"? :) Complex complexity. Dionisio

The discovery of diverse ILC subsets represents a major advance in our understanding of how immune responses are established in order to cope with infection, inflammation and tissue repair. Deciphering the signals that promote ILC subset development and regulate their peripheral function will be key to understanding the balance between these outcomes.

Transcriptional regulation of innate lymphoid cell fate Nicolas Serafini, Christian A. J. Vosshenrich & James P. Di Santo Nature Reviews Immunology 15, 415–428 doi:10.1038/nri3855

Work in progress… stay tuned. Complex complexity. Dionisio

‘Plasticity’ describes how differentiated cells can acquire new characteristics (for example, phenotypes and functions) depending on the environment. A role for epigenetic modifications in this process is likely but has not yet been established.

Transcriptional regulation of innate lymphoid cell fate Nicolas Serafini, Christian A. J. Vosshenrich & James P. Di Santo Nature Reviews Immunology 15, 415–428 doi:10.1038/nri3855

Work in progress… stay tuned. Complex complexity. Dionisio

Lymphocyte lifespan can vary enormously in different cell types, from several days to the host’s lifetime. We have little information on lifespan for other ILC subsets, and additional work is needed to answer this question. [...] it will be interesting to study whether these expanded ILCs have ‘memory’ properties.

Transcriptional regulation of innate lymphoid cell fate Nicolas Serafini, Christian A. J. Vosshenrich & James P. Di Santo Nature Reviews Immunology 15, 415–428 doi:10.1038/nri3855

Work in progress… stay tuned. Complex complexity. Dionisio

Whether inflammatory ILC2s are an obligate intermediate in ILC2 differentiation under non-inflammatory conditions requires further study. Considering the close relationship between Notch, TCF1 and BCL11B, it is possible that the latter is also involved in ILC2 development. The factors that induce ROR? in the ILC2 lineage are not known [...] The downstream targets of ROR? that promote ILC2 differentiation are similarly undefined. [...] putative precursors for EOMES?ILC1s and for ILC2s have been proposed9,35; however, it is not clear to what extent these are true precursors or simply mature ILCs in the ‘resting’ state. Cytokines of the common ?-chain (?c) family are essential for the development of all known ILC subsets. [...] It remains unclear at what stage these cytokines exert their effects on ILC homeostasis. The role of T cell-derived IL?2 as a generic modifier of ILC homeostasis and the ability of regulatory T cells to indirectly inhibit this process provide an additional mechanism for control of ILC homeostasis.

Transcriptional regulation of innate lymphoid cell fate Nicolas Serafini, Christian A. J. Vosshenrich & James P. Di Santo Nature Reviews Immunology 15, 415–428 doi:10.1038/nri3855

Work in progress… stay tuned. Complex complexity. Dionisio

[...] NFIL3 seems to be an important orchestrator of ILCP emergence from CLPs. More work is required to understand how NFIL3 expression is controlled and to determine the relevant NFIL3 targets in CLPs and ILCPs. An in?depth characterization of CILCPs in GATA3?deficient mice may provide answers. [...] whether ILCPs should be considered to be ‘innate’ versions of naive T cells is not clear. Whether these soluble factors and their associated STAT pathways are involved in early stages of ILC1 commitment from ILCPs is not known. Eomes- and Tbx21-reporter mice will be important tools for identifying ILC1 precursors in future studies. Upstream regulators of ETS1 in lymphoid precursors are poorly characterized [...]

Transcriptional regulation of innate lymphoid cell fate Nicolas Serafini, Christian A. J. Vosshenrich & James P. Di Santo Nature Reviews Immunology 15, 415–428 doi:10.1038/nri3855

Work in progress… stay tuned. Complex complexity. Dionisio

Innate lymphoid cells (ILCs) are a recently described family of lymphoid effector cells that have important roles in immune defence, inflammation and tissue remodelling. Our knowledge of the signals and mechanisms that regulate ILC differentiation from haematopoietic precursors is still in its infancy. [...] the range of functional abilities of different ILC groups is not fully appreciated, leaving room for further refinement (and possible redefinition) of the ILC nomenclature. A better understanding of the critical stages and regulators of ILC differentiation could eventually lead to new experimental or therapeutic approaches for manipulating the immune system in the early stages of pathogenic infection or during inflammatory disease.

Transcriptional regulation of innate lymphoid cell fate Nicolas Serafini, Christian A. J. Vosshenrich & James P. Di Santo Nature Reviews Immunology 15, 415–428 doi:10.1038/nri3855

Complex complexity. Dionisio

[...] the regulatory effects of Ikaros on ILC3 development and function are stage specific. [...] it is unclear whether some ILC1s may express or have expressed Eomes during their development. Transcriptional regulation underlies the functional actions of various lymphoid effectors and is the key to further understanding how the immune system works. [...] more comprehensive studies are still required to understand how recently identified ILC populations are generated and how their functions are controlled. [...] there are still many challenges to address in order to understand how ILCs and ILC-functions are ultimately regulated and controlled.

Transcriptional regulators dictate innate lymphoid cell fates. Zhong C, Zhu J Protein Cell. doi: 10.1007/s13238-017-0369-7.

[emphasis added] Work in progress… stay tuned. Complex complexity. Dionisio

Retinoic acid (RA) is the active metabolite of Vitamin A, which activates the nuclear receptors retinoic acid receptor (RAR) or retinoid X receptor (RXR). Maternal retinoid level is thus required for setting up immune structures in the offspring.

Transcriptional regulators dictate innate lymphoid cell fates. Zhong C, Zhu J Protein Cell. doi: 10.1007/s13238-017-0369-7.

Complex complexity. Dionisio

[...] ROR? may regulate ILC3 cells [...] [...] ILC2s in different tissues might develop from separate progenitors that have distinct developmental requirements —an important question which requires further investigation. [...] it is still not clear whether Runx proteins are specifically required for the development of ILCs.

Transcriptional regulators dictate innate lymphoid cell fates. Zhong C, Zhu J Protein Cell. doi: 10.1007/s13238-017-0369-7.

[emphasis added] Work in progress… stay tuned. Complex complexity. Dionisio

Thus as the field continues to explore the functions of ILCs, new and novel functions of various tissue-resident ILC subsets are being reported. At present, the regulatory mechanisms of innate lymphoid cell development have been quite elusive. [...] the precise mechanisms through which Id2 mediates ILC development and the environmental signals that induce Id2 expression in ChILP cells are still elusive. [...] it is intriguing to explore whether the GATA-3 expression levels in innate lymphocyte progenitors can determine their lineage fates towards either helper-like ILCs or cytotoxic cNK cells, in a similar manner to the function of GATA-3 in CD4+ and CD8+ T cell lineage commitment. Interestingly, PLZF is only transiently expressed at the ILC progenitor stage. [...] Notch signaling seems to be dynamically regulated and its functions may be stage specific during ILC development. [...] a decrease in Notch signals, in concert with their downstream target genes, including Tcf7, Hes1, Gata3, and Bcl11b might be responsible for the developmental defect in ChILPs. Although the above transcription factors are essential for the generation of ILCs, the regulatory network among them in ILC progenitors, and the precise mechanism through which ILCs are developed still need further investigation. Our current knowledge about ILC development is still quite limited. The regulation of ILC development is likely to be far more complicated than we have discussed. Additional un-described transcriptional regulators or environment cues may play large roles in governing progenitor cell fates during development. Further studies of ILC progenitors are ultimately necessary to further understand the evolution and lineage specification of the lymphoid system in mice and clinical patients. [...] the detailed mechanism of how GATA-3 maintains mature ILC2s is still unclear. [...] the function of Bcl11b in non-ILC2s is still elusive. The underlying mechanism of ROR?-mediated ILC2 development is still unclear. [...] it is not clear whether ROR? has any function in mature ILC1 or ILC2 cells.

Transcriptional regulators dictate innate lymphoid cell fates. Zhong C, Zhu J Protein Cell. doi: 10.1007/s13238-017-0369-7.

[emphasis added] Just a few outstanding questions left... Work in progress… stay tuned. Complex complexity. Dionisio

Compared to other cells in the innate immune system, ILCs are unique in that they may produce and secrete cytokines that were classically regarded as CD4+ Th cell products [...] A major feature of innate immunity is the antigen non-specificity. Pattern recongnition (PR) is a well-known manner to initiate an innate response. The innate immune system recognizes pathogen-associated or damage-associated molecular patterns (PAMPs or DAMPs) through pattern recognition receptors (PRRs) in a semi-specific manner [...] Signals transduced downstream of PRRs may promote the production of pro-inflammatory cytokines or chemokines, including IL-1?, TNF?, IFN-?, IL-8, etc.

Transcriptional regulators dictate innate lymphoid cell fates. Zhong C, Zhu J Protein Cell. doi: 10.1007/s13238-017-0369-7.

Complex complexity. Dionisio

[...] a comprehensive understanding of the interactions and regulatory mechanisms mediated by these transcription factors will help us to further understand how ILCs exert their helper-like functions and bridge the innate and adaptive immunity.

Transcriptional regulators dictate innate lymphoid cell fates. Zhong C, Zhu J Protein Cell. doi: 10.1007/s13238-017-0369-7.

Work in progress… stay tuned. Complex complexity. Dionisio

Surprisingly, it has been demonstrated that conventional lymphocytes (both B and T cells) can internalize bacteria in an innate-like manner. CD4+ T cells can capture and kill bacteria by transphagocytosis from infected DCs. The precise role of the CD4+ T cell-dependent bacterial clearance during infections in vivo remains to be determined, as the number of bacteria directly cleared by transphagocytosis seems to be low, suggesting other mechanisms for the reduction of bacterial load (i.e., cytokine release or antigen presentation). In agreement with this hypothesis, transphagocytic T cells secrete large amounts of proinflammatory cytokines, mounting a potent Th-1 response.

Close Encounters of Lymphoid Cells and Bacteria. Cruz-Adalia A, Veiga E Front Immunol. 7:405. DOI: 10.3389/fimmu.2016.00405

Surprisingly? Why? Complex complexity. Dionisio

During infections, the first reaction of the host against microbial pathogens is carried out by innate immune cells, which recognize conserved structures on pathogens, called pathogen-associated molecular patterns. Afterward, some of these innate cells can phagocytose and destroy the pathogens, secreting cytokines that would modulate the immune response to the challenge. This rapid response is normally followed by the adaptive immunity, more specific and essential for a complete pathogen clearance in many cases.

Close Encounters of Lymphoid Cells and Bacteria. Cruz-Adalia A, Veiga E Front Immunol. 7:405. DOI: 10.3389/fimmu.2016.00405

Complex complexity. Dionisio

Vitamin A (VA) is a lipophilic micronutrient obtained by dietary ingestion of primarily pro-vitamin A carotenoids (such as ?-carotene) and retinyl esters (RE) derived from plant and animal food, respectively. [...] atRA works as a crucial regulator of DC function, which dictates T helper and effector cell function in the mucosal sites and in peripheral tissues. Interestingly, the cytokine milieu can influence DCs to induce pro-inflammatory T helper functions, even in the presence of atRA. [...] atRA exerts a crucial role in DC function in order to maintain tolerance against food and microbial antigens and promote tissue homeostasis.

Retinoic Acid and Its Role in Modulating Intestinal Innate Immunity Paulo Czarnewski, Srustidhar Das, Sara M. Parigi, and Eduardo J. Villablanca Nutrients. 9(1): 68. doi: 10.3390/nu9010068

Complex complexity. Dionisio

Vitamin A (VA) is amongst the most well characterized food-derived nutrients with diverse immune modulatory roles. Deficiency in dietary VA has not only been associated with immune dysfunctions in the gut, but also with several systemic immune disorders.

Retinoic Acid and Its Role in Modulating Intestinal Innate Immunity Paulo Czarnewski, Srustidhar Das, Sara M. Parigi, and Eduardo J. Villablanca Nutrients. 9(1): 68. doi: 10.3390/nu9010068

Had we stayed in Eden -where we had all we needed- none of this would have been an issue. Oh, well. Too late now. But still there's hope before this age of grace ends. Saving faith in Christ alone can take us back to where we once belonged. Dionisio

Group 3 ILC play central roles in lymphoid organogenesis, orchestration of adaptive immunity, regulation of peripheral tolerance and as effector cells in the context of immunity and inflammation. [...] challenges remain in resolving the relevance of ILC3 heterogeneity and incorporating recently identified novel transcriptional and metabolic states in the context of current nomenclature. A more nuanced understanding of ILC3 subset?specific roles in intestinal immunity will aid the development of targeted therapeutic interventions aimed at maintaining beneficial homeostatic ILC3 functions, while neutralizing pro?inflammatory ILC3 pathways that contribute to the onset or progression of tissue inflammation.

Functional and phenotypic heterogeneity of group 3 innate lymphoid cells. Melo-Gonzalez F, Hepworth MR Immunology. 150(3):265-275. doi: 10.1111/imm.12697

Work in progress… stay tuned. Complex complexity. Dionisio

Future studies will elucidate further the mechanisms inducing RET expression in ILC3. Notably, neurotrophic factors are the molecular link between glial cell sensing, innate IL-22 and intestinal epithelial defence. [...] coordination of innate immunity and neuronal function may ensure efficient mucosal homeostasis and a co-regulated neuro-immune response to various environmental challenges, including xenobiotics, intestinal infection, dietary aggressions and cancer.

Glial-cell-derived neuroregulators control type 3 innate lymphoid cells and gut defence. Ibiza S, García-Cassani B, Ribeiro H, Carvalho T, Almeida L, Marques R, Misic AM, Bartow-McKenney C, Larson DM, Pavan WJ, Eberl G, Grice EA, Veiga-Fernandes H. Nature. 535(7612): 440–443. doi: 10.1038/nature18644

Work in progress… stay tuned. Complex complexity. Dionisio

[...] a better understanding of the regulation of expression of Ret on ILC subsets or other immune cells will be relevant for chronic inflammatory disease pathogenesis and possibly treatment.

A new edge to immune surveillance by the neural system. Bernink JH, Spits H, de Jonge WJ Cell Res. 26(11):1178-1179. doi: 10.1038/cr.2016.107.

Work in progress... stay tuned. Complex complexity. Dionisio

[...] the role of EGC in immune surveillance may be much more prominent than expected from previous studies.

A new edge to immune surveillance by the neural system. Bernink JH, Spits H, de Jonge WJ Cell Res. 26(11):1178-1179. doi: 10.1038/cr.2016.107.

much more prominent than expected? what else is new? what were those expectations based on? Work in progress... stay tuned. Complex complexity. Dionisio

It would be of interest to explore whether Ret signaling may also regulate innate type 2 cytokine functions [...]

A new edge to immune surveillance by the neural system. Bernink JH, Spits H, de Jonge WJ Cell Res. 26(11):1178-1179. doi: 10.1038/cr.2016.107.

Work in progress... stay tuned. Complex complexity. Dionisio

Dissecting the composition of the distinct ILC3 subsets in wild-type mice, Ret-deficient mice, and mice that have a gain-of-function mutation in Ret would further contribute to our understanding of how this kinase is involved in the regulation of IL-22 production in the distinct CCR6? ILC3 subsets.

A new edge to immune surveillance by the neural system. Bernink JH, Spits H, de Jonge WJ Cell Res. 26(11):1178-1179. doi: 10.1038/cr.2016.107.

Work in progress... stay tuned. Complex complexity. Dionisio

[...] ILC3 can respond to signals from EGCs through Ret, in addition to a variety of previously identified mediators derived from myeloid cells such as IL-1?, IL-23, or dietary products such as retinoic acids and aryl hydrocarbon receptor agonists. It is unclear whether all these signals act on the same cell or on different subsets.

A new edge to immune surveillance by the neural system. Bernink JH, Spits H, de Jonge WJ Cell Res. 26(11):1178-1179. doi: 10.1038/cr.2016.107.

Complex complexity. Dionisio

The enteric nervous system (ENS) acts largely autonomously to regulate intestinal motility and secretion and is often referred to as our “second brain”, because of its complexity and structure. EGC certainly plays an eminent role in mucosal immune homeostasis although their immune-supportive function is incompletely understood at present. Somewhat surprising, the production of another ILC3 signature cytokine IL-17 is not affected by Ret ablation in ILC3 [...]

A new edge to immune surveillance by the neural system. Bernink JH, Spits H, de Jonge WJ Cell Res. 26(11):1178-1179. doi: 10.1038/cr.2016.107.

Did somebody say "surprising"? :) Complex complexity. Dionisio

A recent paper published in Nature demonstrates a multifaceted relation between enteric glial cells (EGC), intestinal epithelia, and ILC3, via the EGC release of neurotrophic factors, a structurally related group of ligands within the TGF-? superfamily of signaling molecules and IL-22 produced by ILC3.

A new edge to immune surveillance by the neural system. Bernink JH, Spits H, de Jonge WJ Cell Res. 26(11):1178-1179. doi: 10.1038/cr.2016.107.

Complex complexity. Dionisio

[...] slithering could be a more widely used mechanism of movement and sorting of epithelial cells that has been overlooked even in well-studied epithelia [...] It will be important to identify the slithering program and indeed the full program of NEB formation including cell selection, migration, differentiation, and innervation [...]

Formation of a neurosensory organ by epithelial cell slithering Christin S. Kuo and Mark A. Krasnow Cell. 163(2): 394–405. doi: 10.1016/j.cell.2015.09.021

Did somebody say "overlooked"? Did somebody say "program"? Complex complexity. Dionisio

Two prominent features of slithering are its selectivity for NE cells and their specific targeting to diametrically opposed positions at the base of each bronchial branch, raising the questions: what provides the guidance cue and its selectivity for NE cells? Perhaps the cue is a combination of more broadly distributed but overlapping signals [...] A high priority now is to identify the signal(s) and their sources and receptors that control slithering and to determine if the same signals also guide outgrowth of neurites that target NEBs.

Formation of a neurosensory organ by epithelial cell slithering Christin S. Kuo and Mark A. Krasnow Cell. 163(2): 394–405. doi: 10.1016/j.cell.2015.09.021

Complex complexity. Dionisio

[...] NEBs form by a targeted mode of epithelial cell sorting we call “slithering,” in which the rearranging cells transiently lose epithelial structure and polarity yet remain intimately associated with the epithelial sheet as they traverse neighboring epithelial cells and converge at the target site. This mechanism of cell rearrangement differs dramatically from intercalation, the classical mode of epithelial cell rearrangement [...] [...] slithering occurs without proliferation and is selective, directed, and purposeful.

Formation of a neurosensory organ by epithelial cell slithering Christin S. Kuo and Mark A. Krasnow Cell. 163(2): 394–405. doi: 10.1016/j.cell.2015.09.021

Did somebody say "selective, directed, and purposeful"? Complex complexity. Dionisio

Epithelia are sheets of cells that line and protect the body and internal organs, and the polarized cells that comprise them play important roles in absorption, secretion, and sensation. Epithelial cells are normally tightly attached to one another through specialized junctions and adhesion proteins along their lateral surface, and anchored to the basement membrane at their basal surface. Although epithelial sheets can grow and change shape, the constituent cells typically maintain their relative positions.

Formation of a neurosensory organ by epithelial cell slithering Christin S. Kuo and Mark A. Krasnow Cell. 163(2): 394–405. doi: 10.1016/j.cell.2015.09.021

Complex complexity. Dionisio

Cxcr4 is a chemokine receptor regulating cell migration, and N-cadherin is a transmembrane protein regulating cell-cell adhesion. [...] NE cells form NEBs by a novel form of cell migration they named “slithering.” [...] epithelial cell context may influence NEB formation. [...] the majority of migrating NE cells is directed toward distal regions, even when the nearest bifurcation point is found in another direction [...]

Directed Migration of Pulmonary Neuroendocrine Cells toward Airway Branches Organizes the Stereotypic Location of Neuroepithelial Bodies. Noguchi M, Sumiyama K, Morimoto M Cell Rep. 13(12):2679-86. doi: 10.1016/j.celrep.2015.11.058.

Complex complexity. Dionisio

[...] we shouldn’t take epithelial cells for granted, as they will certainly continue to surprise us with new exciting mechanisms, especially when studied in situ in their many different contexts.

Epithelial Morphogenesis: Stage Diving with Purpose. Gilmour D Dev Cell. 35(1):7-8. doi: 10.1016/j.devcel.2015.09.025.

Complex complexity. Dionisio

[...] what guides slithering NE progenitors during their coalescence at the branch points [?] [...] how slithering cells physically lift themselves above, or around, neighboring epithelial cells [?] [...] distinct mechanisms may be at work here.

Epithelial Morphogenesis: Stage Diving with Purpose. Gilmour D Dev Cell. 35(1):7-8. doi: 10.1016/j.devcel.2015.09.025.

Complex complexity. Dionisio

[...] there is the possibility that other, potentially novel guidance mechanisms are involved.

Epithelial Morphogenesis: Stage Diving with Purpose. Gilmour D Dev Cell. 35(1):7-8. doi: 10.1016/j.devcel.2015.09.025.

Complex complexity. Dionisio

Like many groundbreaking studies, the paper of Kuo and Krasnow gives plenty food for thought and generates a number of fascinating questions that are still to be answered.

Epithelial Morphogenesis: Stage Diving with Purpose. Gilmour D Dev Cell. 35(1):7-8. doi: 10.1016/j.devcel.2015.09.025.

As some outstanding questions get answered, new ones are generated. Complex complexity. Dionisio

[...] live imaging of slice culture preparations and careful analysis of adhesion and polarity markers reveals a mechanism whereby NE cells first transiently lose epithelial adhesion and polarity, exit the epithelium, extend out, and traverse neighboring cells to converge on the target site before reinserting into the layer. The authors christen this previously undescribed mode of migration “slithering.”

Epithelial Morphogenesis: Stage Diving with Purpose. Gilmour D Dev Cell. 35(1):7-8. doi: 10.1016/j.devcel.2015.09.025.

Complex complexity. Dionisio

[...] surprisingly, cell division plays no role in NEB formation; rather, these clusters form through the coalescence of individual NE progenitors that can be placed into five different morphological categories [...]

Epithelial Morphogenesis: Stage Diving with Purpose. Gilmour D Dev Cell. 35(1):7-8. doi: 10.1016/j.devcel.2015.09.025.

Did somebody say "surprisingly"? Complex complexity. Dionisio

Amazingly, when individual NE cells within the epithelium coalesce to form NEB clusters, they do so via the cellular equivalent of “stage diving,” a highly risky maneuver made famous by rock stars.

Epithelial Morphogenesis: Stage Diving with Purpose. Gilmour D Dev Cell. 35(1):7-8. doi: 10.1016/j.devcel.2015.09.025.

Did somebody say "amazingly"? Complex complexity. Dionisio

Cells can enter into a dormant state when faced with unfavorable conditions. However, how cells enter into and recover from this state is still poorly understood.

A pH-driven transition of the cytoplasm from a fluid- to a solid-like state promotes entry into dormancy Matthias Christoph Munder,1 Daniel Midtvedt,2 Titus Franzmann,1 Elisabeth Nüske,1 Oliver Otto,3 Maik Herbig,3 Elke Ulbricht,3 Paul Müller,3 Anna Taubenberger,3 Shovamayee Maharana,1 Liliana Malinovska,1 Doris Richter,1 Jochen Guck,3 Vasily Zaburdaev,2 and Simon Alberti eLife. 2016; 5: e09347. doi: 10.7554/eLife.09347

Complex complexity. Dionisio

Due to the polygenic nature of most human complex traits and diseases, the effect sizes of individual genetic variants are usually very small, limiting the statistical power to detect them, even in large samples1. Emerging evidence have suggested that disease- or trait-associated genetic variants identified from genome-wide association studies (GWAS) tend to be in enriched genic regions, and often there are multiple associated variants at a single locus4

Fast set-based association analysis using summary data from GWAS identifies novel gene loci for human complex traits Andrew Bakshi, Zhihong Zhu, Anna A. E. Vinkhuyzen, W. David Hill, Allan F. McRae, Peter M. Visscher & Jian Yang Scientific Reports 6, Article number: 32894 (2016) doi:10.1038/srep32894

Complex complexity. Dionisio

Genome-wide association studies (GWAS) typically generate lists of trait- or disease-associated SNPs. Yet, such output sheds little light on the underlying molecular mechanisms and tools are needed to extract biological insight from the results at the SNP level.

Lamparter D, Marbach D, Rueedi R, Kutalik Z, Bergmann S (2016) Fast and Rigorous Computation of Gene and Pathway Scores from SNP-Based Summary Statistics. PLoS Comput Biol 12(1): e1004714. doi:10.1371/journal.pcbi.1004714

Complex complexity. Dionisio

While further work is still required to dissect the biological role of individual TR-lincRNAs, our genome-wide results provide the much needed mechanistic insights into their functions, furthering the understanding of the intricate genetic networks underlying complex human traits and diseases.

cis-Acting Complex-Trait-Associated lincRNA Expression Correlates with Modulation of Chromosomal Architecture Jennifer Yihong Tan, Adam Alexander Thil Smith, Maria Ferreira da Silva, Cyril Matthey-Doret, Rico Rueedi, Reyhan Sönmez, David Ding, Zoltán Kutalik, Sven Bergmann, Ana Claudia Marques Cell Reports 18(9):2280-2288 DOI: 10.1016/j.celrep.2017.02.009

Complex complexity. Dionisio

[...] TR-lincRNA transcription affects the levels of trait-relevant genes in their vicinity, likely by modulating local chromosomal organization, thus impacting complex normal and disease phenotypes in humans. The correlation observed between TR-lincRNA expression and intra-TAD DNA-DNA interactions in LCLs provides genome-wide support for this hypothesis.

cis-Acting Complex-Trait-Associated lincRNA Expression Correlates with Modulation of Chromosomal Architecture Jennifer Yihong Tan, Adam Alexander Thil Smith, Maria Ferreira da Silva, Cyril Matthey-Doret, Rico Rueedi, Reyhan Sönmez, David Ding, Zoltán Kutalik, Sven Bergmann, Ana Claudia Marques Cell Reports 18(9):2280-2288 DOI: 10.1016/j.celrep.2017.02.009

Complex complexity. Dionisio

[...] the transcription of trait-relevant lincRNAs contributes to chromosomal architecture and thereby the regulation of nearby trait-associated protein-coding gene expression levels.

cis-Acting Complex-Trait-Associated lincRNA Expression Correlates with Modulation of Chromosomal Architecture Jennifer Yihong Tan, Adam Alexander Thil Smith, Maria Ferreira da Silva, Cyril Matthey-Doret, Rico Rueedi, Reyhan Sönmez, David Ding, Zoltán Kutalik, Sven Bergmann, Ana Claudia Marques Cell Reports 18(9):2280-2288 DOI: 10.1016/j.celrep.2017.02.009

Complex complexity. Dionisio

[...] most GWAS variants map within noncoding regulatory regions that are enriched in population and tissue-specific expression quantitative trait loci (eQTLs) [...]

cis-Acting Complex-Trait-Associated lincRNA Expression Correlates with Modulation of Chromosomal Architecture Jennifer Yihong Tan, Adam Alexander Thil Smith, Maria Ferreira da Silva, Cyril Matthey-Doret, Rico Rueedi, Reyhan Sönmez, David Ding, Zoltán Kutalik, Sven Bergmann, Ana Claudia Marques Cell Reports 18(9):2280-2288 DOI: 10.1016/j.celrep.2017.02.009

Complex complexity. Dionisio

An increasing number of reports suggest that long intergenic noncoding RNAs (lincRNAs), which were previously regarded as “junk RNA” (Hüttenhofer et al., 2005), can contribute to normal and disease phenotypes in humans (Esteller, 2011).

cis-Acting Complex-Trait-Associated lincRNA Expression Correlates with Modulation of Chromosomal Architecture Jennifer Yihong Tan, Adam Alexander Thil Smith, Maria Ferreira da Silva, Cyril Matthey-Doret, Rico Rueedi, Reyhan Sönmez, David Ding, Zoltán Kutalik, Sven Bergmann, Ana Claudia Marques Cell Reports 18(9):2280-2288 DOI: 10.1016/j.celrep.2017.02.009

Complex complexity. Dionisio

Intergenic long noncoding RNAs (lincRNAs) are the largest class of transcripts in the human genome. Although many have recently been linked to complex human traits, the underlying mechanisms for most of these transcripts remain undetermined. [...] TR-lincRNAs likely regulate proximal trait-relevant gene expression in cis by modulating local chromosomal architecture.

cis-Acting Complex-Trait-Associated lincRNA Expression Correlates with Modulation of Chromosomal Architecture Jennifer Yihong Tan, Adam Alexander Thil Smith, Maria Ferreira da Silva, Cyril Matthey-Doret, Rico Rueedi, Reyhan Sönmez, David Ding, Zoltán Kutalik, Sven Bergmann, Ana Claudia Marques Cell Reports 18(9):2280-2288 DOI: 10.1016/j.celrep.2017.02.009

Complex complexity. Dionisio

The paper "Pom1 gradient buffering through intermolecular auto-phosphorylation" is referenced @861, 1088, 1561. Dionisio

Discussion among biologists and philosophers is one way by which we may increase the awareness of our guiding assumptions. But progress requires that the evaluation of research methodologies goes beyond an analysis of the truth value of guiding assumptions, to study the productivity and pitfalls of epistemic tools used in practice.

Can biological complexity be reverse engineered? Green S Stud Hist Philos Biol Biomed Sci. 53:73-83. doi: 10.1016/j.shpsc.2015.03.008.

Complex complexity. Dionisio

The paper referenced @2760-2764 is also referenced @2829. Dionisio

[...] the notion of design principles is a regulative abstraction that illuminates how different mechanisms relate to general types due to common physical, functional and developmental constraints on the dynamics of the system. A systemic approach accounting for the concerted changes in expression levels of the network over time can better clarify aspects of the degeneracy, flexibility and evolvability of living systems. Integrating different methodological strategies is necessary because no single framework can uncover all relevant aspects of living systems. Modeling all measurable details of organisms does not necessarily provide the information needed for understanding how the system is functionally organized.

Can biological complexity be reverse engineered? Green S Stud Hist Philos Biol Biomed Sci. 53:73-83. doi: 10.1016/j.shpsc.2015.03.008.

Complex complexity. Dionisio

The major knowledge gap involves our understanding of how complex shape arises from, and is dynamically remodeled by, the physical activity and information processing of smaller subunits (not necessarily cells). A key aspect of top-down models that make them particularly appealing for the field of patterning and regeneration is that they offer an intuitive starting point to control outcomes that are too complex to implement directly. Future research should investigate in depth what models can be adapted from computational neuroscience to biological modelling—especially if the molecular conservation of mechanisms can be exploited for parallel insights into pattern memory. Future models of how cells interpret incoming signals may use a similar (predictive coding) scheme, not a purely feedforward scheme. Establishing a quantitative, predictive, mechanistic understanding of goal-directed morphogenesis will enrich many fields, forging new links to information and cognitive sciences, and perhaps even help neuroscientists understand the semantics of electrical states in the brain.

Top-down models in biology: explanation and control of complex living systems above the molecular level Giovanni Pezzulo and Michael Levin J R Soc Interface. 13(124): 20160555. doi: 10.1098/rsif.2016.0555

Complex complexity. Dionisio

Most biological phenomena are complex—they depend on the interplay of many factors [...] One of the most salient examples is the regulation of body anatomy. A single fertilized egg gives rise to a cell mass that reliably self-assembles into the complex three-dimensional structure of a body. Crucially, however, bioscience needs to understand more than the feedforward progressive emergence of a stereotypical pattern. [...] biological structures implement closed-loop controls that pursue shape homeostasis at many levels, from individual cells to the entire body plan.

Top-down models in biology: explanation and control of complex living systems above the molecular level Giovanni Pezzulo and Michael Levin J R Soc Interface. 13(124): 20160555. doi: 10.1098/rsif.2016.0555

Complex complexity. Dionisio

Future studies will have to determine which cues could contribute to the initial polarization of the lateral mesoderm. The fact that both BMP signaling as well as cadherin mechanotransduction contribute to mesoderm convergence underscores the notion that tissue morphogenesis is the combined result of regulation by chemical and mechanical cues. Future studies using the tools developed may elucidate additional aspects of zebrafish morphogenesis controlled by forces at cadherin junctions.

?E-catenin-dependent mechanotransduction is essential for proper convergent extension in zebrafish Mitchell K. L. Han, Esteban Hoijman, Emily Nöel, Laurence Garric, Jeroen Bakkers and Johan de Rooij Biol Open. 5(10): 1461–1472. doi: 10.1242/bio.021378

Complex complexity. Dionisio

Cadherin complexes mediate cell-cell adhesion and are crucial for embryonic development. Besides their structural function, cadherin complexes also transduce tension across the junction-actomyosin axis into proportional biochemical responses. Central to this mechanotransduction is the stretching of the cadherin-F-actin-linker ?-catenin, which opens its central domain for binding to effectors such as vinculin. [...] cadherin mechanotransduction is crucial for proper zebrafish morphogenesis, and uncover one of the essential processes affected by its perturbation.

?E-catenin-dependent mechanotransduction is essential for proper convergent extension in zebrafish Mitchell K. L. Han, Esteban Hoijman, Emily Nöel, Laurence Garric, Jeroen Bakkers and Johan de Rooij Biol Open. 5(10): 1461–1472. doi: 10.1242/bio.021378

Complex complexity. Dionisio

[...] villus topography may induce changes in the cortical contractility along the orthoradial direction from the bottom to the top, whereas cortical contractility remains isotropic on 2D substrates. We thus speculate that these changes of cell contractility may also promote tuft formation in absence of EpCAM, and further studies including various villus dimensions may help to clarify this point.

Contractile forces at tricellular contacts modulate epithelial organization and monolayer integrity. Salomon J, Gaston C, Magescas J, Duvauchelle B, Canioni D, Sengmanivong L, Mayeux A, Michaux G, Campeotto F, Lemale J, Viala J, Poirier F, Minc N, Schmitz J, Brousse N, Ladoux B, Goulet O, Delacour D Nat Commun. 2017 Jan 13;8:13998. doi: 10.1038/ncomms13998.

Complex complexity. Dionisio

[...] knowledge of the spatial activation of myosin-II and related kinases is fragmented, and distribution of the kinases responsible for myosin-II activation, taking into account the geometry of a columnar epithelial cell, remains to be clearly established. [...] the proper balance of cortical tension within epithelial tissues provides the link between tissue integrity and intercellular adhesion.

Contractile forces at tricellular contacts modulate epithelial organization and monolayer integrity. Salomon J, Gaston C, Magescas J, Duvauchelle B, Canioni D, Sengmanivong L, Mayeux A, Michaux G, Campeotto F, Lemale J, Viala J, Poirier F, Minc N, Schmitz J, Brousse N, Ladoux B, Goulet O, Delacour D Nat Commun. 2017 Jan 13;8:13998. doi: 10.1038/ncomms13998.

Complex complexity. Dionisio

[...] adequate distribution of cortical tension is crucial for individual cell organization, but also for epithelial monolayer maintenance. [...] EpCAM modulation protects against epithelial dysplasia and stabilizes human tissue architecture.

Contractile forces at tricellular contacts modulate epithelial organization and monolayer integrity. Salomon J, Gaston C, Magescas J, Duvauchelle B, Canioni D, Sengmanivong L, Mayeux A, Michaux G, Campeotto F, Lemale J, Viala J, Poirier F, Minc N, Schmitz J, Brousse N, Ladoux B, Goulet O, Delacour D Nat Commun. 2017 Jan 13;8:13998. doi: 10.1038/ncomms13998.

Complex complexity. Dionisio

In-depth understanding of the relative roles played by passive mechanical forces and buckling or wrinkling will require continued combination of experimental systems and computational models.

On Buckling Morphogenesis Celeste M. Nelson J Biomech Eng. 138(2): 0210051–0210056. doi: 10.1115/1.4032128

Complex complexity. Dionisio

One open question that remains, however, is how can this mechanical mechanism result in precise tissue architectures? That is, how does one achieve stereotypy with buckling morphogenesis? For example, the branches of the airways of the lungs are identical between individuals within a given species—How can buckling lead to such complexity and order?

On Buckling Morphogenesis Celeste M. Nelson J Biomech Eng. 138(2): 0210051–0210056. doi: 10.1115/1.4032128

Complex complexity. Dionisio

All organisms need a central processing unit, an ability to digest food into key nutrients, and a mechanism to acquire oxygen from their surrounding environment. Despite their different functions, the human brain, mouse gut, and bird lung all share one special feature: the tissues that make up these organs have an undulated topology, one that arises from an initially flat sheet of cells during embryonic development [...] These simple sheets are transformed in the embryo into complex three-dimensional structures through the process of morphogenesis.

On Buckling Morphogenesis Celeste M. Nelson J Biomech Eng. 138(2): 0210051–0210056. doi: 10.1115/1.4032128

Did somebody say "central processing unit"? :) Complex complexity. Dionisio

The genome encodes a gene regulatory network (GRN) that is switched on by environmental cues and, following the rules of transcriptional regulation, provides output signals to actuators. Whereas the genome represents the full encoding of the transcriptional network, the agent-based system mimics the active regulatory network and signal transduction system also present in naturally occurring biological systems.

Emergent adaptive behaviour of GRN-controlled simulated robots in a changing environment Yao Yao, Veronique Storme, Kathleen Marchal and Yves Van de Peer DOI: 10.7717/peerj.2812

Complex complexity. Dionisio

The assumption about the dual interaction between hb and Kr leads to the most consistent modeling results, but, on the other hand, may obscure existence of indirect interactions between binding sites in regulatory regions of distinct genes. The analysis confirms the previously formulated regulation concept of many weak binding sites working in concert. The model predicts a more or less uniform distribution of functionally important binding sites over the sets of experimentally characterized regulatory modules and other open chromatin domains. The construction of a quantitative genotype-phenotype map is one of the most challenging problems in current biology. [...] additional experimental validation is necessary to make a definite decision.

Analysis of functional importance of binding sites in the Drosophila gap gene network model Konstantin Kozlov, Vitaly V Gursky, Ivan V Kulakovskiy, Arina Dymova, Maria Samsonova DOI: 10.1186/1471-2164-16-S13-S7 BMC Genomics 16(Suppl 13):S7 http://www.biomedcentral.com/1471-2164/16/S13/S7

Complex complexity. Dionisio

Detailed descriptions of brain-scale sensorimotor circuits underlying vertebrate behavior remain elusive. We thus reveal how distributed neurons collaborate to generate behavior and illustrate a paradigm for distilling functional circuit models from whole-brain data.

From Whole-Brain Data to Functional Circuit Models: The Zebrafish Optomotor Response. Naumann EA, Fitzgerald JE, Dunn TW, Rihel J, Sompolinsky H, Engert F Cell. 167(4):947-960.e20. doi: 10.1016/j.cell.2016.10.019.

Complex complexity. Dionisio

One can envision a future in which every retinal cell type comes with a genetic handle, by which it can be visually marked or its function manipulated. Such a state of affairs would greatly enhance our ability to dissect neuronal circuitry, in the retina as elsewhere in the brain.

Eye smarter than scientists believed: Neural computations in circuits of the retina Tim Gollisch1 and Markus Meister Neuron. 65(2): 150–164. doi: 10.1016/j.neuron.2009.12.009

Complex complexity. Dionisio

Reverse-engineering the connectivity and function in a neural network made of 50 different component types is a daunting challenge. The task would be more plausible if each of the neuron types had a part number stamped on it, much as one finds for components in a radio. Actually, methods to tag specific cell types are now within reach.

Eye smarter than scientists believed: Neural computations in circuits of the retina Tim Gollisch1 and Markus Meister Neuron. 65(2): 150–164. doi: 10.1016/j.neuron.2009.12.009

Complex complexity. Dionisio

Whereas the conventional wisdom treats the eye as a simple prefilter for visual images, it now appears that the retina solves a diverse set of specific tasks and provides the results explicitly to downstream brain areas.

Eye smarter than scientists believed: Neural computations in circuits of the retina Tim Gollisch1 and Markus Meister Neuron. 65(2): 150–164. doi: 10.1016/j.neuron.2009.12.009

Complex complexity. Dionisio

[...] the degree to which the central transmission of retinal waves, or spontaneous activity in other systems, requires similar specializations is unknown. Spindle-bursts are not limited to VC, but are ubiquitous throughout neonatal cortex. [...] understanding their central generative mechanisms would be a critical contribution to neonatal health and development.

An excitatory cortical feedback loop gates retinal wave transmission in rodent thalamus Yasunobu Murata and Matthew T Colonnese eLife. 5: e18816. doi: 10.7554/eLife.18816

Work in progress... stay tuned. Complex complexity. Dionisio

Throughout the central nervous system, before the development of sensory input or behavioral experience, specialized circuitry generates spontaneous activity that is required for circuit formation [...] Retinal waves drive robust firing in LGN, superior colliculus, and VC (Ackman and Crair, 2014) through a complex interaction between these structures (Weliky and Katz, 1999) that remains poorly understood.

An excitatory cortical feedback loop gates retinal wave transmission in rodent thalamus Yasunobu Murata and Matthew T Colonnese eLife. 5: e18816. doi: 10.7554/eLife.18816

Complex complexity. Dionisio

The next step following on from this work is to find out how the braking mechanism forms in young animals. Future studies will also focus on understanding the precise role the booster circuit plays in early brain development.

An excitatory cortical feedback loop gates retinal wave transmission in rodent thalamus Yasunobu Murata and Matthew T Colonnese eLife. 5: e18816. doi: 10.7554/eLife.18816

Work in progress... stay tuned. Complex complexity. Dionisio

The brain of a developing fetus has a big job to do: it needs to create the important connections between neurons that the individual will need later in life. This is a challenge because the first connections that form between neurons are sparse, weak and unreliable. They would not be expected to be able to transmit signals in a robust or effective way, and yet they do. How the nervous system solves this problem is an important question [...]

An excitatory cortical feedback loop gates retinal wave transmission in rodent thalamus Yasunobu Murata and Matthew T Colonnese eLife. 5: e18816. doi: 10.7554/eLife.18816

Complex complexity. Dionisio

Spontaneous retinal waves are critical for the development of receptive fields in visual thalamus (LGN) and cortex (VC). [...] whether central circuit specializations also exist to control their propagation through visual pathways of the brain is unknown. [...] the early retino-thalamo-cortical circuit uses developmentally specialized feedback amplification to ensure powerful, high-fidelity transmission of retinal activity despite immature connectivity.

An excitatory cortical feedback loop gates retinal wave transmission in rodent thalamus Yasunobu Murata and Matthew T Colonnese eLife. 5: e18816. doi: 10.7554/eLife.18816

Complex complexity. Dionisio

Neuronal activity has been shown to be essential for the proper formation of neuronal circuits, affecting developmental processes like neurogenesis, migration, programmed cell death, cellular differentiation, formation of local and long-range axonal connections, synaptic plasticity or myelination. Accordingly, neocortical areas reveal distinct spontaneous and sensory-driven neuronal activity patterns already at early phases of development. [...] spontaneous activity patterns become more complex, involve larger networks and propagate over several neocortical areas. [...] a number of key questions remain to be addressed in the near future: [...]

Spontaneous Neuronal Activity in Developing Neocortical Networks: From Single Cells to Large-Scale Interactions Heiko J. Luhmann, Anne Sinning, Jenq-Wei Yang, Vicente Reyes-Puerta, Maik C. Stüttgen, Sergei Kirischuk and Werner Kilb Front Neural Circuits. 10: 40. doi: 10.3389/fncir.2016.00040

Complex complexity. Dionisio

Infancy, childhood, and adolescence are times of dramatic change in the brain, characterized by widespread synaptogenesis, myelination, and synaptic pruning. During these years, spindle amplitude, duration, density, frequency, and topology change. [...] sleep spindles change over the course of a lifetime, in parallel with the multitude of changes in the developing and aging brain. Spindles may serve different functions throughout the lifespan. Future studies focused on age-specific brain anatomical and functional differences will ultimately help us understand these functions.

Form and Function of Sleep Spindles across the Lifespan. Clawson BC, Durkin J, Aton SJ Neural Plast. 2016:6936381. doi: 10.1155/2016/6936381.

Complex complexity. Dionisio

[...] a major gap in our knowledge remains with regard to causality. We currently do not know for certain whether (and how) network activity in wakefulness promotes local spindle activity. Neither do we know whether (and how) global and local spindles contribute to thalamocortical network plasticity and cognitive functions associated with this plasticity.

Form and Function of Sleep Spindles across the Lifespan. Clawson BC, Durkin J, Aton SJ Neural Plast. 2016:6936381. doi: 10.1155/2016/6936381.

Complex complexity. Dionisio

Since the advent of EEG recordings, sleep spindles have been identified as hallmarks of non-REM sleep. Despite a broad general understanding of mechanisms of spindle generation gleaned from animal studies, the mechanisms underlying certain features of spindles in the human brain, such as "global" versus "local" spindles, are largely unknown. Neither the topography nor the morphology of sleep spindles remains constant throughout the lifespan. It is likely that changes in spindle phenomenology during development and aging are the result of dramatic changes in brain structure and function.

Form and Function of Sleep Spindles across the Lifespan. Clawson BC, Durkin J, Aton SJ Neural Plast. 2016:6936381. doi: 10.1155/2016/6936381.

Complex complexity. Dionisio

It is the persistence of twitching into adulthood, in humans and other mammals, that raises the intriguing possibility that twitching has much more to reveal to us about its functional contributions to neural plasticity within the sensorimotor system. If evidence of twitch-related spindle bursts is found, there will be a strong basis for expanding our understanding of the functions of spindle activity during non-REM sleep—about which we currently know a lot—to include REM sleep as well.

The Case of the Disappearing Spindle Burst Alexandre Tiriac and Mark S. Blumberg Neural Plast. 2016: 3467832. doi: 10.1155/2016/3467832

Complex complexity. Dionisio

The cerebral cortex of mammals, including humans, displays oscillatory spindle activity (10–15?Hz) across the lifespan. In adults, sleep spindles, a specific type of spindle activity, occur exclusively during non-REM sleep [1–4] and have been implicated in memory retention and skill learning [5–7]. In humans, sleep spindles first appear 4–9 weeks postterm and become more prominent and frequent over the next several months [2]. There exists another type of spindle activity—called spindle bursts—that is phenomenologically similar to sleep spindles in that they share a similar frequency range, duration, and spindle-shaped waveform [8]. However, spindle bursts differ from sleep spindles in a variety of ways.

The Case of the Disappearing Spindle Burst Alexandre Tiriac and Mark S. Blumberg Neural Plast. 2016: 3467832. doi: 10.1155/2016/3467832

Complex complexity. Dionisio

The more biology research papers get reviewed, it seems like the complex complexity is getting more complex, doesn't it? :) Dionisio

Curiously, despite the persistence of twitching into adulthood, twitch-related spindle bursts have not been reported in adult sensorimotor cortex. This raises the question of whether such spindle burst activity does not occur in adulthood or, alternatively, occurs but has yet to be discovered. If twitch-related spindle bursts do occur in adults, they could contribute to the calibration, maintenance, and repair of sensorimotor systems.

The Case of the Disappearing Spindle Burst Alexandre Tiriac and Mark S. Blumberg Neural Plast. 2016: 3467832. doi: 10.1155/2016/3467832

Complex complexity. Dionisio

Sleep spindles are brief cortical oscillations at 10–15?Hz that occur predominantly during non-REM (quiet) sleep in adult mammals and are thought to contribute to learning and memory. Spindle bursts are phenomenologically similar to sleep spindles, but they occur predominantly in early infancy and are triggered by peripheral sensory activity (e.g., by retinal waves); accordingly, spindle bursts are thought to organize neural networks in the developing brain and establish functional links with the sensory periphery.

The Case of the Disappearing Spindle Burst Alexandre Tiriac and Mark S. Blumberg Neural Plast. 2016: 3467832. doi: 10.1155/2016/3467832

Complex complexity. Dionisio

Causal links from specific cellular mechanisms to oscillatory activity need to be established. Knowledge about NSB-related plasticity, especially, is still sparse.

Spindle Activity Orchestrates Plasticity during Development and Sleep Christoph Lindemann, Joachim Ahlbeck, Sebastian H. Bitzenhofer and Ileana L. Hanganu-Opatz Neural Plast. 2016: 5787423. doi: 10.1155/2016/5787423

Work in progress... stay tune. Complex complexity. Dionisio

ASSs and NSBs represent distinct patterns of network synchronization in the adult and developing brain. While ASSs support memory consolidation through synchronous activation of large cortical areas, NSBs coordinate the maturation of local neocortical networks. Both patterns coordinate activity in sensory and limbic systems and modulate local plasticity critical for network refinement.

Spindle Activity Orchestrates Plasticity during Development and Sleep Christoph Lindemann, Joachim Ahlbeck, Sebastian H. Bitzenhofer and Ileana L. Hanganu-Opatz Neural Plast. 2016: 5787423. doi: 10.1155/2016/5787423

Complex complexity. Dionisio

Information processing within the brain critically depends on rhythmic oscillatory activity that synchronizes neuronal networks. Synchronization leads to local and global coupling of network elements and times neuronal firing. By these means, it enables the precise selection of relevant information.

Spindle Activity Orchestrates Plasticity during Development and Sleep Christoph Lindemann, Joachim Ahlbeck, Sebastian H. Bitzenhofer and Ileana L. Hanganu-Opatz Neural Plast. 2016: 5787423. doi: 10.1155/2016/5787423

Complex complexity. Dionisio

Spindle oscillations have been described during early brain development and in the adult brain. Besides similarities in temporal patterns and involved brain areas, neonatal spindle bursts (NSBs) and adult sleep spindles (ASSs) show differences in their occurrence, spatial distribution, and underlying mechanisms.

Spindle Activity Orchestrates Plasticity during Development and Sleep Christoph Lindemann, Joachim Ahlbeck, Sebastian H. Bitzenhofer and Ileana L. Hanganu-Opatz Neural Plast. 2016: 5787423. doi: 10.1155/2016/5787423

Complex complexity. Dionisio

[...] neuronal activity impacts the development and integration of cortical interneurons, by influencing their migration and maturation [...] [...] activity-dependent transcription programs control the electrophysiological properties and output of mature interneurons. [...] a complex, dynamic interplay between intrinsic genetic programs and environmental influences shape cortical circuits from early developmental stages into adulthood. [...] it is of high importance to determine the factors regulating interneuron maturation [...]

Neuronal activity controls the development of interneurons in the somatosensory cortex Rachel Babij and Natalia De Marco Garcia Front Biol (Beijing). 11(6): 459–470. doi: 10.1007/s11515-016-1427-x

Did somebody say "programs"? :) Complex complexity. Dionisio

[...] neuronal activity is required for the proper regulation of GABA expression in mature interneurons. [...] the expression of GABA-synthesizing enzymes, glutamic acid decarboxylase (GAD) ?65 and 67, is also activity dependent [...] [...] activity can influence interneuron output even after these neurons become integrated into the mature circuit.

Neuronal activity controls the development of interneurons in the somatosensory cortex Rachel Babij and Natalia De Marco Garcia Front Biol (Beijing). 11(6): 459–470. doi: 10.1007/s11515-016-1427-x

Complex complexity. Dionisio

[...] cortical activity can trigger changes in intrinsic properties in the adult animal. [...] Er81, a member of the ETS family of transcription factors that delineates PV interneurons in layers II/III, is required for the modulation of their intrinsic properties in mature animals. It would be interesting to assess whether the expression of genes that confer interneurons with subtype identity are also subject changes in neuronal excitability.

Neuronal activity controls the development of interneurons in the somatosensory cortex Rachel Babij and Natalia De Marco Garcia Front Biol (Beijing). 11(6): 459–470. doi: 10.1007/s11515-016-1427-x

Complex complexity. Dionisio

Development of neocortical areas follows a defined sequence in which excitatory and inhibitory neurons, generated in the dorsal and ventral telencephalon respectively, migrate to their final locations [...] As they mature, neurons participate in nascent electrical patterns, and ultimately extend dendritic and axonal branches to form functional connections. During these periods, proper development is dependent not only on genetic patterns and progression of intrinsic programs, but also on the activity of input connections [...]

Neuronal activity controls the development of interneurons in the somatosensory cortex Rachel Babij and Natalia De Marco Garcia Front Biol (Beijing). 11(6): 459–470. doi: 10.1007/s11515-016-1427-x

Did somebody say "programs"? :) Complex complexity. Dionisio

Neuronal activity shapes the developmental assembly of functional circuitry in the somatosensory cortical interneurons. This activity impacts nearly every aspect of development and acquisition of mature neuronal characteristics, and may contribute to changing phenotypes, altered transmitter expression, and plasticity in the adult. Progressively changing oscillatory network patterns contribute to this activity in the early postnatal period, although a direct requirement for specific patterns and origins of activity remains to be demonstrated.

Neuronal activity controls the development of interneurons in the somatosensory cortex Rachel Babij and Natalia De Marco Garcia Front Biol (Beijing). 11(6): 459–470. doi: 10.1007/s11515-016-1427-x

Complex complexity. Dionisio

[...] it is unclear to what extent and how this activity connects to other cortical and subcortical regions [...] [...] it remains to be studied whether the immature brain shows a spindle burst related “resting state” and how this network state is altered by sensory activation or by pathophysiological events. [...] it would be most interesting and important to correlate specific patterns of spontaneous activity (e.g., delta brush) recorded by means of full-band direct-current EEG in preterm und full-term human neonates with the acute functional state and with the further development of the child [...]

Spindle Bursts in Neonatal Rat Cerebral Cortex. Yang JW, Reyes-Puerta V, Kilb W, Luhmann HJ Neural Plast. 2016;2016:3467832. doi: 10.1155/2016/3467832 .

Complex complexity. Dionisio

Network-driven spindle-like oscillations are a functional hallmark of the developing cerebral cortex. [...] it remains an open question whether the specific properties of spindle burst are required or fulfill a distinct role in development. [...] the role of GABAergic synaptic activity during spindle bursts is currently unclear. [...] it is tempting to speculate that spindle bursts control the spatially confined release of GABA in developing local networks.

Spindle Bursts in Neonatal Rat Cerebral Cortex. Yang JW, Reyes-Puerta V, Kilb W, Luhmann HJ Neural Plast. 2016;2016:3467832. doi: 10.1155/2016/3467832.

Complex complexity. Dionisio

[...] it is reasonable to suggest that spindle bursts represent the network correlate of NMDA receptor mediated activity-dependent plasticity in the developing cortex. In the adult, SWA is a prominent pattern activity seen during sleep or light sedation. In the developing brain, spindle bursts are the dominant feature of sleep activity. The precise roles for spindle bursts remain unclear, but their contribution in synaptogenesis and circuit connectivity is unquestionable. [...] the independence of these patterns is a key message regarding the spontaneous activity of the brain. We believe it is neither noise nor a wasteful consequence of brain structure; it is an useful activity, purposefully generated, and used for specific and definable purposes.

Large Scale Cortical Functional Networks Associated with Slow-Wave and Spindle-Burst-Related Spontaneous Activity David A. McVea, Timothy H. Murphy and Majid H. Mohajerani Front Neural Circuits. 10: 103. doi: 10.3389/fncir.2016.00103

Complex complexity. Dionisio

Cortical sensory systems are active with rich patterns of activity during sleep and under light anesthesia. Remarkably, this activity shares many characteristics with those present when the awake brain responds to sensory stimuli. While the sleep-related functions of both slow-wave and spindle-burst activity may not be entirely clear, they reflect robust regulated phenomena which can engage select wide-spread cortical circuits. These circuits are similar to those activated during sensory processing and volitional events. [...] prominent and well-studied forms of spontaneous activity that will yield valuable insights into brain function in the coming years.

Large Scale Cortical Functional Networks Associated with Slow-Wave and Spindle-Burst-Related Spontaneous Activity David A. McVea, Timothy H. Murphy and Majid H. Mohajerani Front Neural Circuits. 10: 103. doi: 10.3389/fncir.2016.00103

Complex complexity. Dionisio

More statistics will make it possible to build more explicit models of Bicoid dependent activation. [...] the precision in determining the position of the nuclei is not only encoded in the time averaged gene readout, but probably relies either on spatial averaging mechanisms [...] or more detailed features of the temporal information encoded in the full trace [...] [...] transcription is a bursty process with relatively large inter-nuclei variability, suggesting that simply the templated one to one time-averaged readout of the Bicoid gradient is unlikely. Comparing mutant experiments can shed light on exactly how the decision to form the sharp hunchback mRNA and protein boundary is made.

Precision of Readout at the hunchback Gene: Analyzing Short Transcription Time Traces in Living Fly Embryos Jonathan Desponds, Huy Tran, Teresa Ferraro, Tanguy Lucas, Carmina Perez Romero, Aurelien Guillou, Cecile Fradin, Mathieu Coppey, Nathalie Dostatni, Aleksandra M. Walczak PLoS Computational Biology 12(12): e1005256. DOI: 10.1371/journal.pcbi.1005256

Complex complexity. Dionisio

[...] mRNAs are generally produced in bursts, which result from periods of activation and inactivation. [...] the promoter has distinct periods of enhanced polymerase transcription followed by identifiable periods of basal polymerase activity. [...] the promoter states cycle through at least three states [...] In one of these states the polymerase transcribes at enhanced levels, while in most of the remaining states the transcription machinery gets reassembled or the chromatin remodels. [...] independently of the question of the nature of the bursts, it would be very interesting to see whether and how it changes when the nature of regulation changes.

Precision of Readout at the hunchback Gene: Analyzing Short Transcription Time Traces in Living Fly Embryos Jonathan Desponds, Huy Tran, Teresa Ferraro, Tanguy Lucas, Carmina Perez Romero, Aurelien Guillou, Cecile Fradin, Mathieu Coppey, Nathalie Dostatni, Aleksandra M. Walczak PLoS Computational Biology 12(12): e1005256. DOI: 10.1371/journal.pcbi.1005256

Complex complexity. Dionisio

[...] the initial mRNA readout of the maternal Bicoid gradient by the hunchback gene is remarkably accurate and reproducible between embryos [...] [...] it is highly expressed in the anterior part of the embryo, quickly decreasing in the middle and not expressed in the posterior part. This precision is even more surprising given the very short duration of the cell cycles (6±15 minutes) during which the initial Bicoid readout takes place and the intrinsic molecular noise in transcription regulation [...]

Precision of Readout at the hunchback Gene: Analyzing Short Transcription Time Traces in Living Fly Embryos Jonathan Desponds, Huy Tran, Teresa Ferraro, Tanguy Lucas, Carmina Perez Romero, Aurelien Guillou, Cecile Fradin, Mathieu Coppey, Nathalie Dostatni, Aleksandra M. Walczak PLoS Computational Biology 12(12): e1005256. DOI: 10.1371/journal.pcbi.1005256

remarkably accurate? hmm... This precision is even more surprising? precision? surprising? why surprising? Complex complexity. Dionisio

#2776 error correction: The word "different" was misspelled. Dionisio

The same paper referenced @1404 & @1560.

Only accessible information is useful: insights from gradient-mediated patterning Mikhail Tikhonov, Shawn C. Little, Thomas Gregor DOI: 10.1098/rsos.150486 http://rsos.royalsocietypublishing.org/content/2/11/150486

Dionisio

The search for real theories is more ambitious. It is important that we have concrete examples of biological systems that are operating near an optimum of information transmission or efficiency of representation, [...] [...] we don’t know is whether these are isolated instances, or examples of a general principle. [...] we believe that the coming years will see much more meaningful confrontations between theory and experiment, in a wide range of systems.

Information processing in living systems Gasper Tkacik and William Bialek DOI: 10.1146/annurev-conmatphys-031214-014803 arXiv:1412.8752 [q-bio.QM] arXiv:1412.8752v1 [q-bio.QM]

Complex complexity. Dionisio

[...] connections between information and the phenomena of life have two very different flavors, one grounded in data and the other aiming for a theory in which the behaviors of real biological systems are derivable from some sort of optimization principle.

Information processing in living systems Gasper Tkacik and William Bialek DOI: 10.1146/annurev-conmatphys-031214-014803 arXiv:1412.8752 [q-bio.QM] arXiv:1412.8752v1 [q-bio.QM]

Complex complexity. Dionisio

Cells and organisms sense, compute, and make decisions: to proliferate, to find food, to protect themselves against predators and unfavorable environmental changes, to act in unison with their neighbors within a collective, and—broadly speaking—to invest their limited resources to their maximal benefit.

Information processing in living systems Gasper Tkacik and William Bialek DOI: 10.1146/annurev-conmatphys-031214-014803 arXiv:1412.8752 [q-bio.QM] arXiv:1412.8752v1 [q-bio.QM]

cells make decisions? Wow! Complex complexity. Dionisio

Life depends as much on the flow of information as on the flow of energy. Many of these analyses are motivated by the idea that biological systems may have evolved to optimize the gathering and representation of information.

Information processing in living systems Gasper Tkacik and William Bialek DOI: 10.1146/annurev-conmatphys-031214-014803 arXiv:1412.8752 [q-bio.QM] arXiv:1412.8752v1 [q-bio.QM]

may have evolved to optimize? huh? say what? evolved with a goal? evolution with purpose? Complex complexity. Dionisio

During development the dierent identities of cells are determined by sequentially expressing particular subsets of genes in dierent parts of the embryo. Proper development relies on the correct spatial-temporal assignment of cell types. [...] the initial information about the position along the anterior-posterior (AP) axis is encoded in the exponentially decaying Bicoid gradient.

Precision of readout at the hunchback gene Jonathan Desponds, Huy Tran, Teresa Ferraro, Tanguy Lucas, Carmina Perez Romero, Aurelien Guillou, Cecile Fradin, Mathieu Coppey, Nathalie Dostatni, Aleksandra M Walczak doi: https://doi.org/10.1101/063784 PLOS Computational Biology doi: 10.1371/journal.pcbi.1005256

Complex complexity. Dionisio

[...] the precision of the expression of the hunchback gene to measure its position along the anterior-posterior axis is low both at the boundary and in the anterior even at cycle 13, suggesting additional post-translational averaging mechanisms to provide the precision observed in fixed material.

Precision of readout at the hunchback gene Jonathan Desponds, Huy Tran, Teresa Ferraro, Tanguy Lucas, Carmina Perez Romero, Aurelien Guillou, Cecile Fradin, Mathieu Coppey, Nathalie Dostatni, Aleksandra M Walczak doi: https://doi.org/10.1101/063784 PLOS Computational Biology doi: 10.1371/journal.pcbi.1005256

Complex complexity. Dionisio

It is commonly agreed that the most challenging problems in modern science and engineering involve the concurrent and nonlinear interaction of multiple phenomena, acting on a broad and disparate spectrum of scales in space and time. The multiscale and multi-level nature of these problems commands a paradigm shift in the way they need to be handled, both conceptually and in terms of the corresponding problem-solving computational tools.

Bridging the gaps at the physics–chemistry–biology interface P. V. Coveney,1 J. P. Boon,2 and S. Succi Philos Trans A Math Phys Eng Sci. 374(2080): 20160335. doi: 10.1098/rsta.2016.0335

Complex complexity. Dionisio

Complex interactions between the host immune system and microbiota are of dynamic nature and hence, of fundamental importance when homeostasis is considered, as the host is exposed to trillions of indigenous microorganisms; bacteria, archaea, fungi, and viruses [...]

Pharmacometabolomics Informs Viromics toward Precision Medicine Angeliki Balasopoulou,1 George P. Patrinos,1,2 and Theodora Katsila Front Pharmacol. 7: 411. doi: 10.3389/fphar.2016.00411

Dionisio

[...] through collection, analyses and sharing of standardized medically relevant data globally, evidence-based precision medicine will shift progressively from therapy to prevention, thus leading eventually to improved, clinician-to-patient communication, citizen-centered healthcare and sustained well-being.

Reconciling evidence-based medicine and precision medicine in the era of big data: challenges and opportunities. Beckmann JS, Lew D. Genome Med. ;8(1):134. DOI: 10.1186/s13073-016-0388-7

Dionisio

We anticipate that our metabolomics community will have representation in large precision medicine initiatives to provide input with regard to sample acquisition/preservation, selection of optimal omics technologies, and key issues regarding data collection, interpretation, and dissemination. We strongly recommend the collection and biobanking of samples for precision medicine initiatives that will take into consideration needs for large-scale metabolic phenotyping studies.

Metabolomics enables precision medicine: "A White Paper, Community Perspective". Beger RD1, Dunn W2, Schmidt MA3, Gross SS4, Kirwan JA5, Cascante M6, Brennan L7, Wishart DS8, Oresic M9, Hankemeier T10, Broadhurst DI11, Lane AN12, Suhre K13, Kastenmüller G14, Sumner SJ15, Thiele I16, Fiehn O17, Kaddurah-Daouk R18; for “Precision Medicine and Pharmacometabolomics Task Group”-Metabolomics Society Initiative Metabolomics. 2016;12(10):149. Epub 2016 Sep 2. DOI: 10.1007/s11306-016-1094-6

Dionisio

[...] the predictive power of genetic testing could be improved by taking a more comprehensive view of human genetics that encompasses our human and microbial genomes. Furthermore, unlike the human genome, the microbiome is rapidly altered by diet, pharmaceuticals, and other interventions, providing the potential to improve patient care by re-shaping our associated microbial communities.

Mirror, mirror on the wall: which microbiomes will help heal them all? Renuka R. Nayak and Peter J. Turnbaugh BMC Med. 14: 72. doi: 10.1186/s12916-016-0622-6

Complex complexity. Dionisio

Intuitively, the explanatory power of models would increase as the number of molecular details increase. Failing to account for environmental and systemic constraints on lower-scale processes often result in a failure to understand the functionality of the system (Noble, 2012). The requirement of boundary conditions to represent such top-down influences may thus provide a concrete interpretation of top-down effects. Taken together, these aspects provide resistance to the view that macroscale properties are dispensable for explaining multi-scale biological systems.

Biology meets Physics: Reductionism and Multi-scale Modeling of Morphogenesis Sara Greena, Robert Batterman DOI: 10.1016/j.shpsc.2016.12.003 http://philsci-archive.pitt.edu/12711/

Complex complexity. Dionisio

[...] although the composition of polypeptides is reducible to a sequence of amino acids, it has been argued that it is not possible to explain protein folding from physical laws and knowledge about amino acids alone (Love & Hütteman, 2011).

Biology meets Physics: Reductionism and Multi-scale Modeling of Morphogenesis Sara Greena, Robert Batterman DOI: 10.1016/j.shpsc.2016.12.003 http://philsci-archive.pitt.edu/12711/

Complex complexity. Dionisio

The view that an ideal or fundamental physics would be sufficient to explain all macro-scale phenomena has been met with criticism from philosophers of biology. Scholars have stressed the irreducibility of biological features [...] [...] biological explanations are irreducible to physical laws and principles (e.g., Bechtel & Richardson, 1993; Bertalanffy, 1969; Burian et al., 1996; Dupré, 1993; Machamer et al., 2000; Mayr, 1988; 2004; Winther, 2009)

Biology meets Physics: Reductionism and Multi-scale Modeling of Morphogenesis Sara Greena, Robert Batterman DOI: 10.1016/j.shpsc.2016.12.003 http://philsci-archive.pitt.edu/12711/

Complex complexity. Dionisio

An important reductionist assumption is that multi-scale systems can be described “bottom-up”, if only sufficient details about the states of the components are available. Historically, this assumption has been debated in philosophical discussions about whether biology is reducible to physics.

Biology meets Physics: Reductionism and Multi-scale Modeling of Morphogenesis Sara Greena, Robert Batterman DOI: 10.1016/j.shpsc.2016.12.003 http://philsci-archive.pitt.edu/12711/

Complex complexity. Dionisio

A common reductionist assumption is that macro-scale behaviors can be described "bottom-up" if only sufficient details about lower-scale processes are available. The view that an "ideal" or "fundamental" physics would be sufficient to explain all macro-scale phenomena has been met with criticism from philosophers of biology. Specifically, scholars have pointed to the impossibility of deducing biological explanations from physical ones, and to the irreducible nature of distinctively biological processes such as gene regulation and evolution.

Biology meets Physics: Reductionism and Multi-scale Modeling of Morphogenesis Sara Greena, Robert Batterman DOI: 10.1016/j.shpsc.2016.12.003 http://philsci-archive.pitt.edu/12711/

Complex complexity. Dionisio

Systems biology is a relatively new interdisciplinary approach that applies mathematical modeling and engineering approaches to the interpretation of biological datasets on regulatory interactions (e.g. gene regulation). An example is the pioneering work on motif-detection in transcriptional regulatory networks by Uri Alon’s group, at the Weizmann Institute of Science, Israel

Can biological complexity be reverse engineered? Green S Stud Hist Philos Biol Biomed Sci. 53:73-83. doi: 10.1016/j.shpsc.2015.03.008.

Professor Uri Alon's 2014 course is available online. Is it criticized here? Why? Complex complexity. Dionisio

Request for clarification: Is this paper referenced @2760-2762 addressing a potential conflict between the approaches of traditional experimental biologists and systems biologists or neuroscience researchers? Are they raising an alarm in light of the growing number of references to design principles in biology? This paper mentions the word "design" or "designed" many times. Also are the papers referenced @2752-2754 and @2755-2759 respectively related to a criticism of certain systems biology concepts or approaches that may be considered biased by some traditional experimental biologists? Can somebody comment on this? Here's the paper: https://www.researchgate.net/profile/Sara_Green3/publication/275360137_Can_biological_complexity_be_reverse_engineered/links/557563eb08aeacff1ffcd01b/Can-biological-complexity-be-reverse-engineered.pdf Dionisio

[...] they criticize so-called reverse engineering approaches for investigating biological systems as if these were programmed and fully decomposable engineering systems, designed to conduct pre-designed functions

Can biological complexity be reverse engineered? Green S Stud Hist Philos Biol Biomed Sci. 53:73-83. doi: 10.1016/j.shpsc.2015.03.008.

apparently somebody is concerned about the idea of things being designed Complex complexity. Dionisio

Reverse engineering methodologies are currently gaining terrain in biological fields such as systems biology and neuroscience. In response to these developments, experimental biologists have raised concerns regarding the associated quest for design principles that they take to imply an assumption of a rather static and modular design of organisms.

Can biological complexity be reverse engineered? Green S Stud Hist Philos Biol Biomed Sci. 53:73-83. doi: 10.1016/j.shpsc.2015.03.008.

Complex complexity. Dionisio

Concerns with the use of engineering approaches in biology have recently been raised. I examine two related challenges to biological research that I call the synchronic and diachronic underdetermination problem. The former refers to challenges associated with the inference of design principles underlying system capacities when the synchronic relations between lower-level processes and higher-level systems capacities are degenerate (many-to-many). The diachronic underdetermination problem regards the problem of reverse engineering a system where the non-linear relations between system capacities and lower-level mechanisms are changing over time. Braun and Marom argue that recent insights to biological complexity leave the aim of reverse engineering hopeless - in principle as well as in practice. While I support their call for systemic approaches to capture the dynamic nature of living systems, I take issue with the conflation of reverse engineering with naïve reductionism. I clarify how the notion of design principles can be more broadly conceived and argue that reverse engineering is compatible with a dynamic view of organisms. It may even help to facilitate an integrated account that bridges the gap between mechanistic and systems approaches.

Can biological complexity be reverse engineered? Green S Stud Hist Philos Biol Biomed Sci. 53:73-83. doi: 10.1016/j.shpsc.2015.03.008.

Complex complexity. Dionisio

Biological objects, i.e., organisms, are specific and hence they are not interchangeable. [...] biological objects are the result of a history that represents a cascade of changes of their regularities, they exhibit variability and show contextuality; unlike inert objects they are agents. [...] the zygote is both a cell and an organism, and with each cell division, these two levels of individuation become more obvious.

Toward a theory of organisms: Three founding principles in search of a useful integration Ana M. Soto, Giuseppe Longo, Paul-Antoine Miquel, Maël Montevil, Matteo Mossio, Nicole Perret, Arnaud Pocheville, Carlos Sonnenschein http://dx.doi.org/10.1016/j.pbiomolbio.2016.07.006 Progress in Biophysics and Molecular Biology Volume 122, Issue 1, Pages 77–82 From the Century of the Genome to the Century of the Organism: New Theoretical Approaches Edited By Ana M Soto, Giuseppe Longo and Denis Noble

Complex complexity. Dionisio

[...] organismal biology still lacks a widely accepted global theory. [...] biological systems are characterized by the simultaneous co-existence of opposites as exemplified by change and stability, the incomplete separation between internal and external (topology), and before and after (time) the notions of extended present, memory and anticipation [...] [...] the system is historical and in relentless change from fertilization to death, being built and remodeled throughout life.

Toward a theory of organisms: Three founding principles in search of a useful integration Ana M. Soto, Giuseppe Longo, Paul-Antoine Miquel, Maël Montevil, Matteo Mossio, Nicole Perret, Arnaud Pocheville, Carlos Sonnenschein http://dx.doi.org/10.1016/j.pbiomolbio.2016.07.006 Progress in Biophysics and Molecular Biology Volume 122, Issue 1, Pages 77–82 From the Century of the Genome to the Century of the Organism: New Theoretical Approaches Edited By Ana M Soto, Giuseppe Longo and Denis Noble

Complex complexity. Dionisio

[...] three principles are proposed to postulate a theory of organisms, namely: 1) the default state of proliferation with variation and motility, which is rooted in the cell theory, 2) the principle of organization, and 3) the principle of variation which applies to morphogenesis and inheritance.

Toward a theory of organisms: Three founding principles in search of a useful integration Ana M. Soto, Giuseppe Longo, Paul-Antoine Miquel, Maël Montevil, Matteo Mossio, Nicole Perret, Arnaud Pocheville, Carlos Sonnenschein http://dx.doi.org/10.1016/j.pbiomolbio.2016.07.006 Progress in Biophysics and Molecular Biology Volume 122, Issue 1, Pages 77–82 From the Century of the Genome to the Century of the Organism: New Theoretical Approaches Edited By Ana M Soto, Giuseppe Longo and Denis Noble

Complex complexity. Dionisio

The first decade of the new millennium was dubbed as the beginning of “the post-genomic era.” Its arrival was greeted by the biological sciences establishment and the pharmaceutical industry with the exceedingly optimistic view that new technology and the usual reductionist approaches that characterized the last half of the 20th century [...] [...] the limitations posed by the hegemonic, reductionist, dominant world view which is metaphor rich and theory poor.

Toward a theory of organisms: Three founding principles in search of a useful integration Ana M. Soto, Giuseppe Longo, Paul-Antoine Miquel, Maël Montevil, Matteo Mossio, Nicole Perret, Arnaud Pocheville, Carlos Sonnenschein http://dx.doi.org/10.1016/j.pbiomolbio.2016.07.006 Progress in Biophysics and Molecular Biology Volume 122, Issue 1, Pages 77–82 From the Century of the Genome to the Century of the Organism: New Theoretical Approaches Edited By Ana M Soto, Giuseppe Longo and Denis Noble

Dionisio

Organisms, be they uni- or multi-cellular, are agents capable of creating their own norms; they are continuously harmonizing their ability to create novelty and stability, that is, they combine plasticity with robustness. [...] principles for a theory of organisms [...] [1] the default state of proliferation with variation and motility, [2] the principle of variation and [3] the principle of organization. These principles profoundly change both biological observables and their determination with respect to the theoretical framework of physical theories. This radical change opens up the possibility of anchoring mathematical modeling in biologically proper principles

Toward a theory of organisms: Three founding principles in search of a useful integration Ana M. Soto, Giuseppe Longo, Paul-Antoine Miquel, Maël Montevil, Matteo Mossio, Nicole Perret, Arnaud Pocheville, Carlos Sonnenschein http://dx.doi.org/10.1016/j.pbiomolbio.2016.07.006 Progress in Biophysics and Molecular Biology Volume 122, Issue 1, Pages 77–82 From the Century of the Genome to the Century of the Organism: New Theoretical Approaches Edited By Ana M Soto, Giuseppe Longo and Denis Noble

Complex complexity. Dionisio

Often times, modelers entering biological research treat biological objects as if they were either physical objects or computer programs. [...] the metaphorical use of information pushes the experimenter to seek causality in terms of discrete structures, namely molecules, in particular DNA. In this initial modeling effort, applying the two principles (default state and constraints leading to closure) were sufficient to show the formation of ducts and acini. Cells generated forces that were transmitted to neighboring cells and collagen fibers, which in turn created constraints to movement and proliferation.

Modeling mammary organogenesis from biological first principles: Cells and their physical constraints Maël Montévil, Lucia Speroni, Carlos Sonnenschein, Ana M. Soto DOI: http://dx.doi.org/10.1016/j.pbiomolbio.2016.08.004 Progress in Biophysics and Molecular Biology Volume 122, Issue 1, Pages 58–69 From the Century of the Genome to the Century of the Organism: New Theoretical Approaches Edited By Ana M Soto, Giuseppe Longo and Denis Noble

Complex complexity. Dionisio

Scientific theories provide organizing principles and construct objectivity by framing observations and experiments (Longo & Soto, this issue). On the one hand, theories construct the proper observables and on the other they provide the framework for studying them. [...] a theory does not need to be “right” to guide the praxis of good experiments. Even a wrong theory can be useful if, when proven incorrect it is modified or even dismissed. [...] the application of the principles we propose to use for the construction of a theory of organisms results in a better understanding of morphogenesis (the generation of biological form) than the common practice of using metaphors derived from the mathematical theory of information as theoretical background [...]

Modeling mammary organogenesis from biological first principles: Cells and their physical constraints Maël Montévil, Lucia Speroni, Carlos Sonnenschein, Ana M. Soto DOI: http://dx.doi.org/10.1016/j.pbiomolbio.2016.08.004 Progress in Biophysics and Molecular Biology Volume 122, Issue 1, Pages 58–69 From the Century of the Genome to the Century of the Organism: New Theoretical Approaches Edited By Ana M Soto, Giuseppe Longo and Denis Noble

Complex complexity. Dionisio

In multicellular organisms, relations among parts and between parts and the whole are contextual and interdependent. These organisms and their cells are ontogenetically linked: an organism starts as a cell that divides producing non-identical cells, which organize in tri-dimensional patterns. These association patterns and cells types change as tissues and organs are formed. Implementing the mathematical model shows that constraints to the default state are sufficient to explain ductal and acinar formation, and points to a target of future research, namely, to inhibitors of cell proliferation and motility generated by the epithelial cells.

Modeling mammary organogenesis from biological first principles: Cells and their physical constraints Maël Montévil, Lucia Speroni, Carlos Sonnenschein, Ana M. Soto DOI: http://dx.doi.org/10.1016/j.pbiomolbio.2016.08.004 Progress in Biophysics and Molecular Biology Volume 122, Issue 1, Pages 58–69 From the Century of the Genome to the Century of the Organism: New Theoretical Approaches Edited By Ana M Soto, Giuseppe Longo and Denis Noble

Complex complexity. Dionisio

[...] limiting the contractile forces of the cell cortex is an integral part of epithelial cell adhesion to blood capillaries. [...] the altered biomechanical properties of the endocrine tissue prompted the observed vascular phenotype [...] [...] the biomechanical stiffness of several tissues inversely correlates with their microvascular densities [...] By stepping away from a pure endothelial-centric perspective, future studies might leverage the biomechanical properties of growing or hypertrophic tissues to inhibit or promote vascularization.

The biomechanical properties of an epithelial tissue determine the location of its vasculature Martin Kragl, Rajib Schubert, Haiko Karsjens, Silke Otter, Barbara Bartosinska, Kay Jeruschke, Jürgen Weiss, Chunguang Chen, David Alsteens, Oliver Kuss, Stephan Speier, Daniel Eberhard, Daniel J. Müller and Eckhard Lammert Nat Commun. 7: 13560. doi: 10.1038/ncomms13560

Dionisio

Formation and maintenance of a blood vessel network has a key role both during development [...] The data suggest a mechanical sorting event, rather than a chemotactic one in response to angiogenic growth factors, driving the segregation of vascular endothelial cells and Ilk-deficient endocrine cells during pancreatic islet growth.

The biomechanical properties of an epithelial tissue determine the location of its vasculature Martin Kragl, Rajib Schubert, Haiko Karsjens, Silke Otter, Barbara Bartosinska, Kay Jeruschke, Jürgen Weiss, Chunguang Chen, David Alsteens, Oliver Kuss, Stephan Speier, Daniel Eberhard, Daniel J. Müller and Eckhard Lammert Nat Commun. 7: 13560. doi: 10.1038/ncomms13560

Complex complexity. Dionisio

An important question is how growing tissues establish a blood vessel network. [...] a sorting event is driving the segregation of endothelial and epithelial cells and indicate that the epithelial biomechanical properties determine whether the blood vasculature invades or envelops a growing epithelial tissue.

The biomechanical properties of an epithelial tissue determine the location of its vasculature Martin Kragl, Rajib Schubert, Haiko Karsjens, Silke Otter, Barbara Bartosinska, Kay Jeruschke, Jürgen Weiss, Chunguang Chen, David Alsteens, Oliver Kuss, Stephan Speier, Daniel Eberhard, Daniel J. Müller and Eckhard Lammert Nat Commun. 7: 13560. doi: 10.1038/ncomms13560

Complex complexity. Dionisio

[...] the ECM and integrin signaling are particularly critical for the initiation of branching morphogenesis during a short early time window of pancreas development. [...] it is possible that mature acinar cells co-opt mechanisms used during embryogenesis to gain motility during malignant transformation. [...] the here described time-lapse imaging technology will allow us to systematically study how niche cues affect cell behaviors in development and disease.

ECM signaling regulates collective cellular dynamics to control pancreas branching morphogenesis Hung Ping Shih, Devin Panlasigui, Vincenzo Cirulli and Maike Sander Cell Rep. 14(2): 169–179. doi: 10.1016/j.celrep.2015.12.027

Complex complexity. Dionisio

[...] a reduction in cell-cell adhesion through down-regulation of E-cadherin plays a role in the initiation of pancreas branching. [...] pancreas branching morphogenesis is initiated via ECM-integrin signaling-mediated regulation of cell adhesion in cap cells.

ECM signaling regulates collective cellular dynamics to control pancreas branching morphogenesis Hung Ping Shih, Devin Panlasigui, Vincenzo Cirulli and Maike Sander Cell Rep. 14(2): 169–179. doi: 10.1016/j.celrep.2015.12.027

Complex complexity. Dionisio

[...] the cellular mechanisms by which the pancreatic epithelium transforms into a highly branched organ remain unclear. The cellular behaviors that drive tissue morphogenesis require the actomyosin network to change cell shape and cell contacts [...] [...] the role of cell-cell and cell-ECM contacts in pancreatic organ morphogenesis is unknown.

ECM signaling regulates collective cellular dynamics to control pancreas branching morphogenesis Hung Ping Shih, Devin Panlasigui, Vincenzo Cirulli and Maike Sander Cell Rep. 14(2): 169–179. doi: 10.1016/j.celrep.2015.12.027

Complex complexity. Dionisio

Branch formation is a morphogenetic process to construct organs comprised of elaborate epithelial networks. Branching allows organs to maximize their surface area, which is critical for absorptive and secretory functions. [...] the mechanisms underlying pancreas branching morphogenesis are still unknown.

ECM signaling regulates collective cellular dynamics to control pancreas branching morphogenesis Hung Ping Shih, Devin Panlasigui, Vincenzo Cirulli and Maike Sander Cell Rep. 14(2): 169–179. doi: 10.1016/j.celrep.2015.12.027

Complex complexity. Dionisio

During pancreas development, epithelial buds undergo branching morphogenesis to form an exocrine and endocrine gland. Proper morphogenesis is necessary for correct lineage allocation of pancreatic progenitors; however, the cellular events underlying pancreas morphogenesis are unknown. [...] regulation of cell motility and adhesion by local niche cues initiates pancreas branching morphogenesis.

ECM signaling regulates collective cellular dynamics to control pancreas branching morphogenesis Hung Ping Shih, Devin Panlasigui, Vincenzo Cirulli and Maike Sander Cell Rep. 14(2): 169–179. doi: 10.1016/j.celrep.2015.12.027

Complex complexity. Dionisio

As the complexity of the geometry increases over time, the phase field approach, however, seems not to suffer from numerical instabilities. We will use the phase field method in our future research to understand how size and shape are controlled during development, and during branching morphogenesis in particular.

Simulating Organogenesis in COMSOL: Phase-­Field Based Simulations of Embryonic Lung Branching Morphogenesis Lucas D. Wittwer, Roberto Croce, Sebastian Aland and Dagmar Iber arXiv:1610.09189 [q-bio.QM] arXiv:1610.09189v1 [q-bio.QM]

Work in progress... stay tuned. Complex complexity. Dionisio

The general idea to use a phase field for coupled bulk and surface equations is intriguingly simple: the integrals of the weak form of the equations are multiplied by characteristic functions, which allows to extend the integration domains to a larger computational box ? (see Fig. 1).

Simulating Organogenesis in COMSOL: Phase-­Field Based Simulations of Embryonic Lung Branching Morphogenesis Lucas D. Wittwer, Roberto Croce, Sebastian Aland and Dagmar Iber arXiv:1610.09189 [q-bio.QM] arXiv:1610.09189v1 [q-bio.QM]

"intriguingly simple"? Oh, yeah, very simple. :) BTW, why "intriguingly"? What's the intrigue about? :) Also, we've noticed all this interesting math describing biological processes in the research literature. Kind of cool, isn't it? :) Complex complexity. Dionisio

While experiments have confirmed the Turing mechanism in chemical reaction systems [8, 9], their proof in a biological system is still outstanding. In fact, alternative mechanisms are more likely in several systems where Turing mechanisms have previously been proposed [10, 11].

Simulating Organogenesis in COMSOL: Phase-­Field Based Simulations of Embryonic Lung Branching Morphogenesis Lucas D. Wittwer, Roberto Croce, Sebastian Aland and Dagmar Iber arXiv:1610.09189 [q-bio.QM] arXiv:1610.09189v1 [q-bio.QM]

"...their proof in a biological system is still outstanding"? What about this? "Turing’s theory of morphogenesis validated" http://www.brandeis.edu/now/2014/march/turingpnas.html Are they referring to different problems? Please, can somebody explain this? Complex complexity. Dionisio

The development of an organism from a single cell, the fertilized oocyte, involves innumerous symmetry breaks that need to occur at the right time and the right place to give rise to a functional organism. The underlying mechanism that repetitively guides such a highly deterministic patterning and growth process has long fascinated biologists and theoreticians.

Simulating Organogenesis in COMSOL: Phase-­Field Based Simulations of Embryonic Lung Branching Morphogenesis Lucas D. Wittwer, Roberto Croce, Sebastian Aland and Dagmar Iber arXiv:1610.09189 [q-bio.QM] arXiv:1610.09189v1 [q-bio.QM]

"need to occur at the right time and the right place"? How exactly do we get that kind of coordination/synchronization? Complex complexity. Dionisio

Organogenesis has been studied for decades, but fundamental questions regarding the control of growth and shape remain unsolved.

Simulating Organogenesis in COMSOL: Phase-­Field Based Simulations of Embryonic Lung Branching Morphogenesis Lucas D. Wittwer, Roberto Croce, Sebastian Aland and Dagmar Iber arXiv:1610.09189 [q-bio.QM] arXiv:1610.09189v1 [q-bio.QM]

Complex complexity. Dionisio

[...] it would be worthwhile to check whether murine Dlg5 promotes apical polarity by primarily regulating one of the three mammalian CRB paralogs (CRB1, CRB2, CRB3). [...] MAGUK core and PDZ3’s requirement for Dlg5’s membrane localization in general and PDZ3-PDZ4’s requirement for Dlg5’s apical membrane localization may be critical for Dlg5’s functions in the follicle cells. [...] the N-terminal coiled coil domain, the middle linker region and the MAGUK core could be individually membrane-targeted to apical, AJ and all (apical, AJ and basolateral) regions respectively.

Dlg5 maintains apical polarity by promoting membrane localization of Crumbs during Drosophila oogenesis Jun Luo,1 Heng Wang,1 Di Kang,1 Xuan Guo,1 Ping Wan,1 Dou Wang,1 and Jiong Chen Sci Rep. 2016; 6: 26553. doi: 10.1038/srep26553

Complex complexity. Dionisio

How cell polarity is established and maintained is an important question in the fields of cell and developmental biology. During animal development, polarized cells such as epithelial cells maintain their apical-basal polarity despite undergoing dramatic shape changes and tissue remodeling during morphogenesis.

Dlg5 maintains apical polarity by promoting membrane localization of Crumbs during Drosophila oogenesis Jun Luo,1 Heng Wang,1 Di Kang,1 Xuan Guo,1 Ping Wan,1 Dou Wang,1 and Jiong Chen Sci Rep. 2016; 6: 26553. doi: 10.1038/srep26553

Complex complexity. Dionisio

Apical-basal polarity plays critical roles in the functions of epithelial tissues. However, the mechanisms of epithelial polarity establishment and maintenance remain to be fully elucidated.

Dlg5 maintains apical polarity by promoting membrane localization of Crumbs during Drosophila oogenesis Jun Luo,1 Heng Wang,1 Di Kang,1 Xuan Guo,1 Ping Wan,1 Dou Wang,1 and Jiong Chen Sci Rep. 2016; 6: 26553. doi: 10.1038/srep26553

Complex complexity. Dionisio

The integration of morphogenic signals by cells is not well understood. Morphogenic signals provide extracellular information needed for cells to make decisions during development and differentiation [...] It is not fully understood at which level of processing cells decode combinations of extracellular signals. The concept of dynamic crosstalk is particularly important for developmental pathways, where long time scales may be required for cells to process signals and initiate cellular fate transcriptional programs. [...] many questions remain unresolved regarding downstream signaling dynamics and mechanisms including the stoichiometric and stability requirements for Smad4 interactions [...] It will be important to determine whether, by separating temporal points of crosstalk, similar simplifications may be found across additional developmental pathways, (e.g. Notch and Hedgehog), biological contexts, and information channels.

Examining Crosstalk among Transforming Growth Factor ?, Bone Morphogenetic Protein, and Wnt Pathways* Adam D. Coster,‡,1 Curtis A. Thorne,‡,1 Lani F. Wu,‡§,2 and Steven J. Altschuler J Biol Chem. 2017 Jan 6; 292(1): 244–250. doi: 10.1074/jbc.M116.759654

Complex complexity. Dionisio

It is also possible that unliganded RA receptors act to repress the entire array, while liganded RA receptors preferentially activate LWS1 over LWS2. Identification of the receptor(s) mediating these effects will be required to pursue this latter hypothesis. The tandemly quadruplicated RH2 (green-sensitive) opsin genes of the zebrafish also show concentric expression domains with a dorsal-ventral gradient [12], but it is not known whether this array responds to RA signaling. [...] direct interactions of any RAR or RXR with an opsin gene regulatory region have not been demonstrated, and so this idea remains highly speculative.

Retinoic Acid Signaling Regulates Differential Expression of the Tandemly-Duplicated Long Wavelength-Sensitive Cone Opsin Genes in Zebrafish Diana M. Mitchell, Craig B. Stevens, Ruth A. Frey, Samuel S. Hunter, Ryuichi Ashino, Shoji Kawamura and Deborah L. Stenkamp PLoS Genet. 11(8): e1005483. doi: 10.1371/journal.pgen.1005483

Complex complexity. Dionisio

The complexity of just what is a gene–environment interaction and how these impact human development are major hurdles that must be overcome. How do we precisely define what is the environment? [...] even in a ‘simple’ model of gene–environment interactions, it becomes clear that our resulting phenotype is driven by interwoven, layered, and potentially interdependent gene–environment interactions [...]

Gene–environment interactions in development and disease C. Lovely, Mindy Rampersad, Yohaan Fernandes, Johann Eberhart DOI: 10.1002/wdev.247 WIREs Dev Biol, 6: n/a, e247.

Complex complexity. Dionisio

Recent chemical experiments have revealed that while Turing’s original reaction-diffusion equations portray certain aspects of morphogenesis, they do not account for heterogeneity (Tompkins et al., 2014) or the multistep hierarchical differentiation of cells into different types (Gordon, 2015).

Dionisio

The amazing imitation capabilities of songbirds show that they can memorize sensory sequences and transform them into motor activities which in turn generate the original sound sequences. This suggests that the bird's brain can learn (1) to reliably reproduce spatio-temporal sensory representations and (2) to transform them into corresponding spatio-temporal motor activations by using an inverse mapping. Neither the synaptic mechanisms nor the network architecture enabling these two fundamental aspects of imitation learning are known. [...] MPDP2 provides a unique and novel learning mechanism for establishing both, inverse models as well the connections in recurrent networks that putatively underlie the memories of sound sequences.

A Comprehensive Account of Sound Sequence Imitation in the Songbird. Westkott M, Pawelzik KR Front Comput Neurosci. 10:71. doi: 10.3389/fncom.2016.00071.

Dionisio

It is becoming increasingly clear that the relative timings of spikes transmitted by neurons, and not just their firing rates, is used to convey information regarding the features of input stimuli [1]. Spike-timing as an encoding mechanism is advantageous over rate-based codes in the sense that it is capable of tracking rapidly changing features, for example briefly presented images projected onto the retina [2] or tactile events signalled by the fingertip during object manipulations [3]. It is also apparent that spikes are generated with high temporal precision, typically on the order of a few milliseconds under variable conditions [4–6]. [...] it would be of increased biological significance to test the performance of a learning method as applied to a much larger network size: containing on the order of 104 synapses per neuron as is typical in the nervous system.

Supervised Learning in Spiking Neural Networks for Precise Temporal Encoding. Gardner B, Grüning A PLoS One. 11(8):e0161335. doi: 10.1371/journal.pone.0161335.

Complex complexity. Dionisio

Precise spike timing as a means to encode information in neural networks is biologically supported, and is advantageous over frequency-based codes by processing input features on a much shorter time-scale. For these reasons, much recent attention has been focused on the development of supervised learning rules for spiking neural networks that utilise a temporal coding scheme. However, despite significant progress in this area, there still lack rules that have a theoretical basis, and yet can be considered biologically relevant.

Supervised Learning in Spiking Neural Networks for Precise Temporal Encoding. Gardner B, Grüning A PLoS One. 11(8):e0161335. doi: 10.1371/journal.pone.0161335.

Complex complexity. Dionisio

[...] the question of how many trials are needed to learn a given task in model RNNs and animals merits further investigation. Many interesting and challenging questions remain. [...] it is not completely clear, at present, how spiking neurons may be directly trained for general tasks [...] [...] we have not addressed the detailed mechanisms by which networks accomplish their tasks. Discovering general methods for the systematic analysis of trained networks remains one of the most important areas of inquiry if RNNs are to provide useful insights into the operation of biological neural circuits. As a platform for theoretical investigation, trained RNNs offer a unified setting in which diverse cognitive computations and mechanisms can be studied.

Training Excitatory-Inhibitory Recurrent Neural Networks for Cognitive Tasks: A Simple and Flexible Framework. Song HF, Yang GR, Wang XJ PLoS Comput Biol. 12(2):e1004792. doi: 10.1371/journal.pcbi.1004792.

Complex complexity. Dionisio

The ability to simultaneously record from large numbers of neurons in behaving animals has ushered in a new era for the study of the neural circuit mechanisms underlying cognitive functions. Our results demonstrate the wide range of neural activity patterns and behavior that can be modeled, and suggest a unified setting in which diverse cognitive computations and mechanisms can be studied.

Training Excitatory-Inhibitory Recurrent Neural Networks for Cognitive Tasks: A Simple and Flexible Framework. Song HF, Yang GR, Wang XJ PLoS Comput Biol. 12(2):e1004792. doi: 10.1371/journal.pcbi.1004792.

Complex complexity. Dionisio

[...] the precise function of CT feedback remains uncertain. [...] postsynaptic mechanisms, requiring T-type Ca2+ channels and NMDA receptors, significantly amplify CT input to TC neurons. This amplification relies on the temporal synchrony of synaptic input, is influenced by the spatial location of synapses within the dendritic tree, and broadens the modulatory influence CT feedback can exert upon TC neuron signaling.

Passive Synaptic Normalization and Input Synchrony-Dependent Amplification of Cortical Feedback in Thalamocortical Neuron Dendrites. Connelly WM, Crunelli V, Errington AC J Neurosci. 36(13):3735-54. doi: 10.1523/JNEUROSCI.3836-15.2016.

Complex complexity. Dionisio

Neurons in first-order thalamic nuclei transmit sensory information from the periphery to the cortex. However, the numerically dominant synaptic input to thalamocortical neurons comes from the cortex, which provides a strong, activity-dependent modulatory feedback influence on information flow through the thalamus. These mechanisms significantly increase the responsiveness of thalamocortical neurons to cortical excitatory input and broaden the "modulatory" influence exerted by corticothalamic synapses.

Passive Synaptic Normalization and Input Synchrony-Dependent Amplification of Cortical Feedback in Thalamocortical Neuron Dendrites. Connelly WM, Crunelli V, Errington AC J Neurosci. 36(13):3735-54. doi: 10.1523/JNEUROSCI.3836-15.2016.

Complex complexity. Dionisio

Thalamocortical neurons have thousands of synaptic connections from layer VI corticothalamic neurons distributed across their dendritic trees. Although corticothalamic synapses provide significant excitatory input, it remains unknown how different spatial and temporal input patterns are integrated by thalamocortical neurons.

Passive Synaptic Normalization and Input Synchrony-Dependent Amplification of Cortical Feedback in Thalamocortical Neuron Dendrites. Connelly WM, Crunelli V, Errington AC J Neurosci. 36(13):3735-54. doi: 10.1523/JNEUROSCI.3836-15.2016.

Complex complexity. Dionisio

The dream to create novel computing hardware that captures aspects of brain computation has occupied the minds of researchers for over 50 y. Driving goals are to carry both the astounding energy efficiency of computations in neural networks of the brain and their learning capability into future generations of electronic hardware.

Energy-efficient neural network chips approach human recognition capabilities Wolfgang Maass PNAS vol. 113 no. 41 11387–11389 doi: 10.1073/pnas.1614109113

Complex complexity. Dionisio

Neuroscience may inform machine learning at multiple levels. Looking at the insights from neuroscience may help machine learning move toward general intelligence in a structured heterogeneous world with access to only small amounts of supervised data. There is not one mechanism of optimization but (potentially) many, not one cost function but a host of them, not one kind of a representation but a representation of whatever is useful, and not one homogeneous structure but a large number of them. All these elements are held together by the optimization of internally generated cost functions, which allows these systems to make good use of one another.

Toward an Integration of Deep Learning and Neuroscience Adam H. Marblestone, Greg Wayne and Konrad P. Kording Front Comput Neurosci. 10: 94. doi: 10.3389/fncom.2016.00094

Complex complexity. Dionisio

[...] if the brain is capable of generic optimization of cost functions, then we need to be aware that rather simple cost functions can give rise to complicated stimulus responses. This potentially leads to a different set of questions. A more in-depth dialog between neuroscience and machine learning could help elucidate some of these questions.

Toward an Integration of Deep Learning and Neuroscience Adam H. Marblestone, Greg Wayne and Konrad P. Kording Front Comput Neurosci. 10: 94. doi: 10.3389/fncom.2016.00094

Complex complexity. Dionisio

Proposed “top down” frameworks for understanding neural computation include entropy maximization, efficient encoding, faithful approximation of Bayesian inference, minimization of prediction error, attractor dynamics, modularity, the ability to subserve symbolic operations, and many others [...]

Toward an Integration of Deep Learning and Neuroscience Adam H. Marblestone, Greg Wayne and Konrad P. Kording Front Comput Neurosci. 10: 94. doi: 10.3389/fncom.2016.00094

Did somebody say "top-down"? :) Glad to see they could eventually realize that biological systems were "top-down" designed. Complex complexity. Dionisio

Due to the complexity and variability of the brain, pure “bottom up” analysis of neural data faces potential challenges of interpretation (Robinson, 1992; Jonas and Kording, 2016).

Toward an Integration of Deep Learning and Neuroscience Adam H. Marblestone, Greg Wayne and Konrad P. Kording Front Comput Neurosci. 10: 94. doi: 10.3389/fncom.2016.00094

We've been saying for quite a while that it's not very efficient to do bottom-up reverse engineering of biological systems that were designed top-down. Complex complexity. Dionisio

When did the division between cost functions and optimization algorithms occur? How is this separation implemented? How did innovations in cost functions and optimization algorithms evolve? And how do our own cost functions and learning algorithms differ from those of other animals?

Toward an Integration of Deep Learning and Neuroscience Adam H. Marblestone, Greg Wayne and Konrad P. Kording Front Comput Neurosci. 10: 94. doi: 10.3389/fncom.2016.00094

At least some references to pseudoscientific nonsense is included in many otherwise-excellent papers in order to get the seal of approval of the establishment. That's pathetically bizarre, but it's the reality we see. Complex complexity. Dionisio

Machine learning and neuroscience speak different languages today. Brain science has discovered a dazzling array of brain areas (Solari and Stoner, 2011), cell types, molecules, cellular states, and mechanisms for computation and information storage. Machine learning, in contrast, has largely focused on instantiations of a single principle: function optimization. We will argue here, however, that neuroscience and machine learning are again ripe for convergence.

Toward an Integration of Deep Learning and Neuroscience Adam H. Marblestone, Greg Wayne and Konrad P. Kording Front Comput Neurosci. 10: 94. doi: 10.3389/fncom.2016.00094

Complex complexity. Dionisio

Here we think about the brain in terms of these ideas. We hypothesize that (1) the brain optimizes cost functions, (2) the cost functions are diverse and differ across brain locations and over development, and (3) optimization operates within a pre-structured architecture matched to the computational problems posed by behavior.

Toward an Integration of Deep Learning and Neuroscience Adam H. Marblestone, Greg Wayne and Konrad P. Kording Front Comput Neurosci. 10: 94. doi: 10.3389/fncom.2016.00094

Complex complexity. Dionisio

[...] the functional and theoretical benefits of networks of neurons with active dendrites as compared to a multi-layer network of neurons without active dendrites are unclear [...] [...] we need an understanding of how biological neurons integrate input from thousands of synapses and whether active dendrites play an essential role. [...] we also need a complementary theory of how networks of neurons, each with active dendrites, work together toward a common purpose.

Why Neurons Have Thousands of Synapses, a Theory of Sequence Memory in Neocortex. Hawkins J, Ahmad S Front Neural Circuits. 10:23. doi: 10.3389/fncir.2016.00023

Work in progress... stay tuned. Complex complexity. Dionisio

[...] pyramidal neurons with thousands of synapses, active dendrites, and multiple integration zones create a robust and powerful sequence memory. Given the prevalence and similarity of excitatory neurons throughout the neocortex and the importance of sequence memory in inference and behavior, we propose that this form of sequence memory may be a universal property of neocortical tissue.

Why Neurons Have Thousands of Synapses, a Theory of Sequence Memory in Neocortex. Hawkins J, Ahmad S Front Neural Circuits. 10:23. doi: 10.3389/fncir.2016.00023

Complex complexity. Dionisio

We then present a network model based on neurons with these properties that learns time-based sequences. The network relies on fast local inhibition to preferentially activate neurons that are slightly depolarized. Through simulation we show that the network scales well and operates robustly over a wide range of parameters as long as the network uses a sparse distributed code of cellular activations.

Why Neurons Have Thousands of Synapses, a Theory of Sequence Memory in Neocortex. Hawkins J, Ahmad S Front Neural Circuits. 10:23. doi: 10.3389/fncir.2016.00023

Complex complexity. Dionisio

[...] patterns detected on proximal dendrites lead to action potentials, defining the classic receptive field of the neuron, and patterns detected on basal and apical dendrites act as predictions by slightly depolarizing the neuron without generating an action potential. By this mechanism, a neuron can predict its activation in hundreds of independent contexts.

Why Neurons Have Thousands of Synapses, a Theory of Sequence Memory in Neocortex. Hawkins J, Ahmad S Front Neural Circuits. 10:23. doi: 10.3389/fncir.2016.00023

Complex complexity. Dionisio

[...] a neuron with several thousand synapses segregated on active dendrites can recognize hundreds of independent patterns of cellular activity even in the presence of large amounts of noise and pattern variation.

Why Neurons Have Thousands of Synapses, a Theory of Sequence Memory in Neocortex. Hawkins J, Ahmad S Front Neural Circuits. 10:23. doi: 10.3389/fncir.2016.00023

Complex complexity. Dionisio

Pyramidal neurons represent the majority of excitatory neurons in the neocortex. Each pyramidal neuron receives input from thousands of excitatory synapses that are segregated onto dendritic branches. The dendrites themselves are segregated into apical, basal, and proximal integration zones, which have different properties. It is a mystery how pyramidal neurons integrate the input from thousands of synapses, what role the different dendrites play in this integration, and what kind of network behavior this enables in cortical tissue.

Why Neurons Have Thousands of Synapses, a Theory of Sequence Memory in Neocortex. Hawkins J, Ahmad S Front Neural Circuits. 10:23. doi: 10.3389/fncir.2016.00023

Did somebody say "mystery"? :) Complex complexity. Dionisio

The surprising power of spike timing to predict behavior might reflect synchrony between motor units in the respiratory muscles [...] [...] respiration is driven by a brainstem central pattern generator (CPG) but modified by descending inputs from the forebrain [...]. It remains unknown which of these is the source of timing precision/variability [...]

Motor control by precisely timed spike patterns Kyle H. Srivastava, Caroline M. Holmes, Michiel Vellema, Andrea R. Pack, Coen P. H. Elemans, Ilya Nemenman and Samuel J. Sober PNAS doi: 10.1073/pnas.1611734114

Complex complexity. Dionisio

The brain uses sequences of spikes to encode sensory and motor signals. ...] it is unknown whether or how subtle differences in spike timing drive differences in perception or behavior, leaving it unclear whether the information in spike timing actually plays a role in brain function. [...] precise cortical spike timing contains much more information about upcoming behavior than does rate. [...] it remains unclear whether spike timing actually controls variations in behavior. [...] cortical neurons upstream of vocal and respiratory muscles also use spike timing to encode behavior [...] [...] precise spike timing predicts behavioral variations [...] [...] the small, precisely-regulated differences in motor neuron spike patterns in vivo cause muscles to produce different forces. [...] respiratory motor unit activity is controlled on millisecond timescales [...]

Motor control by precisely timed spike patterns Kyle H. Srivastava, Caroline M. Holmes, Michiel Vellema, Andrea R. Pack, Coen P. H. Elemans, Ilya Nemenman and Samuel J. Sober PNAS doi: 10.1073/pnas.1611734114

Complex complexity. Dionisio

A crucial problem in neuroscience is understanding how neural activity (sequences of action potentials or “spikes”) controls muscles, and hence motor behaviors. In principle, neurons can encode this information via their firing rates, the precise timing of their spikes, or both [...] [...] the precise timing of spikes, rather than just their number, plays a crucial role in predicting and causally controlling behavior. [...] basic assumptions about neural motor control require revision [...]

Motor control by precisely timed spike patterns Kyle H. Srivastava, Caroline M. Holmes, Michiel Vellema, Andrea R. Pack, Coen P. H. Elemans, Ilya Nemenman and Samuel J. Sober PNAS doi: 10.1073/pnas.1611734114

Complex complexity. Dionisio

The developmental systems view also informs how we think about the brain. Some researchers insist that the brain is a modular system, hardwired for specialized abilities. But recent findings have revealed tremendous plasticity, particularly early in development. At the extreme, plasticity can take hold, restoring complex cognitive functions even when infants experience substantial brain damage due to stroke or other health complications. Simply put, none of us is hardwired or preprogrammed. Each of us develops.

Introduction to the collection ‘How We Develop—Developmental Systems and the Emergence of Complex Behaviors’ Mark S. Blumberg, John P. Spencer, David Shenk DOI: 10.1002/wcs.1413 WIREs Cogn Sci, 8: n/a, e1413

Complex complexity. Dionisio

The new understanding starts with a new conception of the gene. Genes are not like automatons, reciting the same lines in exactly the same way regardless of changing circumstances. Instead, they are more like jazz musicians, interacting with their surroundings from moment to moment in complex and often surprising ways. Beyond this more dynamic view of gene action, the developmental systems perspective provides a broad framework for thinking about individual development at multiple levels (molecular, neural, and behavioral) and timescales.

Introduction to the collection ‘How We Develop—Developmental Systems and the Emergence of Complex Behaviors’ Mark S. Blumberg, John P. Spencer, David Shenk DOI: 10.1002/wcs.1413 WIREs Cogn Sci, 8: n/a, e1413

Complex complexity. Dionisio

[...] a new ‘systems’ view of research in such domains as fetal development, neuroplasticity, the functional organization of the brain, and cognition suggests that the old debates about nature and nurture should be thrown out in favor of something new—a unified ‘developmental systems’ perspective.

Introduction to the collection ‘How We Develop—Developmental Systems and the Emergence of Complex Behaviors’ Mark S. Blumberg, John P. Spencer, David Shenk DOI: 10.1002/wcs.1413 WIREs Cogn Sci, 8: n/a, e1413

Complex complexity. Dionisio

In his classic essay, ‘Seven Wonders,’ the physician and essayist Lewis Thomas wrote that childhood was one of life's great mysteries. Why, he pondered, did evolution not allow us to skip childhood altogether, ‘to jump catlike from our juvenile to our adult [and] productive stage of life?’ It is indeed extraordinary how long it takes for humans to develop into mature, capable adults.

Introduction to the collection ‘How We Develop—Developmental Systems and the Emergence of Complex Behaviors’ Mark S. Blumberg, John P. Spencer, David Shenk DOI: 10.1002/wcs.1413 WIREs Cogn Sci, 8: n/a, e1413

Complex complexity. Dionisio

A rather disquieting characteristic of EBs and specifically gastruloids is that they appear to uncouple processes that in the embryo are tightly linked, such as specification of the anterior-posterior axis and anterior neural development or endoderm specification and axial elongation. Are these processes truly independent? Are they uncoupled as early progenitors (ESCs), when freed from some of the constraints placed on them in normal development, can opt for differentiation pathways not available in vivo? Perhaps with the right combination of imaging, a new generation of reporters and an understanding of lineage with in these structures, these questions will be answered.

Properties of embryoid bodies Joshua M. Brickman, Palle Serup DOI: 10.1002/wdev.259 WIREs Dev Biol

Work in progress... stay tuned. Complex complexity. Dionisio

One of the most remarkable properties of embryonic stem cells (ESCs) is their capacity to organize themselves into structures that are able to mimic some of the three-dimensional (3D) qualities of embryonic development. These so-called embryoid bodies (EBs) represent an experimental model that has provided many important clues for unraveling early embryonic development.

Properties of embryoid bodies Joshua M. Brickman, Palle Serup DOI: 10.1002/wdev.259 WIREs Dev Biol

Complex complexity. Dionisio

[...] formation of EBs constitutes an important initial step in directed differentiation protocols aimed at generated specific cell types from undifferentiated stem cells. Recent studies that employ modern signaling reporters and tracers of lineage commitment have revealed both the strengths and the weaknesses of EBs as a model of embryonic axis formation.

Properties of embryoid bodies Joshua M. Brickman, Palle Serup DOI: 10.1002/wdev.259 WIREs Dev Biol

Complex complexity. Dionisio

The history of neural plasticity research is one of surprises. Decades ago, large-scale reorganization of the adult brain was considered impossible. We now know differently. Similarly, it was also long thought that no new neurons were born in an adult brain. We now know that in at least some areas of the human brain, new neurons are born. [...] developmental plasticity once thought to be confined to early development may in the future have relevance for adulthood [...]

Neural plasticity across the lifespan Jonathan D. Power, Bradley L. Schlaggar DOI: 10.1002/wdev.216 WIREs Dev Biol, 6: n/a, e216.

Work in progress... stay tuned. Complex complexity. Dionisio

[...] molecular gradients, spontaneous neural activity, and peripherally driven neural activity are all critical for proper development of the brain.

Neural plasticity across the lifespan Jonathan D. Power, Bradley L. Schlaggar DOI: 10.1002/wdev.216 WIREs Dev Biol, 6: n/a, e216.

Complex complexity. Dionisio

Physical changes at a cellular level manifest as circuit-level changes in patterns of neuronal firing, and it is these circuit-level changes that allow us to learn, to remember, and to adapt to changing conditions of the body and environment. These physical changes in neuronal structure result from a combination of the very thoughts we have (i.e., prior patterns of neural firing), as well as genetic and biochemical influences.

Neural plasticity across the lifespan Jonathan D. Power, Bradley L. Schlaggar DOI: 10.1002/wdev.216 WIREs Dev Biol, 6: n/a, e216.

Complex complexity. Dionisio

An essential feature of the brain is its capacity to change. Neuroscientists use the term ‘plasticity’ to describe the malleability of neuronal connectivity and circuitry. How does plasticity work?

Neural plasticity across the lifespan Jonathan D. Power, Bradley L. Schlaggar DOI: 10.1002/wdev.216 WIREs Dev Biol, 6: n/a, e216.

Complex complexity. Dionisio

Articles on mitochondria: http://www.reasons.org/articles/complex-protein-biogenesis-hints-at-intelligent-design http://www.reasons.org/blogs/the-cells-design/can-a-creation-model-explain-the-origin-of-mitochondria Dionisio

[...] only in mammals there is an additional upregulation of dorsal and anterior signaling centers (the cortical hem and the anterior forebrain, respectively) that promoted a laminar and a columnar structure into the neocortex.

Pallial patterning and the origin of the isocortex Juan F. Montiel and Francisco Aboitiz Front Neurosci. 9: 377. doi: 10.3389/fnins.2015.00377

Complex complexity. Dionisio

Together with a complex variety of behavioral, physiological, morphological, and neurobiological innovations, mammals are characterized by the development of an extensive isocortex (also called neocortex) that is both laminated and radially organized, as opposed to the brain of birds and reptiles.

Pallial patterning and the origin of the isocortex Juan F. Montiel and Francisco Aboitiz Front Neurosci. 9: 377. doi: 10.3389/fnins.2015.00377

Complex complexity. Dionisio

Rnd proteins are atypical members of the Rho GTPase family that induce actin cytoskeletal reorganization and cell rounding. [...] plexin-B2 is a downstream target for Rnd3, which contributes to its cellular function.

Rnd3-induced cell rounding requires interaction with Plexin-B2 Brad McColl,*¶ Ritu Garg,¶ Philippe Riou,‡ Kirsi Riento,§ and Anne J. Ridley J Cell Sci. 129(21): 4046–4056. doi: 10.1242/jcs.192211

Complex complexity. Dionisio

It remains to be determined if disruptions to Bacurd levels alter the binding of Rnd2 and Rnd3 to their other partners in neurons (such as p190RhoGAP and Plexin B2), or influence RhoA signalling, or both.

Bacurd1/Kctd13 and Bacurd2/Tnfaip1 are interacting partners to Rnd proteins which influence the long-term positioning and dendritic maturation of cerebral cortical neurons Ivan Gladwyn-Ng, Lieven Huang, Linh Ngo, Shan Shan Li, Zhengdong Qu, Hannah Kate Vanyai, Hayley Daniella Cullen, John Michael Davis, and Julian Ik-Tsen Heng Neural Dev. 11: 7. doi: 10.1186/s13064-016-0062-1

Complex complexity. Dionisio

During development, newborn neurons undergo directional cell migration to position themselves appropriately within the embryonic cerebral cortex before establishing their branching characteristics and finally establishing dendritic spine connections [...] [...] Bacurd1/Kctd13 and Bacurd2/Tnfaip1 are interacting partners to Rnd2 and Rnd3 [...]

Bacurd1/Kctd13 and Bacurd2/Tnfaip1 are interacting partners to Rnd proteins which influence the long-term positioning and dendritic maturation of cerebral cortical neurons Ivan Gladwyn-Ng, Lieven Huang, Linh Ngo, Shan Shan Li, Zhengdong Qu, Hannah Kate Vanyai, Hayley Daniella Cullen, John Michael Davis, and Julian Ik-Tsen Heng Neural Dev. 11: 7. doi: 10.1186/s13064-016-0062-1

Complex complexity. Dionisio

The development of neural circuits within the embryonic cerebral cortex relies on the timely production of neurons, their positioning within the embryonic cerebral cortex as well as their terminal differentiation and dendritic spine connectivity.

Bacurd1/Kctd13 and Bacurd2/Tnfaip1 are interacting partners to Rnd proteins which influence the long-term positioning and dendritic maturation of cerebral cortical neurons Ivan Gladwyn-Ng, Lieven Huang, Linh Ngo, Shan Shan Li, Zhengdong Qu, Hannah Kate Vanyai, Hayley Daniella Cullen, John Michael Davis, and Julian Ik-Tsen Heng Neural Dev. 11: 7. doi: 10.1186/s13064-016-0062-1

Complex complexity. Dionisio

[...] future studies will seek to identify neural genes regulated by Akirin2, identify the proteins with which it interacts in telencephalic cells, and determine the impact of Akirin2 disruption in postmitotic neuron populations.

Akirin2 is essential for the formation of the cerebral cortex. Bosch PJ, Fuller LC, Sleeth CM, Weiner JA Neural Dev. 11(1):21. DOI: 10.1186/s13064-016-0076-8

Work in progress... stay tuned. Complex complexity. Dionisio

Clearly, elucidating further the molecular mechanisms through which Akirin2 regulates corticogenesis will require identifying gene expression patterns that are disrupted in its absence.

Akirin2 is essential for the formation of the cerebral cortex. Bosch PJ, Fuller LC, Sleeth CM, Weiner JA Neural Dev. 11(1):21. DOI: 10.1186/s13064-016-0076-8

Work in progress... stay tuned. Complex complexity. Dionisio

Perhaps most relevant to the cortical phenotypes we have discovered are the known interactions between Akirins and components of the SWI/SNF chromatin remodeling machinery, referred to as the BAP complex in Drosophila and the BAF complex in mammals.

Akirin2 is essential for the formation of the cerebral cortex. Bosch PJ, Fuller LC, Sleeth CM, Weiner JA Neural Dev. 11(1):21. DOI: 10.1186/s13064-016-0076-8

Work in progress... stay tuned. Complex complexity. Dionisio

It should thus be interesting in future studies to investigate TDP-43 as a potential interactor of mammalian Akirin2 and regulator of corticogenesis.

Akirin2 is essential for the formation of the cerebral cortex. Bosch PJ, Fuller LC, Sleeth CM, Weiner JA Neural Dev. 11(1):21. DOI: 10.1186/s13064-016-0076-8

Work in progress... stay tuned. Complex complexity. Dionisio

Based on our current, incomplete, understanding of Akirins in Drosophila, C. elegans, and mammals, Akirin2 can act as a bridge between a number of transcription factors and chromatin remodeling machinery; therefore, knockout of Akirin2 is likely to affect multiple gene pathways in a cell and tissue-specific manner.

Akirin2 is essential for the formation of the cerebral cortex. Bosch PJ, Fuller LC, Sleeth CM, Weiner JA Neural Dev. 11(1):21. DOI: 10.1186/s13064-016-0076-8

Did somebody say "machinery"? :) BTW, "incomplete understanding" seems like a nice way to put it. :) Complex complexity. Dionisio

Further studies that investigate more closely how Akirin2 knockout progenitor cells behave in an in vitro environment may allow us better temporal resolution of the transition between cycling progenitors and neurons.

Akirin2 is essential for the formation of the cerebral cortex. Bosch PJ, Fuller LC, Sleeth CM, Weiner JA Neural Dev. 11(1):21. DOI: 10.1186/s13064-016-0076-8

Work in progress... stay tuned. Complex complexity. Dionisio

[...] further studies aimed at identifying Akirin2-regulated gene expression patterns will be informative.

Akirin2 is essential for the formation of the cerebral cortex. Bosch PJ, Fuller LC, Sleeth CM, Weiner JA Neural Dev. 11(1):21. DOI: 10.1186/s13064-016-0076-8

Complex complexity. Dionisio

The proper spatial and temporal regulation of dorsal telencephalic progenitor behavior is a prerequisite for the formation of the highly-organized, six-layered cerebral cortex. [...] our understanding remains incomplete. Our data demonstrate a previously-unsuspected role for Akirin2 in early cortical development and, given its known nuclear roles, suggest that it may act to regulate gene expression patterns critical for early progenitor cell behavior and cortical neuron production.

Akirin2 is essential for the formation of the cerebral cortex. Bosch PJ, Fuller LC, Sleeth CM, Weiner JA Neural Dev. 11(1):21. DOI: 10.1186/s13064-016-0076-8

Complex complexity. Dionisio

These and many other scientific discoveries have made it clear that the nervous system is a masterpiece of embryology.

Neuroembryology Diana Darnell, Scott F. Gilbert WIREs Developmental Biology Volume 6, Issue 1 WIREs Dev Biol 2017, 6:e215. doi: 10.1002/wdev.215

Complex complexity. Dionisio

[...] stem cells spur the emergence of cells required for the development of the central nervous system.

Neuroembryology Diana Darnell, Scott F. Gilbert WIREs Developmental Biology Volume 6, Issue 1 WIREs Dev Biol 2017, 6:e215. doi: 10.1002/wdev.215

Complex complexity. Dionisio

[...] coordination of cytoskeleton, gene expression, and extracellular proteins is required for such complicated processes as neurulation.

Neuroembryology Diana Darnell, Scott F. Gilbert WIREs Developmental Biology Volume 6, Issue 1 WIREs Dev Biol 2017, 6:e215. doi: 10.1002/wdev.215

Complex complexity. Dionisio

[...] gastrulation is the time when the fate of many vertebrate cells is determined [...]

Neuroembryology Diana Darnell, Scott F. Gilbert WIREs Developmental Biology Volume 6, Issue 1 WIREs Dev Biol 2017, 6:e215. doi: 10.1002/wdev.215

Complex complexity. Dionisio

[...] cell specification depends both on the source of the cell within the embryo (lineage) and what signals the cell receives from its neighbors (induction).

Neuroembryology Diana Darnell, Scott F. Gilbert WIREs Developmental Biology Volume 6, Issue 1 WIREs Dev Biol 2017, 6:e215. doi: 10.1002/wdev.215

Complex complexity. Dionisio

Gregor Eichele wrote: ‘What is perhaps the most intriguing question of all is whether the brain is powerful enough to solve the problem of its own creation.’

Neuroembryology Diana Darnell, Scott F. Gilbert WIREs Developmental Biology Volume 6, Issue 1 WIREs Dev Biol 2017, 6:e215. doi: 10.1002/wdev.215

http://www.mpibpc.mpg.de/employees/11307/101421 Complex complexity. Dionisio

How is it that some cells become neurons? And how is it that neurons become organized in the spinal cord and brain to allow us to walk and talk, to see, recall events in our lives, feel pain, keep our balance, and think? The cells that are specified to form the brain and spinal cord are originally located on the outside surface of the embryo. They loop inward to form the neural tube in a process called neurulation. Structures that are nearby send signals to the posterior neural tube to form and pattern the spinal cord so that the dorsal side receives sensory input and the ventral side sends motor signals from neurons to muscles. In the brain, stem cells near the center of the neural tube migrate out to form a mantel zone, and a set of dividing cells from the mantle zone migrate further to produce a second set of neurons at the outer surface of the brain. These neurons will form the cerebral cortex, which contains six discrete layers. Each layer has different connections and different functions.

Neuroembryology Diana Darnell, Scott F. Gilbert WIREs Developmental Biology Volume 6, Issue 1 WIREs Dev Biol 2017, 6:e215. doi: 10.1002/wdev.215

Complex complexity. Dionisio

[...] we hope that this helps us to understand the aspects of cortical development critical to its expansion and folding during embryogenesis. Again, more and more refined molecular and genomic analyses are shedding some light on this problem, [...] but the truth is that we remain far from having a significant level of understanding. Hopefully, our understanding of the mechanisms and consequences of cortical expansion and folding will be much deeper 25 years from now.

Cerebral cortex expansion and folding: what have we learned? Virginia Fernández†, Cristina Llinares-Benadero† and Víctor Borrell* The EMBO Journal Volume 35, Issue 10, pages 1021–1044 DOI: 10.15252/embj.201593701

Work in progress... stay tuned. Complex complexity. Dionisio

The expansion and folding of the mammalian cerebral cortex during embryonic development is a rather complex process regulated by multiple factors, where the abundance, type, and lineage of cortical progenitor cells play central roles. These cellular mechanisms are subject to molecular regulation by multiple proteins and signaling pathways, the expression of which is tightly controlled by a variety of enhancer elements and non-protein-coding genes. The specific spatial–temporal expression patterns of some of these proteins on the embryonic cortex faithfully map the prospective pattern of folds and fissures, and their mutation frequently leads to malformations of cortical size and folding in human patients. Yet, we are still far from identifying the specific role of these genes and their spatial–temporal regulation on the normal development of the human cerebral cortex.

Cerebral cortex expansion and folding: what have we learned? Virginia Fernández†, Cristina Llinares-Benadero† and Víctor Borrell* The EMBO Journal Volume 35, Issue 10, pages 1021–1044 DOI: 10.15252/embj.201593701

Complex complexity. Dionisio

One of the most prominent features of the human brain is the fabulous size of the cerebral cortex and its intricate folding. Cortical folding takes place during embryonic development and is important to optimize the functional organization and wiring of the brain, as well as to allow fitting a large cortex in a limited cranial volume.

Cerebral cortex expansion and folding: what have we learned? Virginia Fernández†, Cristina Llinares-Benadero† and Víctor Borrell* The EMBO Journal Volume 35, Issue 10, pages 1021–1044 DOI: 10.15252/embj.201593701

Complex complexity. Dionisio

A detailed understanding of the critical mitochondrial metabolic circuits in adult neurogenesis and of the impact of aging on mitochondrial dysfunction in the neurogenic lineage and the neurogenic niche could support the development of novel strategies to ameliorate neurogenesis-dependent cognitive deficits in aging.

Role of Mitochondrial Metabolism in the Control of Early Lineage Progression and Aging Phenotypes in Adult Hippocampal Neurogenesis Ruth Beckervordersandforth,1,10,* Birgit Ebert,1,2,10 Iris Sch€affner,1 Jonathan Moss,3 Christian Fiebig,1 Jaehoon Shin,4 Darcie L. Moore,5 Laboni Ghosh,5 Mariela F. Trinchero,6 Carola Stockburger,7 Kristina Friedland,7 Kathrin Steib,2 Julia von Wittgenstein,1 Silke Keiner,8 Christoph Redecker,8 Sabine M. Ho¨ lter,2 Wei Xiang,1 Wolfgang Wurst,2 Ravi Jagasia,2,9 Alejandro F. Schinder,6 Guo-li Ming,4 Nicolas Toni,3 Sebastian Jessberger,5 Hongjun Song,4 and D. Chichung Lie1,11 Beckervordersandforth et al., 2017, Neuron 93, 1–14 February 8, 2017 ª 2016 Elsevier Inc. http://dx.doi.org/10.1016/j.neuron.2016.12.017

Complex complexity. Dionisio

[...] the specific impact of astrocytic Tfam deletion on neurogenesis should be investigated in the future. The precise mechanisms and the identity of contributing factors underlying the age-associated impairment in hippocampal neurogenesis remain, however, largely unknown. [...] the function of metabolic pathways in stem cell and neurogenesis regulation is only beginning to unfold [...]

Role of Mitochondrial Metabolism in the Control of Early Lineage Progression and Aging Phenotypes in Adult Hippocampal Neurogenesis Ruth Beckervordersandforth,1,10,* Birgit Ebert,1,2,10 Iris Sch€affner,1 Jonathan Moss,3 Christian Fiebig,1 Jaehoon Shin,4 Darcie L. Moore,5 Laboni Ghosh,5 Mariela F. Trinchero,6 Carola Stockburger,7 Kristina Friedland,7 Kathrin Steib,2 Julia von Wittgenstein,1 Silke Keiner,8 Christoph Redecker,8 Sabine M. Ho¨ lter,2 Wei Xiang,1 Wolfgang Wurst,2 Ravi Jagasia,2,9 Alejandro F. Schinder,6 Guo-li Ming,4 Nicolas Toni,3 Sebastian Jessberger,5 Hongjun Song,4 and D. Chichung Lie1,11 Beckervordersandforth et al., 2017, Neuron 93, 1–14 February 8, 2017 ª 2016 Elsevier Inc. http://dx.doi.org/10.1016/j.neuron.2016.12.017

Complex complexity. Dionisio

Precise regulation of cellular metabolism is hypothesized to constitute a vital component of the developmental sequence underlying the life-long generation of hippocampal neurons from quiescent neural stem cells (NSCs). The identity of stage-specific metabolic programs and their impact on adult neurogenesis are largely unknown.

Role of Mitochondrial Metabolism in the Control of Early Lineage Progression and Aging Phenotypes in Adult Hippocampal Neurogenesis Ruth Beckervordersandforth,1,10,* Birgit Ebert,1,2,10 Iris Sch€affner,1 Jonathan Moss,3 Christian Fiebig,1 Jaehoon Shin,4 Darcie L. Moore,5 Laboni Ghosh,5 Mariela F. Trinchero,6 Carola Stockburger,7 Kristina Friedland,7 Kathrin Steib,2 Julia von Wittgenstein,1 Silke Keiner,8 Christoph Redecker,8 Sabine M. Ho¨ lter,2 Wei Xiang,1 Wolfgang Wurst,2 Ravi Jagasia,2,9 Alejandro F. Schinder,6 Guo-li Ming,4 Nicolas Toni,3 Sebastian Jessberger,5 Hongjun Song,4 and D. Chichung Lie1,11 Beckervordersandforth et al., 2017, Neuron 93, 1–14 February 8, 2017 ª 2016 Elsevier Inc. http://dx.doi.org/10.1016/j.neuron.2016.12.017

Complex complexity. Dionisio

Dietary restriction (DR) is a non-genetic intervention that reproducibly increases mean and maximum lifespan and delays the onset of age-related pathologies in a wide range of tissues including in the brain. [...] TERT protein might be a mediator of the beneficial effects of DR by improving mitochondrial function in brain through reduced mTOR signalling.

Decreased mTOR signalling reduces mitochondrial ROS in brain via accumulation of the telomerase protein TERT within mitochondria Satomi Miwa, Rafal Czapiewski, Tengfei Wan, Amy Bell, Kirsten N. Hill, Thomas von Zglinicki, Gabriele Saretzki

Dionisio

An intriguing question is whether these exons serve only for fine-tuning homeostatic RBP expression or for regulating expression more dramatically in certain conditions we currently do not know. In addition to a greatly expanded list of AS exon that are likely functional, our study led to an unexpected finding revealing the widespread regulation of chromatin regulators through NMD.

Cell Type-specific Alternative Splicing Governs Cell Fate in the Developing Cerebral Cortex Xiaochang Zhang, Ming Hui Chen, Xuebing Wu, Andrew Kodani, Jean Fan, Ryan Doan, Manabu Ozawa, Jacqueline Ma, Nobuaki Yoshida, Jeremy F. Reiter, Douglas L. Black, Peter V. Kharchenko, Phillip A. Sharp, and Christopher A. Walsh Cell. 166(5): 1147–1162.e15. doi: 10.1016/j.cell.2016.07.025

Did somebody say "unexpected"? Why? Complex complexity. Dionisio

Molecular diversity derived from alternative splicing (AS) is believed to be critical for the creation of different cell types and tissues with distinct physiological properties and functions (1). This is particularly relevant to the central nervous system (CNS), which requires a large protein repertoire to generate its intricate and complex neural circuits (2).

Cell Type-specific Alternative Splicing Governs Cell Fate in the Developing Cerebral Cortex Xiaochang Zhang, Ming Hui Chen, Xuebing Wu, Andrew Kodani, Jean Fan, Ryan Doan, Manabu Ozawa, Jacqueline Ma, Nobuaki Yoshida, Jeremy F. Reiter, Douglas L. Black, Peter V. Kharchenko, Phillip A. Sharp, and Christopher A. Walsh Cell. 166(5): 1147–1162.e15. doi: 10.1016/j.cell.2016.07.025

Complex complexity. Dionisio

Alternative splicing (AS) dramatically expands the complexity of the mammalian brain transcriptome, but its atlas remains incomplete. [...] 72% of multiexon genes express multiple splice variants in this single tissue. Unexpectedly, a second group of NMD exons reside in genes encoding chromatin regulators.

Cell Type-specific Alternative Splicing Governs Cell Fate in the Developing Cerebral Cortex Xiaochang Zhang, Ming Hui Chen, Xuebing Wu, Andrew Kodani, Jean Fan, Ryan Doan, Manabu Ozawa, Jacqueline Ma, Nobuaki Yoshida, Jeremy F. Reiter, Douglas L. Black, Peter V. Kharchenko, Phillip A. Sharp, and Christopher A. Walsh Cell. 166(5): 1147–1162.e15. doi: 10.1016/j.cell.2016.07.025

Did somebody say "Unexpectedly"? Why? Complex complexity. Dionisio

Alternative splicing (AS) plays an important role in the mammalian brain, but our atlas of AS events is incomplete. [...] thousands of newly discovered events are regulated, conserved, and likely functional. Surprisingly, we discovered a number of chromatin regulators as novel targets of this mechanism, revealing a new regulatory link between epigenetics and AS that primarily emerged in the mammalian lineage.

Cell Type-specific Alternative Splicing Governs Cell Fate in the Developing Cerebral Cortex Xiaochang Zhang, Ming Hui Chen, Xuebing Wu, Andrew Kodani, Jean Fan, Ryan Doan, Manabu Ozawa, Jacqueline Ma, Nobuaki Yoshida, Jeremy F. Reiter, Douglas L. Black, Peter V. Kharchenko, Phillip A. Sharp, and Christopher A. Walsh Cell. 166(5): 1147–1162.e15. doi: 10.1016/j.cell.2016.07.025

Did somebody say "surprisingly"? Why? Complex complexity. Dionisio

Whether the presence of both isoforms and at different ratios can produce additional conformations of the ligand-receptor complex is completely unknown. How the architecturally distinct complexes can lead to different intracellular signaling also remains an intriguing question. It remains to be seen if altered Dcc alternative splicing accounts for additional cases of colorectal cancers and other cancers. [...] it is important to determine if Dcc alternative splicing is also important for other biological processes.

NOVA regulates Dcc alternative splicing during neuronal migration and axon guidance in the spinal cord Janelle C Leggere, Yuhki Saito, Robert B Darnell, Marc Tessier-Lavigne, Harald J Junge and Zhe Chen eLife. 5: e14264. doi: 10.7554/eLife.14264

Complex complexity. Dionisio

Neuronal and axonal migration requires dynamic regulation of cell signaling, particularly evident as cells/axons encounter an intermediate target such as the midline of the central nervous system [...] Alternative splicing has been increasingly implicated as an important means to generate temporal and spatial specific functions for guidance molecules [...] [...] it is important to identify the relevant splicing factors and their targets. [...] Nova1/2 are key regulators of both neuronal and axonal migration in the spinal cord interneurons.

NOVA regulates Dcc alternative splicing during neuronal migration and axon guidance in the spinal cord Janelle C Leggere, Yuhki Saito, Robert B Darnell, Marc Tessier-Lavigne, Harald J Junge and Zhe Chen eLife. 5: e14264. doi: 10.7554/eLife.14264

Complex complexity. Dionisio

Alternative splicing generates gene function complexity in many neural developmental processes, including neuronal differentiation, neuronal migration, axon growth and guidance, and synapse formation and function [...] A large number of axon guidance molecules undergo alternative splicing [...] [...] the functional significance of these alternative splicing events and the splicing factors responsible for generating protein variants for these molecules remain largely uncharacterized.

NOVA regulates Dcc alternative splicing during neuronal migration and axon guidance in the spinal cord Janelle C Leggere, Yuhki Saito, Robert B Darnell, Marc Tessier-Lavigne, Harald J Junge and Zhe Chen eLife. 5: e14264. doi: 10.7554/eLife.14264

Complex complexity. Dionisio

Leggere et al. will now carry out additional studies to determine the unique role of each protein variant produced from the Dcc gene. Future research will also investigate how NOVA proteins help generate these variants at the right time and in the right place.

NOVA regulates Dcc alternative splicing during neuronal migration and axon guidance in the spinal cord Janelle C Leggere, Yuhki Saito, Robert B Darnell, Marc Tessier-Lavigne, Harald J Junge and Zhe Chen eLife. 5: e14264. doi: 10.7554/eLife.14264

Work in progress... remain tuned. Complex complexity. Dionisio

[...] the NOVA family of splicing factors are essential for the development of the nervous system. In particular, the NOVA splicing factors control the alternative splicing of a gene called Dcc. This gene produces proteins that play a number of roles, including helping axons to grow and guiding the axons to the correct location in the developing nervous system.

NOVA regulates Dcc alternative splicing during neuronal migration and axon guidance in the spinal cord Janelle C Leggere, Yuhki Saito, Robert B Darnell, Marc Tessier-Lavigne, Harald J Junge and Zhe Chen eLife. 5: e14264. doi: 10.7554/eLife.14264

Complex complexity. Dionisio

Many genes that play important roles in the nervous system have been reported to undergo alternative splicing to generate different protein variants. However, it is unclear whether alternative splicing is important for controlling how the nervous system develops, during which time the neurons connect to the cells that they will communicate with. Forming these connections involves part of the neuron, called the axon, growing along a precise path through the nervous system to reach its destination. If alternative splicing is important for this process, it is also important to ask: which splicing factors are relevant and which genes do these splicing factors regulate?

NOVA regulates Dcc alternative splicing during neuronal migration and axon guidance in the spinal cord Janelle C Leggere, Yuhki Saito, Robert B Darnell, Marc Tessier-Lavigne, Harald J Junge and Zhe Chen eLife. 5: e14264. doi: 10.7554/eLife.14264

Complex complexity. Dionisio

RNA-binding proteins (RBPs) control multiple aspects of post-transcriptional gene regulation and function during various biological processes in the nervous system. [...] the production of DCC splice variants controlled by NOVA has a crucial function during many stages of commissural neuron development.

NOVA regulates Dcc alternative splicing during neuronal migration and axon guidance in the spinal cord Janelle C Leggere, Yuhki Saito, Robert B Darnell, Marc Tessier-Lavigne, Harald J Junge and Zhe Chen eLife. 5: e14264. doi: 10.7554/eLife.14264

Complex complexity. Dionisio

[...] our observations suggest that protein/RNA diversity provided by NOVA2-mediated RNA regulation is required for proper axon pathfinding and formation of complex synapses/neural networks, particularly in dorsal/ventral choices, and that alternative splicing switches mediated by NOVA2 may regulate key developmental steps in mammalian biology and pathogenesis of neurological diseases.

NOVA2-mediated RNA regulation is required for axonal pathfinding during development Yuhki Saito, Soledad Miranda-Rottmann, Matteo Ruggiu, Christopher Y Park, John J Fak, Ru Zhong, Jeremy S Duncan, Brian A Fabella, Harald J Junge, Zhe Chen, Roberto Araya, Bernd Fritzsch, A J Hudspeth, and Robert B Darnell eLife. 2016; 5: e14371. doi: 10.7554/eLife.14371

Complex complexity. Dionisio

Alternative splicing and alternative polyadenylation can produce multiple messenger RNAs (mRNAs) possessing distinct coding and regulatory sequences from a single gene. The regulated processes that generate such mRNA diversity are orchestrated by RNA-binding proteins (RBPs). In the nervous system, alternative splicing has many important roles, including controlling the spatial and temporal expression of protein isoforms that are necessary for neurodevelopment and the modification of synaptic plasticity [...]

NOVA2-mediated RNA regulation is required for axonal pathfinding during development Yuhki Saito, Soledad Miranda-Rottmann, Matteo Ruggiu, Christopher Y Park, John J Fak, Ru Zhong, Jeremy S Duncan, Brian A Fabella, Harald J Junge, Zhe Chen, Roberto Araya, Bernd Fritzsch, A J Hudspeth, and Robert B Darnell eLife. 2016; 5: e14371. doi: 10.7554/eLife.14371

Complex complexity. Dionisio

During central nervous system (CNS) development, a neuron extends its axon through a complex yet precise path to reach its final destination by sensing extracellular signals called guidance cues. These cues are sensed by the growth cone, a motile structure at the extending axon edge, and they control growth cone motility through directed cytoskeletal remodeling. Netrins, slits, semaphorins, and ephrins are the major classic guidance cues and elicit attractive or repulsive responses in growth cones via specific receptors [...] An important aspect of axon guidance is the spatial and temporal control of response to the guidance cues. [...] spatiotemporally regulated protein isoform expression and diversity is crucial to establish proper neuronal networks.

NOVA2-mediated RNA regulation is required for axonal pathfinding during development Yuhki Saito, Soledad Miranda-Rottmann, Matteo Ruggiu, Christopher Y Park, John J Fak, Ru Zhong, Jeremy S Duncan, Brian A Fabella, Harald J Junge, Zhe Chen, Roberto Araya, Bernd Fritzsch, A J Hudspeth, and Robert B Darnell eLife. 2016; 5: e14371. doi: 10.7554/eLife.14371

Complex complexity. Dionisio

The first step of producing a protein involves the DNA of a gene being copied to form a molecule of RNA. This RNA molecule can often be processed to create several different “messenger” RNAs (mRNAs), each of which are used to produce a different protein by a process known as alternative splicing. A class of proteins that bind to RNA molecules controls alternative splicing. These “splicing factors” ensure that the right protein variant is produced at the right time and in the right place to carry out the appropriate activity.

NOVA2-mediated RNA regulation is required for axonal pathfinding during development Yuhki Saito, Soledad Miranda-Rottmann, Matteo Ruggiu, Christopher Y Park, John J Fak, Ru Zhong, Jeremy S Duncan, Brian A Fabella, Harald J Junge, Zhe Chen, Roberto Araya, Bernd Fritzsch, A J Hudspeth, and Robert B Darnell eLife. 2016; 5: e14371. doi: 10.7554/eLife.14371

Also we have the post-Translational Modifications (PTM). How does this relate to the central dogma and the selfish gene? Complex complexity. Dionisio

The neuron specific RNA-binding proteins NOVA1 and NOVA2 are highly homologous alternative splicing regulators. NOVA proteins regulate at least 700 alternative splicing events in vivo, yet relatively little is known about the biologic consequences of NOVA action and in particular about functional differences between NOVA1 and NOVA2. [...] NOVA2 uniquely regulates alternative splicing of a coordinate set of transcripts encoding key components in cortical, brainstem and spinal axon guidance/outgrowth pathways during neural differentiation, with severe functional consequences in vivo.

NOVA2-mediated RNA regulation is required for axonal pathfinding during development Yuhki Saito, Soledad Miranda-Rottmann, Matteo Ruggiu, Christopher Y Park, John J Fak, Ru Zhong, Jeremy S Duncan, Brian A Fabella, Harald J Junge, Zhe Chen, Roberto Araya, Bernd Fritzsch, A J Hudspeth, and Robert B Darnell eLife. 2016; 5: e14371. doi: 10.7554/eLife.14371

Complex complexity. Dionisio

[...] neurons within the hippocampus regionally utilize different isoforms generated by alternative splicing control according to SLM2 protein concentrations. [...] SLM2 protein levels affect interactions between electrically coupled pyramidal cells and interneurons [...] [...] ? oscillations have been shown to be important for various cognitive tasks such as working memory [...]

A SLM2 Feedback Pathway Controls Cortical Network Activity and Mouse Behavior Ingrid Ehrmann, Matthew R. Gazzara, Vittoria Pagliarini, Caroline Dalgliesh, Mahsa Kheirollahi-Chadegani, Yaobo Xu, Eleonora Cesari, Marina Danilenko,1 Marie Maclennan, Kate Lowdon, Tanja Vogel, Piia Keskivali-Bond, Sara Wells, Heather Cater, Philippe Fort, Mauro Santibanez-Koref, Silvia Middei, Claudio Sette, Gavin J. Clowry, Yoseph Barash, Mark O. Cunningham and David J. Elliott Cell Rep. 17(12): 3269–3280. doi: 10.1016/j.celrep.2016.12.002

Complex complexity. Dionisio

These feedback pathways would fine-tune expression of these splicing regulators to ensure stable physiological splicing patterns for the Neurexin genes, and the maintenance of normal patterns of synaptic connectivity.

A SLM2 Feedback Pathway Controls Cortical Network Activity and Mouse Behavior Ingrid Ehrmann, Matthew R. Gazzara, Vittoria Pagliarini, Caroline Dalgliesh, Mahsa Kheirollahi-Chadegani, Yaobo Xu, Eleonora Cesari, Marina Danilenko,1 Marie Maclennan, Kate Lowdon, Tanja Vogel, Piia Keskivali-Bond, Sara Wells, Heather Cater, Philippe Fort, Mauro Santibanez-Koref, Silvia Middei, Claudio Sette, Gavin J. Clowry, Yoseph Barash, Mark O. Cunningham and David J. Elliott Cell Rep. 17(12): 3269–3280. doi: 10.1016/j.celrep.2016.12.002

Complex complexity. Dionisio

forexhr @2645: Very insightful comment. Thank you. Please, you may want to read the comment @2644. Dionisio

Auto-regulatory pathways have been described for a number of splicing regulator proteins where they play an important role in splicing factor homeostasis and likely maintain stable transcriptomes (Jangi and Sharp, 2014), but the physiological importance of these feedback pathways are not usually well understood.

A SLM2 Feedback Pathway Controls Cortical Network Activity and Mouse Behavior Ingrid Ehrmann, Matthew R. Gazzara, Vittoria Pagliarini, Caroline Dalgliesh, Mahsa Kheirollahi-Chadegani, Yaobo Xu, Eleonora Cesari, Marina Danilenko,1 Marie Maclennan, Kate Lowdon, Tanja Vogel, Piia Keskivali-Bond, Sara Wells, Heather Cater, Philippe Fort, Mauro Santibanez-Koref, Silvia Middei, Claudio Sette, Gavin J. Clowry, Yoseph Barash, Mark O. Cunningham and David J. Elliott Cell Rep. 17(12): 3269–3280. doi: 10.1016/j.celrep.2016.12.002

Complex complexity. Dionisio

Alternative splicing expands the coding information in the genome many fold. More than 95% of human genes encode alternative mRNAs, and on average each human gene makes 11 different mRNAs [...] Alternative splicing is controlled by a large set of ubiquitous, as well as tissue-specific RNA binding proteins and is functionally important in the brain and across development [...]

A SLM2 Feedback Pathway Controls Cortical Network Activity and Mouse Behavior Ingrid Ehrmann, Matthew R. Gazzara, Vittoria Pagliarini, Caroline Dalgliesh, Mahsa Kheirollahi-Chadegani, Yaobo Xu, Eleonora Cesari, Marina Danilenko,1 Marie Maclennan, Kate Lowdon, Tanja Vogel, Piia Keskivali-Bond, Sara Wells, Heather Cater, Philippe Fort, Mauro Santibanez-Koref, Silvia Middei, Claudio Sette, Gavin J. Clowry, Yoseph Barash, Mark O. Cunningham and David J. Elliott Cell Rep. 17(12): 3269–3280. doi: 10.1016/j.celrep.2016.12.002

So much for the central dogma? Complex complexity. Dionisio

There is no mystery of life. Life is designed, and this is not a mystery but a fact and here is why. All bio-structures, are built from the same six essential elemental ingredients: carbon, hydrogen, nitrogen, oxygen, phosphorus and sulfur(CHNOPS). Thus, all bio-structures differ only in the number and spatial arrangements of these ingredients. If we start with the simple self replicating molecule - starting point of evolution, then the only way to find evolutionary selectable spatial arrangements of CHNOPS is by re-arrangements. The theory of evolution is based on two fundamental premises. The first one says that mutations cause variations, a.k.a. re-arrangements or different spatial arrangements of CHNOPS. The second one says that the certain variations will be selectively preserved in response to environment. For example, when variation or arrangement of CHNOPS, that we call - a photosensitive cell(evolutionary step) exists, and it is beneficial in the current environment, then - it will be selected. That's fine. But that begs the question: how did this selectable combination of CHNOPS came to be? This is the crucial and the most important question that is completely ignored by the theory of evolution. Why it is ignored? Because there are virtually infinite number of ways in which CHNOPS atoms can be arranged, and most are junk, or non-selectable arrangements. For example, for a protein 92 amino acid long, with 10e122, possible amino acid re-arrangements, there is only 1 in every 10e63 evolutionary selectable arrangement. (Reidhaar-Olson&Sauer). On the other hand, published extreme upper limit estimates puts the maximum number of mutations, or CHNOPS re-arrangements, at 10e50. So, the total number of evolutionary CHNOPS re-arrangements is insufficient to find only one selectable state for evolution to preserve - a protein. Let alone molecular machines, organs or organ systems. That is why, the question posted above, is completely ignored by the theory of evolution. Any attempt to answer it, leads to only one conclusion. Evolution is impossible, and it didn't happen. In the evolutionary literature, the answer to the question is ignored through the following appeals: appeared, emerged, arose, gave rise to, burst onto the scene, derived, optimized, radiated into, modified itself, was making the transition to, manufactured itself, evolution's way of dealing with, derived emergent properties, evolution optimize it etc. forexhr

#2643 addendum: [Note that only humans were created in Imago Dei, hence our souls -guided by the spirit of their Creator- may overwrite the established biochemical circuits. The rest of Creation can behave only accordingly to their established physicochemical structure. BTW, since we are in an accursed world, most things are different than they were designed to be. Had we remained in Eden, many problems we see today would not have been an issue at all. Too late now. We screwed up things big time. Fortunately, in this age of grace the Creator has given us the Way to go back to Him. Run to it! Don't miss that unique opportunity. At the end of this Age of Grace every knee will bow and every tongue will confess that Christ is Lord of lords and King of kings. But then it will be too late for those who didn't choose Him. Now is the moment. Don't let it pass. Christ is the Way, the Truth and the Light. Delight in the Lord, and He will give you the desires of our heart that will fill your time, so that you may stay away from the evil things this lost world offers.] Dionisio

The brain is made up of trillions of synaptic connections that together form neural networks needed for normal brain function and behavior. SLM2 is a member of a conserved family of RNA binding proteins, including Sam68 and SLM1, that control splicing of Neurexin1-3 pre-mRNAs. Whether SLM2 affects neural network activity is unknown. [...] SLM2 levels are maintained by a homeostatic feedback control pathway [...] SLM2 also controls the splicing of Tomosyn2, LysoPLD/ATX, Dgkb, Kif21a, and Cask, each of which are important for synapse function.

A SLM2 Feedback Pathway Controls Cortical Network Activity and Mouse Behavior Ingrid Ehrmann, Matthew R. Gazzara, Vittoria Pagliarini, Caroline Dalgliesh, Mahsa Kheirollahi-Chadegani, Yaobo Xu, Eleonora Cesari, Marina Danilenko,1 Marie Maclennan, Kate Lowdon, Tanja Vogel, Piia Keskivali-Bond, Sara Wells, Heather Cater, Philippe Fort, Mauro Santibanez-Koref, Silvia Middei, Claudio Sette, Gavin J. Clowry, Yoseph Barash, Mark O. Cunningham and David J. Elliott Cell Rep. 17(12): 3269–3280. doi: 10.1016/j.celrep.2016.12.002

"SLM2 also controls the splicing..." Well, that's not quite accurate. SLM2 is used in the mechanisms underlying the control of splicing. Complex complexity. Dionisio

With growing data, there is a need for platform development for data distribution. Cloud computing-based analysis may serve as the most practical option. While sequencing-based variant analysis provides a big boost for the future of precision medicine, handling genomics data is one of the most pressing challenges for the next decade.

Advances in analyzing RNA diversity in eukaryotic transcriptomes: peering through the Omics lens Sushant Bangru1 and Auinash Kalsotra Version 1. F1000Res. 5: 2668. doi: 10.12688/f1000research.9511.1

Complex complexity. Dionisio

[...] the ENCODE project has generated unprecedented information about the many different RNA variants present in model organisms and human cells. Systematic discovery of cis-acting RNA elements, trans-acting RBPs that bind to these elements to control the production of variants, and their expression and subcellular localization is paving the way to uncovering the underlying code for generating much of the RNA diversity [...]

Advances in analyzing RNA diversity in eukaryotic transcriptomes: peering through the Omics lens Sushant Bangru1 and Auinash Kalsotra Version 1. F1000Res. 5: 2668. doi: 10.12688/f1000research.9511.1

Complex complexity. Dionisio

[...] the variants play key roles in generating mRNA diversity by altering their coding sequences, half-lives, and translation efficiencies, allowing complex organisms to control temporal and tissue-specific transcriptome patterns.

Advances in analyzing RNA diversity in eukaryotic transcriptomes: peering through the Omics lens Sushant Bangru1 and Auinash Kalsotra Version 1. F1000Res. 5: 2668. doi: 10.12688/f1000research.9511.1

Complex complexity. Dionisio

Recent transcriptome studies, which capture nearly every transcript in a cell, have revealed an overwhelming number of RNA variants resulting from multiple transcription initiation sites, alternative pre-mRNA splicing and polyadenylation, post-transcriptional editing, and direct chemical modifications of RNA [...]

Advances in analyzing RNA diversity in eukaryotic transcriptomes: peering through the Omics lens Sushant Bangru1 and Auinash Kalsotra Version 1. F1000Res. 5: 2668. doi: 10.12688/f1000research.9511.1

Did somebody say "overwhelming number"? overwhelming? :) Complex complexity. Dionisio

Alternative splicing, polyadenylation, and chemical modifications of RNA generate astonishing complexity within eukaryotic transcriptomes. [...] RNA is a highly complex and diverse macromolecule, which plays central roles in protein synthesis by serving as the encoder (mRNA), the decoder (tRNA), and the catalyst (rRNA). But our understanding of RNA diversity, form, and function continues to evolve as we keep discovering new and exciting classes of RNAs that carry out unexpected functions.

Advances in analyzing RNA diversity in eukaryotic transcriptomes: peering through the Omics lens Sushant Bangru1 and Auinash Kalsotra Version 1. F1000Res. 5: 2668. doi: 10.12688/f1000research.9511.1

Here's an undisputable example of evolution: "[...] our understanding [...] continues to evolve [...]" :) Complex complexity. Dionisio

Our approach to synthesizing large public RNA-sequencing datasets offers the opportunity to study transcription more deeply than ever before. Further, intropolis is a step toward establishing public resources that facilitate rapidly querying existing RNA-seq data.

Human splicing diversity and the extent of unannotated splice junctions across human RNA-seq samples on the Sequence Read Archive Abhinav Nellore, Andrew E. Jaffe, Jean-Philippe Fortin, José Alquicira-Hernández, Leonardo Collado-Torres, Siruo Wang, Robert A. Phillips III, Nishika Karbhari, Kasper D. Hansen, Ben Langmead and Jeffrey T. Leek Genome Biol. 17: 266. doi: 10.1186/s13059-016-1118-6

Work in progress... stay tuned. Complex complexity. Dionisio

The next challenge is to use these tools to better understand the regulation and purpose of splicing variants [...] [...] tissue dependent binary and complex LSVs both tend to occur in unstructured regions known to affect protein-protein interactions, as well as in specific yet distinct protein domains and families.

A new view of transcriptome complexity and regulation through the lens of local splicing variations Jorge Vaquero-Garcia, Alejandro Barrera, Matthew R Gazzara, Juan González-Vallinas, Nicholas F Lahens, John B Hogenesch, Kristen W Lynch and Yoseph Baras eLife. 5: e11752. doi: 10.7554/eLife.11752

Complex complexity. Dionisio

Alternative splicing (AS) can critically affect gene function and disease, yet mapping splicing variations remains a challenge. Genes contain coded instructions to build other molecules that are collectively referred to as gene products. Building these products requires the gene’s instructions to be copied into a molecule of RNA in a process called transcription. Over 90% of human genes undergo a process by which different segments of the transcribed RNA molecule are either removed or retained. This process, termed alternative splicing, results in a single gene encoding different gene products that can perform in different ways.

A new view of transcriptome complexity and regulation through the lens of local splicing variations Jorge Vaquero-Garcia, Alejandro Barrera, Matthew R Gazzara, Juan González-Vallinas, Nicholas F Lahens, John B Hogenesch, Kristen W Lynch and Yoseph Baras eLife. 5: e11752. doi: 10.7554/eLife.11752

Complex complexity. Dionisio

Much remains to be learnt about how these mechanisms contribute to the complexity of gene regulation and the diversity of protein isoforms produced in the brain. [...] understanding of non-canonical splicing events that are hidden deep within introns will be crucial to help explain those interactions for which a function has not yet been identified [...] It remains to be seen if these factors cooperate in the control of non-canonical splicing.

Lessons from non-canonical splicing Christopher R Sibley, Lorea Blazquez and Jernej Ule Nat Rev Genet. 17(7): 407–421. doi: 10.1038/nrg.2016.46

Complex complexity. Dionisio

The next challenge will be to systematically examine non-canonical splicing events that occur as a result of genetic variation [...] Dedicated genomic and transcriptomic experiments and computational approaches will therefore be needed to detect the full range of mutations that cause disease via non-canonical splicing. Even though it is clear that many non-canonical splicing events take place in human transcripts, our understanding of their roles in disease and physiology remains limited.

Lessons from non-canonical splicing Christopher R Sibley, Lorea Blazquez and Jernej Ule Nat Rev Genet. 17(7): 407–421. doi: 10.1038/nrg.2016.46

Complex complexity. Dionisio

Recent improvements in experimental and computational techniques used to study the transcriptome have enabled an unprecedented view of RNA processing, revealing many previously unknown non-canonical splicing events. This includes cryptic events located far from the currently annotated exons, and unconventional splicing mechanisms that have important roles in regulating gene expression.

Lessons from non-canonical splicing Christopher R Sibley, Lorea Blazquez and Jernej Ule Nat Rev Genet. 17(7): 407–421. doi: 10.1038/nrg.2016.46

Complex complexity. Dionisio

An intriguing question is whether these exons serve only for fine-tuning homeostatic RBP expression or for regulating expression more dramatically in certain conditions we currently do not know.

Systematic discovery of regulated and conserved alternative exons in the mammalian brain reveals NMD modulating chromatin regulators. Yan Q, Weyn-Vanhentenryck SM, Wu J, Sloan SA, Zhang Y, Chen K, Wu JQ Barres BA, Zhang C Proc Natl Acad Sci U S A. 112(11):3445-50. doi: 10.1073/pnas.1502849112.

Complex complexity. Dionisio

In addition to a greatly expanded list of AS exon that are likely functional, our study led to an unexpected finding revealing the widespread regulation of chromatin regulators through NMD.

Systematic discovery of regulated and conserved alternative exons in the mammalian brain reveals NMD modulating chromatin regulators. Yan Q, Weyn-Vanhentenryck SM, Wu J, Sloan SA, Zhang Y, Chen K, Wu JQ Barres BA, Zhang C Proc Natl Acad Sci U S A. 112(11):3445-50. doi: 10.1073/pnas.1502849112.

did anybody say "unexpected"? why? what did they expect? Complex complexity. Dionisio

Alternative splicing (AS) dramatically expands the complexity of the mammalian brain transcriptome, but its atlas remains incomplete. Our results highlight previously uncharacterized complexity and evolution in the mammalian brain transcriptome.

Systematic discovery of regulated and conserved alternative exons in the mammalian brain reveals NMD modulating chromatin regulators. Yan Q, Weyn-Vanhentenryck SM, Wu J, Sloan SA, Zhang Y, Chen K, Wu JQ Barres BA, Zhang C Proc Natl Acad Sci U S A. 112(11):3445-50. doi: 10.1073/pnas.1502849112.

Complex complexity. Dionisio

The specification of different cell fates by morphogen gradients has been a longstanding focus within developmental biology. [...] gradients of diffusible morphogens produce complex pattern during development [...] [...] BMP gradients can form and be stabilized through molecular feedback circuits [...]

Functional evolution of a morphogenetic gradient Chun Wai Kwan, Jackie Gavin-Smyth, Edwin L Ferguson, Urs Schmidt-Ott DOI: http://dx.doi.org/10.7554/eLife.20894 eLife 2016;5:e20894

Complex complexity. Dionisio

#2626 addendum 001 They are comparing morphogen gradients of two fly species: 1) Megaselia abdita: http://schmidt-ottlab.uchicago.edu/pdfs/fly-pages/megaselia-abdita-1.html 2) Drosophila melanogaster: https://en.wikipedia.org/wiki/Drosophila_melanogaster Flies are flies like birds are birds. A masterfully-designed informational framework that allows (through specifically-designed changes introduced at different points) for the great variety of plastic and robust biological systems observed in nature. However, do they explain exactly how -spatiotemporally- can we get the morphogen gradients -the whole enchilada- to begin with? Nope. Still no consensus on how exactly they are formed and interpreted. Well, with the exception of a distinguished Canadian professor who at one point indicated he knew exactly how the morphogen gradients are formed. The Italian singer Mina's popular song 'Parole, parole, parole' comes to mind, doesn't it? :) Where's the beef? This question belongs in the "third way" thread, but couldn't resist the temptation to write it here too. :) Dionisio

Bone Morphogenetic Proteins (BMPs) pattern the dorsal-ventral axis of bilaterian embryos; however, their roles in the evolution of body plan are largely unknown. We examined their functional evolution in fly embryos. BMP signaling specifies two extraembryonic tissues, the serosa and amnion, in basal-branching flies such as Megaselia abdita, but only one, the amnioserosa, in Drosophila melanogaster. The BMP signaling dynamics are similar in both species until the beginning of gastrulation, when BMP signaling broadens and intensifies at the edge of the germ rudiment in Megaselia, while remaining static in Drosophila. Here we show that the differences in gradient dynamics and tissue specification result from evolutionary changes in the gene regulatory network that controls the activity of a positive feedback circuit on BMP signaling, involving the tumor necrosis factor alpha homolog eiger. These data illustrate an evolutionary mechanism by which spatiotemporal changes in morphogen gradients can guide tissue complexity.

Functional evolution of a morphogenetic gradient Chun Wai Kwan, Jackie Gavin-Smyth, Edwin L Ferguson, Urs Schmidt-Ott DOI: http://dx.doi.org/10.7554/eLife.20894 eLife 2016;5:e20894

This paper contains pseudoscientific statements that qualify for the discussion thread "A third way of evolution?" with a "Where's the beef?" stamp, but since it has very good scientific information about morphogen gradient formation and interpretation, it can be in this thread too. But with a big well-deserved "Where's the beef?" stamp on it anyway. :) This paper is just pointing at another example of a designed built-in framework that allows the wide variety of plastic and robust biological systems we observe in nature. Complex complexity. Dionisio

[...] the field of lung bioengineering is still in its infancy. [...] there are still key questions that need to be clarified and much better understood. [...] better understanding how static and dynamic stretch modulate stem cell fate should be useful [...]

Lung bioengineering: physical stimuli and stem/progenitor cell biology interplay towards biofabricating a functional organ Paula N. Nonaka, Juan J. Uriarte, Noelia Campillo, Vinicius R. Oliveira, Daniel Navajas and Ramon Farré Respir Res. 17: 161. doi: 10.1186/s12931-016-0477-6

Complex complexity. Dionisio

A current approach to obtain bioengineered lungs as a future alternative for transplantation is based on seeding stem cells on decellularized lung scaffolds. A fundamental question to be solved in this approach is how to drive stem cell differentiation onto the different lung cell phenotypes.

Lung bioengineering: physical stimuli and stem/progenitor cell biology interplay towards biofabricating a functional organ Paula N. Nonaka, Juan J. Uriarte, Noelia Campillo, Vinicius R. Oliveira, Daniel Navajas and Ramon Farré Respir Res. 17: 161. doi: 10.1186/s12931-016-0477-6

Complex complexity. Dionisio

The findings are novel and interesting because we have identified a new mechanism rather than those involving cytoskeleton activity, by which substrate stiffness regulates hMSC behavior.

A newly identified mechanism involved in regulation of human mesenchymal stem cells by fibrous substrate stiffness. Yuan H, Zhou Y, Lee MS, Zhang Y, Li WJ Acta Biomater. 42:247-57. doi: 10.1016/j.actbio.2016.06.034

Oh, no! A new regulatory mechanism? More stuff to learn about? Is there an end this? Seen the light at the end of the tunnel yet? :) Complex complexity. Dionisio

Stiffness of biomaterial substrates plays a critical role in regulation of cell behavior. Although the effect of substrate stiffness on cell behavior has been extensively studied, molecular mechanisms of regulation rather than those involving cytoskeletal activities still remain elusive. [...] substrate stiffness dictates hMSC differentiation through the MIF-mediated AKT/YAP/RUNX2 pathway.

A newly identified mechanism involved in regulation of human mesenchymal stem cells by fibrous substrate stiffness. Yuan H, Zhou Y, Lee MS, Zhang Y, Li WJ Acta Biomater. 42:247-57. doi: 10.1016/j.actbio.2016.06.034

Oh, no! Another regulatory mechanism? Are they kidding? :) Complex complexity. Dionisio

We strongly believe that the current presented simple non-functionalized HNPC-fibrous scaffold system can serve as an excellent model in further studies exploring topics including brain development and function, [...]

Englund-Johansson, U., Netanyah, E. and Johansson, F. (2017) Human Neural Progenitor Cell Behavior—Studies on Cellular Migration and Phenotypic Differentiation. Journal of Biomaterials and Nanobiotechnology , 8, 1-21. http://dx.doi.org/10.4236/jbnb.2017.81001

Did somebody say that they "strongly believe"? Is faith OK within serious science too? :) Did somebody say "further studies"? More studies? Are they kidding? How long are they going to be studying? Did somebody say "exploring topics including brain development and function"? Hasn't the enormous amount of exploring done until now been enough? Have all the topics been explored sufficiently yet? Did they see the light at the end of the tunnel yet? :) Complex complexity. Dionisio

[...] the physical cues significantly affect basic human brain progenitor behavior, including migration and phenotypic differentiation potential.

Englund-Johansson, U., Netanyah, E. and Johansson, F. (2017) Human Neural Progenitor Cell Behavior—Studies on Cellular Migration and Phenotypic Differentiation. Journal of Biomaterials and Nanobiotechnology , 8, 1-21. http://dx.doi.org/10.4236/jbnb.2017.81001

Complex complexity. Dionisio

In further studies it is of great interest to in detail investigate the functional development of the HNPC-derived neurons, by studying e.g. expression of markers for late neuronal differentiation, such as MAP-2 and neurofilament as well as for synaptic formation (e.g., the markers synaptophysin and SV2 [29]. Studies of electrical activity are also needed [...]

Englund-Johansson, U., Netanyah, E. and Johansson, F. (2017) Human Neural Progenitor Cell Behavior—Studies on Cellular Migration and Phenotypic Differentiation. Journal of Biomaterials and Nanobiotechnology , 8, 1-21. http://dx.doi.org/10.4236/jbnb.2017.81001

Work in progress... stay tuned. Complex complexity. Dionisio

We believe that radial-glial like GFAP+ cells are formed preferable at the aligned fibers.

Englund-Johansson, U., Netanyah, E. and Johansson, F. (2017) Human Neural Progenitor Cell Behavior—Studies on Cellular Migration and Phenotypic Differentiation. Journal of Biomaterials and Nanobiotechnology , 8, 1-21. http://dx.doi.org/10.4236/jbnb.2017.81001

Did somebody say that they "believe"? Is faith ok in science too? :) Complex complexity. Dionisio

For proper central nervous system (CNS) development, homeostasis and overall function, neural cells normally depend on a close interaction with neighboring cells and the extracellular matrix (ECM), a mixture of structural- and functional proteins. In the brain, normal cells experience a three-dimensional environment, completely surrounded by other cells, membranes, fibrous layers, and adhesion proteins. The fact that the different fiber substrates generate different morphologies of neurons, lead to the question whether a specific substrate have the potential to enrich for a regions-specific neuronal population.

Englund-Johansson, U., Netanyah, E. and Johansson, F. (2017) Human Neural Progenitor Cell Behavior—Studies on Cellular Migration and Phenotypic Differentiation. Journal of Biomaterials and Nanobiotechnology , 8, 1-21. http://dx.doi.org/10.4236/jbnb.2017.81001

Complex complexity. Dionisio

[...] the molecular mechanistic pathways are not yet fully understood. It is imperative to understand the molecular mechanisms [...] Future studies with neuronal cells should further explore three-dimensional (3D) cultures in combination with native microenvironmental factors, such as soluble factors and electrical potentials to develop bioscaffolds more likely to succeed when transplanted to the in vivo setting.

Exploration of physical and chemical cues on retinal cell fate Marina Castro Zalisa, Sebastian Johanssona, Fredrik Johanssonb, Ulrica Englund Johansson http://dx.doi.org/10.1016/j.mcn.2016.07.006 Molecular and Cellular Neuroscience Volume 75, Pages 122–132

Complex complexity. Dionisio

[...] a detailed analysis of E-NTPDase subtype expression during postnatal retina will be necessary to evaluate the function of each enzyme during retina development. [...] proliferation mediated by adenine nucleotides occurs only in a subset of RPCs, such as bipolar or Müller glia. [...] we need to assess how these retinal populations behave after P2Y1 receptor blockage. [...] changes in cell cycle proteins alter proliferation of RPC, causing changes in the number of mature retinal cells. [...] further analysis will be necessary to evaluate the possible consequences of P2Y1 receptor blockade in retinal populations. [...] adenine nucleotides control RPC proliferation in vivo modulating the transition from G1 to S through P2Y1 receptor.

Adenine Nucleotides Control Proliferation In Vivo of Rat Retinal Progenitors by P2Y1 Receptor Luana de Almeida-Pereira, Camila Feitosa Magalhães, Marinna Garcia Repossi, Maria Luiza Prates Thorstenberg, Alfred Sholl-Franco, Robson Coutinho-Silva, Ana Lucia Marques Ventura, Lucianne Fragel-Madeira DOI: 10.1007/s12035-016-0059-0 Molecular Neurobiology pp 1–14

Complex complexity. Dionisio

The retina is a part of the central nervous system (CNS) with morphological and biochemical features that make it an excellent model to study the development of this system. [...] P2Y1 receptor modulates the transition from G1 to S phase, by modulating the p57KIP2 protein during postnatal retina development in vivo. [...] adenine nucleotides are important to sustain RPC proliferation in rat retina contributing to this balance in agreement with the literature data [...] [...] the endogenous adenine nucleotides are involved with developmental events (cell death and proliferation, for example) and its action occurs through different receptors. [...] the proliferation is preferentially stimulated by ADP [...]

Adenine Nucleotides Control Proliferation In Vivo of Rat Retinal Progenitors by P2Y1 Receptor Luana de Almeida-Pereira, Camila Feitosa Magalhães, Marinna Garcia Repossi, Maria Luiza Prates Thorstenberg, Alfred Sholl-Franco, Robson Coutinho-Silva, Ana Lucia Marques Ventura, Lucianne Fragel-Madeira DOI: 10.1007/s12035-016-0059-0 Molecular Neurobiology pp 1–14

Complex complexity. Dionisio

We would like to know the nature of the signal that lies upstream of the earliest known activators of neurogenesis and how this signal is acting independently of the retinal growth stage. Future studies should clarify how these components affect signalling and how they influence the onset of neurogenesis. It remains to be seen whether, in the central area of the primate retina, the epithelium exerts, like in pigeon, an inhibitory effect on neuronal differentiation. Very little is known about the function of the proteins these genes encode, nor do we know whether they are expressed early in foetal human retina. [...] the pigeon retina could prove to be a useful new model system to uncover some of the intricate mechanisms underlying growth and neurogenesis in the macula of primates.

Delayed neurogenesis with respect to eye growth shapes the pigeon retina for high visual acuity Tania Rodrigues, Michal Krawczyk, Dorota Skowronska-Krawczyk, Last Jean-Marc Matter Development 143(24):4701-4712 DOI: 10.1242/dev.138719

Complex complexity. Dionisio

Future experiments should help to determine if newly generated cells actively translocate from the CMZ to the neural retina or whether, as it has been observed in zebrafish, they are pushed centrally as a consequence of tissue growth (Wan et al., 2016). [...] it is unclear whether cells undergoing lateral migration translocate as differentiated cells or as progenitors. [...] whether the mouse CMZ provides the neural retina with retinal cells under normal conditions in the mature retina has remained elusive. [...] during embryogenesis the proximal superficial CMZ could act as a neurogenic area, giving rise to subsets of RGCs ultimately located in the peripheral neural retina.

The Ciliary Margin Zone of the Mammalian Retina Generates Retinal Ganglion Cells. Marcucci F, Murcia-Belmonte V, Wang Q, Coca Y, Ferreiro-Galve S, Kuwajima T, Khalid S, Ross ME, Mason C, Herrera E Cell Rep. 17(12):3153-3164. doi: 10.1016/j.celrep.2016.11.016.

Complex complexity. Dionisio

During development, as the eyecup emerges and expands in size, a wave of neurogenesis progresses from the central retina to the periphery. It is unknown, however, whether the mammalian CMZ is a source of retinal cells during embryogenesis, and whether the loss of neurogenic potential in the CMZ occurs during this period or emerges postnatally.

The Ciliary Margin Zone of the Mammalian Retina Generates Retinal Ganglion Cells. Marcucci F, Murcia-Belmonte V, Wang Q, Coca Y, Ferreiro-Galve S, Kuwajima T, Khalid S, Ross ME, Mason C, Herrera E Cell Rep. 17(12):3153-3164. doi: 10.1016/j.celrep.2016.11.016.

Complex complexity. Dionisio

The retina of lower vertebrates grows continuously by integrating new neurons generated from progenitors in the ciliary margin zone (CMZ). Whether the mammalian CMZ provides the neural retina with retinal cells is controversial. Together, these results implicate the mammalian CMZ as a neurogenic site that produces RGCs and whose proper generation depends on Cyclin D2 activity.

The Ciliary Margin Zone of the Mammalian Retina Generates Retinal Ganglion Cells. Marcucci F, Murcia-Belmonte V, Wang Q, Coca Y, Ferreiro-Galve S, Kuwajima T, Khalid S, Ross ME, Mason C, Herrera E Cell Rep. 17(12):3153-3164. doi: 10.1016/j.celrep.2016.11.016.

Complex complexity. Dionisio

[...] given the complex molecular mechanisms involved in G9a/GLP targeting in other contexts (Cedar and Bergman, 2009), additional investigations are needed to define the precise functions of ZNF644 and WIZ in G9a/GLP-mediated silencing during neurogenesis. Further investigations are needed to determine the precise role of ZNF644 (and impact of mutations associated with high-grade myopia) in controlling G9a/H3K9me2 during retinal growth and differentiation in adult stem cell populations.

G9a and ZNF644 Physically Associate to Suppress Progenitor Gene Expression during Neurogenesis Jonathan B. Olsen, Loksum Wong, Steven Deimling, Amanda Miles, Hongbo Guo, Yue Li, Zhaolei Zhang, Jack F. Greenblatt, Andrew Emili and Vincent Tropepe Stem Cell Reports. 7(3): 454–470. doi: 10.1016/j.stemcr.2016.06.012

Complex complexity. Dionisio

[...] ZNF644 physically interacts with G9a and GLP and serves as a co-regulator of H3K9me2. [...] the functions of g9a and znf644a/b are recapitulated in midbrain progenitor cells, suggesting a common gene-silencing complex mediating differentiation in distinct neuronal progenitor populations.

G9a and ZNF644 Physically Associate to Suppress Progenitor Gene Expression during Neurogenesis Jonathan B. Olsen, Loksum Wong, Steven Deimling, Amanda Miles, Hongbo Guo, Yue Li, Zhaolei Zhang, Jack F. Greenblatt, Andrew Emili and Vincent Tropepe Stem Cell Reports. 7(3): 454–470. doi: 10.1016/j.stemcr.2016.06.012

Complex complexity. Dionisio

Although G9a/GLP-associated proteins have been reported [...] their precise contributions to G9a/GLP-mediated neural differentiation are largely unknown. Co-regulators that facilitate G9a/H3K9me2-mediated silencing during neurogenesis are unknown. [...] a role for ZNF644 in maintaining proper eye morphology and/or growth, yet its function in neural contexts is currently uncharacterized.

G9a and ZNF644 Physically Associate to Suppress Progenitor Gene Expression during Neurogenesis Jonathan B. Olsen, Loksum Wong, Steven Deimling, Amanda Miles, Hongbo Guo, Yue Li, Zhaolei Zhang, Jack F. Greenblatt, Andrew Emili and Vincent Tropepe Stem Cell Reports. 7(3): 454–470. doi: 10.1016/j.stemcr.2016.06.012

Complex complexity. Dionisio

Alterations in histone methylation instruct developmental gene-expression programs that enable proliferating progenitor cells to exit the cell cycle and differentiate. These changes are mediated by conserved, multiprotein macromolecules that “write” and “read” histone methylation marks [...] [...] the composition of relevant HMT complexes and, specifically, the identity of physically associated co-regulators that modulate activity during cellular differentiation are incompletely defined.

G9a and ZNF644 Physically Associate to Suppress Progenitor Gene Expression during Neurogenesis Jonathan B. Olsen, Loksum Wong, Steven Deimling, Amanda Miles, Hongbo Guo, Yue Li, Zhaolei Zhang, Jack F. Greenblatt, Andrew Emili and Vincent Tropepe Stem Cell Reports. 7(3): 454–470. doi: 10.1016/j.stemcr.2016.06.012

Complex complexity. Dionisio

Proliferating progenitor cells undergo changes in competence to give rise to post-mitotic progeny of specialized function. These cell-fate transitions typically involve dynamic regulation of gene expression by histone methyltransferase (HMT) complexes. However, the composition, roles, and regulation of these assemblies in regulating cell-fate decisions in vivo are poorly understood. [...] critical aspects of retinal differentiation programs regulated by differential G9a-ZNF644 associations, such as transitioning proliferating progenitor cells toward differentiation. [...] ZNF644 as a critical co-regulator of G9a/H3K9me2-mediated gene silencing during neuronal differentiation.

G9a and ZNF644 Physically Associate to Suppress Progenitor Gene Expression during Neurogenesis Jonathan B. Olsen, Loksum Wong, Steven Deimling, Amanda Miles, Hongbo Guo, Yue Li, Zhaolei Zhang, Jack F. Greenblatt, Andrew Emili and Vincent Tropepe Stem Cell Reports. 7(3): 454–470. doi: 10.1016/j.stemcr.2016.06.012

Complex complexity. Dionisio

During eye development, retinal cells differentiate in a conserved sequence from a pool of multipotent progenitor cells directed by intrinsic properties and extrinsic cues. [...] during early retinal development, sAC activity and expression in the retina play a critical role in retinal progenitor cell fate specification and RGC development. These data motivate further investigation to clarify the precise roles played by sAC during retinal development [...]

Soluble Adenylyl Cyclase Is Required for Retinal Ganglion Cell and Photoreceptor Differentiation Peter X. Shaw, Jiahua Fang, Alan Sang, Yan Wang, Michael S. Kapiloff and Jeffrey L. Goldberg Invest Ophthalmol Vis Sci. 57(11): 5083–5092. doi: 10.1167/iovs.16-19465

Complex complexity. Dionisio

sAC plays an important role in the early retinal development of RGCs as well as in the development of amacrine cells and to a lesser degree photoreceptors. The function of sAC in retinal development remains largely unknown. Molecular signaling mechanisms that govern the differentiation and maturation of retinal neurons remain a subject of intense study. cAMP plays an important role in the differentiation of neural progenitor cells, for example, through cAMP response element binding protein phosphorylation.

Soluble Adenylyl Cyclase Is Required for Retinal Ganglion Cell and Photoreceptor Differentiation Peter X. Shaw, Jiahua Fang, Alan Sang, Yan Wang, Michael S. Kapiloff and Jeffrey L. Goldberg Invest Ophthalmol Vis Sci. 57(11): 5083–5092. doi: 10.1167/iovs.16-19465

Complex complexity. Dionisio

Special Morphological Features at the Interface of the Renal Stem/Progenitor Cell Niche Force to Reinvestigate Transport of Morphogens During Nephron Induction Will W. Minuth* and Lucia Denk Biores Open Access. 5(1): 49–60. doi: 10.1089/biores.2015.0039

This paper is referenced @1704-1707 & @2218-2221. Dionisio

Regarding the information posted @2582-2600, did somebody -a politely dissenting & highly educated commenter in UD- indicate -not too long ago- that they knew exactly how morphogen gradients are formed? Dionisio

Future studies using similar approaches will undoubtedly continue to shed light on the molecular mechanisms of morphogen gradient formation. [...] it is becoming clear that a single source of morphogen is not always sufficient to generate a proper gradient. [...] to completely understand the nature of morphogen gradients in the future, it will be essential to reconsider models that are based on single sources of morphogen for gradient formation.

Morphogen transport: theoretical and experimental controversies. Akiyama T, Gibson MC Wiley Interdiscip Rev Dev Biol. 4(2):99-112. doi: 10.1002/wdev.167.

Work in progress... stay tuned. Complex complexity on steroids. Dionisio

[...] we still do not completely understand whether and how veritable extracellular morphogen gradients are established and maintained during development. [...] morphogen production is tightly regulated at multiple levels, such as precursor cleavage and post-translational modifications, to create the proper gradient. [...] it will be crucial for future studies to visualize and study endogenous morphogen gradients.

Morphogen transport: theoretical and experimental controversies. Akiyama T, Gibson MC Wiley Interdiscip Rev Dev Biol. 4(2):99-112. doi: 10.1002/wdev.167.

Work in progress... stay tuned. Complex complexity on steroids. Dionisio

HSPGs are also required for facilitating morphogen gradient formation. [...] yet unknown feedback loops are likely to play an important role in shaping the final DPP morphogen gradient.

Morphogen transport: theoretical and experimental controversies. Akiyama T, Gibson MC Wiley Interdiscip Rev Dev Biol. 4(2):99-112. doi: 10.1002/wdev.167.

Complex complexity on steroids. Dionisio

[...] for diffusion to work as a mechanism of gradient formation, morphogen molecules would have to exhibit both rapid dispersal and efficient elimination from the extracellular space. [...] the FGF8 gradient is established through free diffusion coupled with rapid degradation by a receptor-mediated endocytosis. [...] it remains unclear whether free diffusion itself is sufficient to establish a morphogen gradient.

Morphogen transport: theoretical and experimental controversies. Akiyama T, Gibson MC Wiley Interdiscip Rev Dev Biol. 4(2):99-112. doi: 10.1002/wdev.167.

Complex complexity on steroids. Dionisio

[...] it is still unclear whether cytonemes influence formation of the DPP morphogen gradient. [...] cytonemes transport DPP from its expressing cells to the receiving cells in a contact-dependent manner through receptor-mediated retrograde trafficking. [...] the role of cytonemes in DPP gradient formation is still speculative. It will be critical to examine how interfering with cytoneme function (e.g., inhibition of actin polymerization) influences DPP morphogen gradient formation in the future.

Morphogen transport: theoretical and experimental controversies. Akiyama T, Gibson MC Wiley Interdiscip Rev Dev Biol. 4(2):99-112. doi: 10.1002/wdev.167.

Complex complexity on steroids. Dionisio

[...] Hh transport via cytonemes/filipodia is critical for proper gradient formation. [...] the molecular mechanism by which cytonemes utilize HSPGs on the receiving cells remains elusive. [...] molecular mechanisms by which the orientation of cytonemes is controlled and how Hh transport via cytonemes creates a precise concentration gradient remain elusive.

Morphogen transport: theoretical and experimental controversies. Akiyama T, Gibson MC Wiley Interdiscip Rev Dev Biol. 4(2):99-112. doi: 10.1002/wdev.167.

Complex complexity on steroids. Dionisio

Cytonemes, long cellular extensions, represent a completely distinct model for the formation of morphogen gradients [...] [...] morphogens are proposed to be directly delivered from the producing cells to the receiving cells via a contact-dependent mechanism. Cytonemes are filopodial protrusions, which contain actin filament bundles oriented with their plus ends at the tips of filopodia. [...] cytonemes are thought to be highly specialized for each signaling pathway.

Morphogen transport: theoretical and experimental controversies. Akiyama T, Gibson MC Wiley Interdiscip Rev Dev Biol. 4(2):99-112. doi: 10.1002/wdev.167.

Complex complexity on steroids. Dionisio

[...] the evidence supporting Tkv-mediated transcytosis as a mechanism for DPP gradient formation remains inconclusive. [...] crucial insight will come from further studies to probe the endogenous regulation of ligand and receptor trafficking without wholesale disruption of the endocytic machinery.

Morphogen transport: theoretical and experimental controversies. Akiyama T, Gibson MC Wiley Interdiscip Rev Dev Biol. 4(2):99-112. doi: 10.1002/wdev.167.

Complex complexity on steroids. Dionisio

#2591 follow up: Did somebody indicate that they knew exactly how morphogen gradients are formed? :) Dionisio

According to morphogen gradient theory, secreted ligands disperse into a morphogenetic field and establish a concentration gradient. [...] it is increasingly clear that developmental systems employ different means to the same end. [...] the molecular basis for the spreading of morphogens remains unclear and controversial [...] [...] the mechanisms of gradient formation are still hotly debated.

Morphogen transport: theoretical and experimental controversies. Akiyama T, Gibson MC Wiley Interdiscip Rev Dev Biol. 4(2):99-112. doi: 10.1002/wdev.167.

Complex complexity on steroids. Dionisio

A tight connection between post-translational modification and intracellular trafficking also regulates Wg/Wnt production. [...] whether the enzyme is responsible for both lipid modifications remains unclear. The precise requirement for each lipid modification in Wg/Wnt secretion and signaling is still debated.

Morphogen transport: theoretical and experimental controversies. Akiyama T, Gibson MC Wiley Interdiscip Rev Dev Biol. 4(2):99-112. doi: 10.1002/wdev.167.

Complex complexity on steroids. Dionisio

In both vertebrates and invertebrates, the production of active Hh ligands requires two essential intracellular processes: autoproteolysis and lipid modification. [...] lipid modifications are important for Hh oligomerization, which enhances signaling activity and is critical for the gradient formation by solubilizing Hh proteins.

Morphogen transport: theoretical and experimental controversies. Akiyama T, Gibson MC Wiley Interdiscip Rev Dev Biol. 4(2):99-112. doi: 10.1002/wdev.167.

Complex complexity on steroids. Dionisio

[...] differential cleavage may be responsible for differential signaling outputs in each tissue. [...] it will be of great importance to examine the endogenous distribution of alternative BMP ligands in future studies. Combined, differential cleavages and dimerization play essential roles in modulating the TGF-beta/BMP signaling pathway in disparate developmental contexts.

Morphogen transport: theoretical and experimental controversies. Akiyama T, Gibson MC Wiley Interdiscip Rev Dev Biol. 4(2):99-112. doi: 10.1002/wdev.167.

Complex complexity on steroids. Dionisio

[...] ligand production can critically influence extracellular ligand gradient formation. [...] differential cleavage can elicit context-dependent behavior of these proteins. The identification of an alternative cleavage site in the BMP prodomain opens a new avenue to address the long-standing question of how BMP signaling establishes different signaling outputs in a context-dependent manner.

Morphogen transport: theoretical and experimental controversies. Akiyama T, Gibson MC Wiley Interdiscip Rev Dev Biol. 4(2):99-112. doi: 10.1002/wdev.167.

Complex complexity on steroids. Dionisio

The first critical step for the formation of a morphogen gradient is production. [...] a balance between morphogen production (source) and degradation (sink) critically impacts the final form of the gradient. [...] to ensure normal development, morphogen production needs to be tightly regulated at different levels.

Morphogen transport: theoretical and experimental controversies. Akiyama T, Gibson MC Wiley Interdiscip Rev Dev Biol. 4(2):99-112. doi: 10.1002/wdev.167.

Complex complexity on steroids. Dionisio

In light of the first paragraph @2583, did somebody say that they knew exactly how morphogen gradients are formed? :) Dionisio

The paper referenced @2582 was initially posted @1382. Dionisio

Despite a long history and many recent advances, precisely how morphogens generate robust concentration gradients in different developmental contexts remains both controversial and inconclusive. [...] beyond the difference between spreading and accumulation, most secreted signals are also regulated through intracellular processing,[...] controlled trafficking,[...] post-translational modification,[...] and extracellular modulation.

Morphogen transport: theoretical and experimental controversies. Akiyama T, Gibson MC Wiley Interdiscip Rev Dev Biol. 4(2):99-112. doi: 10.1002/wdev.167.

Complex complexity on steroids. Dionisio

Before the dawn of modern developmental biology, experimental embryologists postulated that diffusing factors governed body plan formation during development and regeneration. As the number of identified morphogens has increased, two distinct mechanisms for gradient formation have been observed [...] [...] morphogens are widely expressed and subsequently transported to a local area to establish a concentration gradient [...]

Morphogen transport: theoretical and experimental controversies. Akiyama T, Gibson MC Wiley Interdiscip Rev Dev Biol. 4(2):99-112. doi: 10.1002/wdev.167.

Complex complexity on steroids. Dionisio

Many characteristics, challenges, and questions associated with the complexity of morphogen systems will require new mathematics and new computational tools, likely leading to an emerging research area: mathematical and computational morphogenesis.

Mathematical models of morphogen dynamics and growth control Jinzhi Lei, Wing-Cheong Lo and Qing Nie DOI: 10.4310/AMSA.2016.v1.n2.a6 Annals of Mathematical Sciences and Applications Volume 1, Number 2, 427–471

An emerging research area? Another one? Work in progress... stay tuned. :) Complex complexity. Dionisio

On the experimental side, numerous aspects of morphogen systems need more study [...] On the modeling side, more advanced models need to include [...] On the side of mathematical analysis and computational tools, several major challenges and unanswered questions remain.

Mathematical models of morphogen dynamics and growth control Jinzhi Lei, Wing-Cheong Lo and Qing Nie DOI: 10.4310/AMSA.2016.v1.n2.a6 Annals of Mathematical Sciences and Applications Volume 1, Number 2, 427–471

Work in progress... stay tuned. :) Complex complexity. Dionisio

The major contribution of mathematical models is in the areas of morphogen gradient formation and the mechanisms controlling the gradient. While modeling has significantly enhanced our understanding of morphogens, many important mathematical questions associated with the models remain to be addressed, and many biological questions remain unanswered.

Mathematical models of morphogen dynamics and growth control Jinzhi Lei, Wing-Cheong Lo and Qing Nie DOI: 10.4310/AMSA.2016.v1.n2.a6 Annals of Mathematical Sciences and Applications Volume 1, Number 2, 427–471

Work in progress... stay tuned. :) Complex complexity. Dionisio

@2577: Did somebody say "complex machineries"? :) Dionisio

‘Wet’ experiments alone are usually insufficient for understanding the complex machineries used for morphogen-mediated patterning and growth control.

Mathematical models of morphogen dynamics and growth control Jinzhi Lei, Wing-Cheong Lo and Qing Nie DOI: 10.4310/AMSA.2016.v1.n2.a6 Annals of Mathematical Sciences and Applications Volume 1, Number 2, 427–471

Work in progress... stay tuned. :) Complex complexity. Dionisio

How distinct cell types and organs are generated from a single cell or a small number of cells is a fundamental question in studying multicellular organisms. The concept of the morphogen is at the center of answering this question [...] Morphogens are signaling molecules that can diffuse and act over several cell diameters to induce concentration-dependent cellular responses. This process involves various control strategies due to the complexity and diversity among different types of organ development.

Mathematical models of morphogen dynamics and growth control Jinzhi Lei, Wing-Cheong Lo and Qing Nie DOI: 10.4310/AMSA.2016.v1.n2.a6 Annals of Mathematical Sciences and Applications Volume 1, Number 2, 427–471

Work in progress... stay tuned. :) Complex complexity. Dionisio

During the past two decades, sophisticated mathematical models have been utilized to decipher the complex biological mechanisms that regulate the spatial and temporal dynamics of morphogens.

Mathematical models of morphogen dynamics and growth control Jinzhi Lei, Wing-Cheong Lo and Qing Nie DOI: 10.4310/AMSA.2016.v1.n2.a6 Annals of Mathematical Sciences and Applications Volume 1, Number 2, 427–471

Work in progress... stay tuned. :) Complex complexity. Dionisio

Morphogens are diffusive molecules produced by cells, sending signals to neighboring cells in tissues for communication. As a result, tissues develop cellular patterns that depend on the concentration levels of the morphogens. The formation of morphogen gradients is among the most fundamental biological processes during development, regeneration, and disease.

Mathematical models of morphogen dynamics and growth control Jinzhi Lei, Wing-Cheong Lo and Qing Nie DOI: 10.4310/AMSA.2016.v1.n2.a6 Annals of Mathematical Sciences and Applications Volume 1, Number 2, 427–471

Complex complexity. Dionisio

While Set7 has been shown to bind RNA [28] and is implicated in its processing [22], the mechanisms regulating these events are yet to be fully elucidated. Since AMI-5 inhibits the activities of arginine and lysine methyltransferases the regulatory mechanisms involved are yet to be elucidated. Some of the connections between Set7 inhibition and stem cell differentiation are starting to be revealed at the molecular level. [...] the challenge now will be to experimentally assess whether PFI-2 perturbs epigenetic memory during stem cell plasticity.

Current perspectives in Set7 mediated stem cell differentiation Nazanin Karimnia, Haloom Rafehi, Natasha K Tuano, Mark Ziemann, Harikrishnan K.N, Jun Okabe and Assam El-Osta Non-Coding RNA, 2(4), 14; doi:10.3390/ncrna2040014

Complex complexity. Dionisio

The upregulation of Set7 might be a critical switch facilitating cell differentiation through transcriptional regulation, activity and degradation of Set7 target proteins. [...] Set7 induces the expression of ncRNAs associated with development and differentiation. Little is known about the regulatory events, binding specificity and dynamics of many of the Set7 associated complexes that carry out ncRNA functions.

Current perspectives in Set7 mediated stem cell differentiation Nazanin Karimnia, Haloom Rafehi, Natasha K Tuano, Mark Ziemann, Harikrishnan K.N, Jun Okabe and Assam El-Osta Non-Coding RNA, 2(4), 14; doi:10.3390/ncrna2040014

Complex complexity. Dionisio

Histone lysine methylation has emerged as a key epigenetic signature in the transcriptional regulation of gene expression [1]. As such, lysine methyltransferase enzymes catalyse the methyl-writing ability at specific lysine residues of histone and non-histone proteins and have important regulatory roles in defining both gene activation and repression. The challenge now is to understand the diverse substrate specificity of Set7 with that of biological function and one notable example of this increasing complexity is hyperglycemic memory.

Current perspectives in Set7 mediated stem cell differentiation Nazanin Karimnia, Haloom Rafehi, Natasha K Tuano, Mark Ziemann, Harikrishnan K.N, Jun Okabe and Assam El-Osta Non-Coding RNA, 2(4), 14; doi:10.3390/ncrna2040014

Complex complexity. Dionisio

Set7 is a key regulatory enzyme involved in the methylation of lysine residues of histone and non-histone proteins. This lysine methyltransferase is induced during stem cell differentiation and regulates lineage specific gene transcription and cell fate.

Current perspectives in Set7 mediated stem cell differentiation Nazanin Karimnia, Haloom Rafehi, Natasha K Tuano, Mark Ziemann, Harikrishnan K.N, Jun Okabe and Assam El-Osta Non-Coding RNA, 2(4), 14; doi:10.3390/ncrna2040014

Complex complexity. Dionisio

there yet? :) bottom-up reverse engineering of a top-down-designed system? unending revelation of the ultimate reality (c) Dionisio

This fascinating link with extracellular signaling also carries with it precise instructions for Set7 activity that include broad substrate specificity [...] [...] understanding how SRF methylation is regulated by Set7 is an area of future investigation. [...] studies examining aspects of demethylation may provide clues to the control of cytoplasmic and nuclear location.

Set7 mediated interactions regulate transcriptional networks in embryonic stem cells Natasha K. Tuano, Jun Okabe, Mark Ziemann, Mark E. Cooper, and Assam El-Osta Nucleic Acids Res. 44(19): 9206–9217. doi: 10.1093/nar/gkw621

Work in progress… stay tuned. Complex complexity. Dionisio

[...] explanations for the discordant experimental results remain unclear [...] [...] further studies are required to characterize the role of the lysine methyltransferase during embryogenesis to investigate the mechanistic link between the Set7 enzyme with differentiation and smooth muscle function. [...] we speculate that Set7 cooperatively regulates transcription by context-dependent mechanisms. [...] a major gap in our knowledge relates to the dynamic yet subtle sequestration of Set7 between cellular compartments.

Set7 mediated interactions regulate transcriptional networks in embryonic stem cells Natasha K. Tuano, Jun Okabe, Mark Ziemann, Mark E. Cooper, and Assam El-Osta Nucleic Acids Res. 44(19): 9206–9217. doi: 10.1093/nar/gkw621

Work in progress… stay tuned. Complex complexity. Dionisio

[...] we still do not know the regulatory machineries and epigenetic determinants that segregate and define different cell fates. We speculate the inactivation of Set7 by Oct4 and Sox2 is important for ESC maintenance. Whether Set7 coordinates the expression of other downstream factors necessary for differentiation remains unknown and an area for future investigation. [...] the role of the lysine methyltransferase during embryogenesis remain poorly understood.

Set7 mediated interactions regulate transcriptional networks in embryonic stem cells Natasha K. Tuano, Jun Okabe, Mark Ziemann, Mark E. Cooper, and Assam El-Osta Nucleic Acids Res. 44(19): 9206–9217. doi: 10.1093/nar/gkw621

Work in progress… stay tuned. Complex complexity. Dionisio

Together with transcription factors, histone-modifying complexes supervise the expression of genes that are critical for cell fate decisions and differentiation [...] Intrinsic to gene regulation are a handful of critical signaling molecules [...] regulate the expression of genes in embryonic stem cells (ESCs) whilst maintaining pluripotent cell fate [...] [...] the epigenetics field remains largely uncharted with respect to understanding the physiological function of histone modifications [...] Uncovering their function in vivo remains challenging and to this end the extensive mapping of chromatin modifications has identified critical domains implicated in the regulation of developmental genes [...]

Set7 mediated interactions regulate transcriptional networks in embryonic stem cells Natasha K. Tuano, Jun Okabe, Mark Ziemann, Mark E. Cooper, and Assam El-Osta Nucleic Acids Res. 44(19): 9206–9217. doi: 10.1093/nar/gkw621

Work in progress… stay tuned. Complex complexity. Dionisio

Histone methylation by lysine methyltransferase enzymes regulate the expression of genes implicated in lineage specificity and cellular differentiation. [...] the functional importance of this enzyme in stem cell differentiation remains poorly understood. [...] the broad substrate specificity of Set7 serves to control key transcriptional networks in embryonic stem cells.

Set7 mediated interactions regulate transcriptional networks in embryonic stem cells Natasha K. Tuano, Jun Okabe, Mark Ziemann, Mark E. Cooper, and Assam El-Osta Nucleic Acids Res. 44(19): 9206–9217. doi: 10.1093/nar/gkw621

Complex complexity. Dionisio

Stem cells are crucial components of many animal tissues and organs. Stem cells are regulated both intrinsically and externally, including by signals from the local environment and distant organs. [...] mitosis/cytokinesis proteins are especially important for male GSC maintenance. [...] it is difficult to fully appreciate the complexity of stem cell regulation if we limit our screen to intrinsic regulators. Further characterization of these genes by knocking them down with cell-type-specific Gal4s will lead to a better understanding of GSC regulation in the whole animal.

Whole-animal genome-wide RNAi screen identifies networks regulating male germline stem cells in Drosophila Ying Liu,1,* Qinglan Ge,1,* Brian Chan,1 Hanhan Liu,1 Shree Ram Singh,1 Jacob Manley,1 Jae Lee,1 Ann Marie Weideman,1 Gerald Hou,1 and Steven X. Houa Nat Commun. 7: 12149. doi: 10.1038/ncomms12149

Work in progress… stay tuned. Complex complexity. Dionisio

[...] some questions remain, such as the mechanism by which these mutants bypass the COC and allow for GSC division despite a loss of proper centrosome anchoring. Additional study is required to determine whether expanded niche signaling and ectopic localization of other centrosome-anchoring components are detected in these mutant and knockdown animals.

Heparan sulfate regulates the number and centrosome positioning of Drosophila male germline stem cells Daniel C. Levings, Takeshi Arashiro, and Hiroshi Nakato Mol Biol Cell. 27(6): 888–896. doi: 10.1091/mbc.E15-07-0528

Complex complexity. Dionisio

Stem cell division is tightly controlled via secreted signaling factors and cell adhesion molecules provided from local niche structures. Molecular mechanisms by which each niche component regulates stem cell behaviors remain to be elucidated. [...] specific HS modifications provide a novel regulatory mechanism for stem cell asymmetric division. [...] HS-mediated niche signaling acts upstream of GSC division orientation control.

Heparan sulfate regulates the number and centrosome positioning of Drosophila male germline stem cells Daniel C. Levings, Takeshi Arashiro, and Hiroshi Nakato Mol Biol Cell. 27(6): 888–896. doi: 10.1091/mbc.E15-07-0528

Complex complexity. Dionisio

Some questions remain to be addressed—for example, which molecule(s) acts as the force generator to invaginate the plasma membrane and establish a link with the centrosome. it should be further addressed how the PCP pathway participates in the regulation of centrosome dynamics and the polarization of the membrane invagination. It will also be intriguing to investigate whether the PCP pathway regulates the asymmetric distribution of the actomyosin network and/or plus-end motors in ascidian epidermal cells. [...] our present work uncovers a previously unknown mechanism associating the centrosome and the plasma membrane, and may open new avenues of investigation into the hidden mechanisms of oriented cell division that underlie embryogenesis and organogenesis.

Physical association between a novel plasma-membrane structure and centrosome orients cell division Takefumi Negishi,1,2,* Naoyuki Miyazaki,3 Kazuyoshi Murata,3 Hitoyoshi Yasuo,2,* and Naoto Ueno eLife. 5: e16550. doi: 10.7554/eLife.16550

Work in progress... stay tuned. Complex complexity. Dionisio

In the last mitotic division of the epidermal lineage in the ascidian embryo, the cells divide stereotypically along the anterior-posterior axis. [...] a unique membrane structure invaginates from the posterior to the centre of the cell, in a microtubule-dependent manner. The invagination projects toward centrioles on the apical side of the nucleus and associates with one of them. Further, a cilium forms on the posterior side of the cell and its basal body remains associated with the invagination. [...] the invagination is under tensile force and promotes the posterior positioning of the centrosome. [...] the orientation of the invaginations is coupled with the polarized dynamics of centrosome movements and the orientation of cell division. [...] this novel membrane structure orchestrates centrosome positioning and thus the orientation of cell division axis.

Physical association between a novel plasma-membrane structure and centrosome orients cell division Takefumi Negishi,1,2,* Naoyuki Miyazaki,3 Kazuyoshi Murata,3 Hitoyoshi Yasuo,2,* and Naoto Ueno eLife. 5: e16550. doi: 10.7554/eLife.16550

Did somebody say "orchestrates"? :) Complex complexity. Dionisio

Answers to some of these [the outstanding] questions may be forthcoming, whereas others may prove more challenging. [...] the other stages of recombination (e.g. end processing, strand invasion, choice of pathway, etc.) remain just as interesting as the homology search and are in many ways still just as mystifying. This abundance of open questions will help ensure that homologous recombination remains a fruitful area of scientific inquiry.

DNA Sequence Alignment during Homologous Recombination Eric C. Greene doi: 10.1074/jbc.R116.724807 jbc.R116.724807

Job security for the biology researchers. And maybe some textbook changes ahead? Work in progress… stay tuned. Complex complexity. Dionisio

We are beginning to grasp the basic principles of the homology search, but the problem is far from solved and future advances will likely require contributions from a number of distinct disciplines, including cell biology, biochemistry, biophysics and molecular modeling approaches.

DNA Sequence Alignment during Homologous Recombination Eric C. Greene doi: 10.1074/jbc.R116.724807 jbc.R116.724807

Well, it takes time to understand difficult problems. Hopefully the outstanding HR-related questions will get answered sooner than "the hard problem of consciousness". :) Work in progress… stay tuned. Complex complexity. Dionisio

Eukaryotic chromosomes are not randomly organized, but instead appear to have preferred positions within the nucleus, and the existence of this higher-order spatial organization has important implications replication, transcription, and recombination

DNA Sequence Alignment during Homologous Recombination Eric C. Greene doi: 10.1074/jbc.R116.724807 jbc.R116.724807

Does that mean they are organized for a specific functional purpose? Work in progress… stay tuned. :) Complex complexity. Dionisio

All of these studies raise crucial and interesting questions with respect to what factors influence DSB mobility in living cells and how changes in mobility might be related to the homology search.

DNA Sequence Alignment during Homologous Recombination Eric C. Greene doi: 10.1074/jbc.R116.724807 jbc.R116.724807

Work in progress… stay tuned. :) Complex complexity. Dionisio

[...] regulatory cofactors, accessory proteins, chromatin, and chromosome organization must impact the homology search in ways that we do not yet fully understand. [...] it will be essential to more fully define the length and protein composition of the “search entity” that exists within living cells. Future work will be essential to fully understand how all the activities of these proteins [Rad54/Rdh54] contribute to recombination. [...] why it would phosphorylate sites of the chromosome that have already been searched (and rejected) remains unclear.

DNA Sequence Alignment during Homologous Recombination Eric C. Greene doi: 10.1074/jbc.R116.724807 jbc.R116.724807

Work in progress… stay tuned. :) Complex complexity. Dionisio

Note @ 2550 that back in 1979 a scientist used the word "intriguing" when referring to the HR search&locate mechanism. @2551 & @2552 we see that 36 years later the term "intriguing" remains valid, doesn't it? Work in progress... stay tuned. Complex complexity. Dionisio

Despite recent experimental advances we still do not have a full grasp of the molecular details that make genetic recombination possible. [...] we do not understand how recombinases access sequence information within a bound dsDNA molecule and then compare this information to the presynaptic ssDNA. [...] exactly how this might take place remains poorly understood. [...] the continued combination of theory and experiment will be necessary for developing a deeper understanding of genetic recombination.

DNA Sequence Alignment during Homologous Recombination Eric C. Greene doi: 10.1074/jbc.R116.724807 jbc.R116.724807

Work in progress... stay tuned. :) Complex complexity. Dionisio

These studies also point toward new avenues of investigation that should help expand our understanding of the homology. All of these questions might be accessible to single molecule approaches, or other emerging technologies.

DNA Sequence Alignment during Homologous Recombination Eric C. Greene doi: 10.1074/jbc.R116.724807 jbc.R116.724807

Work in progress... stay tuned. :) Complex complexity. Dionisio

In 1979 Charles Radding wrote, “Nothing is more intriguing about homologous recombination than its beginning” The homology search underlies all homologous recombination reactions, and its importance can be understood by recognizing that misalignment by even a single base pair can potentially render crucial genetic information inaccessible.

DNA Sequence Alignment during Homologous Recombination Eric C. Greene doi: 10.1074/jbc.R116.724807 jbc.R116.724807

Complex complexity. Dionisio

Homologous recombination enables the exchange of genetic information between different DNA molecules [...] Homologous recombination contributes to double-strand DNA break (DSB) repair, the rescue of stalled or collapsed replication forks, programmed and aberrant chromosomal rearrangements, horizontal gene transfer, and meiosis [...]

DNA Sequence Alignment during Homologous Recombination Eric C. Greene doi: 10.1074/jbc.R116.724807 jbc.R116.724807

Complex complexity. Dionisio

Homologous recombination allows for the regulated exchange of genetic information between two different DNA molecules of identical or nearly identical sequence composition, and is a major pathway for the repair of double-stranded DNA breaks. A key facet of homologous recombination is the ability of recombination proteins to perfectly align the damaged DNA with homologous sequence located elsewhere in the genome. This reaction is referred to as the homology search and is akin to the target searches conducted by many different DNA-binding proteins.

DNA Sequence Alignment during Homologous Recombination Eric C. Greene doi: 10.1074/jbc.R116.724807 jbc.R116.724807

Complex complexity. Dionisio

The mechanism of HR during genome editing and targeting in human, and other cell types, is still being worked out [...] It would be useful to gain a better understanding of both precise HR mechanisms required for CRISPR editing and whether helicase anti-recombinase activities negatively impact on genome editing.

Remodeling and Control of Homologous Recombination by DNA Helicases and Translocases that Target Recombinases and Synapsis Sarah J. Northall, Ivana Ivan?i?-Ba?e, Panos Soultanas, and Edward L. Bolt Genes (Basel). 7(8): 52. doi: 10.3390/genes7080052

Complex complexity. Dionisio

Homologous recombination (HR) is genetic exchange between identical or similar DNA molecules that provides the basis for meiosis and various mechanisms of DNA repair. When DNA replication forks encounter DNA damage, in the form of template breaks or lesions, HR provides repair by utilizing an undamaged DNA strand to reactivate the stricken replication fork [...]

Remodeling and Control of Homologous Recombination by DNA Helicases and Translocases that Target Recombinases and Synapsis Sarah J. Northall, Ivana Ivan?i?-Ba?e, Panos Soultanas, and Edward L. Bolt Genes (Basel). 7(8): 52. doi: 10.3390/genes7080052

Complex complexity. Dionisio

Recombinase enzymes catalyse invasion of single-stranded DNA (ssDNA) into homologous duplex DNA forming “Displacement loops” (D-loops), a process called synapsis. This triggers homologous recombination (HR), which can follow several possible paths to underpin DNA repair and restart of blocked and collapsed DNA replication forks. Therefore, synapsis can be a checkpoint for controlling whether or not, how far, and by which pathway, HR proceeds to overcome an obstacle or break in a replication fork. Synapsis can be antagonized by limiting access of a recombinase to ssDNA and by dissociation of D-loops or heteroduplex formed by synapsis. Antagonists include DNA helicases and translocases that are identifiable in eukaryotes, bacteria and archaea, and which target synaptic and pre-synaptic DNA structures thereby controlling HR at early stages.

Remodeling and Control of Homologous Recombination by DNA Helicases and Translocases that Target Recombinases and Synapsis Sarah J. Northall, Ivana Ivan?i?-Ba?e, Panos Soultanas, and Edward L. Bolt Genes (Basel). 7(8): 52. doi: 10.3390/genes7080052

Complex complexity. Dionisio

We expect that advances in super-resolution microscopy and single molecule manipulation and detection methods will be essential in future studies probing the dynamics of the search process in living cells, and that those findings will impact not only our understanding of recombination and DNA repair but will also directly inform the development of template-directed gene therapies using RNA-guided CRISPRs

RecA: Regulation and Mechanism of a Molecular Search Engine. Bell JC, Kowalczykowski SC Trends Biochem Sci. 41(6):491-507. doi: 10.1016/j.tibs.2016.04.002.

https://www.researchgate.net/profile/Jason_Bell/publication/301904870_RecA_Regulation_and_Mechanism_of_a_Molecular_Search_Engine/links/573dff4508ae9f741b300084.pdf Work in progress... stay tuned. Complex complexity. Dionisio

The precise factors that contribute to this ‘nuclear jiggling’ and how these dynamics contribute to chromosome pairing remain controversial and are still being defined. Defining and characterizing the factors that are required to accelerate and facilitate the eukaryotic homology search, either through conformational changes in global or local chromatin structure or directed, motor-dependent motion will be important steps in understanding how the recombination machinery finds its homologous target [...]

RecA: Regulation and Mechanism of a Molecular Search Engine. Bell JC, Kowalczykowski SC Trends Biochem Sci. 41(6):491-507. doi: 10.1016/j.tibs.2016.04.002.

Complex complexity. Dionisio

Whether these processes are sufficient to explain the in vivo homology search in larger eukaryotic cells remains unclear. Complicating the problem of an expanded search volume and larger genome is that eukaryotic DNA is densely packaged into chromatin that is tightly regulated and organized into stable ‘territories’ within a single cell's nucleus.

RecA: Regulation and Mechanism of a Molecular Search Engine. Bell JC, Kowalczykowski SC Trends Biochem Sci. 41(6):491-507. doi: 10.1016/j.tibs.2016.04.002.

Complex complexity. Dionisio

Homologous recombination maintains genomic integrity by repairing broken chromosomes. The broken chromosome is partially resected to produce single-stranded DNA (ssDNA) that is used to search for homologous double-stranded DNA (dsDNA). This homology driven 'search and rescue' is catalyzed by a class of DNA strand exchange proteins that are defined in relation to Escherichia coli RecA, which forms a filament on ssDNA.

RecA: Regulation and Mechanism of a Molecular Search Engine. Bell JC, Kowalczykowski SC Trends Biochem Sci. 41(6):491-507. doi: 10.1016/j.tibs.2016.04.002.

Complex complexity. Dionisio

[...] it will be interesting to analyze the interplay between the nematode BRCA2 ortholog, BRC-2, and RFS-1/RIP-1 during filament assembly and remodeling, since these proteins may synergize in these processes on naked and/or RPA-bound ssDNA. Another critical structural question is exactly how RFS-1/RIP-1 propagates a biophysical change along the filament to a point considerably distal to its binding site, manifested as stabilization and nuclease-sensitization of the filament beyond the region in immediate proximity to the 5? filament end where RFS-1/RIP-1 binds. In conclusion, our study provides insights into the molecular mechanism of RAD51-ssDNA filament remodeling by RAD51 paralogs, paving the way for future structural studies of this process, and interplay with other HR mediators.

A Polar and Nucleotide-Dependent Mechanism of Action for RAD51 Paralogs in RAD51 Filament Remodeling Martin R.G. Taylor, Mário Špírek, Chu Jian Ma, Raffaella Carzaniga, Tohru Takaki, Lucy M. Collinson, Eric C. Greene, Lumir Krejci, and Simon J. Boulton Mol Cell. 64(5): 926–939. doi: 10.1016/j.molcel.2016.10.020

Complex complexity. Dionisio

A major question arising from our work is how RFS-1/RIP-1 engages with the 5? filament end. In the future, it will be important to establish tractable methods to obtain atomic resolution structural models of RAD51 paralogs bound to RAD51 filaments, to better understand the intricacies underlying filament capping and remodeling. Another key question is how do nucleotide co-factors contribute to 5? filament end recognition?

A Polar and Nucleotide-Dependent Mechanism of Action for RAD51 Paralogs in RAD51 Filament Remodeling Martin R.G. Taylor, Mário Špírek, Chu Jian Ma, Raffaella Carzaniga, Tohru Takaki, Lucy M. Collinson, Eric C. Greene, Lumir Krejci, and Simon J. Boulton Mol Cell. 64(5): 926–939. doi: 10.1016/j.molcel.2016.10.020

Complex complexity. Dionisio

Central to homologous recombination in eukaryotes is the RAD51 recombinase, which forms helical nucleoprotein filaments on single-stranded DNA (ssDNA) and catalyzes strand invasion with homologous duplex DNA. Various regulatory proteins assist this reaction including the RAD51 paralogs. These data define the mechanism of RAD51 filament remodeling by RAD51 paralogs.

A Polar and Nucleotide-Dependent Mechanism of Action for RAD51 Paralogs in RAD51 Filament Remodeling Martin R.G. Taylor, Mário Špírek, Chu Jian Ma, Raffaella Carzaniga, Tohru Takaki, Lucy M. Collinson, Eric C. Greene, Lumir Krejci, and Simon J. Boulton Mol Cell. 64(5): 926–939. doi: 10.1016/j.molcel.2016.10.020

Complex complexity. Dionisio

Here we discuss recent advances in our understanding of Rad51 regulation during HR and how repair of replicative damage has opened many new areas of investigation and experimentation. For example, although the Rad51 paralogues were identified more than twenty years ago, our understanding of their mechanistic function of the Rad51 paralogues is still limited. As new findings emerge in one model system, it is imperative that we apply those paradigms to other models such as mammalian cells. By determining how well conserved the mechanistic function of the Rad51 paralogues are from yeast to humans, we will develop novel ways of investigating the human paralogues [...]

Novel insights into RAD51 activity and regulation during homologous recombination and DNA replication Stephen K. Godin, Meghan R. Sullivan, and Kara A. Bernstein Biochem Cell Biol. 94(5): 407–418. doi: 10.1139/bcb-2016-0012

Complex complexity. Dionisio

Mechanisms of DNA damage and repair signaling are not completely understood [...] This study describes a new mechanism of DNA repair activation initiated by auto-/paracrine signaling of membrane receptors PLAUR/TLR4. The fate of MDA-MB-231 cells that harbor DNA damage, or use inefficient forms of DNA repair will be interesting to study.

CHK1 and RAD51 activation after DNA damage is regulated via urokinase receptor/TLR4 signaling Pavan B Narayanaswamy, Sergey Tkachuk, Hermann Haller, Inna Dumler, and Yulia Kiyan Cell Death Dis. 7(9): e2383. doi: 10.1038/cddis.2016.291

Complex complexity. Dionisio

Future work will be essential to more fully understand how ATP hydrolysis is coupled to dsDNA turnover. [...] during strand exchange the relative change in free energy change associated with each base triplet step remains unaffected by ATP hydrolysis. It will be a continuing challenge to marry in vivo and in vitro results to help more fully understand the biological implications of these biochemical and physical studies.

ATP Hydrolysis Promotes Duplex DNA Release by the RecA Presynaptic Complex Ja Yil Lee, Zhi Qi and Eric C. Greene

Complex complexity. Dionisio

Homologous recombination allows for the regulated exchange of genetic information between two different DNA molecules of identical or nearly identical sequence composition [...] Homologous recombination contributes to double-strand DNA break (DSB) repair, the rescue of stalled or collapsed replication forks, programmed and aberrant chromosomal rearrangements, horizontal gene transfer, and meiosis [...]

ATP Hydrolysis Promotes Duplex DNA Release by the RecA Presynaptic Complex Ja Yil Lee, Zhi Qi and Eric C. Greene

Complex complexity. Dionisio

Homologous recombination is an important DNA repair pathway that plays key roles in maintaining genome stability. ATP plays an unanticipated role in promoting the turnover of captured duplex DNA intermediates as RecA attempts to align homologous sequences during the early stages of recombination.

ATP Hydrolysis Promotes Duplex DNA Release by the RecA Presynaptic Complex Ja Yil Lee, Zhi Qi and Eric C. Greene

Complex complexity. Dionisio

Innate lymphoid cells (ILCs) are innate immune cells that are ubiquitously distributed in lymphoid and nonlymphoid tissues and enriched at mucosal and barrier surfaces. [...] numerous challenges remain in the field of ILC biology. In particular, recent work has highlighted key new questions regarding how these cells communicate with their environment and other cell types during health and disease.

Emerging concepts and future challenges in innate lymphoid cell biology Elia D. Tait Wojno, David Artis J Exp Med. 2016 Oct 17; 213(11): 2229–2248. doi: 10.1084/jem.20160525 PMCID: PMC5068238

Complex complexity. Dionisio

During embryonic development, distinct TF combinations are produced in different tissues and cell types, resulting in a unique code of TFs that ultimately determines whether a given gene is turned on or off in a given tissue or cell type or at a specific time during development. [...] little is known about the in vivo genomic targets of these transcription factors. Additional studies of enhancer-chromatin state, including an assessment of DNA accessibility, will be required in order to assess a “pioneering” role for HOX13.

Distal Limb Patterning Requires Modulation of cis-Regulatory Activities by HOX13. Sheth R, Barozzi I, Langlais D, Osterwalder M, Nemec S, Carlson HL, Stadler HS, Visel A, Drouin J, Kmita M Cell Rep. 17(11):2913-2926. doi: 10.1016/j.celrep.2016.11.039.

Complex complexity. Dionisio

During organogenesis, appropriate spatial and temporal gene expression is necessary for the specification of individual cell identities and, ultimately, establishment of organ structure and function. As a paradigmatic system, the developing limb bud is used to understand the principles of pattern formation, the process through which cells are specified, determined, and subsequently differentiate to form a morphological structure [...]

Distal Limb Patterning Requires Modulation of cis-Regulatory Activities by HOX13. Sheth R, Barozzi I, Langlais D, Osterwalder M, Nemec S, Carlson HL, Stadler HS, Visel A, Drouin J, Kmita M Cell Rep. 17(11):2913-2926. doi: 10.1016/j.celrep.2016.11.039.

Complex complexity. Dionisio

The combinatorial expression of Hox genes along the body axes is a major determinant of cell fate and plays a pivotal role in generating the animal body plan. [...] proper termination of the early limb transcriptional program and activation of the late-distal limb program are coordinated by the dual action of HOX13 on cis-regulatory modules.

Distal Limb Patterning Requires Modulation of cis-Regulatory Activities by HOX13. Sheth R, Barozzi I, Langlais D, Osterwalder M, Nemec S, Carlson HL, Stadler HS, Visel A, Drouin J, Kmita M Cell Rep. 17(11):2913-2926. doi: 10.1016/j.celrep.2016.11.039.

Complex complexity. Dionisio

An intriguing major question is how HOX13 proteins can differentially regulate the activity in the two TADs, acting as repressors at the T-DOM and activators at the C-DOM. The actual mechanisms may involve interactions with other cofactors, the identification of which seems a major challenge. Another point that remains to be clarified is how the switch between the telomeric and centromeric regulation leads to the down-regulation of Hoxd expression in the wrist/ankle precursors and whether the C-DOM regulation is ever activated in these progenitors.

HOX13 proteins: the molecular switcher in Hoxd bimodal regulation Marian A. Ros Genes Dev. 30(10): 1135–1137. doi: 10.1101/gad.283598.116

Work in progress... stay tuned. Complex complexity. Dionisio

Hox genes encode transcription factors critical for the establishment of the basic body plan of bilaterian animals (Lewis 1978). Through the acquisition of new regulatory strategies, Hox genes were subsequently co-opted to pattern novel structures such as the appendages.

HOX13 proteins: the molecular switcher in Hoxd bimodal regulation Marian A. Ros Genes Dev. 30(10): 1135–1137. doi: 10.1101/gad.283598.116

co-opted? huh? say what? Complex complexity. [emphasis added] Dionisio

The striking correlation between the genomic arrangement of Hox genes and their temporal and spatial pattern of expression during embryonic development has been a source of fascination since its discovery. This correspondence has been used as a privileged example in the investigation of the connection between genomic architecture and function.

HOX13 proteins: the molecular switcher in Hoxd bimodal regulation Marian A. Ros Genes Dev. 30(10): 1135–1137. doi: 10.1101/gad.283598.116

Complex complexity. Dionisio

[...] while Hox genes are critical for the development of distal structures, they are not the sole genetic determinants of a “distal” limb identity. [...] the molecular mechanisms underlying these antagonistic activities are unclear [...]

A role for HOX13 proteins in the regulatory switch between TADs at the HoxD locus. Beccari L, Yakushiji-Kaminatsui N, Woltering JM, Necsulea A, Lonfat N, Rodríguez-Carballo E, Mascrez B, Yamamoto S, Kuroiwa A, Duboule D Genes Dev. 30(10):1172-86. doi: 10.1101/gad.281055.116

Complex complexity. Dionisio

During vertebrate limb development, Hoxd genes are regulated following a bimodal strategy involving two topologically associating domains (TADs) located on either side of the gene cluster. These regulatory landscapes alternatively control different subsets of Hoxd targets, first into the arm and subsequently into the digits. [...] the activation of Hox13 gene expression in distal limb cells both interrupts the proximal Hox gene regulation and re-enforces the distal regulation. In the absence of HOX13 proteins, a proximal limb structure grows without any sign of wrist articulation, likely related to an ancestral fish-like condition.

A role for HOX13 proteins in the regulatory switch between TADs at the HoxD locus. Beccari L, Yakushiji-Kaminatsui N, Woltering JM, Necsulea A, Lonfat N, Rodríguez-Carballo E, Mascrez B, Yamamoto S, Kuroiwa A, Duboule D Genes Dev. 30(10):1172-86. doi: 10.1101/gad.281055.116

Complex complexity. Dionisio

[...] the precise mechanisms behind these regulations remain to be elucidated [...] The nature of these upstream factors is currently under study.

Control of Hoxd gene transcription in the mammary bud by hijacking a preexisting regulatory landscape Ruben Schep, Anamaria Necsulea, Eddie Rodríguez-Carballo, Isabel Guerreiro, Guillaume Andrey, Thi Hanh Nguyen Huynh, Virginie Marcet, Jozsef Zákány, Denis Duboule and Leonardo Beccari Proc Natl Acad Sci U S A. 113(48): E7720–E7729. doi: 10.1073/pnas.1617141113

Complex complexity. Dionisio

It remains to be determined in future research whether the shared regulatory states between cidaroids and euechinoids elucidated here are the product of conserved stretches of genomic DNA hardwired in the cis-regulatory regions of orthologous regulatory genes or the result of diverged cis-regulatory modules producing similar developmental outcomes.

Divergence of ectodermal and mesodermal gene regulatory network linkages in early development of sea urchins. Erkenbrack EM Proc Natl Acad Sci U S A. 113(46):E7202-E7211 DOI: 10.1073/pnas.1612820113 https://www.researchgate.net/profile/Eric_Erkenbrack/publication/309716656_Divergence_of_ectodermal_and_mesodermal_gene_regulatory_network_linkages_in_early_development_of_sea_urchins/links/58206e6d08ae12715afbba55.pdf

Complex complexity. Dionisio

These observations suggest that in the ancestral echinoid lineage, the adult skeletogenesis program was co-opted to run in the micromeres.

Divergence of ectodermal and mesodermal gene regulatory network linkages in early development of sea urchins. Erkenbrack EM Proc Natl Acad Sci U S A. 113(46):E7202-E7211 DOI: 10.1073/pnas.1612820113 https://www.researchgate.net/profile/Eric_Erkenbrack/publication/309716656_Divergence_of_ectodermal_and_mesodermal_gene_regulatory_network_linkages_in_early_development_of_sea_urchins/links/58206e6d08ae12715afbba55.pdf

Did somebody say program? co-opted? huh? say what? Complex complexity. [emphasis added] Dionisio

Pointedly, it is clear that the regulatory apparatus running in SM was specifically installed into the micromere embryonic address by co-option of the adult GRN skeletogenic program [...]

Divergence of ectodermal and mesodermal gene regulatory network linkages in early development of sea urchins. Erkenbrack EM Proc Natl Acad Sci U S A. 113(46):E7202-E7211 DOI: 10.1073/pnas.1612820113 https://www.researchgate.net/profile/Eric_Erkenbrack/publication/309716656_Divergence_of_ectodermal_and_mesodermal_gene_regulatory_network_linkages_in_early_development_of_sea_urchins/links/58206e6d08ae12715afbba55.pdf

co-option? huh? say what? Complex complexity. [emphasis added] Dionisio

Developmental gene regulatory networks (GRNs) are assemblages of gene regulatory interactions that direct ontogeny of animal body plans. Integral to early development of a bilaterian is the development of the three embryonic tissue-layer domains: endoderm, ectoderm, and mesoderm. Asymmetrically distributed RNA and proteins in the egg provide the initial inputs into this process and thereby determine the spatial coordinates of domain formation [...]

Divergence of ectodermal and mesodermal gene regulatory network linkages in early development of sea urchins. Erkenbrack EM Proc Natl Acad Sci U S A. 113(46):E7202-E7211 DOI: 10.1073/pnas.1612820113 https://www.researchgate.net/profile/Eric_Erkenbrack/publication/309716656_Divergence_of_ectodermal_and_mesodermal_gene_regulatory_network_linkages_in_early_development_of_sea_urchins/links/58206e6d08ae12715afbba55.pdf

Complex complexity. Dionisio

[...] essential difference in the underlying mechanism between unidirectional chemotactic cells and bi-directional growth cones has been largely unknown. [...] the turning response of the growth cone could multi-phasically change, e.g., from repulsion, attraction to repulsion, as intracellular Ca2+ increased [...] [...] our reverse-engineered model suggested monotonical dose-response of CaMKII [...]

Multi-phasic bi-directional chemotactic responses of the growth cone Honda Naoki, Makoto Nishiyama, Kazunobu Togashi, Yasunobu Igarashi, Kyonsoo Hong, and Shin Ishii Sci Rep. 6: 36256. doi: 10.1038/srep36256

Did somebody say "reverse-engineered" ? Does that mean something has been engineered? Complex complexity. Dionisio

The elucidation of the molecular mechanisms by which bi-directional attractive and repulsive responses of the growth cone are regulated is key for understanding circuit formation in the developing nervous system.

Multi-phasic bi-directional chemotactic responses of the growth cone Honda Naoki, Makoto Nishiyama, Kazunobu Togashi, Yasunobu Igarashi, Kyonsoo Hong, and Shin Ishii Sci Rep. 6: 36256. doi: 10.1038/srep36256

Complex complexity. Dionisio

The nerve growth cone is bi-directionally attracted and repelled by the same cue molecules depending on the situations, while other non-neural chemotactic cells usually show uni-directional attraction or repulsion toward their specific cue molecules. However, how the growth cone differs from other non-neural cells remains unclear. [...] the balance between activator and inhibitor underlies the multi-phasic bi-directional turning response of the growth cone.

Multi-phasic bi-directional chemotactic responses of the growth cone Honda Naoki, Makoto Nishiyama, Kazunobu Togashi, Yasunobu Igarashi, Kyonsoo Hong, and Shin Ishii Sci Rep. 6: 36256. doi: 10.1038/srep36256

Complex complexity. Dionisio

As future work, a more detailed model will be helpful to capture the exact molecular mechanism of the system. In summary, we have combined two major concepts in quantitative biology, namely, FCD and the LEGI framework, and have proposed a new system-level mechanism to explain the rescaling behaviors of the gradient sensing system. We hope that our results promote deeper understanding of the directional sensing in eukaryotic cells.

Rescaling of Spatio-Temporal Sensing in Eukaryotic Chemotaxis Keita Kamino, and Yohei Kondo PLoS One. 11(10): e0164674. doi: 10.1371/journal.pone.0164674

Complex complexity. Dionisio

In spite of intensive molecular genetic study [3], the system-level design principle that governs the flexible and dynamic behavior of gradient sensing has remained elusive. Crucially, experiments on Dictyostelium have revealed two characteristic features of gradient sensing that can potentially challenge the LEGI hypothesis. Our results suggest that the scale invariance is the underlying design principle of the directional sensing system of eukaryotic cells.

Rescaling of Spatio-Temporal Sensing in Eukaryotic Chemotaxis Keita Kamino, and Yohei Kondo PLoS One. 11(10): e0164674. doi: 10.1371/journal.pone.0164674

Complex complexity. Dionisio

Eukaryotic cells respond to a chemoattractant gradient by forming intracellular gradients of signaling molecules that reflect the extracellular chemical gradient—an ability called directional sensing. [...] a system with the invariance detects relative steepness even in dynamic gradient stimuli as well as in static gradients. [...] the relation between the response properties and the scale invariance is general in that it can be implemented by models with different network topologies.

Rescaling of Spatio-Temporal Sensing in Eukaryotic Chemotaxis Keita Kamino, and Yohei Kondo PLoS One. 11(10): e0164674. doi: 10.1371/journal.pone.0164674

Complex complexity. Dionisio

While this shift in cell fates has been shown experimentally, the mechanisms underlying this frequency decoding are still unknown. The importance of IFFLs in signal processing is implied with its presence in many natural networks that are able to respond differentially to oscillatory and sustained signals [...] Natural systems including those involved in cell proliferation, cell death, and neural regeneration convert oscillatory and sustained signals into distinct biological outcomes. In the case of disease, these circuits become deregulated, altering the function of networks required for information encoding or decoding. Insights derived from our model for the pulse counting mechanism will be important for future work in understanding the ways in which these perturbations impact the way cells decode information.

Processing Oscillatory Signals by Incoherent Feedforward Loops Carolyn Zhang, Ryan Tsoi, Feilun Wu, and Lingchong You Gabor Balazsi, Editor PLoS Comput Biol. 12(9): e1005101. doi: 10.1371/journal.pcbi.1005101

Complex complexity. Dionisio

From circadian clocks to ultradian rhythms, oscillatory signals are found ubiquitously in nature. These oscillations are crucial in the regulation of cellular processes. While the fundamental design principles underlying the generation of these oscillations are extensively studied, the mechanisms for decoding these signals are underappreciated.

Processing Oscillatory Signals by Incoherent Feedforward Loops Carolyn Zhang, Ryan Tsoi, Feilun Wu, and Lingchong You Gabor Balazsi, Editor PLoS Comput Biol. 12(9): e1005101. doi: 10.1371/journal.pcbi.1005101

Complex complexity. Dionisio

[...] the system’s ability to translate pulsatile dynamics is limited by two constraints. The kinetics of the IFFL components dictate the input range for which the network is able to decode pulsatile dynamics. In addition, a match between the network parameters and input signal characteristics is required for optimal “counting”. We elucidate one potential mechanism by which information processing occurs in natural networks [...]

Processing Oscillatory Signals by Incoherent Feedforward Loops Carolyn Zhang, Ryan Tsoi, Feilun Wu, and Lingchong You Gabor Balazsi, Editor PLoS Comput Biol. 12(9): e1005101. doi: 10.1371/journal.pcbi.1005101

Complex complexity. Dionisio

From the timing of amoeba development to the maintenance of stem cell pluripotency, many biological signaling pathways exhibit the ability to differentiate between pulsatile and sustained signals in the regulation of downstream gene expression. While the networks underlying this signal decoding are diverse, many are built around a common motif, the incoherent feedforward loop (IFFL), where an input simultaneously activates an output and an inhibitor of the output. With appropriate parameters, this motif can exhibit temporal adaptation, where the system is desensitized to a sustained input. This property serves as the foundation for distinguishing input signals with varying temporal profiles.

Processing Oscillatory Signals by Incoherent Feedforward Loops Carolyn Zhang, Ryan Tsoi, Feilun Wu, and Lingchong You Gabor Balazsi, Editor PLoS Comput Biol. 12(9): e1005101. doi: 10.1371/journal.pcbi.1005101

Complex complexity. Dionisio

[...] it would be interesting to see whether allosteric proteins may also generally act as quantitative sensors, adjusting detection on a logarithmic scale to maintain sensitivity over a broad response range.

Allosteric proteins as logarithmic sensors Noah Olsmana and Lea Goentoro Proc Natl Acad Sci U S A. 113(30): E4423–E4430. doi: 10.1073/pnas.1601791113 PMCID: PMC4968753 PNAS Plus Systems Biology

Complex complexity. Dionisio

This logarithmic-feedback circuit is an appealing architecture because feedback regulation is another ubiquitous feature of biological systems, and raises the questions of whether logarithmic sensing and the related phenomenon of fold-change detection occurs more broadly in biological processes than is currently appreciated.

Allosteric proteins as logarithmic sensors Noah Olsmana and Lea Goentoro Proc Natl Acad Sci U S A. 113(30): E4423–E4430. doi: 10.1073/pnas.1601791113 PMCID: PMC4968753 PNAS Plus Systems Biology

Complex complexity. Dionisio

It is remarkable that the seemingly complex task of computing a logarithm can be encoded within a single protein, and further that this can be accomplished through such a pervasive form of regulation in biological systems.

Allosteric proteins as logarithmic sensors Noah Olsmana and Lea Goentoro Proc Natl Acad Sci U S A. 113(30): E4423–E4430. doi: 10.1073/pnas.1601791113 PMCID: PMC4968753 PNAS Plus Systems Biology

Complex complexity. Dionisio

[...] allosteric proteins play a prominent role in systems where fold-change detection has been proposed.

Allosteric proteins as logarithmic sensors Noah Olsmana and Lea Goentoro Proc Natl Acad Sci U S A. 113(30): E4423–E4430. doi: 10.1073/pnas.1601791113 PMCID: PMC4968753 PNAS Plus Systems Biology

Complex complexity. Dionisio

It is an ongoing search in the field to understand the ways in which a logarithmic sensor can be implemented at the molecular level.

Allosteric proteins as logarithmic sensors Noah Olsmana and Lea Goentoro Proc Natl Acad Sci U S A. 113(30): E4423–E4430. doi: 10.1073/pnas.1601791113 PMCID: PMC4968753 PNAS Plus Systems Biology

Complex complexity. Dionisio

Biological sensory systems have the capacity to respond to signals over a broad range of intensities, be it vision in animals or signal transduction in cells. Such a broad response range is thought to be mediated by the system’s ability to sense signal logarithmically.

Allosteric proteins as logarithmic sensors Noah Olsmana and Lea Goentoro Proc Natl Acad Sci U S A. 113(30): E4423–E4430. doi: 10.1073/pnas.1601791113 PMCID: PMC4968753 PNAS Plus Systems Biology

Complex complexity. Dionisio

As we gain more information on the structure and function of gene regulatory networks we can start asking why are specific architectures used more than others and why are they so deeply conserved? It seems that any regulatory change within these critical control circuits must have reduced the circuit precision [...] [...] understanding the control properties of repeatedly used regulatory architectures illuminates their function in developing embryos [...]

Robustness and Accuracy in Sea Urchin Developmental Gene Regulatory Networks Smadar Ben-Tabou de-Leon Front Genet. 7: 16. doi: 10.3389/fgene.2016.00016

Complex complexity. Dionisio

Developmental gene regulatory networks robustly control the timely activation of regulatory and differentiation genes. The structure of these networks underlies their capacity to buffer intrinsic and extrinsic noise and maintain embryonic morphology. [...] the use of compound positive feedback circuitry provides the endodermal cells enough time to turn off mesodermal genes and ensures correct mesoderm vs. endoderm fate decision. [...] understanding the control properties of repeatedly used regulatory architectures illuminates their role in embryogenesis [...]

Robustness and Accuracy in Sea Urchin Developmental Gene Regulatory Networks Smadar Ben-Tabou de-Leon Front Genet. 7: 16. doi: 10.3389/fgene.2016.00016

Complex complexity. Dionisio

We found it particularly interesting that the gene that correlated the most highly with Chordin was Noggin, and vice versa. The close correlation indicates that they share very similar transcriptional regulatory mechanisms. It maybe worthwhile in the future to explore whether Chordin and Noggin interact with each other or with other components of the D–V biochemical pathway at the protein level. Our next step will be to define gene-response signatures for the Wnt, BMP, Nodal and FGF pathways during gastrulation. As more transcriptomes in different experimental conditions are obtained, we hope this will further illuminate the molecular mechanisms of embryonic induction, and in particular how half-embryos can regenerate the missing part.

Genome-wide analysis of dorsal and ventral transcriptomes of the Xenopus laevis gastrula. Ding Y, Colozza G, Zhang K, Moriyama Y, Ploper D, Sosa EA, Benitez MD, De Robertis EM Dev Biol. pii: S0012-1606(15)30329-8. doi: 10.1016/j.ydbio.2016.02.032.

Work in progress... stay tuned. :) Complex complexity. Dionisio

[...] we have learned the molecular basis of fundamental processes such as egg cytoplasmic determinants, mesoderm induction, Hox genes, signaling by Spemann's organizer, induction of the central nervous system, and many other processes that are conserved among all vertebrates [...] D–V patterning relies on the formation of a gradient of BMP activity, in which low BMP levels promote the formation of dorsal structures such as the neural plate, notochord or somites while high BMP activity induces tissues with ventral characteristics like the lateral plate mesoderm and blood islands [...] We present complete lists of genes correlated with D–V patterning, which provide new avenues for understanding the signaling pathways and gene signatures involved in early vertebrate development.

Genome-wide analysis of dorsal and ventral transcriptomes of the Xenopus laevis gastrula. Ding Y, Colozza G, Zhang K, Moriyama Y, Ploper D, Sosa EA, Benitez MD, De Robertis EM Dev Biol. pii: S0012-1606(15)30329-8. doi: 10.1016/j.ydbio.2016.02.032.

Complex complexity. Dionisio

[...] Pkdcc can act as a negative regulator of Wnt/ ?-catenin signaling independently of its kinase activity. [...] RNA-Seq in combination with the X. laevis complete genome now available provides a powerful tool for unraveling cell-cell signaling pathways during embryonic induction.

Genome-wide analysis of dorsal and ventral transcriptomes of the Xenopus laevis gastrula. Ding Y, Colozza G, Zhang K, Moriyama Y, Ploper D, Sosa EA, Benitez MD, De Robertis EM Dev Biol. pii: S0012-1606(15)30329-8. doi: 10.1016/j.ydbio.2016.02.032.

Complex complexity. Dionisio

The tolloid family exert such a broad influence over matrix deposition and homeostasis that this is a promising pathway for future therapeutic intervention, for example, in cancers and bone disorders, however, it needs to be better understood. Further structural study of this family, in particular in complex with its binding partners is needed to enhance our knowledge of its regulation and context?dependent specificity.

Mammalian tolloid proteinases: role in growth factor signalling Helen Troilo, 1 Christopher P. Bayley, 1 Anne L. Barrett, 1 Michael P. Lockhart?Cairns, 1 , 2 Thomas A. Jowitt, 1 and Clair Baldock FEBS Lett. 590(15): 2398–2407. doi: 10.1002/1873-3468.12287

Complex complexity. Dionisio

[...] it is unclear where the gradient is actually formed. It will be important in the future to determine directly whether a Sog gradient diffuses in the perivitelline ECM or is generated by a cell-to-cell relay mechanism. [...] there are many other later “secondary” self-organizing fields that are formed during organogenesis (e.g., eye, olfactory, pituitary, and limb fields) and regeneration.

Chordin forms a self-organizing morphogen gradient in the extracellular space between ectoderm and mesoderm in the Xenopus embryo. Plouhinec JL1, Zakin L, Moriyama Y, De Robertis EM Proc Natl Acad Sci U S A. 110(51):20372-9. doi: 10.1073/pnas.1319745110

Complex complexity. Dionisio

The orchestration of tissue differentiation in the embryo to form a perfect individual time-after-time is a fascinating problem in developmental biology. The three germ layers—ectoderm, mesoderm and endoderm—are coordinately regulated to generate a well-organized body plan in which the various organs of the body develop.

Chordin forms a self-organizing morphogen gradient in the extracellular space between ectoderm and mesoderm in the Xenopus embryo. Plouhinec JL1, Zakin L, Moriyama Y, De Robertis EM Proc Natl Acad Sci U S A. 110(51):20372-9. doi: 10.1073/pnas.1319745110

Complex complexity. Dionisio

The vertebrate body plan follows stereotypical dorsal-ventral (D-V) tissue differentiation controlled by bone morphogenetic proteins (BMPs) and secreted BMP antagonists, such as Chordin. The three germ layers--ectoderm, mesoderm, and endoderm--are affected coordinately by the Chordin-BMP morphogen system. [...] as ectoderm and mesoderm undergo morphogenetic movements during gastrulation, cells in both germ layers read their positional information coordinately from a single morphogen gradient located in Brachet's cleft.

Chordin forms a self-organizing morphogen gradient in the extracellular space between ectoderm and mesoderm in the Xenopus embryo. Plouhinec JL1, Zakin L, Moriyama Y, De Robertis EM Proc Natl Acad Sci U S A. 110(51):20372-9. doi: 10.1073/pnas.1319745110

Complex complexity. Dionisio

Fundamental biological processes of development of tissues and organs in multicellular organisms are governed by various signaling molecules, which are called morphogens. It is known that spatial and temporal variations in the concentration profiles of signaling molecules, which are frequently referred as morphogen gradients, lead to a cell differentiation via activating specific genes in a concentration-dependent manner. It is widely accepted that the establishment of the morphogen gradients involves multiple biochemical reactions and diffusion processes. One of the critical elements in the formation of morphogen gradients is a degradation of signaling molecules.

Theoretical analysis of degradation mechanisms in the formation of morphogen gradients. Bozorgui B, Teimouri H, Kolomeisky AB J Chem Phys. 143(2):025102. doi: 10.1063/1.4926461.

Complex complexity. Dionisio

[...] phase shift for waves propagating through the segmentation region doesn’t depend on the size of this region [...] The preservation of the phase shift indicates that the velocity of waves crossing the tissue is proportional to the size of the tissue. This proportionality can be explained by modulation mechanism, i.e. the velocity is regulated by a concentration of modulator which, in turn, depends on the size of the tissue (Signon et al., 2016). Application of scaling mechanisms presented in this article to patterns forming in dynamical systems and to patterns in their transient phase (before reaching stationary state) (Bergmann et al., 2007) opens another large area for future research.

Scaling of morphogenetic patterns in reaction-diffusion systems. Rasolonjanahary M, Vasiev B J Theor Biol. 404:109-19. doi: 10.1016/j.jtbi.2016.05.035.

Work in progress... stay tuned. Complex complexity. Dionisio

Morphogenetic patterns observed in experimental conditions are, as a rule, not linear and exploring and understanding their scaling properties is one of the biggest challenges in contemporary biology. [...] what mechanisms allow the scaling with a given precision rather than what mechanisms allow perfect scaling. Differentiation of cells can be affected by more than one morphogen. Besides, while some morphogens promote the differentiation others can inhibit it. The problem of scaling of morphogenetic patterns has been addressed by many researchers and becomes increasingly attractive for mathematical studies in developmental biology [...]

Scaling of morphogenetic patterns in reaction-diffusion systems. Rasolonjanahary M, Vasiev B J Theor Biol. 404:109-19. doi: 10.1016/j.jtbi.2016.05.035.

Complex complexity. Dionisio

The greatest manifestation of biological development is given by embryogenesis when fully functional multicellular organisms arise from a single fertilised cell. The “elementary” processes underlining embryogenesis are cellular proliferation, differentiation and migration. Cellular differentiation is considered as being most directly related to biological pattern formation and as such was studied in great details. It is known that cells differentiate according to their position and positional information is commonly given by concentrations of biochemical substances which are called “morphogens”.

Scaling of morphogenetic patterns in reaction-diffusion systems. Rasolonjanahary M, Vasiev B J Theor Biol. 404:109-19. doi: 10.1016/j.jtbi.2016.05.035.

Complex complexity. Dionisio

Development of multicellular organisms is commonly associated with the response of individual cells to concentrations of chemical substances called morphogens. Concentration fields of morphogens form a basis for biological patterning and ensure its properties including ability to scale with the size of the organism. While mechanisms underlying the formation of morphogen gradients are reasonably well understood, little is known about processes responsible for their scaling.

Scaling of morphogenetic patterns in reaction-diffusion systems. Rasolonjanahary M, Vasiev B J Theor Biol. 404:109-19. doi: 10.1016/j.jtbi.2016.05.035.

reasonably well understood? Whatever that means. :) Complex complexity. [emphasis added] Dionisio

A beautiful example of how an ’incorrect’ model dramatically affected the way scientists think about pattern formation in development is the Turing model described earlier. It is clear that modeling is leading to new discoveries and mathematical thinking has had tremendous impact in developmental biology for decades. As the networks continue to expand and the questions become more complex, biologists with additional training in mathematics will have a definitive advantage when it comes to addressing problems to delineate mechanism. While classical approaches will always be valuable to experimental inquiry, we propose that mathematical modeling is an equally important tool to drive experimental discovery.

The Role of Mathematical Models in Understanding Pattern Formation in Developmental Biology David M. Umulis and Hans G. Othmer Bull Math Biol. 77(5): 817–845. doi: 10.1007/s11538-014-0019-7

Complex complexity. Dionisio

Development of an organism such as a human that contains many interacting components involves numerous complex processes, including signal transduction, gene expression, pattern formation, transport of material, growth, and mechanical forces, and thus, it is not surprising that mathematical models and analysis have played a role in understanding development. The first morphogen-based mathematical theory of how patterns in biology can arise is due to Turing, who demonstrated that suitable interactions between reacting and diffusing chemical species could lead to stable spatial patterns that emerge from an unstable state. Whether or not a system that generates biological pattern in a developmental context via a Turing mechanism is identified, Turing’s theory has had an enormous impact by demonstrating that it is necessary to understand the interactions of the processes that are involved, and not only their characteristics in isolation.

The Role of Mathematical Models in Understanding Pattern Formation in Developmental Biology David M. Umulis and Hans G. Othmer Bull Math Biol. 77(5): 817–845. doi: 10.1007/s11538-014-0019-7

Complex complexity. Dionisio

[...] mathematics has been used to make new and experimentally verified discoveries in developmental biology [...] [...] mathematics is essential for understanding a problem that has puzzled experimentalists for decades—that of how organisms can scale in size. Mathematical analysis alone cannot “solve” these problems since the validation lies at the molecular level, but conversely, a growing number of questions in biology cannot be solved without mathematical analysis and modeling.

The Role of Mathematical Models in Understanding Pattern Formation in Developmental Biology David M. Umulis and Hans G. Othmer Bull Math Biol. 77(5): 817–845. doi: 10.1007/s11538-014-0019-7

Complex complexity. Dionisio

[...] dynamics of signaling processes can be well tuned by modifying not only the strength of the degradation but also a spatial distribution of the receptors. It will be important to test our predictions in more advanced theoretical studies as well as directly in experiments.

Development of Morphogen Gradients with Spatially Varying Degradation Rates. Teimouri H, Bozorgui B, Kolomeisky AB J Phys Chem B. 120(10):2745-50. doi: 10.1021/acs.jpcb.6b00695 http://python.rice.edu/~kolomeisky/articles/JPhysChemB2745.pdf

What about the spatiotemporal* determination of the morphogen synthesis? IOW, how are the morphogen source locations and the timing for starting/stopping producing those signaling molecules determined? (*) or is it temporospatial? Complex complexity. Dionisio

[...] many features of the biological development processes still remain not well understood. The simplest and widely popular approach for the description of the signaling profiles formation is called a synthesis?diffusion?degradation (SDD) model. [...] spatial inhomogeneity in degradation rates has dramatic effects on concentration profiles and on dynamics of their formation. [...] the dynamics of formation of morphogen gradients can be modified by changing the spatial distribution of degradation rates, even without changing the amplitudes of the degradation rates. To explain these surprising observations we can invoke the idea of effective potential due to degradation [...] LAT is smaller when the effective potentials, that drive morphogens along the interval, are stronger.

Development of Morphogen Gradients with Spatially Varying Degradation Rates. Teimouri H, Bozorgui B, Kolomeisky AB J Phys Chem B. 120(10):2745-50. doi: 10.1021/acs.jpcb.6b00695 http://python.rice.edu/~kolomeisky/articles/JPhysChemB2745.pdf

Complex complexity. Dionisio

The development of various living organisms from initially very small group of identical embryo cells is one of the most fascinating and complex processes in biology. A critical stage in biological development is a pattern formation during which the eventual fates of cells become determined at different times and different positions. Several classes of signaling molecules, known as morphogens, play the central role in tissue patterning and organ formation.

Development of Morphogen Gradients with Spatially Varying Degradation Rates. Teimouri H, Bozorgui B, Kolomeisky AB J Phys Chem B. 120(10):2745-50. doi: 10.1021/acs.jpcb.6b00695 http://python.rice.edu/~kolomeisky/articles/JPhysChemB2745.pdf

Complex complexity. Dionisio

Successful biological development via spatial and temporal regulations of cell differentiation relies on the action of multiple signaling molecules that are known as morphogens. It is now well established that biological signaling molecules create nonuniform concentration profiles, called morphogen gradients, that activate different genes, leading to patterning in the developing organisms. The current view of the formation of morphogen gradients is that it is a result of complex reaction-diffusion processes that include production, diffusion, and degradation of signaling molecules. Recent studies also suggest that the degradation of morphogens is a critically important step in the whole process. [...] the spatial inhomogeneities in degradation might strongly influence the dynamics of formation of signaling profiles.

Development of Morphogen Gradients with Spatially Varying Degradation Rates. Teimouri H, Bozorgui B, Kolomeisky AB J Phys Chem B. 120(10):2745-50. doi: 10.1021/acs.jpcb.6b00695 http://python.rice.edu/~kolomeisky/articles/JPhysChemB2745.pdf

Complex complexity. Dionisio

I've heard this before:

[...] the amazing thing is that as much as I work on a particular research questions, there's always something new to discover. The more you discover, the more you discover that there is to discover. Biological life is unbelievably complex. And it only gets more complex the more we dig.

http://www.evolutionnews.org/2017/01/interview_bioch103408.html The more we know, the more we have to learn. Work in progress... stay tuned. Complex complexity. Dionisio

Another critical question is related to the fact that embryo cells during the formation of morphogen gradients are not frozen as implicitly assumed in current theoretical models. New theoretical ideas are needed in order to couple the chemical and biophysical processes of the formation of morphogen gradients with mechanical stability and transformations in embryo cells. [...] it is still unclear how exactly the embryo cells read the information from the signaling profiles. It is critically important to combine multiple theoretical, computational and experimental methods to advance our knowledge on the mechanisms of these fundamental biological processes.

Mechanisms of the formation of biological signaling profiles Hamid Teimouri and Anatoly B Kolomeisky Journal of Physics A: Mathematical and Theoretical J. Phys. A: Math. Theor. 49 (2016) 483001 (30pp) doi:10.1088/1751-8113/49/48/483001

Work in progress... stay tuned. Complex complexity. Dionisio

Although many features of the development of signaling profiles are now better understood, there are many puzzling questions and observations in the field [...] It is not clear how to take into account the temporal effect in the source and what effect it might have on dynamics. Another challenging problem is whether the morphogen gradient needs to reach the stationary state or not in order to properly transfer the information. There are controversial views about the possibility of the pre-steady state decoding as the more efficient mechanism of information transfer [...]

Mechanisms of the formation of biological signaling profiles Hamid Teimouri and Anatoly B Kolomeisky Journal of Physics A: Mathematical and Theoretical J. Phys. A: Math. Theor. 49 (2016) 483001 (30pp) doi:10.1088/1751-8113/49/48/483001

Work in progress... stay tuned. Complex complexity. Dionisio

Recent experimental advances in studying the development processes in various systems revealed that there is a significant number of experimental observations that cannot be explained by reaction–diffusion mechanisms [...] In embryo systems with complex internal structures, simple free diffusion might not always be very efficient in establishing the morphogen gradient [...] The direct-delivery mechanism thus avoids the problems where a geometrically complex environment prevents the free diffusion forming the signaling profiles.

Mechanisms of the formation of biological signaling profiles Hamid Teimouri and Anatoly B Kolomeisky Journal of Physics A: Mathematical and Theoretical J. Phys. A: Math. Theor. 49 (2016) 483001 (30pp) doi:10.1088/1751-8113/49/48/483001

Complex complexity. Dionisio

[...] the possibility of alternative mechanisms of the direct delivery of morphogens to the target cells utilizing dynamic cellular extensions called cytonemes was predicted [...] It has been argued that the complex environment of the embryo systems might prevent the free diffusion from establishing the distinguishable morphogen gradients at different regions, implying a different mechanism of the biological signal transduction [...]

Mechanisms of the formation of biological signaling profiles Hamid Teimouri and Anatoly B Kolomeisky Journal of Physics A: Mathematical and Theoretical J. Phys. A: Math. Theor. 49 (2016) 483001 (30pp) doi:10.1088/1751-8113/49/48/483001

Complex complexity. Dionisio

The development of various living organisms from an initially very small group of identical embryo cells is one of the most fascinating and complex processes in biology [...] [...] the developmental pattern formation is a result of the interpretation of spatial positions decoded in external signals from biological signaling molecules. Cells obtain the spatial information by somehow ‘measuring’ the concentration of morphogens around them. Different genes are turned on or off depending on several concentration thresholds, eventually producing morphologically different cells.

Mechanisms of the formation of biological signaling profiles Hamid Teimouri and Anatoly B Kolomeisky Journal of Physics A: Mathematical and Theoretical J. Phys. A: Math. Theor. 49 (2016) 483001 (30pp) doi:10.1088/1751-8113/49/48/483001

Complex complexity. Dionisio

The formation and growth of multi-cellular organisms and tissues from several genetically identical embryo cells is one of the most fundamental natural phenomena. These processes are stimulated and governed by multiple biological signaling molecules, which are also called morphogens. Embryo cells are able to read and pass genetic information by measuring the non-uniform concentration profiles of signaling molecules

Mechanisms of the formation of biological signaling profiles Hamid Teimouri and Anatoly B Kolomeisky Journal of Physics A: Mathematical and Theoretical J. Phys. A: Math. Theor. 49 (2016) 483001 (30pp) doi:10.1088/1751-8113/49/48/483001

Complex complexity. Dionisio

Sonic hedgehog (Shh) is a secreted protein that controls the patterning of neural progenitor cells, and their neuronal and glial progeny, during development. Emerging findings suggest that Shh also has important roles in the formation and plasticity of neuronal circuits in the hippocampus, a brain region of fundamental importance in learning and memory. Shh mediates activity-dependent and injury-induced hippocampal neurogenesis. Activation of Shh receptors in the dendrites of hippocampal neurons engages a trans-neuronal signaling pathway that accelerates axon outgrowth and enhances glutamate release from presynaptic terminals. Impaired Shh signaling may contribute to the pathogenesis of several developmental and adult-onset neurological disorders that affect the hippocampus, suggesting a potential for therapeutic interventions that target Shh pathways.

Sonic Hedgehog Signaling and Hippocampal Neuroplasticity. Yao PJ, Petralia RS, Mattson MP Trends Neurosci. 39(12):840-850. doi: 10.1016/j.tins.2016.10.001

Complex complexity. Dionisio

Paper referenced @1941, 1959: Regulation of Hedgehog Signalling Inside and Outside the Cell Simon A. Ramsbottom, and Mary E. Pownall J Dev Biol. 4(3): 23. doi: 10.3390/jdb4030023 Dionisio

One of the most important problems of the biological development is to understand the mechanisms of the morphogen gradients formation.

New Model for Understanding Mechanisms of Biological Signaling: Direct Transport via Cytonemes. Teimouri H, Kolomeisky AB J Phys Chem Lett. 7(1):180-5. doi: 10.1021/acs.jpclett.5b02703.

Complex complexity. Dionisio

The formation of multi-cellular organisms is one of the most fundamental and mysterious phenomena in nature. [...] the central role in the biological development, that leads to a complex spatio-temporal patterning in living systems, is played by multiple signaling molecules or morphogens. These biological signaling molecules develop non-uniform concentration profiles, known as morphogen gradients. A large number of experimental and theoretical investigations on the formation and functioning of morphogen gradients has appeared in recent years. However, many aspects of biological signaling remain not well understood.

New Model for Understanding Mechanisms of Biological Signaling: Direct Transport via Cytonemes. Teimouri H, Kolomeisky AB J Phys Chem Lett. 7(1):180-5. doi: 10.1021/acs.jpclett.5b02703.

http://python.rice.edu/~kolomeisky/articles/acs%252Ejpclett%252E5b02703.pdf https://scholarship.rice.edu/bitstream/handle/1911/87815/paper.cytoneme_jpcl2.pdf https://www.researchgate.net/profile/Hamid_Teimouri2/publication/287971356_A_New_Model_for_Understanding_Mechanism_of_Biological_Signaling_Direct_Transport_via_Cytonemes/links/56d9de6808aee73df6cf6563.pdf Complex complexity. Dionisio

Biological signaling is a crucial natural process that governs the formation of all multicellular organisms. It relies on efficient and fast transfer of information between different cells and tissues. It has been presumed for a long time that these long-distance communications in most systems can take place only indirectly via the diffusion of signaling molecules, also known as morphogens, through the extracellular fluid; however, recent experiments indicate that there is also an alternative direct delivery mechanism. It utilizes dynamic tubular cellular extensions, called cytonemes, that directly connect cells, supporting the flux of morphogens to specific locations. [...] the direct-delivery mechanism is more robust with respect to fluctuations in comparison with the passive diffusion mechanism.

New Model for Understanding Mechanisms of Biological Signaling: Direct Transport via Cytonemes. Teimouri H, Kolomeisky AB J Phys Chem Lett. 7(1):180-5. doi: 10.1021/acs.jpclett.5b02703.

Is the passive diffusion mechanism associated with a 1952 paper by Alan Turing? Not exactly as they thought. What else is new? :) How are the morphogen destinations determined? Complex complexity. Dionisio

With the continuous implementation of novel tools, imaginal discs retain significant potential as model systems to address emerging questions in biology and medicine. [...] it will be interesting for future studies to determine how these observations and models will fit together. Upon disc fragmentation, for example, along the D-V axis of the leg disc, the anterior portion can regenerate while the posterior half undergoes duplication where a mirror image of the tissue arises, instead of forming the missing part. Interestingly, the mechanism for this difference still remains a mystery [...] The reprogramming challenge poses some issues regarding developmental robustness, thus hinting that the regenerative process is likely very tightly regulated ensuring accurate re-patterning and growth. The mechanisms ensuring such control are only starting to be explored, as demonstrated by the recent identification of a factor protecting regenerating tissues from cell fate changes. Several open questions remain in the regeneration field. The involvement of JNK has become clear, yet how it integrates with other pathways or genes that are differentially expressed in the blastema is unknown. Furthermore, the regulation conferring the plasticity of chromatin states necessary for cellular reprogramming depends on the PcG/TrxG system, but little is known about the mechanisms ensuring a tightly regulated response at the chromatin level.

The legacy of Drosophila imaginal discs Jorge V. Beira and Renato Paro Chromosoma. 125(4): 573–592. doi: 10.1007/s00412-016-0595-4

Work in progress... stay tuned. Complex complexity. Dionisio

The study of Drosophila imaginal discs has contributed to a number of discoveries in developmental and cellular biology. In addition to the elucidation of the role of tissue compartments and organ-specific master regulator genes during development, imaginal discs have also become well established as models for studying cellular interactions and complex genetic pathways. With the continuous implementation of novel tools, imaginal discs retain significant potential as model systems to address emerging questions in biology and medicine.

The legacy of Drosophila imaginal discs Jorge V. Beira and Renato Paro Chromosoma. 125(4): 573–592. doi: 10.1007/s00412-016-0595-4

Complex complexity. Dionisio

It will be interesting to precisely determine the timings at which these different early Dpp target genes are required. [...] [the Dpp-responsive regulatory network] represents a relatively simple framework for future studies aimed at understanding how gene expression changes drive cell fate changes.

Regulation of the BMP Signaling-Responsive Transcriptional Network in the Drosophila Embryo. Deignan L, Pinheiro MT, Sutcliffe C, Saunders A, Wilcockson SG, Zeef LA, Donaldson IJ, Ashe HL PLoS Genet. 12(7):e1006164. doi: 10.1371/journal.pgen.1006164.

Work in progress... stay tuned. Complex complexity. Dionisio

The Bone Morphogenetic Protein (BMP) signaling pathway is used repeatedly throughout development to regulate a diverse array of processes. Studies in flies and vertebrates have revealed complex regulation of Smad transcription factors by phosphorylation, dephosphorylation, SUMOylation and ubiquitination, which controls their subcellular localization, transcriptional activity and degradation [...] Despite progress in deciphering the Dorsal gene regulatory network during early patterning of the embryo, details relating to the transcription network underpinning dorsal ectoderm differentiation in response to Dpp are sparse. Our data identify multiple target genes and enhancers, and reveal that the EGF pathway activity is constrained in the embryo to facilitate correct Dpp-dependent patterning. In addition, we show roles for Zelda (Zld), Zerknüllt (Zen) and the BEAF-32 insulator protein in Dpp gradient interpretation.

Regulation of the BMP Signaling-Responsive Transcriptional Network in the Drosophila Embryo. Deignan L, Pinheiro MT, Sutcliffe C, Saunders A, Wilcockson SG, Zeef LA, Donaldson IJ, Ashe HL PLoS Genet. 12(7):e1006164. doi: 10.1371/journal.pgen.1006164.

to facilitate? Purpose? Complex complexity. [emphasis added] Dionisio

Embryogenesis involves the patterning of many different cell fates by a limited number of types of signals. One way that these signals promote a particular cell fate is through the induction of a complex, yet highly reproducible, gene expression programme that instructs changes in the cell. Overall, our data will provide a platform for exploiting the tractability of the Drosophila embryo to determine which features of the network are critical drivers of BMP-induced cell fate changes during embryogenesis.

Regulation of the BMP Signaling-Responsive Transcriptional Network in the Drosophila Embryo. Deignan L, Pinheiro MT, Sutcliffe C, Saunders A, Wilcockson SG, Zeef LA, Donaldson IJ, Ashe HL PLoS Genet. 12(7):e1006164. doi: 10.1371/journal.pgen.1006164.

Complex complexity. Dionisio

Our results delineate the molecular pathway that connects a patterning cue (Dpp), with its effector gene (the transcription factor broad) and its morphological output (positioning of the dorsal appendages). Our work complements recent studies demonstrating that the posterior extent of br expression and DA-primordia are also confined by repression (Fregoso Lomas et al., 2013), and highlights the complexity of the circuit involved in eggshell patterning.

BMP-dependent gene repression cascade in Drosophila eggshell patterning Enrica Charbonnier, Alisa Fuchs, Lily S. Cheung, Mrinal Chayengia, Ville Veikkolainen, Janine Seyfferth, Stanislav Y. Shvartsman and George Pyrowolakis Dev Biol. 400(2): 258–265. doi: 10.1016/j.ydbio.2015.02.004

Complex complexity. Dionisio

Taken together, our findings shed light on the molecular mechanism and design features of the transcriptional network that establishes the pattern in the vertebrate neural tube. The regulatory links between the repressors in the transcriptional network provide a mechanism to interpret the dynamic morphogen input and select the appropriate transcriptional identity for the position along the patterning axes [...] Given the similarity in the operating principles of this system with other developmental systems, this suggests a general architecture for morphogen-controlled GRNs that is likely to be relevant for other tissues.

Neural Progenitors Adopt Specific Identities by Directly Repressing All Alternative Progenitor Transcriptional Programs. Kutejova E, Sasai N, Shah A, Gouti M, Briscoe J Dev Cell. 36(6):639-53. doi: 10.1016/j.devcel.2016.02.013

Did somebody say “design”? ???? Complex complexity. [emphasis added] Dionisio

Together the data reveal four design features of the GRN. First, activating inputs in the network are promiscuous, with broadly active morphogen mediators and transcriptional activators promoting the transcriptional programs of multiple progenitor domains [...] Second, specific cell identity is determined by a network of transcriptional repressors, which form a densely connected network, assuring that cells select a single definitive identity by repressing all inappropriate cell fates [...] Third, specification of identity requires not only repression of the “master regulator” TFs (NP-TFs) of other progenitor domains but also the direct repression of the “effector” genes expressed in other progenitor domains. Finally, the regulatory input into many target genes appears highly combinatorial and distributed over multiple CREs

Neural Progenitors Adopt Specific Identities by Directly Repressing All Alternative Progenitor Transcriptional Programs. Kutejova E, Sasai N, Shah A, Gouti M, Briscoe J Dev Cell. 36(6):639-53. doi: 10.1016/j.devcel.2016.02.013

Did somebody say “design”? ???? Complex complexity. [emphasis added] Dionisio

Pattern formation in developing tissues relies on the cells adopting one of several alternative fates. These decisions are determined by extrinsic signals, often in the form of morphogen gradients, and the transcriptional network that responds to the gradients. Together these form gene-regulatory networks (GRNs) that control gene expression and specify cell identity

Neural Progenitors Adopt Specific Identities by Directly Repressing All Alternative Progenitor Transcriptional Programs. Kutejova E, Sasai N, Shah A, Gouti M, Briscoe J Dev Cell. 36(6):639-53. doi: 10.1016/j.devcel.2016.02.013

Complex complexity. Dionisio

In the vertebrate neural tube, a morphogen-induced transcriptional network produces multiple molecularly distinct progenitor domains, each generating different neuronal subtypes. In the ventral neural tube, sonic hedgehog (Shh) signaling, together with broadly expressed transcriptional activators, concurrently activates the gene expression programs of several domains. The specific outcome is selected by repressive input provided by Shh-induced transcription factors that act as the key nodes in the network, enabling progenitors to adopt a single definitive identity from several initially permitted options. Together, the data suggest design principles relevant to many developing tissues.

Neural Progenitors Adopt Specific Identities by Directly Repressing All Alternative Progenitor Transcriptional Programs. Kutejova E, Sasai N, Shah A, Gouti M, Briscoe J Dev Cell. 36(6):639-53. doi: 10.1016/j.devcel.2016.02.013

Did somebody say “design”? ???? Complex complexity. [emphasis added] Dionisio

Cellular decisions are made by complex networks that are difficult to analyze. Although it is common to analyze smaller sub-networks known as network motifs, it is unclear whether this is valid, because these motifs are embedded in complex larger networks. [...] the feedforward motif controlling the cell-cycle inhibitor Far1 is insulated from cell-cycle dynamics by the positive feedback switch that drives reentry to the cell cycle. Before cells switch on positive feedback, the feedforward motif model predicts the behavior of the larger network. Conversely, after the switch, the feedforward motif is dismantled and has no discernable effect on the cell cycle. When insulation is broken, the feedforward motif no longer predicts network behavior.

Switch-like Transitions Insulate Network Motifs to Modularize Biological Networks. Atay O, Doncic A, Skotheim JM Cell Syst. 3(2):121-32. doi: 10.1016/j.cels.2016.06.010.

Complex complexity. Dionisio

paper referenced @ 1673, 1712-1713, 1926, 1990-1991, 2100-2104

Extracellular interactions and ligand degradation shape the nodal morphogen gradient Yin Wang, Xi Wang, Thorsten Wohland, and Karuna Sympathy eLife. 2016; 5: e13879. doi: 10.7554/eLife.13879 https://elifesciences.org/content/5/e13879

Are they saying that diffusion alone is not sufficient to explain the morphogen gradient formation? Does this mean that all the hype about Turing's 1952 paper on diffusion being referred as the explanation for the morphogen gradient formation was premature? Why did it take them so long to figure that out? A 7-year old child would have asked the right questions leading to the correct conclusion. Just ask professor L.M. of the U of T in Canada. But make sure to ask only honest questions, whatever that means. Are we ever going to see more humility (open-mind thinking out of preconceived boxes) in scientific research papers? As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. The big picture looks more interesting with every new discovery. That’s why we look forward, with increasing anticipation, to reading newer research papers that shed more light on the elaborate cellular and molecular choreographies operating within the biological systems. Unending Revelation of the Ultimate Reality (c) Dionisio

[...] the recruitment of plus?end?directed kinesin motors to mRNPs and their regulation remains poorly understood [...] [...] the underlying mechanisms of the Khc loading and activation processes remain cryptic [...] Further dissection of the structure and the precise molecular functions of Tm1?I/C and its binding partners will be crucial to determining the nature and the minimal number of features necessary for such unconventional yet vital kinesin?1?mediated localization of mRNA.

An RNA-binding atypical tropomyosin recruits kinesin-1 dynamically to oskar mRNPs. Gáspár I, Sysoev V, Komissarov A, Ephrussi A EMBO J. pii: e201696038. doi: 10.15252/embj.201696038.

Complex complexity. Dionisio

The germ line is that lineage of cells that eventually forms the eggs and sperm in the adult. The precursor germ line cells, the primordial germ cells, are formed in the early embryo and will eventually migrate to the developing gonad, form the germ line stem cells, and in the adult, make the gametes, the eggs or sperm.

Germ Line Mechanics--And Unfinished Business. Wessel GM Curr Top Dev Biol. 117:553-66. doi: 10.1016/bs.ctdb.2015.11.030

Complex complexity. Dionisio

Primordial germ cells are usually made early in the development of an organism. These are the mother of all stem cells that are necessary for propagation of the species, yet use highly diverse mechanisms between organisms. How they are specified, and when and where they form, are central to developmental biology.

Germ Line Mechanics--And Unfinished Business. Wessel GM Curr Top Dev Biol. 117:553-66. doi: 10.1016/bs.ctdb.2015.11.030

Complex complexity. Dionisio

[...] fate-specifying mechanisms are unclear. What is less clear is the potential interplay between interstitial cell types and the renal tubular component of the nephron. Here the shape, size and close apposition of key cellular players makes resolving cell-type specific interactions a particular challenge. [...] the renal vasculature is poorly understood from a developmental perspective. The molecular programs establishing renal vasculature architecture, and endothelial cell differentiation and function have not been extensively characterized. [...] the developmental programs generating the neural network have not been comprehensively addressed with modern tracing, fate mapping and molecular approaches [...] [...] it seems reasonable to speculate that the physical linkage of arterial and sympathetic systems may reflect coordinated sensing of shared guidance cues.

Development of the Mammalian Kidney Andrew P. McMahon Curr Top Dev Biol. 117: 31–64. doi: 10.1016/bs.ctdb.2015.10.010

Work in progress… stay tuned. Complex complexity. Dionisio

The cellular complexity of the mammalian kidney is not well understood. [...] in the human kidney nephrogenesis ceases around 36 weeks so that nephrogenesis is complete at birth [...] A more detailed comparative molecular anatomy of nephron morphogenesis coupled with extensive regional fate mapping can provide a much clearer view of how early domains of gene expression relate to mature structures of the adult kidney [...] Mechanisms regulating organ size across different species are generally poorly understood; the kidney is no exception in this regard.

Development of the Mammalian Kidney Andrew P. McMahon Curr Top Dev Biol. 117: 31–64. doi: 10.1016/bs.ctdb.2015.10.010

Work in progress... stay tuned. Complex complexity. Dionisio

More work will also be needed to understand exactly how bacterial cells coordinate the cell wall synthesis and cell wall degradation. Future experiments and modeling should address the role of these and other potential contributors to LE migration, which will allow us to refine our biophysical model and obtain a comprehensive view of membrane dynamics during engulfment. Furthermore, understanding the cooperation between PBPs and DMP will provide valuable clues about the structure of the cell wall in Gram-positive bacteria.

Cell-wall remodeling drives engulfment during Bacillus subtilis sporulation Nikola Ojkic, Javier López-Garrido, Kit Pogliano and Robert G Endres eLife. 5: e18657. doi: 10.7554/eLife.18657

Complex complexity. Dionisio

[...] the mechanism of force generation to push or pull the mother cell membrane around the forespore remains unknown [...] [...] the mechanistic details of membrane migration and for the coordination between PG synthesis and degradation remain unclear. [...] engulfment entails coordination of PG synthesis and degradation between the two compartments of the sporangium, with forespore-associated PBPs synthesizing PG ahead of the LE and the mother-cell DMP complex degrading this PG to drive membrane migration. [...] the junction between the septum and the cell wall moves around the forespore to make room for the mother cell’s membrane for expansion.

Cell-wall remodeling drives engulfment during Bacillus subtilis sporulation Nikola Ojkic, Javier López-Garrido, Kit Pogliano and Robert G Endres eLife. 5: e18657. doi: 10.7554/eLife.18657

Complex complexity. Dionisio

In the hypothetical (implausible?) case that one could answer the myriad outstanding questions related to the basic biological components, we still have to deal with many difficult unresolved mysteries related to the actual controlling procedures within the biological systems. What recent research is discovering about these mysteries points to intelligently designed biological systems. One feels sorry for the Darwinian folks. Poor things. BTW, here's an almost 15 years old quote:

“In view of the large number of variables involved and of the complexity of feedback processes that generate oscillations, mathematical models and numerical simulations are needed to fully grasp the molecular mechanisms and functions of biological rhythms.”

Computational approaches to cellular rhythms. Goldbeter A Nature. 420(6912):238-45. DOI: 10.1038/nature01259

This was 15 years ago. Later we'll see what has been discovered more recently. Have the outstanding questions been answered? Have new questions been raised? Complex complexity. Dionisio

Biological oscillators [...] usually show a more complex structure. The reasons for this complexity are in many cases not fully understood, and many efforts are devoted to identify design principles underlying the complex architectures [...] (either organism- or function-specific properties or design principles shared by different organisms and functions).

Design Principles of Biological Oscillators through Optimization: Forward and Reverse Analysis Irene Otero-Muras* and Julio R. Banga PLoS One. 11(12): e0166867. doi: 10.1371/journal.pone.0166867

BTW, did somebody say “design”? ???? Complex complexity. [emphasis added] Dionisio

From cyanobacteria to human, sustained oscillations coordinate important biological functions. Although much has been learned concerning the sophisticated molecular mechanisms underlying biological oscillators, design principles linking structure and functional behavior are not yet fully understood.

Design Principles of Biological Oscillators through Optimization: Forward and Reverse Analysis Irene Otero-Muras* and Julio R. Banga PLoS One. 11(12): e0166867. doi: 10.1371/journal.pone.0166867

BTW, did somebody say “design”? ???? Complex complexity. [emphasis added] Dionisio

[...] a central question still remains, and that is why a specific network-design is chosen during evolution, when alternative designs yield similar outcomes. In the light of all these observations, we consider a thorough stochastic analysis of all reinforced IFFMs as the logic and necessary future work that could explain the abundance of certain patterning designs in nature.

Design principles of stripe-forming motifs: the role of positive feedback. Munteanu A, Cotterell J, Solé RV, Sharpe J Sci Rep. 4:5003. doi: 10.1038/srep05003.

Work in progress... stay tuned. But don't hold your breath waiting for what they want to prove. It ain't gonna happen. They are off track heading the wrong way. Poor things. Oh, well. Unending revelation of the Ultimate reality. BTW, did somebody say “design”? :) Complex complexity. [emphasis added] Dionisio

While there is now clear evidence that patterning by morphogens is more complicated than previously thought[...], our goal here was the understanding of minimal regulatory motifs with the aim of elucidating the mechanistic issues and underlying design principles of this patterning process. [...] these observations support the hypothesis of design principles that conceives morphogenesis in terms of decomposable functional parts carefully assembled by evolution.

Design principles of stripe-forming motifs: the role of positive feedback. Munteanu A, Cotterell J, Solé RV, Sharpe J Sci Rep. 4:5003. doi: 10.1038/srep05003.

more complicated than previously thought? What else is new? carefully assembled by evolution? Really? How? Why did they write such a pseudoscientific nonsensical hogwash? That's a paper-pooper. Since when evolution can assemble anything carefully? Do they know the meaning of "carefully"? What does "care" mean? Did somebody say “design”? :) Complex complexity. [emphasis added] Dionisio

[...] within developmental biology, the biphasic dose-dependent behaviour addressed here under the term “single-stripe formation” relates to the positional-information mechanism. By this mechanism, cells directly read and thus interpret morphogen concentration-gradients leading to their subsequent differentiation in the early developmental stages.

Design principles of stripe-forming motifs: the role of positive feedback. Munteanu A, Cotterell J, Solé RV, Sharpe J Sci Rep. 4:5003. doi: 10.1038/srep05003.

cells directly read and thus interpret? Wow! those cells are really smart, aren't they? :) Did somebody say “design”? :) Complex complexity. [emphasis added] Dionisio

In endogenous tissues, proteins can diffuse between cells. However, Jaeger et al.17 found that diffusion is not required for qualitatively generating the expression pattern of the gap genes in Drosophila. Cotterell & Sharpe28 reached the same conclusion by means of an exhaustive computational study of all stripe-forming 3-gene networks. Therefore, the current study considers that proteins are non-diffusible, making our framework a positional-information scenario.

Design principles of stripe-forming motifs: the role of positive feedback. Munteanu A, Cotterell J, Solé RV, Sharpe J Sci Rep. 4:5003. doi: 10.1038/srep05003.

Did somebody say “design”? :) Complex complexity. [emphasis added] Dionisio

Modularity is a central principle to both systems and synthetic biology. It implies the reduction of large gene networks to a collection of small, separable subsystems. [...] in spite of their similarities, the motifs respond differently to the addition of positive feedbacks. [...] we explain this unexpected behaviour by coupling network architecture and dynamics.

Design principles of stripe-forming motifs: the role of positive feedback. Munteanu A, Cotterell J, Solé RV, Sharpe J Sci Rep. 4:5003. doi: 10.1038/srep05003.

Did somebody say “design”? :) Complex complexity. [emphasis added] Dionisio

Interpreting a morphogen gradient into a single stripe of gene-expression is a fundamental unit of patterning in early embryogenesis. [...] the feed-forward motifs stand out as minimal networks capable of this patterning function. The addition of positive-feedback can have different effects on two different designs of feed-forward motif- it increases the parametric robustness of one design, while being neutral or detrimental to the other. These results shed light on the abundance of the former motif and especially of mutual-inhibition positive feedback in developmental networks.

Design principles of stripe-forming motifs: the role of positive feedback. Munteanu A, Cotterell J, Solé RV, Sharpe J Sci Rep. 4:5003. doi: 10.1038/srep05003.

Did somebody say “design”? :) Complex complexity. [emphasis added] Dionisio

Taken together, the proposed concept and the simulations can be used to unravel the design principle of developmental gene regulatory networks. [...] we conclude we could infer the design principles of Drosophila development in a holistic manner using our approach [...] Network motifs cannot uniquely determine the whole dynamical properties of a regulatory network. In general, the dynamics of a regulatory network depends on multiple factors such as initial conditions, cellular environments, and randomness [...] [...] our approach is useful to infer developmental functions of spatiotemporally varying cells based on identification of network motifs. We proposed a novel concept called the “spatiotemporal network motif,” which is a sequence of network motifs in sub-networks that are spatiotemporally active. [...] we can gain new insights into the organizing principles of a developmental network whose structures change spatially and temporally, and can be widely used to investigate the relationship between dynamic network structures and their regulatory functions.

Spatiotemporal network motif reveals the biological traits of developmental gene regulatory networks in Drosophila melanogaster. Kim MS1, Kim JR, Kim D, Lander AD, Cho KH BMC Syst Biol. 6:31. doi: 10.1186/1752-0509-6-31.

Did somebody say "design"? :) Complex complexity. Dionisio

The development of multi-cellular organisms relies on the coordinated spatiotemporal regulation of gene expressions. To unravel the organizing principles of developmental gene regulatory networks, it is crucial to understand the relationship between the structure and function of spatiotemporal subnetworks. [...] developmental processes related to cell fate must be robust in relation to noises [...] [...] nested feedback loops were frequently observed in the gap gene network and most of the nested feedback loops contain mutual inhibition structures. [...] the dynamics of a regulatory network depends on multiple factors such as initial conditions, cellular environments, and randomness [...]

Spatiotemporal network motif reveals the biological traits of developmental gene regulatory networks in Drosophila melanogaster. Kim MS1, Kim JR, Kim D, Lander AD, Cho KH BMC Syst Biol. 6:31. doi: 10.1186/1752-0509-6-31.

Complex complexity. Dionisio

Taken together, the proposed concept and the simulations can be used to unravel the design principle of developmental gene regulatory networks. To uncover the governing principles underlying complex biological processes, it is important to understand the relationship between topological structures and the dynamical characteristics of gene regulatory networks [...] One promising method of investigation is to disassemble the large regulatory network into its more basic, constituent building blocks called network motifs, which recur within a network much more often than expected in random networks. [...] network motifs are constructed by re-organizing the regulations between spatiotemporally expressed genes.

Spatiotemporal network motif reveals the biological traits of developmental gene regulatory networks in Drosophila melanogaster. Kim MS1, Kim JR, Kim D, Lander AD, Cho KH BMC Syst Biol. 6:31. doi: 10.1186/1752-0509-6-31.

Complex complexity. Dionisio

Further quantitative studies of this system (such as measurements of Gal4/Gal80 protein ratios, Gal4 and Gal80 diffusivities, and protein/mRNA spatiotemporal dynamics) would help uncover the precise mechanism for switching between an attenuation regime and a shuttling regime. [...] comparisons to other systems suggest that shuttling may exist in other negative feedback systems [...] This shows the complexity of gene networks in tissue patterning and other multi-cellular systems. While much previous work has been carried out to understand synthetic gene networks in single-celled systems, much care must be taken to extrapolate these findings into multi-cellular systems.

Analyzing negative feedback using a synthetic gene network expressed in the Drosophila melanogaster embryo Ashley A. Jermusyk, Nicholas P. Murphy and Gregory T. Reeves BMC Systems Biology – 10:85 DOI: 10.1186/s12918-016-0330-z

Complex complexity. Dionisio

A complex network of gene interactions controls gene regulation throughout development and the life of the organisms. Shuttling has been found in other systems, and in some cases produces robust gradients from an initial broad morphogen signal [...] Shuttling requires a diffusible morphogen and a shuttling molecule that forms a complex with, and thereby extends the spatial range of, the morphogen. Previous studies have found evidence for morphogen gradients which enhance their own degradation, this form of negative feedback is known as self-enhanced ligand degradation.

Analyzing negative feedback using a synthetic gene network expressed in the Drosophila melanogaster embryo Ashley A. Jermusyk, Nicholas P. Murphy and Gregory T. Reeves BMC Systems Biology – 10:85 DOI: 10.1186/s12918-016-0330-z

Complex complexity. Dionisio

Lactic acid bacteria are associated with the human gastrointestinal tract. They are important for maintaining the balance of microflora in the human gut. An increasing number of published research reports in recent years have denoted the importance of producing interferon-gamma and IgA for treatment of disease. These agents can enhance the specific and nonspecific immune systems that are dependent on specific bacterial strains. The mechanisms of these effects were revealed in this investigation, where the cell walls of these bacteria were modulated by the cytokine pathways, while the whole bacterial cell mediated the host cell immune system and regulated the production of tumor necrosis factors and interleukins. A supplement of highly active lactic acid bacteria strains provided significant potential to enhance host's immunity, offering prevention from many diseases including some cancers. This review summarizes the current understanding of the function of lactic acid bacteria immunity enhancement and cancer prevention.

Capacity of lactic acid bacteria in immunity enhancement and cancer prevention Muhammad Shahid Riaz Rajoka, Junling Shi, Jing Zhu, Mingliang Jin Applied Microbiology and Biotechnology DOI: 10.1007/s00253-016-8005-7

Had we stayed in Eden none of this would have been an issue. But we decided to do it our way. Dionisio

The same "juicy" paper referenced @1768-1770 and @2431-2434 Bicoid gradient formation and function in the Drosophila pre-syncytial blastoderm Zehra Ali-Murthy and Thomas B Kornberg eLife. 2016; 5: e13222. doi: 10.7554/eLife.13222 Dionisio

Morphogens such as Hedgehog, Wingless, Decapentaplegic, and Fibroblast growth factor distribute in concentration gradients across fields of cells in the tissues of developing animals. Their distributions are generated by transport along actin-based cytonemes [...] and direct exchange between producing and receiving cells at morphogenetic synapses where release and uptake of secreted proteins is regulated [...] Neither appears to be dependent on passive diffusion and both appear to involve dispersion along cytoskeletal cables. The critical attribute that these mechanisms share is that they provide ways to regulate movement in space and time.

Bicoid gradient formation and function in the Drosophila pre-syncytial blastoderm Zehra Ali-Murthy and Thomas B Kornberg eLife. 2016; 5: e13222. doi: 10.7554/eLife.13222

Complex complexity. Dionisio

Whether the protein gradient forms by passive diffusion following synthesis of Bcd protein at more anterior locations [...] or is produced in place by the bcd mRNA concentration gradient is in dispute [...] [...] it may be that yet unexplored mechanisms produce and use transcripts more rapidly at early stages. [...] development of the early embryo is not entirely pre-programmed and that the processes that orchestrate the early stages are actively and directly regulated. [...] the processes that generate the Bcd protein gradient are more complex and operate earlier than had been appreciated, and that the function of the Bcd gradient begins prior to formation of the syncytial blastoderm.

Bicoid gradient formation and function in the Drosophila pre-syncytial blastoderm Zehra Ali-Murthy and Thomas B Kornberg eLife. 2016; 5: e13222. doi: 10.7554/eLife.13222

Complex complexity. Dionisio

Several assumptions had been made about how this gradient is established. [...] Bicoid protein is present in the unfertilized fruit fly egg in the same region as the mRNA molecules that make Bicoid. [...] the Bicoid gradient forms when the embryo has fewer than 32 nuclei, much earlier in development than previously thought. The Bicoid protein also does not appear to spread passively towards the rear of the embryo, but is transported in a more orchestrated manner. [...] the early fruit fly embryo is more organized and actively regulated than had been previously understood. This paves the way for further studies that use sensitive techniques to investigate this early stage of development.

Bicoid gradient formation and function in the Drosophila pre-syncytial blastoderm Zehra Ali-Murthy and Thomas B Kornberg eLife. 2016; 5: e13222. doi: 10.7554/eLife.13222

Complex complexity. Dionisio

Bicoid (Bcd) protein distributes in a concentration gradient that organizes the anterior/posterior axis of the Drosophila embryo. It has been understood that bcd RNA is sequestered at the anterior pole during oogenesis, is not translated until fertilization, and produces a protein gradient that functions in the syncytial blastoderm after 9–10 nuclear divisions. As an embryo develops, a single cell transforms into a collection of different types of cells. One protein that is crucial for this process in fruit fly embryos is Bicoid.

Bicoid gradient formation and function in the Drosophila pre-syncytial blastoderm Zehra Ali-Murthy and Thomas B Kornberg eLife. 2016; 5: e13222. doi: 10.7554/eLife.13222

Complex complexity. Dionisio

Contents: 1: Models for Studying Organogenetic Gene Networks in the 21st Century - Page 1 James Castelli-Gair Hombría and Paola Bovolenta 2: Organogenesis of the C. elegans Vulva and Control of Cell Fusion - Page 9 Nathan Weinstein and Benjamin Podbilewicz 3: Advances in Understanding the Generation and Specification of Unique Neuronal Sub-types from Drosophila Neuropeptidergic Neurons - Page 57 Stefan Thor and Douglas W. Allan 4: Fast and Furious 800. The Retinal Determination Gene Network in Drosophila - Page 95 Fernando Casares and Isabel Almudi 5: Genetic Control of Salivary Gland Tubulogenesis in Drosophila - Page 125 Clara Sidor and Katja Röper 6: Organogenesis of the Drosophila Respiratory System - Page 151 Rajprasad Loganathan, Yim Ling Cheng and Deborah J. Andrew 7: Organogenesis of the Zebrafish Kidney - Page 213 Hao-Han Chang, Richard W. Naylor and Alan J. Davidson 8: Morphogenetic Mechanisms of Inner Ear Development - Page 235 Berta Alsina and Andrea Streit 9: Vertebrate Eye Gene Regulatory Networks - Page 259 Juan R. Martinez-Morales 10: Vertebrate Eye Evolution - Page 275 Juan R. Martinez-Morales and Annamaria Locascio 11: Principles of Early Vertebrate Forebrain Formation - Page 299 Florencia Cavodeassi, Tania Moreno-Mármol, María Hernandez-Bejarano and Paola Bovolenta 12: Control of Organogenesis by Hox Genes - Page 319 J. Castelli-Gair Hombría, C. Sánchez-Higueras and E. Sánchez-Herrero

Organogenetic Gene Networks Genetic Control of Organ Formation Editors: James Castelli-Gair Hombría, Paola Bovolenta ISBN: 978-3-319-42765-2 (Print) 978-3-319-42767-6 (Online)

Juicy material to discuss. Including the controversially pseudoscientific chapter 10 title, which apparently belongs in the thread "A third way of evolution?" :) Complex complexity. Dionisio

[...] elements define a bistable network that controls the choice between two alternative outcomes of [...] signaling. [...] antiparallel signaling gradients can be integrated during epithelial patterning. Tissue patterning by opposing morphogen gradients is observed in developmental contexts as diverse as [...] Mutual repression between downstream transcription factors helps define the position and boundaries of cell fate domains, but how the opposing gradients are integrated is not well understood [...] Together, these elements define the framework of a regulatory network that integrates localized positional information to regulate a binary choice of EGFR signaling outcome. The ability of Dpp and Upd to influence the outcome of EGFR signaling allows a single signaling input, namely localized secretion of Grk by the oocyte, to generate multiple distinct outputs that are localized in space and time, thus establishing both the AP and DV polarity of the epithelium and generating a complex and reproducible pattern of cell fates.

Determination of EGFR Signaling Output by Opposing Gradients of BMP and JAK/STAT Activity, Mariana Fregoso Lomas, Scott De Vito, Jean-Francois Boisclair Lachance, Josée Houde and Laura A. Nilson Current Biology (2016) http://dx.doi.org/10.1016/j.cub.2016.07.073

Very interesting paper, but it's not clear how the opposing gradients are formed to begin with. Is that explained in this paper? I don't see it. Can someone point at it for me? Thank you. Complex complexity. Dionisio

Intercellular signaling plays a central role in the development and function of multicellular organisms, where extracellular signals convey spatial and temporal information that orchestrates cellular processes such as proliferation, differentiation, and migration. The identification of the specific signals that control a wide range of developmental processes has revealed that the large number of cell types and behaviors that need to be specified during development is actually achieved by a fairly small number of signaling pathways [...] This observation implies that the same ligand-receptor pair can induce different transcriptional outcomes, but how this diversity is achieved is not well understood [...]

Determination of EGFR Signaling Output by Opposing Gradients of BMP and JAK/STAT Activity, Mariana Fregoso Lomas, Scott De Vito, Jean-Francois Boisclair Lachance, Josée Houde and Laura A. Nilson Current Biology (2016) http://dx.doi.org/10.1016/j.cub.2016.07.073

Complex complexity. Dionisio

A relatively small number of signaling pathways drive a wide range of developmental decisions, but how this versatility in signaling outcome is generated is not clear. [...] localized epidermal growth factor receptor (EGFR) activation induces distinct cell fates depending on its location. [...] the choice between these alternative outputs of EGFR signaling is regulated by antiparallel gradients of JAK/STAT and BMP pathway activity [...] [...] regulatory network ultimately allows the same ligand-receptor pair to establish both the anterior-posterior (AP) and dorsal-ventral (DV) axes of the issue.

Determination of EGFR Signaling Output by Opposing Gradients of BMP and JAK/STAT Activity, Mariana Fregoso Lomas, Scott De Vito, Jean-Francois Boisclair Lachance, Josée Houde and Laura A. Nilson Current Biology (2016) http://dx.doi.org/10.1016/j.cub.2016.07.073

Complex complexity. Dionisio

Very interesting paper. Definitely worth reading it.

"Finally, there have been several works that combine biological and theoretical studies to analyze filopodia architecture and function [131][132][133], actin dynamics in filopodia [134,135] or active transport in filopodia [136], but none of them has been applied to filopodia-mediated signaling mechanisms, cytonemes or gradient formation. In summary, several theoretical models in gradient formation have been proposed and improved over the years [118,119,[137][138][139][140][141][142][143]. Large efforts are currently being made to develop new biophysical theories trying to model gradient formation at different levels taking into account the biological mechanism implicated in signaling processes [81,126,127,144,145] and the literature cited therein. "

Perspectives on Intra- and Intercellular Trafficking of Hedgehog for Tissue Patterning Eléanor Simon?, Adrián Aguirre-Tamaral †?, Gustavo Aguilar †? and Isabel Guerrero J. Dev. Biol. 4(4), 34; doi:10.3390/jdb4040034

Does this mean that diffusion is not sufficient to form the morphogen gradients? Does this mean that Turing’s 1952 paper on diffusion as the mechanism for morphogen gradient formation is kind of obsolete or at least incomplete? Complex complexity. Dionisio

Hh has to be transported from producing to receiving cells to activate its targets. [...] there is increasing evidence that the precise spatial control of Hh dispersion is most likely due to cytonemes-mediated transport [...] [...] their [cytonemes'] extension correlates in space and time with gradient formation during development [...] Several issues regarding the mechanism of cytoneme growth and orientation have to be considered. The dynamics of extension and retraction of cytonemes, both in Drosophila [...] and vertebrate tissues [...], indicates a prospective plasticity of these structures and gives an exciting dimension to the mechanism of morphogen gradient formation. Interestingly, the mechanism of signaling proteins transfer through sites of direct cell contact at a long distance is reminiscent of the contact-mediated signaling used by specialized cells like neurons. Axonal and cytoneme-mediated signaling share significant similarities [...] [...] previous knowledge on the synaptic process in neuronal cells could open up future investigations to further understand cytoneme function in cell–cell signaling.

Perspectives on Intra- and Intercellular Trafficking of Hedgehog for Tissue Patterning Eléanor Simon?, Adrián Aguirre-Tamaral †?, Gustavo Aguilar †? and Isabel Guerrero J. Dev. Biol. 4(4), 34; doi:10.3390/jdb4040034

Does this mean that Turing's 1952 paper on diffusion is kind of obsolete or at least incomplete? Complex complexity. Dionisio

Intercellular communication is a fundamental process for correct tissue development. [...] Hedgehog (Hh) proteins are secreted ligands, which trigger the Hh signaling pathway upon binding to their receptor complex present at the cell surface. Hh signaling controls different cellular processes: cell survival, division, differentiation, cell migration or axonal pathfinding [...] It is secreted from a localized source, the producing cells, to reach the receiving cells to activate its targets in a concentration-dependent manner. The interest of such a mechanism is that a single molecule is sufficient to genetically specify different domains in an undifferentiated field. [...] establishment of the Hh morphogen gradient. [...] the understanding of the mechanism underlying Hh transport from producing to receiving cells is one of the current challenges.

Perspectives on Intra- and Intercellular Trafficking of Hedgehog for Tissue Patterning Eléanor Simon?, Adrián Aguirre-Tamaral †?, Gustavo Aguilar †? and Isabel Guerrero J. Dev. Biol. 4(4), 34; doi:10.3390/jdb4040034

Complex complexity. Dionisio

[...] the exact mechanism for the regulation of centrosome architecture and/or numbers by KDACs is unclear. [...] the mechanisms controlling PLK4 kinase activity have remained elusive. In the future, it will be interesting to investigate whether these PTMs act independently or in a coordinated fashion during cell cycle progression to accurately regulate PLK4 function.

KAT2A/KAT2B-targeted acetylome reveals a role for PLK4 acetylation in preventing centrosome amplification Marjorie Fournier, Meritxell Orpinell, Cédric Grauffe, Elisabeth Scheer, Jean-Marie Garnier, Tao Ye, Virginie Chavant, Mathilde Joint, Fumiko Esashi, Annick Dejaegere, Pierre Gönczy, and László Torab Nat Commun. 7: 13227. doi: 10.1038/ncomms13227

Complex complexity. Dionisio

Centriole-to-centrosome conversion and centriole disengagement, respectively, license daughter and mother centrioles for duplication [...] but the underlying reason for cartwheel removal is not fully clear. [...] the cartwheel-bound PLK4 directly suppresses centriole reduplication.

Promotion and Suppression of Centriole Duplication Are Catalytically Coupled through PLK4 to Ensure Centriole Homeostasis. Kim M, O'Rourke BP, Soni RK, Jallepalli PV, Hendrickson RC, Tsou MF Cell Rep. 16(5):1195-203. doi: 10.1016/j.celrep.2016.06.069.

Complex complexity. Dionisio

Union of sperm and egg brings together two haploid genomes around which the first bipolar mitotic spindle is assembled. Each zygotic spindle pole contains one centrosome composed of a mother-daughter centriole pair surrounded by the microtubule (MT)-nucleating pericentriolar material (PCM). While both studies uncover aspects of CE that were previously unknown, many questions still remain. The mechanism by which mother centrioles avoid CE also remains unclear. It also remains to be determined what ensures timely Polo downregulation and its removal from the centrioles to initiate CE, as well as which targets of Polo kinase activity in the PCM are responsible for its protective role. [...] it remains to be shown whether PCM-loss is coupled to a specialized “Centriole Destruction” (CD) mechanism that can target centriole components for degradation after PCM is removed [...] More work will be required, but the footing has suddenly become more solid for future excursions into CE.

Taking Centrioles to the Elimination Round. Schoborg TA, Rusan NM Dev Cell. 38(1):10-2. doi: 10.1016/j.devcel.2016.06.027.

Complex complexity. Dionisio

Many aspects of the RC function during meiosis remain to be elucidated. [...] future studies are needed to address the role of SUMO proteases in RC disassembly. A remarkable feature of the RC is that within a 30-min period, it undergoes two cycles of assembly/disassembly linked to two waves of SUMO modification/deconjugation that are regulated with exquisite precision both temporally and spatially. [...] it remains to be shown what signal(s) regulate the balance between E3 and protease activities [...] [...] precise mechanisms that guarantee proper chromosome orientation, congression, and segregation might differ between meiosis and mitosis and also among species [...] [...] highly dynamic, coordinated, and spatially constrained sumoylation regulates chromosome congression during meiosis in C. elegans oocytes.

A SUMO-Dependent Protein Network Regulates Chromosome Congression during Oocyte Meiosis Federico Pelisch, Triin Tammsalu, Bin Wang, Ellis G. Jaffray, Anton Gartner, Ronald T. Hay DOI: http://dx.doi.org/10.1016/j.molcel.2016.11.001 Molecular Cell

Complex complexity. Dionisio

Meiosis is a specialized division in which a single round of DNA replication is followed by two consecutive segregation steps. Homologous chromosomes segregate in Meiosis I, while sister chromatids segregate in Meiosis II, giving rise to haploid gametes (Duro and Marston, 2015). In contrast to mitotic spindles, meiotic spindles in many animal species (including humans and nematodes) lack centrosomes (Dumont and Desai, 2012), and how these spindles are organized is poorly understood (Ohkura, 2015).

A SUMO-Dependent Protein Network Regulates Chromosome Congression during Oocyte Meiosis Federico Pelisch, Triin Tammsalu, Bin Wang, Ellis G. Jaffray, Anton Gartner, Ronald T. Hay DOI: http://dx.doi.org/10.1016/j.molcel.2016.11.001 Molecular Cell

Complex complexity. Dionisio

[...] acetylated segments observed far from MT ends in vivo most likely results from the dynamicity of MTs. [...] in vitro and cellular MTs may differ in their intrinsic properties. [...] the shaft of in vitro reconstituted MTs is permeable to ?TAT1 while the one of cellular MTs is not. [...] in vitro assembled MTs presents holes or defects along their shaft that allow lateral entry of ?TAT1 to the lumen. The nature of such holes and why in vitro MTs would display more holes as compare to cellular MTs is not clear. [...] in vitro reconstituted MTs do not recapitulate the properties of cellular MTs [...] [...] multiple contacts between MTs and these structures would enhance ?TAT1 acquisition by front-oriented MTs leading to the progressive acetylation of this MT subset from their open extremities. This selective, tip-oriented acetylation mechanism has important consequences since cell-front oriented acetylated MTs are instrumental in controlling directional cell migration.

?TAT1 controls longitudinal spreading of acetylation marks from open microtubules extremities. Ly N, Elkhatib N, Bresteau E, Piétrement O, Khaled M, Magiera MM, Janke C, Le Cam E, Rutenberg AD, Montagnac G Sci Rep. 6:35624. doi: 10.1038/srep35624.

Sometimes in-vitro results differ from in-vivo or ex-vivo experiments. Complex complexity. Dionisio

Acetylation of the lysine 40 of ?-tubulin (K40) is a post-translational modification occurring in the lumen of microtubules (MTs) and is controlled by the ?-tubulin acetyl-transferase ?TAT1. How ?TAT1 accesses the lumen and acetylates ?-tubulin there has been an open question. [...] ?TAT1 enters the lumen from open extremities and spreads K40 acetylation marks longitudinally along cellular MTs. This mode of tip-directed microtubule acetylation may allow for selective acetylation of subsets of microtubules.

?TAT1 controls longitudinal spreading of acetylation marks from open microtubules extremities. Ly N, Elkhatib N, Bresteau E, Piétrement O, Khaled M, Magiera MM, Janke C, Le Cam E, Rutenberg AD, Montagnac G Sci Rep. 6:35624. doi: 10.1038/srep35624.

Complex complexity. Dionisio

The regional control of lysosome movement is likely critical for cellular processes that require regulated encounters of lysosomes with other organelles in different parts of the cytoplasm. The relationship of PTMs to kinesin selectivity is likely more complex and dependent on combinations of multiple PTMs, MAPs, and cargos. [...] both kinesins are required to counteract the function of dynein in centripetal transport of lysosomes. Our findings are a striking example of cellular processes that depend on cooperation of multiple kinesins. Other such processes are mitosis and cytokinesis [...] intraflagellar particle transport [...] and hyphal growth in filamentous fungi [...] The results reported in the present study represent yet another mechanism in which two co-regulated kinesin types drive movement of the same cytoplasmic organelle in different regions of the cell.

BORC Functions Upstream of Kinesins 1 and 3 to Coordinate Regional Movement of Lysosomes along Different Microtubule Tracks. Guardia CM1, Farías GG1, Jia R1, Pu J1, Bonifacino JS Cell Rep. 17(8):1950-1961. doi: 10.1016/j.celrep.2016.10.062.

Complex complexity. Dionisio

[...] BORC and Arl8a/b function upstream of the kinesin-1 KIF5B and the kinesin-3 KIF1B? and KIF1A proteins to move lysosomes toward the cell periphery along different microtubule tracks and in different regions of the cell [...] In future studies, it will be of interest to determine whether BORC and Arl8 also regulate these kinesins, and, if so, by what mechanism. We were intrigued by the involvement of different kinesin types in lysosome movement toward the cell periphery. Various kinesins exhibit preferences for microtubule tracks that are characterized by specific tubulin PTMs or associated microtubule-associated proteins (MAPs). [...] the biochemical properties of different microtubule populations underlie the preferential recruitment of different kinesins and, in turn, the regional movement of lysosomes, even in non-polarized cells.

BORC Functions Upstream of Kinesins 1 and 3 to Coordinate Regional Movement of Lysosomes along Different Microtubule Tracks. Guardia CM1, Farías GG1, Jia R1, Pu J1, Bonifacino JS Cell Rep. 17(8):1950-1961. doi: 10.1016/j.celrep.2016.10.062.

How to get the right spatiotemporal combination of microtubules and kinesins properties for the correct regional movement of lysosomes? Complex complexity. Dionisio

Classical electron and light microscopy techniques, recently enhanced by the development of super-resolution microscopy, have produced a detailed view of the spatial organization of cytoplasmic organelles within eukaryotic cells. Live-cell imaging methodologies have further revealed that this organization is highly dynamic [...] Indeed, organelles move around the cytoplasm, change their size and shape, and establish transient contacts with one another, all under precise regulatory controls.

BORC Functions Upstream of Kinesins 1 and 3 to Coordinate Regional Movement of Lysosomes along Different Microtubule Tracks. Guardia CM1, Farías GG1, Jia R1, Pu J1, Bonifacino JS Cell Rep. 17(8):1950-1961. doi: 10.1016/j.celrep.2016.10.062.

Complex complexity. Dionisio

The multiple functions of lysosomes are critically dependent on their ability to undergo bidirectional movement along microtubules between the center and the periphery of the cell. Centrifugal and centripetal movement of lysosomes is mediated by kinesin and dynein motors, respectively. Common regulation by BORC enables coordinate control of lysosome movement in different regions of the cell.

BORC Functions Upstream of Kinesins 1 and 3 to Coordinate Regional Movement of Lysosomes along Different Microtubule Tracks. Guardia CM1, Farías GG1, Jia R1, Pu J1, Bonifacino JS Cell Rep. 17(8):1950-1961. doi: 10.1016/j.celrep.2016.10.062.

Complex complexity. Dionisio

The question of how katanin senses lumenal acetylation of MTs remains to be answered. [...] the role of acetylation on motor function [remains] unresolved. [...] physiological roles of ?-tubulin acetylation remain enigmatic. Combining these reagents with the TG2 knockout mouse [...] will further our understanding of tubulin polyamination. Tubulin O-linked glycosylation appears heterogeneous and cell specific, but our knowledge regarding its cellular functions is limited. Low levels of tubulin in membrane fractions are consistently observed [...], but poorly understood. [...] it is not known whether this plays a role in the action of vinblastine on MT polymerization. [...] these modifications play a role in the degradation of tubulin, but may have additional effects that are less well understood. Relating specific tubulin modifications to specific cellular functions remains a major challenge. [...] common themes are emerging and questions continue to arise (Outstanding questions box).

Posttranslational Modifications of Tubulin: Pathways to Functional Diversity of Microtubules Yuyu Song1 and Scott T. Brady Trends Cell Biol. 25(3): 125–136. doi: 10.1016/j.tcb.2014.10.004

Complex complexity. Dionisio

Tubulin PTMs are found in all cells with MTs [...] and they are particularly diverse in neurons [...], but many questions remain, such as the fraction of tubulins with a given modification, the distribution of modifications along a MT or between MTs, and the functional consequences of many modifications. Although ?2-tubulin may represent ?35% of tubulin in the brain [...], the functional role of ?2-MTs remains poorly understood. Additional acetylation sites on tubulin have also been identified in proteomic screens [...] and in studies of other acetyltransferases [...]. The prevalence and function of these sites are not well understood, but may affect MT polymerization [...]

Posttranslational Modifications of Tubulin: Pathways to Functional Diversity of Microtubules Yuyu Song1 and Scott T. Brady Trends Cell Biol. 25(3): 125–136. doi: 10.1016/j.tcb.2014.10.004

Complex complexity. Dionisio

Tubulin and microtubules are subject to a remarkable number of posttranslational modifications. Understanding the roles these modifications play in determining functions and properties of microtubules has presented a major challenge that is only now being met. Many of these modifications are found concurrently, leading to considerable diversity in cellular microtubules, which varies with development, differentiation, cell compartment and cell cycle. We now know that posttranslational modifications of tubulin affect not only the dynamics of the microtubules, but also their organization and interaction with other cellular components. Many early suggestions of how posttranslational modifications affect microtubules have been replaced with new ideas and even new modifications as our understanding of cellular microtubule diversity comes into focus.

Posttranslational Modifications of Tubulin: Pathways to Functional Diversity of Microtubules Yuyu Song1 and Scott T. Brady Trends Cell Biol. 25(3): 125–136. doi: 10.1016/j.tcb.2014.10.004

Many early suggestions [...] have been replaced with new ideas ? Seen that before, haven't we? :) What else is new? Complex complexity. Dionisio

DNA damage acquired during meiosis can lead to infertility and miscarriage. Hence, it should be important for an oocyte to be able to detect and respond to such events in order to make a healthy egg. The Spindle Assembly Checkpoint, which is a well-known mitotic pathway employed by somatic cells to monitor chromosome attachment to spindle microtubules, appears to be utilised by oocytes also to respond to DNA damage. [...] maturing oocytes are arrested at metaphase I due to an active Spindle Assembly Checkpoint. This is surprising given this checkpoint has been previously studied in oocytes and considered to be weak and ineffectual because of its poor ability to be activated in response to microtubule attachment errors. Therefore, the involvement of the Spindle Assembly Checkpoint in DNA damage responses of mature oocytes during meiosis I uncovers a novel second function for this ubiquitous cellular checkpoint.

DNA damage responses in mammalian oocytes. Collins JK, Jones KT Reproduction. 152(1):R15-22. doi: 10.1530/REP-16-0069. http://www.reproduction-online.org/content/152/1/R15

Had we remained in Eden none of this would have been an issue. Dionisio

[...] oocytes respond to DNA damage by arresting in meiosis I through activity of the Spindle Assembly Checkpoint (SAC) and DNA Damage Response (DDR) pathways. It is currently not known if DNA damage is the primary trigger for arrest, or if the pathway is sensitive to levels of DNA damage experienced physiologically. This study establishes a clinical relevance to the DDR induced SAC in oocytes. It helps explain how oocytes respond to a highly prevalent human disease and the reduced fertility associated with endometriosis. In the human ovary, oocytes would be exposed to follicular fluid at higher concentrations and for longer periods of time. Therefore the pathway is likely highly sensitive to diseases such as endometriosis, and possibly others that could elevate ROS. Encouragingly, although the pathway is sensitive it can also be reversed in-vitro by anti-oxidant treatment. Reducing oxidative stress in the oocyte may therefore be of clinical importance when treating sub-fertility in endometriosis either in-vivo or in-vitro.

The sensitivity of the DNA damage checkpoint prevents oocyte maturation in endometriosis Mukhri Hamdan,1,2 Keith T. Jones,3 Ying Cheong,1 and Simon I. R. Lanea Sci Rep. 6: 36994. doi: 10.1038/srep36994 http://www.nature.com/articles/srep36994

Had we remained in Eden none of this would have been an issue. Dionisio

Flavonoids are a large and diverse group of plant secondary metabolites that are mainly present as glycosides. They are often accumulated in response to abiotic stresses such as UV radiation, drought, cold and freezing. The most extensively studied function of flavonoids is their antioxidant activity although their importance as antioxidants in plants has been questioned. Changes in the vibration bands attributed to the phenolic ring structures of the flavonols in the presence of liposomes provided further evidence of interactions of these molecules in particular with the interfacial region of the bilayers.

Effects of flavonol glycosides on liposome stability during freezing and drying Antoaneta V. Popova, Dirk K. Hincha Biochimica et Biophysica Acta (BBA) - Biomembranes Volume 1858, Issue 12, Pages 3050–3060 DOI: http://dx.doi.org/10.1016/j.bbamem.2016.09.020

Complex complexity Dionisio

More direct experimental evidence could be gained only by manipulating each of the two pathways at different times as the cell enters mitosis and forms the bipolar spindle. Unfortunately, this is currently technically not possible. [...] it will be of interest to investigate further the onset timing of the augmin pathway and its effects on spindle assembly. The importance for cell division of the sequential activation of the centrosomal and chromosome-dependent MT assembly pathways may be a general principle in most somatic animal cells [...] Bipolar spindle assembly and correct kinetochore–MT attachment are both critical events for faithful mitosis and may be interconnected. [...] we cannot rule out that other factors may also be limiting for spindle assembly. [...] optimal equilibrium between the level and the timing of centrosome maturation [...] the chromatin MT assembly pathway activity, and the timing of NEBD may be adapted to determine specific spindle assembly dynamics in every cell type [...] [...] a novel important mechanism determines the correct balance between the mitotic MT assembly pathways, ensuring correct bipolar spindle formation and cell division fidelity. This mechanism relies on the sequential activation of the MT assembly pathways defined by centrosome maturation and NEBD.

The sequential activation of the mitotic microtubule assembly pathways favors bipolar spindle formation. Cavazza T, Malgaretti P, Vernos I Mol Biol Cell. 27(19):2935-45. doi: 10.1091/mbc.E16-05-0322

Complex complexity Dionisio

In most animal cells, the mitotic spindle assembles in the presence of two centrosomes. Before mitosis, during G2, a complex network of kinases and feedback loops drives centrosome maturation [...] This process promotes the recruitment of various proteins around the centrosome, increasing the amount of pericentriolar material (PCM) and centrosome microtubule (MT) nucleation activity [...] [...] in most animal cells, centrosome maturation defines the level of activity of the chromosome-dependent MT assembly pathway, thus establishing a balance that favors spindle bipolarity.

The sequential activation of the mitotic microtubule assembly pathways favors bipolar spindle formation. Cavazza T, Malgaretti P, Vernos I Mol Biol Cell. 27(19):2935-45. doi: 10.1091/mbc.E16-05-0322

Complex complexity Dionisio

Centrosome maturation is the process by which the duplicated centrosomes recruit pericentriolar components and increase their microtubule nucleation activity before mitosis. The role of this process in cells entering mitosis has been mostly related to the separation of the duplicated centrosomes and thereby to the assembly of a bipolar spindle. However, spindles can form without centrosomes. In fact, all cells, whether they have centrosomes or not, rely on chromatin-driven microtubule assembly to form a spindle. Our data suggest a novel function for centrosome maturation that determines the contribution of the chromosomal microtubule assembly pathway and favors bipolar spindle formation in most animal cells in which tubulin is in limiting amounts.

The sequential activation of the mitotic microtubule assembly pathways favors bipolar spindle formation. Cavazza T, Malgaretti P, Vernos I Mol Biol Cell. 27(19):2935-45. doi: 10.1091/mbc.E16-05-0322

Complex complexity Dionisio

Polarized epithelial cells exhibit a characteristic array of microtubules that are oriented along the apicobasal axis of the cells. The minus-ends of these microtubules face apically, and the plus-ends face toward the basal side. The mechanisms underlying this epithelial-specific microtubule assembly remain unresolved [...] [...] apically localized CAMSAP3 determines the proper orientation of microtubules, and in turn that of organelles, in mature mammalian epithelial cells.

CAMSAP3 orients the apical-to-basal polarity of microtubule arrays in epithelial cells. Toya M1, Kobayashi S1, Kawasaki M1, Shioi G2, Kaneko M3, Ishiuchi T1, Misaki K4, Meng W1, Takeichi M Proc Natl Acad Sci U S A. 113(2):332-7. doi: 10.1073/pnas.1520638113.

Complex complexity. Dionisio

Polarization is essential for epithelial cells to exert a variety of functions. Epithelial polarization includes characteristic microtubule array formation. The microtubules are oriented along the apicobasal axis with their minus ends facing apically. The molecules that regulate such epithelial-specific microtubule assembly remain unknown [...] Our findings facilitate our understanding of how epithelial cells acquire polarized structures, which are crucial for their physiological functions.

CAMSAP3 orients the apical-to-basal polarity of microtubule arrays in epithelial cells. Toya M1, Kobayashi S1, Kawasaki M1, Shioi G2, Kaneko M3, Ishiuchi T1, Misaki K4, Meng W1, Takeichi M Proc Natl Acad Sci U S A. 113(2):332-7. doi: 10.1073/pnas.1520638113.

Complex complexity. Dionisio

Cadherin-related 23 (CDH23) is an adhesive protein important for hearing and vision, while CAMSAP3/Marshalin is a microtubule (MT) minus-end binding protein that regulates MT networks. [...] CDH23-C is a CAMSAP3/Marshalin-binding protein that can modify MT networks indirectly through its interaction with CAMSAP3/Marshalin. CDH23 is an essential protein for auditory and visual signal transduction and is important for cell adhesion. Function of the cytoplasmic isoforms, however, is not fully understood [...] [...] onal studies are required to further define CDH23-C’s roles in various physiological contexts that may ultimately impact our understanding of the fundamental mechanisms associated with hearing and vision.

Cadherin 23-C Regulates Microtubule Networks by Modifying CAMSAP3's Function. Takahashi S, Mui VJ, Rosenberg SK, Homma K, Cheatham MA, Zheng J Sci Rep. 6: 28706. doi: 10.1038/srep28706

Complex complexity. Dionisio

Efficient use of seed nutrient reserves is crucial for germination and establishment of plant seedlings. Organogenesis in multicellular organ(ism)s involves a coordinated interplay of cell proliferation and differentiation. Control of size is a longstanding issue in developmental biology. [...] our understanding of compensation is limited to the triggering factors, but the link(s) between cell proliferation defects and enhanced post-mitotic cell expansion remain to be elucidated. Although our working model is reasonable, it has to be addressed experimentally in the future for its validation. Compensation is a heterogeneous phenomenon with different inputs and outputs that differ in each individual mutant that displays CCE [...] CCE suppressor screens for each individual mutant background must be conducted to elucidate the molecular mechanism(s) in such mutants.

Suppressor Screen and Phenotype Analyses Revealed an Emerging Role of the Monofunctional Peroxisomal Enoyl-CoA Hydratase 2 in Compensated Cell Enlargement Mana Katano,1,† Kazuki Takahashi,1,† Tomonari Hirano,2 Yusuke Kazama,3 Tomoko Abe,3 Hirokazu Tsukaya,4,5 and Ali Ferjani Front Plant Sci. 7: 132. doi: 10.3389/fpls.2016.00132

Work in progress… stay tuned. Complex complexity. Dionisio

The mechanism through which overexpression of LGO regulates gene activity requires further investigation [...] [...] endoreduplication alone is not a sufficient mechanism to explain all of the gene expression in LGOoe sepals, although it may explain some transcriptomic effects. Further investigation of possible transcriptional complexes upon which LGO might act directly remains for future research. Transcriptional responses to the environment can be highly cell-type specific [...]

Transcriptomic Effects of the Cell Cycle Regulator LGO in Arabidopsis Sepals Erich M. Schwarz and Adrienne H. K. Roeder Sepals. Front. Plant Sci. 7:1744. doi: 10.3389/fpls.2016.01744

Complex complexity. Dionisio

Little is known about how CKK domain activity is regulated [...] In conclusion, we have revealed an unexpected regulatory interaction between DAPK-1 kinase and the MT cytoskeleton in epidermal development and wound responses. Many questions remain to be explored, especially whether PTRN-1 or other MT-associated proteins are direct substrates of DAPK-1. More broadly, the mechanisms and roles of intracellular transport within the epidermis could be a model for intracellular transport in other syncytial tissues.

DAPK interacts with Patronin and the microtubule cytoskeleton in epidermal development and wound repair Marian Chuang, Tiffany I Hsiao, Amy Tong, Suhong Xu,† and Andrew D Chisholm eLife. 5: e15833. doi: 10.7554/eLife.15833

Complex complexity. Dionisio

[...] a reductionist approach by studying single factors in isolation seems insufficient to explain MT behaviours in cellular environments.

A conceptual view at microtubule plus end dynamics in neuronal axons André Voelzmann,a Ines Hahn,a Simon P. Pearce,a,b Natalia Sánchez-Soriano,c and Andreas Prokop Brain Res Bull. 126: 226–237. doi: 10.1016/j.brainresbull.2016.08.006

Complex complexity. Dionisio

Future work is needed to understand how particles containing bicoid mRNA are tethered at the front end of the egg cell and whether other mRNAs are also packaged in a similar manner. In future, it will be interesting to determine whether other localised RNAs are packaged into similar structures.

bicoid mRNA localises to the Drosophila oocyte anterior by random Dynein-mediated transport and anchoring Vítor Trovisco,1,2 Katsiaryna Belaya,1,2† Dmitry Nashchekin,1,2 Uwe Irion,1,2‡ George Sirinakis,1,2 Richard Butler,1 Jack J Lee,3 Elizabeth R Gavis,3 and Daniel St Johnston eLife. 5: e17537. doi: 10.7554/eLife.17537

Complex complexity. Dionisio

It will therefore be interesting to investigate whether the different modes of MT binding by Shot are mutually exclusive and how this is regulated. The combination of Patronin binding to the MT minus ends and Shot binding to the MT lattice may therefore provide a robust anchor to retain MTs at the apical cortex.

Patronin/Shot Cortical Foci Assemble the Noncentrosomal Microtubule Array that Specifies the Drosophila Anterior-Posterior Axis. Nashchekin D, Fernandes AR, St Johnston D Dev Cell. 38(1):61-72. doi: 10.1016/j.devcel.2016.06.010.

Complex complexity. Dionisio

[...] there are a number of studies focused on understanding the required molecular events. Surprisingly, this fascinating genus has been little studied to date. An area of great promise for future research in Naegleria is how the majority of differentiating Naegleria cells assemble exactly two basal bodies and two flagella. Why heat-shock temporarily alters flagellar number, as well as the nature of the normal control mechanism, remain interesting challenges for future investigation. [..] resolving the issues caused by heterologous antibodies as well as more precise colocalization studies are essential to understanding their results. We hope these issues can be resolved in the near future. While NaegleriaPlk1 might play the role of Plk4 in the amoeboflagellate, any role of polo-like kinases in this system remains a challenge for future research, particularly given the current lack of tools for gene manipulation in Naegleria cells. All that is needed is that researchers meet the challenge of learning to apply molecular genetics to this fascinating system.

Naegleria: a classic model for de novo basal body assembly Lillian K. Fritz-Laylin and Chandler Fulton Cilia. 5: 10. doi: 10.1186/s13630-016-0032-6

Work in progress… stay tuned. Complex complexity. Dionisio

The next challenge consists of studying the effect of more than one MAP on the generation of complexity as it occurs in the spindle. Ultimately, it will be necessary to explain how MTs and MAPs, which act at the nanometer scale, build the mitotic spindle, which is a factor of 1,000 larger, in a robust manner. Ever since the first descriptions of cell division 130 years ago, the means by which the mitotic spindle orchestrates cell division has been a mystery. Grasping how hundreds of proteins can self-assemble into the mitotic spindle and segregate chromosomes at biochemical and structural levels is a challenge that may be finally within reach during this century.

Mechanisms of Mitotic Spindle Assembly. Petry S Annu Rev Biochem. 85:659-83. doi: 10.1146/annurev-biochem-060815-014528

Work in progress... stay tuned. Complex complexity. Dionisio

It remains to be demonstrated whether the negative regulation of MT depolymerases is the only mechanism by which the CPC operates. [...] the exact role of MT nucleation from KTs remains to be determined. [...] it is not clear if both the Ran and CPC pathways are activated at the same time, and whether there is a time difference between MT generation from chromosome arms and centromeres/KTs. In the future, quantitative and mechanistic studies of each individual MT nucleation pathway should be performed to determine how MTs are assembled and organized to form the spindle. Although it is difficult enough to resolve individual MTs of any kind, it would be ideal if MT populations from different MTOCs could be separately detected. Independent of this challenge, it is necessary to understand how MTs of two or more MTOCs interdigitate toward creating the metaphase spindle.

Mechanisms of Mitotic Spindle Assembly. Petry S Annu Rev Biochem. 85:659-83. doi: 10.1146/annurev-biochem-060815-014528

Complex complexity. Dionisio

[...] information about the function, activity, and location of spindle MAPs needs to be combined with the directly measured parameters of MT organization to derive a complete molecular model of the metaphase spindle. [...] how this secondary phosphorylation gradient contributes to spindle assembly remains poorly understood. [...] the exact mechanism by which this RanGTP-mediated regulation occurs remains to be determined. It is currently unclear whether these SAFs all act in separate or in common MT nucleation pathways and how exactly they contribute to MT formation and organization toward subsequent spindle assembly. How these factors work together to induce this reaction and what the branch point looks like remain to be resolved.

Mechanisms of Mitotic Spindle Assembly. Petry S Annu Rev Biochem. 85:659-83. doi: 10.1146/annurev-biochem-060815-014528

Complex complexity. Dionisio

How MTs achieve reliable chromosome segregation has been a mystery ever since it was clear that MTs constitute the mitotic spindle. How MTs can be organized into the spindle shape, display these dynamics, and effectively segregate chromosomes has remained mysterious. But how could a spindle be formed if its core constituents are intrinsically unstable? [...] an accurate description of the molecular building plan will require new methods to directly measure parameters that are key to explaining various features of MT organization [...] The precise organization of MTs during spindle assembly remains to be determined [...] The specific factors in these organisms that influence spindle shape, however, still need to be established.

Mechanisms of Mitotic Spindle Assembly. Petry S Annu Rev Biochem. 85:659-83. doi: 10.1146/annurev-biochem-060815-014528

Complex complexity. Dionisio

The MT lattice can also be allosterically regulated by MAPs, which do not directly contact each other, adding a new layer of complexity to the modes of how MAPs can modulate MT dynamics [...] [...] future studies need to take these functional assemblies into account. [...] the next major challenge is to understand how these MAPs work together with MTs at the nanometer scale to assemble the mitotic spindle, which is a factor of 1,000 larger than its constituents, and to orchestrate chromosome segregation, as discussed in the next section.

Mechanisms of Mitotic Spindle Assembly. Petry S Annu Rev Biochem. 85:659-83. doi: 10.1146/annurev-biochem-060815-014528

Complex complexity. Dionisio

As of now, information about a particular spindle MAP still has to be looked up in each separately published database. Hence, a necessary future step to maximize the impact of these valuable studies is their integration into a unified spindle genome and proteome database. It remains to be determined which effectors induce this conformational change, whether ring closure is the only mode of catalysis, and whether this also applies to the larger ?-TuRC. [...] how tubulin dimers are assembled into a tubule from the ?-TuRC base is still unknown [...] [...] it is unclear whether MT minus-end proteins other than ?-TuRC also harbor MT nucleation activity [...]

Mechanisms of Mitotic Spindle Assembly. Petry S Annu Rev Biochem. 85:659-83. doi: 10.1146/annurev-biochem-060815-014528

Complex complexity. Dionisio

Life depends on cell proliferation. This occurs via cell division, during which a single cell generates two daughters, each of which retains the same genetic blueprint packaged into chromosomes via reliable chromosome segregation. [...] several aspects make the mitotic spindle one of the most challenging systems to grasp at quantitative and molecular levels. [...] understanding the exact mechanisms of spindle assembly and chromosome segregation has been complicated by our inability to accurately determine the location of its macromolecular components in space and time. [...] advanced methods for probing MT organization in the metaphase spindle have yet to be applied to determine the molecular mechanisms by which chromosomes are captured, aligned, and reliably segregated during cell division.

Mechanisms of Mitotic Spindle Assembly. Petry S Annu Rev Biochem. 85:659-83. doi: 10.1146/annurev-biochem-060815-014528

Complex complexity. Dionisio

Life depends on cell proliferation and the accurate segregation of chromosomes, which are mediated by the microtubule (MT)-based mitotic spindle and ~200 essential MT-associated proteins. Yet, a mechanistic understanding of how the mitotic spindle is assembled and achieves chromosome segregation is still missing. [...] mechanistic details about MT nucleation pathways and their coordination are starting to be revealed. [...] advances in studying spindle assembly can be applied to address the molecular mechanisms of how the spindle segregates chromosomes.

Mechanisms of Mitotic Spindle Assembly. Petry S Annu Rev Biochem. 85:659-83. doi: 10.1146/annurev-biochem-060815-014528

Complex complexity. Dionisio

[...] KLP-18 and MESP-1 are required to provide an outward force to sort microtubule minus ends away from the chromosomes, enabling bipolar spindle formation. Future work determining the mechanisms by which KLP-18 and MESP-1 act to organize microtubules and generate bipolarity will shed light on this important but poorly understood specialized cell division, as well as on overall kinesin-12 function during cell division.

Assembly of Caenorhabditis elegans acentrosomal spindles occurs without evident microtubule-organizing centers and requires microtubule sorting by KLP-18/kinesin-12 and MESP-1. Wolff ID Tran MV, Mullen TJ, Villeneuve AM, Wignall SM Mol Biol Cell. 27(20):3122-3131. DOI: 10.1091/mbc.E16-05-0291

Complex complexity. Dionisio

Although centrosomes contribute to spindle formation in most cell types, oocytes of many species are acentrosomal and must organize spindles in their absence. [...] KLP-18/kinesin-12 and MESP-1 form a complex that functions to sort microtubules of mixed polarity into a configuration in which minus ends are away from the chromosomes, enabling formation of nascent poles. [...] spindle assembly proceeds through 1) formation of a disordered array of microtubules within the remnants of the nuclear envelope, 2) sorting of microtubule minus ends away from the chromosomes to the periphery of the array, 3) organization of these ends into nascent poles, and 4) progressive coalescence of these poles until bipolarity is achieved.

Assembly of Caenorhabditis elegans acentrosomal spindles occurs without evident microtubule-organizing centers and requires microtubule sorting by KLP-18/kinesin-12 and MESP-1. Wolff ID Tran MV, Mullen TJ, Villeneuve AM, Wignall SM Mol Biol Cell. 27(20):3122-3131. DOI: 10.1091/mbc.E16-05-0291

Evident algorithmic process. Complex complexity. Dionisio

More extensive genetic studies that simultaneously reduce the function of different combinations of these alternative pathways may clarify how they are integrated to execute meiotic cell division. [...] a thorough understanding of the pleiotropic functions of these proteins will likely require techniques that selectively inactivate individual proteins in specific subcellular regions at specific times. Given recent advances in optogenetics, such approaches may soon become possible. [...] the molecular pathways that mediate meiotic spindle assembly appear to be numerous and diverse. To advance our understanding, more systematic genetic analyses are needed. The challenges to achieving a conclusive mechanistic understanding of meiotic spindle assembly and function in any one system extend well beyond a need for further genetic studies. The pace of progress in this field has picked up considerably in the past five years, and recent advances in genetics and microscopy make rapid and significant further progress imminent.

Oocyte Meiotic Spindle Assembly and Function. Severson AF, von Dassow G, Bowerman B Curr Top Dev Biol. 116:65-98. doi: 10.1016/bs.ctdb.2015.11.031.

Work in progress... stay tuned. Complex complexity. Dionisio

It will be interesting to test whether MCAK-mediated removal of improper microtubule–kinetochore attachments is important for oocyte spindle pole coalescence in other organisms. Whether the apparent lack of a substantial role for kinetochores during anaphase in C. elegans oocytes is relevant to other species is not known. Systematic investigations of how microtubule–kinetochore attachments, and kinetochore function more generally, influence spindle assembly and chromosome movement are needed to fully assess and compare the role of these structures during oocyte meiotic cell division in different animal species.

Oocyte Meiotic Spindle Assembly and Function. Severson AF, von Dassow G, Bowerman B Curr Top Dev Biol. 116:65-98. doi: 10.1016/bs.ctdb.2015.11.031.

Complex complexity. Dionisio

The absence of centrosomes and their impressive microtubule organizing activity leaves a mechanistic void in our understanding of how oocyte spindles achieve the bipolar structure required to segregate chromosomes in opposite directions. How the multiple, dispersed MTOCs coalesce to form two poles remains unknown. [...] how ZYG-9 influences oocyte spindle assembly is not well understood and the role of TAC-1 has not been addressed. [...] systematic comparisons of the different gene requirements in each model system are needed to better assess the conservation, and divergence of oocyte spindle assembly mechanisms. [...] the mechanism of MTOC coalescence remains unknown. [...] the importance of microtubule–kinetochore attachment for oocyte spindle assembly in other species remains largely unknown [...]

Oocyte Meiotic Spindle Assembly and Function. Severson AF, von Dassow G, Bowerman B Curr Top Dev Biol. 116:65-98. doi: 10.1016/bs.ctdb.2015.11.031.

Complex complexity. Dionisio

The role of ?-tubulin during oocyte spindle assembly clearly warrants further investigation. Whether these other processes contribute to oocyte meiotic spindle assembly remains poorly understood. [...] it seems likely that multiple pathways contribute to microtubule nucleation and organization during oocyte meiosis, although the relative importance of each pathway may vary from organism to organism. While a gradient of active Ran GTPase can stimulate microtubule assembly around chromosomes, where and how nucleation occurs is not clear. [...] how microtubules are nucleated at more distant sites and are then transported toward the spindle remain poorly understood and are ripe topics for further investigation.

Oocyte Meiotic Spindle Assembly and Function. Severson AF, von Dassow G, Bowerman B Curr Top Dev Biol. 116:65-98. doi: 10.1016/bs.ctdb.2015.11.031.

Complex complexity. Dionisio

[...] mitotic and oocyte meiotic spindles have remarkably distinct structures and dynamics. Why oocyte meiotic spindles should be composed of short, discontinuous microtubules is not known [...] [...] understanding the origin of oocyte meiotic spindle microtubules is of fundamental importance. [...] it remains unclear whether the CPC pathway requires ?-tubulin [...]

Oocyte Meiotic Spindle Assembly and Function. Severson AF, von Dassow G, Bowerman B Curr Top Dev Biol. 116:65-98. doi: 10.1016/bs.ctdb.2015.11.031.

Complex complexity. Dionisio

[...] the zygote inherits one maternal centrosome with a single, unduplicated centriole and one paternal centrosome with a duplicated centriole. While the fate of the remaining oocyte centrosome is unknown, subsequent mitotic divisions use the sperm-derived centrioles [...]

Oocyte Meiotic Spindle Assembly and Function. Severson AF, von Dassow G, Bowerman B Curr Top Dev Biol. 116:65-98. doi: 10.1016/bs.ctdb.2015.11.031.

Complex complexity. Dionisio

A nearly universal feature of animal life is the fusion of two haploid gametes to create a diploid zygote. Most animal cells except gametes have two closely related but genetically distinct copies of each chromosome, called homologous chromosome pairs, one inherited from each parent. The fundamental achievement of gametogenesis is to reduce the diploid genome of germline precursors to a haploid state through two specialized cell divisions, called meiosis I and II [...] When two gamete genomes unite after the fertilization of an egg by a sperm, diploidy is restored and life begins anew.

Oocyte Meiotic Spindle Assembly and Function. Severson AF, von Dassow G, Bowerman B Curr Top Dev Biol. 116:65-98. doi: 10.1016/bs.ctdb.2015.11.031.

life begins anew? Did somebody say "life begins"? Did they mean it does at fertilization? Are they serious? Did I get this right? Complex complexity. Dionisio

Gametogenesis in animal oocytes reduces the diploid genome content of germline precursors to a haploid state in gametes by discarding ¾ of the duplicated chromosomes through a sequence of two meiotic cell divisions called meiosis I and II. The assembly of the microtubule-based spindle structure that mediates this reduction in genome content remains poorly understood [...]

Oocyte Meiotic Spindle Assembly and Function. Severson AF, von Dassow G, Bowerman B Curr Top Dev Biol. 116:65-98. doi: 10.1016/bs.ctdb.2015.11.031.

Complex complexity. Dionisio

The centrosome, an organelle discovered >100 years ago, is the main microtubule-organizing center in mammalian organisms. The centrosome is composed of a pair of centrioles surrounded by the pericentriolar material (PMC) and plays a major role in the regulation of cell cycle transitions (G1-S, G2-M, and metaphase-anaphase), ensuring the normality of cell division. Hundreds of proteins found in the centrosome exert a variety of roles, including microtubule dynamics, nucleation, and kinetochore-microtubule attachments that allow correct chromosome alignment and segregation. The many associated proteins found in the centrosome orchestrate the control of microtubule nucleation and organization for the proper progression of cell cycle.

Centrosome - a promising anti-cancer target. Rivera-Rivera Y, Saavedra HI Biologics. 10:167-176. doi: 10.2147/BTT.S87396.

orchestrate the control? Did somebody say "orchestrate"? Did somebody say "control"? :) Complex complexity. Dionisio

[...] the RDNF circuit might have a crucial role in early differentiation during development since the double-negative feedback loop may interpret information regarding the temporal dynamics of morphogen fluctuation to elaborately decide the cell fate [...] [...] the double-negative feedback mechanism can be obtained in different ways in different biological contexts, and it can provide a general mechanism for controlling the cell-fate decision. [...] the cell can respond differently according to the temporal pattern of stimulation even though the final concentrations are unchanged, which suggests that the delivery mode is important in determining the effect of the molecules.

A Regulated Double-Negative Feedback Decodes the Temporal Gradient of Input Stimulation in a Cell Signaling Network Sang-Min Park, Sung-Young Shin and Kwang-Hyun Cho PLoS One. 11(9): e0162153. doi: 10.1371/journal.pone.0162153

Complex complexity. Dionisio

[...] the mutual inhibitory genetic network having a single input can convert a graded signal into an on/off binary output [...] [...] an interlinked multiple negative feedback mechanism is capable of pre-steady-state decoding a spatial gradient signal to expression of different target genes [...] [...] the double-negative feedback network that was derived from the EPNF can interpret the rate change of an input signal to different response profiles of target proteins before the signal converge to a steady state.

A Regulated Double-Negative Feedback Decodes the Temporal Gradient of Input Stimulation in a Cell Signaling Network Sang-Min Park, Sung-Young Shin and Kwang-Hyun Cho PLoS One. 11(9): e0162153. doi: 10.1371/journal.pone.0162153

Complex complexity. Dionisio

[...] the regulated double-negative feedback (RDNF) circuit performs the function of temporal gradient-sensitive switching. [...] this regulated double-negative feedback is a hidden design principle enabling cells to decode the information that is encoded in the temporal gradient of an input signal.

A Regulated Double-Negative Feedback Decodes the Temporal Gradient of Input Stimulation in a Cell Signaling Network Sang-Min Park, Sung-Young Shin and Kwang-Hyun Cho PLoS One. 11(9): e0162153. doi: 10.1371/journal.pone.0162153

hidden design principle? Did somebody say "design"? :) Complex complexity. Dionisio

How the signaling network encodes and decodes the biological information and what mechanism underlies this process have been a fundamental question in biology [...] our findings bring a new insight into how cells interpret the time-varying cellular environment which they might continuously encounter. Decoding the temporal gradient of input stimulation provides cells with additional useful information about the environment. [...] cells can detect a rapid increase of a toxic molecule’s concentration and cope with it by activating a protection pathway in advance. [...] cells can respond appropriately to a constitutive or regulated secretory mode of molecules by decoding the temporal gradient [...] For a further study, it would be interesting to investigate the possibility of the temporal gradient decoding mechanism with respect to cellular recognition of the frequency of an oscillating signal.

A Regulated Double-Negative Feedback Decodes the Temporal Gradient of Input Stimulation in a Cell Signaling Network Sang-Min Park, Sung-Young Shin and Kwang-Hyun Cho PLoS One. 11(9): e0162153. doi: 10.1371/journal.pone.0162153

Complex complexity. Dionisio

Revealing the hidden mechanism of how cells sense and react to environmental signals has been a central question in cell biology. Our analysis highlights the essential structure and mechanism enabling cells to properly respond to dynamic environmental changes. For survival, cells should continuously sense and process signals to make an appropriate decision under dynamically fluctuating cellular environments [...]. They encode biological information on the identity and quantity of a stimulus in different forms of patterns, for instance, amplitude, frequency, and duration of a stimulus [...]. Such information is decoded and interpreted by specific signaling networks (or circuits) to generate a specific cellular response [...].

A Regulated Double-Negative Feedback Decodes the Temporal Gradient of Input Stimulation in a Cell Signaling Network Sang-Min Park, Sung-Young Shin and Kwang-Hyun Cho PLoS One. 11(9): e0162153. doi: 10.1371/journal.pone.0162153

Complex complexity. Dionisio

Oocytes accumulate maternal stores (proteins, mRNAs, metabolites, etc.) during their growth in the ovary to support development after fertilization. To preserve this cytoplasmic maternal inheritance, they accomplish the difficult task of partitioning their cytoplasm unequally while dividing their chromosomes equally. Added to this complexity, most oocytes, for reasons still speculative, lack the major microtubule organizing centers that most cells use to assemble and position their spindles, namely canonical centrosomes. The challenge of oocyte divisions appears indeed not trivial because in both mice and humans oocyte meiotic divisions are prone to chromosome segregation errors, a leading cause of frequent miscarriages and congenital defects. It might be so that the critical concentration for tubulin to polymerize might be much more difficult to reach than in somatic cells when the nucleus breaks down, reinforcing the importance of pathways acting as catalyzers/amplifiers of tubulin polymerization locally around chromosomes. How these pathways, and yet-to-be-discovered ones, interact to promote early stages of spindle assembly has not been thoroughly addressed and remains an important question for future studies.

Meiotic spindle assembly and chromosome segregation in oocytes. Bennabi I, Terret ME, Verlhac MH Cell Biol. 215(5):611-619. DOI: 10.1083/jcb.201607062

Had we stayed in Eden none of this would have been an issue. Too late now. The whole system is messed up badly. Complex complexity. Dionisio

Although centriole elimination has been studied in many species, the underlying mechanisms are far from being understood. [...] centriole elimination from the oocyte is essential for sexual reproduction of animal species, but the underlying mechanisms are very poorly understood. It will be interesting in the future to test a possible conservation of molecular mechanisms between these processes. [...] mother and daughter centrioles rely on distinct mechanisms for elimination.

Distinct mechanisms eliminate mother and daughter centrioles in meiosis of starfish oocytes. Borrego-Pinto J, Somogyi K, Karreman MA, König J, Müller-Reichert T, Bettencourt-Dias M, Gönczy P, Schwab Y, Lénárt J Cell Biol. 212(7):815-27. doi: 10.1083/jcb.201510083.

Complex complexity. Dionisio

Centriole elimination is an essential process that occurs in female meiosis of metazoa to reset centriole number in the zygote at fertilization. How centrioles are eliminated remains poorly understood. [...] mothers are physically removed, whereas daughters are eliminated in the cytoplasm, preparing the egg for fertilization.

Distinct mechanisms eliminate mother and daughter centrioles in meiosis of starfish oocytes. Borrego-Pinto J, Somogyi K, Karreman MA, König J, Müller-Reichert T, Bettencourt-Dias M, Gönczy P, Schwab Y, Lénárt J Cell Biol. 212(7):815-27. doi: 10.1083/jcb.201510083.

Complex complexity. Dionisio

[...] what underlies the asymmetry in behavior between the mother and daughter centrioles at anaphase I remains to be discovered. The origin of the difference in behavior between mother and daughter centrioles after anaphase II will require further investigation. To explain the loss in nucleation capacity of the daughter centriole, it will be important to check for the presence of various PCM components. It will be interesting to determine whether starfish zygotes express proteins such as HURP or HSET, which are major players in extra-centrosome clustering [...] [...] maternal centrioles must be extruded from or inactivated in the starfish egg before fertilization so that they do not perturb mitotic spindle assembly.

Mother centrioles are kicked out so that starfish zygote can grow. Verlhac MH J Cell Biol. 212(7):759-61. doi: 10.1083/jcb.201602053.

Work in progress... stay tuned. Complex complexity. Dionisio

Most oocytes eliminate their centrioles during meiotic divisions through unclear mechanisms. The biological significance of oocyte centriole riddance remains a mystery. [...] mother centrioles need to be eliminated from starfish oocytes by extrusion into the polar bodies for successful embryo development. [...] the pathway leading to centriole elimination has not been identified [...] Whether the mother centriole migrates to the cortex with its appendages facing or opposite the plasma membrane has not been addressed. It would be interesting to assess whether astral microtubules emanating from the mother centriole progressively depolymerize as the mother centriole approaches the plasma membrane to allow the intimate anchoring of the appendages with the plasma membrane. Future work will tell us why the daughter centriole does not experience such a migration event.

Mother centrioles are kicked out so that starfish zygote can grow. Verlhac MH J Cell Biol. 212(7):759-61. doi: 10.1083/jcb.201602053.

Work in progress... stay tuned. Complex complexity. Dionisio

Looking back... @234, 442, 673: three different comments on the same paper:

Centrosomes back in the limelight Michel Bornens, Pierre Gönczy DOI: 10.1098/rstb.2013.0452 Philos Trans R Soc Lond B Biol Sci. 369(1650).

That was then, what's the latest on this now? Dionisio

[...] centriole and centrosome transmission is still not understood. Neither the molecules involved, nor even precise terminologies are agreed upon. Deciphering the centriole’s molecular architecture raises questions as to how this miniscule structure manages to organize the entire three-dimensional MT cytoskeleton. More challenges, recently insurmountable, can now be addressed. Within the seemingly rigid confines of a dozen or so uniform building blocks, centrioles enable incredible microtubule diversity, which forms the basis for cellular architecture and motility, thereby enabling development and differentiation.

LEGOs® and legacies of centrioles and centrosomes Gerald Schatten and Calvin Simerly EMBO Rep. 16(9): 1052–1054. doi: 10.15252/embr.201540875

Work in progress... stay tuned. Complex complexity. Dionisio

A Regulated Double-Negative Feedback Decodes the Temporal Gradient of Input Stimulation in a Cell Signaling Network. Park SM1, Shin SY1,2,3, Cho KH1. PLoS One. 2016 Sep 1;11(9):e0162153m. doi: 10.1371/journal.pone.0162153 Dionisio

Origin of the hematopoietic system in the human embryo Emmanuelle Julien, Reine El Omar, Manuela Tavian DOI: 10.1002/1873-3468.12389 http://onlinelibrary.wiley.com/doi/10.1002/1873-3468.12389/full Dionisio

Centriole construction, now revealed by crystallography, proteomics, and imaging to be a sophisticated assembly of interlocking bricks, resembles LEGOs—albeit centrioles have remarkable dynamic capabilities, including self-assembly and dis-assembly, kinases and post-translational modifications, self-replication, and still mysterious mechanisms for transmission through each cell cycle and via the gametes during development.

LEGOs® and legacies of centrioles and centrosomes Gerald Schatten and Calvin Simerly EMBO Rep. 16(9): 1052–1054. doi: 10.15252/embr.201540875

[emphasis added] Did somebody say mysterious? :) Complex complexity. Dionisio

Kinetochores bridge centromeric DNA and spindle microtubules (MTs). They contain more than 50 distinct components in budding yeast and an even larger number in multi-cellular organisms, most associated into well-defined subassemblies [...] The complexity of its structure and the conservation (among fungi) of particular features suggest that the Ndc80c junction interacts with additional factors that remain to be identified. The Ndc80c tetramer junction is an elaborately specialized, end-to-end connection between two heterodimeric coiled-coils with the same polarity. The position at which the CH-domain “heads” of Ndc80 and Nuf2 join the coiled-coil stalk has hinge-like characteristics.

Conserved Tetramer Junction in the Kinetochore Ndc80 Complex. Valverde R1, Ingram J2, Harrison SC Cell Rep. 17(8):1915-1922. doi: 10.1016/j.celrep.2016.10.065.

Complex complexity. Dionisio

Kinetochores bridge centromeric DNA and spindle microtubules (MTs). They contain more than 50 distinct components in budding yeast and an even larger number in multi-cellular organisms, most associated into well-defined subassemblies [...] The complexity of its structure and the conservation (among fungi) of particular features suggest that the Ndc80c junction interacts with additional factors that remain to be identified. The Ndc80c tetramer junction is an elaborately specialized, end-to-end connection between two heterodimeric coiled-coils with the same polarity. The position at which the CH-domain “heads” of Ndc80 and Nuf2 join the coiled-coil stalk has hinge-like characteristics.

Conserved Tetramer Junction in the Kinetochore Ndc80 Complex. Valverde R1, Ingram J2, Harrison SC Cell Rep. 17(8):1915-1922. doi: 10.1016/j.celrep.2016.10.065.

Complex complexity. Dionisio

The heterotetrameric Ndc80 complex establishes connectivity along the principal longitudinal axis of a kinetochore. The junction connects two ?-helical coiled coils through regions of four-chain and three-chain overlap. The complexity of its structure depends on interactions among conserved amino-acid residues, suggesting a binding site for additional cellular factor(s) not yet identified.

Conserved Tetramer Junction in the Kinetochore Ndc80 Complex. Valverde R1, Ingram J2, Harrison SC Cell Rep. 17(8):1915-1922. doi: 10.1016/j.celrep.2016.10.065.

Complex complexity. Dionisio

Cytoplasmic dynein 1 is a multi-protein intracellular motor essential for mediating several mitotic functions, including the establishment of proper spindle orientation. The functional relevance and mechanistic distinctions between two discrete dynein subpopulations distinguished only by Light Intermediate Chain (LIC) homologues, LIC1 and LIC2 is unknown during mitosis. Somatic metazoan cells divide via the process of mitosis with high fidelity to generate two daughter cells that contain the correct complement of chromosomes. The long-term developmental consequences of LIC2 depletion and the molecular mechanisms that enable crosstalk with extracellular developmental cues remain to be elucidated. Elucidation of these molecular mechanisms would illuminate mechanistic details governing the biology of the two LIC homologues.

The Light Intermediate Chain 2 Subpopulation of Dynein Regulates Mitotic Spindle Orientation. Mahale S1,2, Kumar M1, Sharma A1,2, Babu A3,4, Ranjan S3, Sachidanandan C3,4, Mylavarapu SV Sci Rep. 6(1):22. doi: 10.1038/s41598-016-0030-3.

Complex complexity. Dionisio

The fidelity of eukaryotic mitotic cell divisions is imperative for viability and function of the daughter cells, and to ensure that the two daughters contain the correct dose of chromosomes. Precise mitotic regulation is ensured through multiple pathways and events at the various stages of mitosis in the mother cell. This aspect of cytoplasmic dynein-dependent kinetochore Zw10 dynamics could be interesting to explore in the future. There however remains the possibility that LIC2-dynein could mediate kinetochore BubR1 removal by alternative mechanisms as well, which would be interesting to explore. In the future, a deeper dissection of the molecular mechanisms governing these functional distinctions would significantly advance our understanding of mitotic progression.

Dynein Light Intermediate Chain 2 Facilitates the Metaphase to Anaphase Transition by Inactivating the Spindle Assembly Checkpoint Sagar P. Mahale,1,2 Amit Sharma,1,2 and Sivaram V. S. Mylavarapu PLoS One. 11(7): e0159646. doi: 10.1371/journal.pone.0159646

Complex complexity. Dionisio

The multi-functional molecular motor cytoplasmic dynein performs diverse essential roles during mitosis. The mechanistic importance of the dynein Light Intermediate Chain homologs, LIC1 and LIC2 is unappreciated, especially in the context of mitosis. [...] the functional importance of LIC2 during mitosis remains elusive. Our study uncovers a novel functional hierarchy during mitotic checkpoint inactivation between the closely related but homologous LIC subunits of cytoplasmic dynein. These subtle functional distinctions between dynein subpopulations could be exploited to study specific aspects of the spindle assembly checkpoint, which is a key mediator of fidelity in eukaryotic cell division.

Dynein Light Intermediate Chain 2 Facilitates the Metaphase to Anaphase Transition by Inactivating the Spindle Assembly Checkpoint Sagar P. Mahale,1,2 Amit Sharma,1,2 and Sivaram V. S. Mylavarapu PLoS One. 11(7): e0159646. doi: 10.1371/journal.pone.0159646

Complex complexity. Dionisio

Cell growth is manifested itself in mass accumulation, which results in increased cell size. This has been intensively studied but the molecular determinants of cell size are still elusive (Ginzberg et al., 2015; Kiyomitsu, 2015; Schmoller and Skotheim, 2015; Amodeo and Skotheim, 2016). Since we have yet to completely understand the regulation of cell size (Lloyd, 2013), it is not surprising that the determinants of organ size are not known either (Hariharan, 2015; Penzo-Méndez and Stanger, 2015). Investigation of the molecular mechanisms controlling cell and organ size is definitely a grand challenge awaiting to be solved.

Quo Vadis Cell Growth and Division? Philipp Kaldis Front Cell Dev Biol. 4: 95. doi: 10.3389/fcell.2016.00095

Complex complexity. Dionisio

The trend over the last 20 years has been to simplify scientific “stories” resulting in a whitewashing that can obscure details that make up the complexity of biological systems. One particular problem is the validity of generalizing in vitro mechanistic data from a particular cell line and extrapolating this to all cell types, tissues, and organisms. Therefore, as we progress, it is important to keep in mind the experimental context in which we study the processes of our interest. In addition, our knowledge of the regulation of the meiotic cell cycle lags behind. There are obvious differences between mitosis and meiosis but meiosis also differs between females [ovary] and males [testis] (Clift and Schuh, 2013; Ohkura, 2015). These are major challenges to be uncovered in the future.

Quo Vadis Cell Growth and Division? Philipp Kaldis Front Cell Dev Biol. 4: 95. doi: 10.3389/fcell.2016.00095

Complex complexity. Dionisio

[...] numerous aspects of the mitotic cell cycle remain elusive. Substantial gaps requiring further investigation exist to fully understand these mechanisms. These include for instance, how the origins of DNA replication are selected, how the spindle assembly checkpoint (SAC) is turned off once all chromosomes are bi-stably attached to microtubules, why the anaphase promoting complex/cyclosome (APC/C) is made up of numerous subunits and the functions of those subunits, how the timing of protein degradation is regulated during mitosis, and many more.

Quo Vadis Cell Growth and Division? Philipp Kaldis Front Cell Dev Biol. 4: 95. doi: 10.3389/fcell.2016.00095

Complex complexity. Dionisio

Many cellular processes, such as cell morphogenesis, migration, and asymmetric cell division, require eukaryotic cells to alter polarity and growth patterns Future experiments will address how phosphorylation of this domain modulates the function of Sts5 and affects its properties in vitro. The mechanisms that modulate cell morphogenesis and polarized cell growth in response to varying growth and environmental conditions are still poorly understood. Future research will seek to identify nutrient-sensitive signaling pathways upstream of Orb6 and define the specific roles of Orb6 kinase and Sts5 in the control of P-body assembly.

Spatial control of translation repression and polarized growth by conserved NDR kinase Orb6 and RNA-binding protein Sts5 Illyce Nuñez,1 Marbelys Rodriguez Pino,1 David J Wiley,1 Maitreyi E Das,2 Chuan Chen,1 Tetsuya Goshima,3 Kazunori Kume,4 Dai Hirata,4 Takashi Toda,4,5 and Fulvia Verde eLife. 5: e14216. doi: 10.7554/eLife.14216

Complex complexity. Dionisio

RNA-binding proteins contribute to the formation of ribonucleoprotein (RNP) granules by phase transition, but regulatory mechanisms are not fully understood. Conserved fission yeast NDR (Nuclear Dbf2-Related) kinase Orb6 governs cell morphogenesis in part by spatially controlling Cdc42 GTPase. In the future, Nuñez et al. would like to determine how Orb6 recognizes and responds to environmental signals to control cell growth. Further studies could also explore how Sts5 and Orb6 kinase affect the assembly of RNA-protein particles that have been implicated in diseases in humans.

Spatial control of translation repression and polarized growth by conserved NDR kinase Orb6 and RNA-binding protein Sts5 Illyce Nuñez,1 Marbelys Rodriguez Pino,1 David J Wiley,1 Maitreyi E Das,2 Chuan Chen,1 Tetsuya Goshima,3 Kazunori Kume,4 Dai Hirata,4 Takashi Toda,4,5 and Fulvia Verde eLife. 5: e14216. doi: 10.7554/eLife.14216

Complex complexity. Dionisio

Understanding the manner in which population of neurons encode information is fundamental to systems neuroscience. [...] what continues to make this problem challenging and mathematically complex is the fact that collective neural activity patterns have enormous dimensionality–for instance, if we only need to keep track of spiking or silence for each neuron, a population of N neurons still has 2N possible activity states [...] [...] neural circuits downstream of the retina can extract meaningful information about the visual stimulus merely by clustering retinal activity patterns into a sequence of collective modes. [...] these modes often encoded features of the stimulus that were not represented by any individual neuron. Future work could apply our model to analyze the collective mode structure of more complex, higher-order, brain areas where the relevant features of the input are unknown.

Prentice JS, Marre O, Ioffe ML, Loback AR, Tka?ik G, Berry MJ II (2016) Error-Robust Modes of the Retinal Population Code. PLoS Comput Biol 12(11): e1005148. doi:10.1371/journal.pcbi.1005148

Complex complexity. Dionisio

Neurons in most parts of the nervous system represent and process information in a collective fashion, yet the nature of this collective code is poorly understood. [...] the complex activity patterns over ~150 retinal ganglion cells, the output neurons of the retina, could be mapped onto collective code words, and that these code words represented precise visual information while suppressing noise. [...] retinal ganglion cells’ collective signaling is endowed with a form of error-correcting code–a principle that may hold in brain areas beyond retina.

Prentice JS, Marre O, Ioffe ML, Loback AR, Tka?ik G, Berry MJ II (2016) Error-Robust Modes of the Retinal Population Code. PLoS Comput Biol 12(11): e1005148. doi:10.1371/journal.pcbi.1005148

Complex complexity. Dionisio

The development of the central nervous system depends on the actions and interactions of transcription factors and morphogens linked together in complex gene regulatory networks. These networks serve to finely control processes such as tissue patterning and neuronal subtype specification Further work is needed to test whether loss of Barhl2 in mice affects the expression of Pax6. It is not clear what function Barhl2 serves in the mature ZLI, if any, and why it is not expressed throughout the entire ZLI.

Expression of Barhl2 and its relationship with Pax6 expression in the forebrain of the mouse embryo Elisa V. Parish, John O. Mason, and David J. Price BMC Neurosci. 17: 76. doi: 10.1186/s12868-016-0311-6

Complex complexity. Dionisio

Despite the fundamental roles played by Sufu in development and cancer, it is largely unclear how Sufu protein itself is regulated. [...] Rusc1 and Rusc2 are novel components of the vertebrate Hh pathway In the future, it will be of great interest to determine if Rusc proteins physically and functionally interact with Kif7 or Rab23 in Hh signaling.

Members of the Rusc protein family interact with Sufu and inhibit vertebrate Hedgehog signaling. Jin Z1, Schwend T1, Fu J1, Bao Z2, Liang J2, Zhao H2, Mei W1, Yang J3 Development. 143(21):3944-3955. DOI: 10.1242/dev.138917

Work in progress… stay tuned. Complex complexity. Dionisio

Optogenetic activation of SOM+ interneurons results in an increase in histamine-evoked itch behavior that may be mediated through the somatostatin neuropeptide and therefore through suppression of SST2AR-expressing neurons, indicating a broader role for these neurons in the regulation of somatosensory stimuli beyond their excitatory role in gating mechanosensory inputs. It remains to be seen whether endogenous activity in SOM+ neurons can result in somatostatin release and, if so, how such release interacts with the inhibition of itch by counter-stimuli (Snyder and Ross, 2015 Future experiments will be required to more completely assess the relative contribution of these two pathways to itch perception.

In Vivo Interrogation of Spinal Mechanosensory Circuits. Christensen AJ1, Iyer SM2, François A3, Vyas S2, Ramakrishnan C2, Vesuna S2, Deisseroth K4, Scherrer G5, Delp SL6 Cell Rep. 17(6):1699-1710. doi: 10.1016/j.celrep.2016.10.010.

Work in progress… stay tuned. Complex complexity. Dionisio

Spinal dorsal horn circuits receive, process, and transmit somatosensory information. To understand how specific components of these circuits contribute to behavior, it is critical to be able to directly modulate their activity in unanesthetized in vivo conditions. The spinal implant approach we describe here is likely to enable a wide range of studies to elucidate spinal circuits underlying pain, touch, itch, and movement.

In Vivo Interrogation of Spinal Mechanosensory Circuits. Christensen AJ1, Iyer SM2, François A3, Vyas S2, Ramakrishnan C2, Vesuna S2, Deisseroth K4, Scherrer G5, Delp SL6 Cell Rep. 17(6):1699-1710. doi: 10.1016/j.celrep.2016.10.010.

Work in progress… stay tuned. Complex complexity. Dionisio

Future studies will need to distinguish among these possibilities in order to define how Hand2 functions in different embryonic contexts. It will be interesting to determine whether the relationship between hand2 and osr1 function is broadly conserved. [...] the influence of Hand2 on IM and kidney development has not yet been carefully interrogated. [...] future investigations in mouse may need to evaluate potential redundancy between the functions of Hand2 and Hand1: both of these genes are expressed in the murine lateral posterior mesoderm (Thomas et al., 1998), whereas zebrafish have only a single Hand gene.

Hand2 inhibits kidney specification while promoting vein formation within the posterior mesoderm Elliot A Perens,1,2 Zayra V Garavito-Aguilar,1,3 Gina P Guio-Vega,3 Karen T Peña,3 Yocheved L Schindler,1 and Deborah Yelon1 eLife. 5: e19941. doi: 10.7554/eLife.19941

Work in progress... stay tuned. Complex complexity. Dionisio

[...] the pathways that set the boundaries of the IM and distinguish this territory from its neighbors are largely unknown. Despite these indications of interconnections between IM and vessel development, the network of factors that link these processes has not been fully elucidated. Currently, the lineage relationships between the IM, the lateral venous progenitors, and the hand2-expressing lateral mesoderm remain undetermined; future work on the generation of appropriate tissue-specific lineage tracing tools will facilitate progress toward the resolution of these open questions. In future studies, it will also be valuable to elucidate the effector genes that act downstream of Hand2 in the posterior mesoderm.

Hand2 inhibits kidney specification while promoting vein formation within the posterior mesoderm Elliot A Perens,1,2 Zayra V Garavito-Aguilar,1,3 Gina P Guio-Vega,3 Karen T Peña,3 Yocheved L Schindler,1 and Deborah Yelon1 eLife. 5: e19941. doi: 10.7554/eLife.19941

Work in progress... stay tuned. Complex complexity. Dionisio

Kidney progenitor cells originate from the intermediate mesoderm (IM), a pair of narrow bilateral stripes within the posterior mesoderm, flanked by lateral mesoderm that gives rise to vessels and blood and by paraxial mesoderm that gives rise to bone, cartilage, and skeletal muscle. The mechanisms that determine the dimensions of the stripes of IM are not fully understood.

Hand2 inhibits kidney specification while promoting vein formation within the posterior mesoderm Elliot A Perens,1,2 Zayra V Garavito-Aguilar,1,3 Gina P Guio-Vega,3 Karen T Peña,3 Yocheved L Schindler,1 and Deborah Yelon1 eLife. 5: e19941. doi: 10.7554/eLife.19941

Complex complexity. Dionisio

Organs arise from precisely defined territories containing progenitor cells with specific developmental potential. Boundary refinement is generally thought to be mediated by interplay between opposing inductive and suppressive factors (Briscoe and Small, 2015). In many cases, however, the identification of and interactions among these factors remain elusive.

Hand2 inhibits kidney specification while promoting vein formation within the posterior mesoderm Elliot A Perens,1,2 Zayra V Garavito-Aguilar,1,3 Gina P Guio-Vega,3 Karen T Peña,3 Yocheved L Schindler,1 and Deborah Yelon1 eLife. 5: e19941. doi: 10.7554/eLife.19941

Complex complexity. Dionisio

Proper organogenesis depends upon defining the precise dimensions of organ progenitor territories. Kidney progenitors originate within the intermediate mesoderm (IM), but the pathways that set the boundaries of the IM are poorly understood. The human body is made up of many different types of cells, yet they are all descended from one single fertilized egg cell. The process by which cells specialize into different types is complex and has many stages. At each step of the process, the selection of cell types that a cell can eventually become is increasingly restricted. The entire system is controlled by switching different genes on and off in different groups of cells. Balancing the activity of these genes ensures that enough cells of each type are made in order to build a complete and healthy body.

Hand2 inhibits kidney specification while promoting vein formation within the posterior mesoderm Elliot A Perens,1,2 Zayra V Garavito-Aguilar,1,3 Gina P Guio-Vega,3 Karen T Peña,3 Yocheved L Schindler,1 and Deborah Yelon1 eLife. 5: e19941. doi: 10.7554/eLife.19941

Complex complexity. Dionisio

references to this paper posted @: 1399-1402; 1553; 1827-1831; 1936-1940

Morphogen rules: design principles of gradient-mediated embryo patterning James Briscoe, Stephen Small Development 2015 142: 3996-4009; doi: 10.1242/dev.129452 http://dev.biologists.org/content/142/23/3996.full

Dionisio

The positive effects of dietary fibre on health are now widely recognised; however, our understanding of the mechanisms involved in producing such benefits remains unclear. [...] this evidence represents a paradigm shift in understanding of how fibre affects the time course of digestion and absorption, as the prevailing view until recently has been that only soluble fibre impedes the digestion process itself. One of the many challenges for researchers in the future will be to improve our understanding of the physico-chemical properties of dietary fibre at different sites of the GI tract and how this impacts on gut function and postprandial metabolism. At a higher-length scale, knowledge of the mechanical properties (e.g. fragmentation) and porosity of cell wall matrices would add greatly to our understanding of the important physiological role(s) of dietary fibre during digestion.

Re-evaluation of the mechanisms of dietary fibre and implications for macronutrient bioaccessibility, digestion and postprandial metabolism. Grundy MM1, Edwards CH1, Mackie AR2, Gidley MJ3, Butterworth PJ1, Ellis PR Br J Nutr. 116(5):816-33. doi: 10.1017/S0007114516002610.

Dionisio

Almond seeds or kernels are highly versatile and can be eaten on their own or as part of a number of food products. [...] mechanisms that explain the physiological effects and the long term benefits of tree nuts like almonds are not well understood, particularly the properties of almond cell walls in each compartment of the GI tract (i.e. mouth, stomach and intestine). [...] it remains unclear to what extent lipolysis occurs inside almond cells and whether the lipids are able to leave the cells as TAG molecules or hydrolysed products. [...] mechanical processing (mainly grinding) or mastication is necessary for the cells to rupture and allow intra?cellular lipid and other nutrients (e.g. proteins) to be made available for digestion. The beneficial health effects of almonds rely not only on their nutritional composition, as they are a good source of unsaturated fatty acids, vitamin E, polyphenols and phytosterols, but also on their structure and properties when ingested. Differences in the physical form of ingested almonds in particular, lead to variability in nutrient digestibility and consequently evoke different blood nutrient profiles and gut hormone responses.

A review of the impact of processing on nutrient bioaccessibility and digestion of almonds. Grundy MM1, Lapsley K2, Ellis PR1. Int J Food Sci Technol. 51(9):1937-1946. DOI: 10.1111/ijfs.13192

Dionisio

The release of bioactives from almond skins could explain the beneficial effects associated with almond consumption. The presence of polyphenols in almond skin has been related to several health benefits associated with almond Nevertheless, one of the major limiting factors affecting the beneficial effects of polyphenols is their bioaccessibility and subsequent absorption in the gastrointestinal tract (GIT), together with their bio-transformation by the gut microbiota enzymes [...] the presence of a food matrix had a significant effect on polyphenol bioaccessibility from almond skin in both the gastric and duodenal environments. The dietary fiber present in almond skin may act as barrier to prevent a total release of phytochemicals during digestion. Further studies are warranted in order to investigate absorption of bioactives, which could explain the beneficial health effects associated with almond consumption.

Food Matrix Effects of Polyphenol Bioaccessibility from Almond Skin during Simulated Human Digestion. Mandalari G1,2, Vardakou M3, Faulks R4, Bisignano C5, Martorana M6, Smeriglio A7, Trombetta D8 Nutrients. 8(9). pii: E568. doi: 10.3390/nu8090568.

Dionisio

Lung cancer is a multi-step process of accumulating genetic and epigenetic alterations caused by chronic exposure to carcinogens, such as smoking, domestic radon, fossil fuel burning, automobile exhaust fumes and pesticide inhalation. Genome instability is the primary cause of lung cancer initiation. Almost all lung carcinogens are able to alter the cell microenvironment, which favors DNA damage. Oxidative DNA damage is the central process causing lung carcinogenesis. Plant polyphenols have exhibited multiple modes of cancer prevention functions Polyphenols can be found ubiquitously in fruits, vegetables, grains, and other plant-based food. Further investigations are required to identify specific polyphenols and their dietary sources that are involved in oxidative protection, regulation of phase I and II enzymes, and regulation of cell survival pathways in relation to lung carcinogenesis.

Plant Polyphenols as Chemopreventive Agents for Lung Cancer. Amararathna M1, Johnston MR2, Rupasinghe HP Int J Mol Sci. 17(8). pii: E1352. doi: 10.3390/ijms17081352.

Had we stayed in Eden, none of this would have ben an issue. There were no carcinogens and there was abundance of fresh fruits and vegetables. But we wanted to do things our own way. Oh, well. Here we are. Dionisio

quercetin (3,3?,4?,5,7-pentahydroxyflavone) is a highly ubiquitous and well-classified dietary polyphenol found in various fruits, vegetables, and other plant products including onions, broccoli, kale, oranges, blueberries, apples, and tea. In general, quercetin could be used to exploit tyrosinase activity to prevent, and/or treat, melanoma with minimal additional side effects. MiRNAs function to negatively regulate gene expression by repressing the translation of target mRNA sequences. Quercetin has demonstrated the capacity to affect miRNA expression in both cell culture and animal models.

Quercetin as an Emerging Anti-Melanoma Agent: A Four-Focus Area Therapeutic Development Strategy Zoey Harris,1,† Micah G. Donovan,1,† Gisele Morais Branco,1 Kirsten H. Limesand,1 and Randy Burd1 Front Nutr. 3: 48. doi: 10.3389/fnut.2016.00048

Dionisio

the vast majority of laboratory studies supported anticancer activities of natural polyphenols, such as anthocyanins, EGCG, resveratrol and curcumin. The mechanisms of action mainly included modulation of molecular events and signaling pathways associated with cell survival, proliferation, differentiation, migration, angiogenesis, hormone activities, detoxification enzymes, immune responses, etc. It is of note that some polyphenols, such as genistein and daidzein, have been suggested to have adverse effects on hormone-related cancer. [...] the anticancer activities of more polyphenols need to be assessed and compared, and the mechanisms of action require further study. [...] the bioavailability of polyphenols should be evaluated and improved. Special attention should be paid to the safety of polyphenols.

Natural Polyphenols for Prevention and Treatment of Cancer Yue Zhou,1 Jie Zheng,1 Ya Li,1 Dong-Ping Xu,1 Sha Li,2 Yu-Ming Chen,1 and Hua-Bin Li Nutrients. 8(8): 515. doi: 10.3390/nu8080515

This is the price of having eaten the forbidden fruit. We've messed up things badly. Dionisio

This study provides evidence that soy intake as a food group is only associated with a small reduction in GI cancer risk. Separate analysis for dietary isoflavone intakes suggests a stronger inverse association.

Soy and isoflavone consumption and risk of gastrointestinal cancer: a systematic review and meta-analysis. Tse G1, Eslick GD Eur J Nutr. 55(1):63-73. doi: 10.1007/s00394-014-0824-7

Dionisio

BBI potently inhibits HIV infection of macrophages. [...] the precise cellular and molecular mechanisms by which BBI inhibits HIV replication remain to be determined [...] [...] there is a necessity of future in vivo studies for the development of BBI-based supplementary therapy for people infected with HIV, particularly those in resource poor settings. [...] future studies with the specific antibody to BBI or BBI receptor are necessary in order to determine the entry mechanism(s) of BBI in macrophages and other cell systems. [...] the precise mechanism(s) of BBI entry into cells remain to be determined. [...] the role of IFNs and ISGs in HIV pathogenesis and treatment remain to be determined. [...] further studies on the interplays between HIV and IFN signaling pathway are necessary to guide future intervention and therapeutic strategies.

Soybean-derived Bowman-Birk Inhibitor (BBI) Inhibits HIV Replication in Macrophages. Ma TC1, Zhou RH1, Wang X2, Li JL2, Sang M1, Zhou L1, Zhuang K1,3, Hou W1,3, Guo DY1,3, Ho WZ Sci Rep. 6:34752. doi: 10.1038/srep34752.

Work in progress… stay tuned. Complex complexity. Dionisio

Although numerous signaling mechanisms have been identified that act directly on axons to regulate their outgrowth, it is not known whether signals transduced in dendrites may also affect axon outgrowth. [...] the Sonic Hedgehog (Shh) signaling pathway mediates the development and maintenance of several different neural circuits in the brain. Future experiments in which the ratio of the Pfn isoforms is altered by selective reduction or elimination will provide a better understanding of the regulation of Pfn in developing neurons. [...] the Shh-signaling pathway promotes axon growth by regulating the expression and activity of actin filament modifiers in developing hippocampal neurons. Future in vivo experiments should provide important next steps in understanding the physiological relevance of Shh signaling in the development of hippocampal neurons.

Dendrosomatic Sonic Hedgehog Signaling in Hippocampal Neurons Regulates Axon Elongation Pamela J. Yao,corresponding author1 Ronald S. Petralia,2,* Carolyn Ott,3,* Ya-Xian Wang,2 Jennifer Lippincott-Schwartz,3 and Mark P. Mattson1 J Neurosci. 35(49): 16126–16141. doi: 10.1523/JNEUROSCI.1360-15.2015

Work in progress... stay tuned Complex complexity. Dionisio

The present results show that two representative serine proteases, endogenous mammalian chymotrypsin and an environmental, bacterial chymotryptic protease, subtilisin, can down-regulate DCC and neogenin expression in cells, increasing cell migration. The reversibility of the changes in adhesion and protein expression would be important for cells which migrate from their home tissue to form metastases elsewhere. Since chymotrypsin secretion is increased by over-eating and increased basal metabolic rate, and it can be absorbed from the intestine where is exists as a normal digestive enzyme, it may provide an explanation of the link between over-eating and cancer incidence. Subtilisin is used in meat tenderisation and processing, and domestic and industrial cleaning products, while its main producer, the bacterium B. subtilis, is added to probiotics and food for farm animals to promote growth. This relationship may contribute to the link between meat consumption and cancer incidence, while inhibition of chymotryptic enzymes by Bowman-Birk inhibitors from plants may explain the protective effects of a plant-based diet. The data reported here, therefore, may help understanding of the causes of many cancers, with the potential to prevent many of them by restricting the industrial and agricultural use of serine proteases. In addition, further work on the efficacy of dietary Bowman-Birk compounds as inhibitors of subtilisin and chymotrypsin might lead to their increased use as protection against cancer.

Selective depletion of tumour suppressors Deleted in Colorectal Cancer (DCC) and neogenin by environmental and endogenous serine proteases: linking diet and cancer Caroline M. Forrest,#1 Kara McNair,#1 Maria C. J. Vincenten,#1 L. Gail Darlington,2 and Trevor W. Stone BMC Cancer. 2016; 16: 772. doi: 10.1186/s12885-016-2795-y http://bmccancer.biomedcentral.com/articles/10.1186/s12885-016-2795-y

Dionisio

There is still much to learn from the C. elegans lineage. [...] answering many of the remaining questions about fate specification will require detailed dissection of individual enhancers and their constituent TF binding sites, where imaging based methods are currently the only practical method. [...] the next ten years should see a clear model emerge of how the remarkable C. elegans lineage is regulated.

Combinatorial decoding of the invariant C. elegans embryonic lineage in space and time. Zacharias AL1, Murray JI1. Genesis. 54(4):182-97. doi: 10.1002/dvg.22928.

Work in progress… stay tuned. Complex complexity. Dionisio

Future work should investigate the exact relationship between the initiation of zygotic transcription and gap/checkpoint introduction. It is also interesting to study how regulatory pathways such as Wnt signaling, interface with cell cycle regulation. Whether an increased E2 cell cycle length contributes to the activation of zygotic transcription in C. elegans remains to be determined. [...] how wee-1.1 plays an E-specific role in regulating cell cycle length remain unclear. It would be intriguing to investigate whether wee-1.1 is a direct target of end-1 and end-3. The exact relationship between E2 division pace and cell migration remains to be determined.

Timing of Tissue-specific Cell Division Requires a Differential Onset of Zygotic Transcription during Metazoan Embryogenesis. Wong MK1, Guan D1, Ng KH1, Ho VW1, An X1, Li R1, Ren X1, Zhao Z2 doi: 10.1074/jbc.M115.705426 jbc.M115.705426.

Work in progress... stay tuned. Complex complexity. Dionisio

Faithful development of metazoans depends on not only precise differentiation of cell fate, but also on tight control over division timing or division pace between cells, which we refer to as temporal coordination. [...] genetic control over temporal coordination of cell division during metazoan development is poorly understood. How cell divisions are timed in a lineal or tissue-specific fashion remains poorly understood. [...] a molecular understanding of genetic control over embryonic cell division timing has only begun to emerge. How asynchrony forms in a tissue- or lineage-specific way remains largely unknown. [...] tissue/lineage-specific regulation of cell cycle length requires a differential onset of gene transcription, which is supported by lineage-specific RNA-seq analysis [...] [...] an earlier onset of transcription in E is triggered by Wnt signaling pathway, [...]

Timing of Tissue-specific Cell Division Requires a Differential Onset of Zygotic Transcription during Metazoan Embryogenesis. Wong MK1, Guan D1, Ng KH1, Ho VW1, An X1, Li R1, Ren X1, Zhao Z2 doi: 10.1074/jbc.M115.705426 jbc.M115.705426.

Complex complexity. Dionisio

[...] the cell fates are specified by stepwise instructions directed by the binary decisions occurring at each division leading to the cell. [...] with more single-cell gene expression data available, more biological insights into cell fate specifications can be revealed by similar analyses. It would be highly valuable to dissect the architecture of regulatory cascades and reveal genes that play essential roles in driving the divergence of two lineages generated at each cell division. Intriguingly, we found that only a small set of genes is sufficient to discriminate a pair of sister lineages.

Identification of genes driving lineage divergence from single-cell gene expression data in C. elegans. Xu C1, Su Z Dev Biol. 393(2):236-44. doi: 10.1016/j.ydbio.2014.07.009.

did somebody say specified? did somebody say instructions? did somebody say decisions? Complex complexity. Dionisio

The nematode Caenorhabditis elegans (C. elegans) is an ideal model organism to study the cell fate specification mechanisms during embryogenesis. It is generally believed that cell fate specification in C. elegans is mainly mediated by lineage-based mechanisms, where the specification paths are driven forward by a succession of asymmetric cell divisions. However, little is known about how each binary decision is made by gene regulatory programs. [...] the cell fate patterns in C. elegans are achieved through stepwise binary decisions punctuated by cell divisions. Our predicted genes driving lineage divergence provide good starting points for future detailed characterization of their roles in the embryogenesis in this important model organism.

Identification of genes driving lineage divergence from single-cell gene expression data in C. elegans. Xu C1, Su Z Dev Biol. 393(2):236-44. doi: 10.1016/j.ydbio.2014.07.009.

Complex complexity. Dionisio

One of the most important problems in development is how epigenetic domains can be first established, and then maintained, within cells. Epigenetic modifications are biochemical marks that form patterns along chromosomes and regulate gene expression. The epigenetic patterning of chromosomes enables cellular differentiation, while leaving the underlying DNA sequence unchanged. How these patterns are established and then maintained across cell division is far from understood, however. [...] an outstanding question is how the epigenetic landscape is established in the first place—and how this can be reset de novo after each cell division.

A Polymer Model with Epigenetic Recolouring Reveals a Pathway for the de novo Establishment and 3D Organisation of Chromatin Domains Davide Michieletto, Enzo Orlandini, Davide Marenduzzo doi: https://doi.org/10.1101/058933 Phys. Rev. X 6, 041047 http://biorxiv.org/content/early/2016/10/23/058933.full.pdf http://journals.aps.org/prx/abstract/10.1103/PhysRevX.6.041047#fulltext

Complex complexity. Dionisio

The kinetochore is the macromolecular protein complex that drives chromosome segregation in eukaryotes. Its most fundamental function is to connect centromeric DNA to dynamic spindle microtubules. [...] extensive studies have been carried out to mechanistically understand how the Ndc80 complex binds to microtubules [...] Another important aspect of kinetochore research is to understand its design principles. [...] it has become clear that the repertoire of kinetochore proteins can be dramatically different among eukaryotes despite functional conservation. [...] understanding the nature of unconventional kinetochore proteins will likely provide important insights into the fundamental principles of eukaryotic segregation machines. Surely a lot of exciting discoveries will be made in the next few decades in the field of chromosome segregation research.

The unconventional kinetoplastid kinetochore: from discovery toward functional understanding. Akiyoshi B Biochem Soc Trans. 44(5):1201-1217. DOI: 10.1042/BST20160112

[emphasis added] design principles? Did somebody say "design"? :) next few decades? Oh, no! that long? :) Complex complexity. Dionisio

Faithful chromosome segregation is accomplished by attachment of chromosomes to spindle microtubules using the kinetochore. In a major step forward in understanding the functional and structural complexity of kinetochores, a 21-subunit human centromere - kinetochore complex has been reconstituted entirely from purified components, recreating the connection between DNA and microtubule.

Chromosome Segregation: Reconstituting the Kinetochore. Westhorpe FG, Straight AF Curr Biol. 26(23):R1242-R1245. doi: 10.1016/j.cub.2016.09.051.

Complex complexity. Dionisio

Separating anaphase chromosomes in crane-fly spermatocytes are connected by elastic tethers [...] [...] telomere-containing arm fragments severed from the arms move backwards to the partner telomeres. [...] the movements of partner anaphase chromosomes in crane-fly spermatocytes are coordinated by elastic tethers connecting the two chromosomes [...] [...] chromosomes speed up in anaphase when their kinetochore microtubules are severed.

Elastic tethers between separating anaphase chromosomes in crane-fly spermatocytes coordinate chromosome movements to the two poles. Sheykhani R1, Berns M2,3, Forer A1 Cytoskeleton (Hoboken). doi: 10.1002/cm.21347.

Complex complexity. Dionisio

It is conceivable that the function of Ascl1 in Xenopus is regulated in a cell-cycle progression-coordinated fashion during blastula to gastrula stages, when embryonic cells face a choice of dividing and/or differentiating. More studies are needed in future to unravel the function of the multifaceted cell fate regulator Ascl1. Further study is needed to better understand how the pre-neurula expression of Ascl1 functions as a transactivator and promotes neurogenesis.

A novel role for Ascl1 in the regulation of mesendoderm formation via HDAC-dependent antagonism of VegT. A novel role for Ascl1 in the regulation of mesendoderm formation via HDAC-dependent antagonism of VegT Li Gao,1,* Xuechen Zhu,1,* Geng Chen,1 Xin Ma,2 Yan Zhang,1 Aftab A. Khand,1 Huijuan Shi,1 Fei Gu,1 Hao Lin,1 Yuemeng Chen,3 Haiyan Zhang,1 Lei He,1 and Qinghua Tao Development. 143(3): 492–503. doi: 10.1242/dev.126292

Complex complexity Dionisio

[...] mitotic tyrosine phosphorylation regulated a key serine/threonine kinase hub in mitotic cells [...] [...] spatially separating tyrosine phosphorylation events can reveal previously unrecognized regulatory events and complexes associated with specific structures of the cell cycle.

Mitotic phosphotyrosine network analysis reveals that tyrosine phosphorylation regulates Polo-like kinase 1 (PLK1). Caron D1, Byrne DP2, Thebault P1, Soulet D3, Landry CR4, Eyers PA2, Elowe S5 Sci Signal. 2016 Dec 13;9(458):rs14. DOI: 10.1126/scisignal.aah3525

Complex complexity. Dionisio

[...] components of both short-term and long-term olfactory memory may be encoded at this synapse. In summary, we have demonstrated burst-induced forms of plasticity of the MTC-GC reciprocal synapse with a fast onset that might endow the olfactory system with the sensitivity required for fast learning of new, weak stimuli, for example during exploration. This property might be particularly relevant for olfaction because of the huge space of potential stimuli most of which is unknown to the organism at any point in its life. The finding of both LTD and LTP at this synapse is relevant for its versatility within bulbar processing.

Sniff-Like Patterned Input Results in Long-Term Plasticity at the Rat Olfactory Bulb Mitral and Tufted Cell to Granule Cell Synapse. Chatterjee M1, Perez de Los Cobos Pallares F2, Loebel A3, Lukas M4, Egger V2 Neural Plast. 2016:9124986. DOI: 10.1155/2016/9124986

Complex complexity. Dionisio

How prior odor experience affects the representation of new odor inputs in olfactory bulb and its underlying network mechanism are still unclear. [...] the degree of prior odor experience facilitates degrees of sparse representations of new odors by the mitral cell network through experience-enhanced inhibition mechanism. [...] the gradual increased inhibitory weight of granule cells together with the slightly increased firing rates of gradual cell populations promote the response sparseness and decorrelated state of mitral populations to new odor inputs. These results may help to better explain how prior sensory experience affects the behavior of animals in response to new odor inputs.

Odor Experience Facilitates Sparse Representations of New Odors in a Large-Scale Olfactory Bulb Model. Zhou S1, Migliore M2, Yu Y1 Front Neuroanat. 10:10. doi: 10.3389/fnana.2016.00010.

Complex complexity. Dionisio

The olfactory system removes correlations in natural odors using a network of inhibitory neurons in the olfactory bulb. It has been proposed that this network integrates the response from all olfactory receptors and inhibits them equally. However, how such global inhibition influences the neural representations of odors is unclear. [...] (i) odors with many molecular species are more difficult to discriminate and (ii) receptor arrays with heterogeneous sensitivities perform badly. Comparing these predictions to experiments will help us to understand the role of global inhibition in shaping normalized odor representations in the olfactory bulb. It would be interesting to extend the model for more complex stimuli and study how the system decorrelates the input, identifies a target odor in a background, and separates multiple odors from each other. [...] adaptation of the inhibition mechanism to the current stimulus statistics and more complex models where the behavioral state of an animal could influence the olfactory bulb by top-down modulation [...] will be interesting to explorer in the future. [...] additional mechanisms are necessary to efficiently discriminate odors of all sizes.

Normalized Neural Representations of Complex Odors David Zwicker PLoS One. 11(11): e0166456. doi: 10.1371/journal.pone.0166456

Complex complexity. Dionisio

[...] how a developing organism manages to adjust inhibition/stimulation in response to genetic and/or environmental changes remains to be uncovered. [...] it should be of primary interest as we begin to investigate feedback on the actual inhibitors/activators for regulating ectopic signaling gradients.

TRANSIENT FEEDBACK AND ROBUST SIGNALING GRADIENTS. Simonyan A, Wan FY Int J Numer Anal Model. 13(2):179-204.

Complex complexity. Dionisio

In different clades different ways may be followed to reach the same result: one cnRNA only and two symmetrical different right/ left receptors on the mother centrioles carry out the overturn of the cnRNA ring. The above analysis shows that well-known molecular and biological mechanisms are capable of easily realizing the circumferential non-equivalence of the triplets and the chirality of the mother centriole.

Centrosome RNA: a Molecular Basis for Non-Equivalence of Triplets in Centrioles and Centrosomes? Marco Regolini Mol Biol 4:125 http://dx.doi.org/10.4172/2168-9547.1000125

Complex complexity. Dionisio

The shape of organs and organisms is the consequence of the spatial disposition of cells and extra cellular matrix fibers: our hands are different from our feet (even though they contain very similar anatomical and histological structures) because of the different spatial disposition of cells (osteocytes above all) and the different geometry of the extra cellular fibers; even more evident is, in our skin, the different cells arrangement between sebaceous and sweat glands: each type of gland possesses its own particular disposition of cells; there are a lot of these glands, often very close, but always and everywhere each type of gland is built in accord with its own characteristic cell arrangement, suggesting that an intrinsic mechanism guides cells. [...] the centrosome possesses an intrinsic rotational chirality: the inverse polarity of the mother centriole appears to be the basis of the bilateral symmetry of Metazoa, a fundamental basic property of Metazoan locomotive system and of their sensor neural apparatus which drives locomotion movements.

Centrosome: is it a geometric, noise resistant, 3D interface that translates morphogenetic signals into precise locations in the cell? Regolini MF Ital J Anat Embryol. 118(1):19-66.

Complex complexity. Dionisio

Study of the hierarchy of domain structure with alternative sets of domains and analysis of discontinuous domains, consisting of remote segments of the polypeptide chain, raised a question about the minimal structural unit of the protein domain. The hypothesis on the decisive role of the polypeptide backbone in determining the elementary units of globular proteins have led to the discovery of closed loops. It is reviewed here how closed loops form the loop-n-lock structure of proteins, providing the foundation for stability and designability of protein folds/domain and underlying their co-translational folding. Simplified protein sequences are considered here with the aim to explore the basic principles that presumably dominated the folding and stability of proteins in the early stages of structural evolution. Elementary functional loops (EFLs), closed loops with one or few catalytic residues, are, in turn, units of the protein function. They are apparent descendants of the prebiotic ring-like peptides, which gave rise to the first functional folds/domains being fused in the beginning of the evolution of protein structure. It is also shown how evolutionary relations between protein functional superfamilies and folds delineated with the help of EFLs can contribute to establishing the rules for design of desired enzymatic functions. Generalized descriptors of the elementary functions are proposed to be used as basic units in the future computational design.

Basic units of protein structure, folding, and function. Berezovsky IN1, Guarnera E2, Zheng Z2 Prog Biophys Mol Biol. . pii: S0079-6107(16)30086-4. doi: 10.1016/j.pbiomolbio.2016.09.009

Complex complexity. Dionisio

Huge numbers of cells form an adult animal body, ranging from several thousands in Placozoa and small nematodes to many billions in mammals. Cells are classified into separate groups known as cell types by their morphological and biochemical features. Six to several hundreds of spatially ordered cell types are recognized in different animals. This complex organization develops from one cell, a zygote, during ontogeny, and its dynamic equilibrium is often maintained in the adult body. One of the key challenges in biology is to understand the mechanisms that sustain the reproducible development of a complex ordered cell ensemble such as the animal body from a single cell. How cells with identical genomes stably maintain one of the numerous possible phenotypes? How the cell differentiation lineage is selected during development? What genes play a key role in maintaining cell identity, and how do they determine expression of other genes characteristic of the relevant cell type? How does the basically stochastic nature of transcription in an isolated cell affect the stability of cell identity, the selection of a cell lineage, and the variability of cell responses to external stimuli?

Single-cell genome-wide studies give new insight into nongenetic cell-to-cell variability in animals. Golov AK1, Razin SV1,2, Gavrilov AA3 Histochem Cell Biol. 146(3):239-54. doi: 10.1007/s00418-016-1466-z.

Work in progress… stay tuned. Complex complexity. Dionisio

The development of the hematopoietic system during early embryonic stages occurs in spatially and temporally distinct waves. Although the precise temporal onset of expression and of the HSC program and initiation of function is debatable, it is certain that it is directed by the expression of a small set of pivotal hematopoietic transcription factors. In combination, these factors create a highly complex network that, depending on the time and levels of expression, drive the determination of hematopoietic progenitors and stem cell fate. It remains a future challenge to determine all the players in this process, to examine all the precursors to HSCs, as well as to cells along the process of endothelial?to?hematopoietic transition on the single?cell level to converge transcriptomics with cell biology and function.

Hematopoietic (stem) cell development - how divergent are the roads taken? Kauts ML, Vink CS, Dzierzak E FEBS Lett. 590(22):3975-3986. doi: 10.1002/1873-3468.12372.

Work in progress... stay tuned. Complex complexity. Dionisio

[...] GFI1 expression provides an ideal novel marker to identify, isolate and study the HE cell population. The next challenge will be to determine how the combination of these transcription factors and the epigenetic machinery together dynamically orchestrate the gene regulatory networks that drive the generation of blood cells. In addition, it will be important to identify the components of the cellular niches that trigger and support the generation of the different types of blood cells by EHT [...] Altogether the Gfi1 GFP knockin model represents a powerful tool to address in the future these outstanding questions and study the EHT process in more detail as the expression of Gfi1 in the endothelium can be used to accurately identify and purify hemogenic endothelium and cells undergoing EHT. This should not only allow a better characterization of the molecular program that underpins blood cell emergence but should also lead to the identification of the specific molecular and cellular mechanisms that control the generation of different lineages during the successive waves of blood generation.

New insights into the regulation by RUNX1 and GFI1(s) proteins of the endothelial to hematopoietic transition generating primordial hematopoietic cells Roshana Thambyrajah,a Rahima Patel,a Milena Mazan,a,* Michael Lie-a-Ling,a Andrew Lilly,b Alexia Eliades,b Sara Menegatti,b Eva Garcia-Alegria,b Magdalena Florkowska,a,# Kiran Batta,a Valerie Kouskoff,b and Georges Lacaud Cell Cycle. 15(16): 2108–2114. doi: 10.1080/15384101.2016.1203491

Work in progress... stay tuned. Complex complexity. Dionisio

Rab GTPases have been reported to define the identity and transport routes of vesicles. Rab6 is one of the most extensively studied Rab proteins involved in regulating organelle trafficking and integrity maintenance. [...] Rab6a not only participates in modulating the organization of oocyte organelles, but also is a novel regulator of meiotic apparatus in mammalian oocytes. Although numerous molecules have been reported to be involved during oocyte maturation, pathways and mechanisms that modulate this process remain to be discovered. [...] the underlying mechanisms on how Rab6a modulates meiosis in mammalian oocytes remain to be explored.

Involvement of Rab6a in organelle rearrangement and cytoskeletal organization during mouse oocyte maturation. Ma R1,2,3, Zhang J2, Liu X1,2, Li L2, Liu H1, Rui R4, Gu L1, Wang Q2 Sci Rep. 2016 Mar 31;6:23560. doi: 10.1038/srep23560.

Work in progress... stay tuned. Complex complexity. Dionisio

Rab family GTPases have been well known to regulate intracellular vesicle transport, however their function in mammalian oocytes has not been addressed. [...] we identify Rab6a as an important player in modulating oocyte meiosis, specifically the chromosome/spindle organization and metaphase-anaphase transition. On the basis of our findings, two important questions are raised [...] [...] the definite molecular mechanism remains unknown, [...] Future experiments aimed to characterize the interaction between Rab6a and kinetochore proteins will help to clarify the above questions.

Rab6a is a novel regulator of meiotic apparatus and maturational progression in mouse oocytes. Hou X1, Zhang J1, Li L1, Ma R1,2, Ge J1, Han L1, Wang Q1 Sci Rep. 2016 Feb 26;6:22209. doi: 10.1038/srep22209.

complex complexity. Dionisio

There is increasing evidence that regulators of the spindle checkpoint, kinetochore-microtubule attachments, and sister chromatid cohesion are part of an interconnected mitotic regulatory circuit with two positive feedback loops and the chromosome passenger complex (CPC) at its center. If true, this conceptual breakthrough needs to be integrated into models of mitosis. In this review, we describe this circuit and point out how the double feedback loops could provide insights into the self-organization of some mitotic processes and the autonomy of every chromosome on the mitotic spindle. We also provide working models for how mitotic events may be coordinated by this circuit.

A Centromere-Signaling Network Underlies the Coordination among Mitotic Events. Trivedi P, Stukenberg PT Trends Biochem Sci. 41(2):160-74. doi: 10.1016/j.tibs.2015.11.002.

complex complexity. Dionisio

Correct orientation of the mitotic spindle determines the plane of cellular cleavage and is crucial for organ development. [...] miRNA-dependent regulation of mitotic spindle orientation is crucial for cell fate specification during mammalian neurogenesis. MicroRNAs (miRNAs) are small noncoding RNAs, which regulate gene expression posttranscriptionally by influencing mRNA stability and/or translation [...] miRNAs are required for brain development in mammals, and growing evidence suggests that they play key roles during cortical neurogenesis [...] [...] multiple miRNA families contribute to cortical neurogenesis by balancing radial glial cell maintenance through different mechanisms. [...] miR?449 might have a more general function in tissue organization through spindle orientation. Connectivity between the cortex and the putamen requires the coordinated development of these structures for timely axogenesis from newborn cortical neurons to receptor spiny neurons [...] [...] by coordinating distinct cell? and forebrain?specific programs, the miR?34/449 family emerges as a critical regulator of mammalian brain development.

MicroRNA-34/449 controls mitotic spindle orientation during mammalian cortex development. Fededa JP, Esk C, Mierzwa B, Stanyte R, Yuan S, Zheng H, Ebnet K, Yan W, Knoblich JA, Gerlich DW EMBO J. 35(22):2386-2398. DOI: 10.15252/embj.201694056

complex complexity. Dionisio

Polarized epithelial cells align the mitotic spindle in the plane of the sheet to maintain tissue integrity and to prevent malignant transformation. The orientation of the spindle apparatus is regulated by the immobilization of the astral microtubules at the lateral cortex and depends on the precise localization of the dynein-dynactin motor protein complex which captures microtubule plus ends and generates pulling forces towards the centrosomes. Recent developments indicate that signals derived from intercellular junctions are required for the stable interaction of the dynein-dynactin complex with the cortex. Here, we review the molecular mechanisms that regulate planar spindle orientation in polarized epithelial cells and we illustrate how different cell adhesion molecules through distinct and non-overlapping mechanisms instruct the cells to align the mitotic spindle in the plane of the sheet.

Cell adhesion molecule control of planar spindle orientation. Tuncay H, Ebnet K Cell Mol Life Sci. 73(6):1195-207. doi: 10.1007/s00018-015-2116-7.

complex complexity. Dionisio

Polarized epithelia form by oriented cell divisions in which the mitotic spindle aligns parallel to the epithelial plane. To orient the mitotic spindle, cortical cues trigger the recruitment of NuMA-dynein-based motors, which pull on astral microtubules via the protein LGN. We demonstrate that the junctional protein Afadin is required for spindle orientation and correct epithelial morphogenesis of Caco-2 cysts. Molecularly, Afadin binds directly and concomitantly to F-actin and to LGN. We determined the crystallographic structure of human Afadin in complex with LGN and show that it resembles the LGN-NuMA complex. In mitosis, Afadin is necessary for cortical accumulation of LGN and NuMA above the spindle poles, in an F-actin-dependent manner. Collectively, our results depict Afadin as a molecular hub governing the enrichment of LGN and NuMA at the cortex. To our knowledge, Afadin is the first-described mechanical anchor between dynein and cortical F-actin.

Concomitant binding of Afadin to LGN and F-actin directs planar spindle orientation. Carminati M1, Gallini S1, Pirovano L1, Alfieri A1, Bisi S2, Mapelli M1 Nat Struct Mol Biol. 23(2):155-63. doi: 10.1038/nsmb.3152.

complex complexity. Dionisio

Spindle positioning is essential for tissue morphogenesis and homeostasis. The signaling network synchronizing spindle placement with mitotic progression relies on timely recruitment at the cell cortex of NuMA:LGN:G?i complexes, in which NuMA acts as a receptor for the microtubule motor Dynein. To study the implication of Aurora-A in spindle orientation, we developed protocols for the partial inhibition of its activity. Under these conditions, in metaphase NuMA and Dynein accumulate abnormally at the spindle poles and do not reach the cortex, while the cortical distribution of LGN remains unperturbed. FRAP experiments revealed that Aurora-A governs the dynamic exchange between the cytoplasmic and the spindle pole-localized pools of NuMA. We show that Aurora-A phosphorylates directly the C terminus of NuMA on three Ser residues, of which Ser1969 determines the dynamic behavior and the spindle orientation functions of NuMA. Most interestingly, we identify a new microtubule-binding domain of NuMA, which does not overlap with the LGN-binding motif. Our study demonstrates that in metaphase the direct phosphorylation of NuMA by Aurora-A controls its cortical enrichment, and that this is the major event underlying the spindle orientation functions of Aurora-A in transformed and non-transformed cells in culture. Phosphorylation of NuMA by Aurora-A does not affect its affinity for microtubules or for LGN but rather determines the mobility of the protein at the spindle poles. The finding that NuMA can associate concomitantly with LGN and microtubules suggests that its microtubule-binding activity contributes to anchor Dynein-loaded microtubule +TIPs at cortical sites with LGN.

NuMA Phosphorylation by Aurora-A Orchestrates Spindle Orientation. Gallini S1, Carminati M1, De Mattia F2, Pirovano L1, Martini E3, Oldani A3, Asteriti IA2, Guarguaglini G4, Mapelli M5 Curr Biol. 26(4):458-69. doi: 10.1016/j.cub.2015.12.051.

complex complexity. Dionisio

Mitotic spindle orientation is essential for cell fate decisions, epithelial maintenance, and tissue morphogenesis. In most animal cell types, the dynein motor complex is anchored at the cell cortex and exerts pulling forces on astral microtubules to position the spindle. Early studies identified the evolutionarily conserved G?i/LGN/NuMA complex as a key regulator that polarizes cortical force generators. In recent years, a combination of genetics, biochemistry, modeling, and live imaging has contributed to decipher the mechanisms of spindle orientation. Here, we highlight the dynamic nature of the assembly of this complex and discuss the molecular regulation of its localization. Remarkably, a number of LGN-independent mechanisms were described recently, whereas NuMA remains central in most pathways involved in recruiting force generators at the cell cortex. We also describe the emerging role of the actin cortex in spindle orientation and discuss how dynamic astral microtubule formation is involved. We further give an overview on instructive external signals that control spindle orientation in tissues. Finally, we discuss the influence of cell geometry and mechanical forces on spindle orientation.

Regulation of mitotic spindle orientation: an integrated view. di Pietro F, Echard A, Morin X EMBO Rep. 17(8):1106-30. doi: 10.15252/embr.201642292.

complex complexity. Dionisio

... Dionisio

In the case of living beings – the very concept of “level” of organization becomes obscure: it suggests a value-based assessment, assigning notions like “lower” and “higher” with rather vague criteria for constructing the ladder of perfection, complexity, importance, etc. We prefer therefore the term “domain”, entities ranking equal. Domains may represent natural entities as well as purely human constructs developed in order to gain understanding of some facets of living things; living, evolved beings (e.g. viviparous animals, eukaryotic cells, etc.) as well as those abstract constructs, such as genotype and ‘niche’ which have been developed in the search for better understanding of such living things. Delimitation of such domains is sometimes a question of the dexterity of the researcher, and sometimes draws from the tradition in a given field. Such domains are not completely (canonically) translatable to each other. Rather, they interact by a process that we call here reciprocal formation. Life (including the biosphere and human cultures which are emergent within the frame of the biosphere) is unique among multi-domain systems. In contrast to purely physical systems, life is a semiotic system driven by the historical experience of lineages, interpreted and re-interpreted by the incessant turnover of both individuals and their communities. This paper provides cases of domain interrelations, and addresses two questions: (1) How do new qualities of inter-domain interaction emerge historically? (2) How do new domains (ways of understanding the world) emerge in evolution. Two approaches, physical and biosemiotic, are discussed as we seek to get a better understanding of the overarching tasks.

Levels or Domains of Life? Biosemiotics · Anton Markoš, Pranab Das DOI: 10.1007/s12304-016-9271-6 Biosemiotics ·

complex complexity. Dionisio

This essay argues that stable, heritable, habituated semiotics on one scale of life allows for opportunism, origination, and the solving of novel problems on others. This is grounded in how interpretation is neither caused nor determined by its object, such that success at interpretation simply cannot be defined by any comparison between an interpretation and its object. Rather, an interpretation is a reciprocated incorporation of a living thing and its environment, and successful if it furthers the living, interpreting thing. By applying biosemiotic theory to seemingly disparate studies of parasitic infections (Jaroslav Flegr), autonomic nervous systems (Stephen Porges), and social change (Charles Tilly) as well as the classical pragmatic notion that biology, psychology and sociology are disparate approaches to the singular, radically continuous, and perennial question of who (or what) am I (Dewey, James, Mead). I argue that the distinction (e.g.,) between voluntary and autonomic behavior is but a ghost of older dualisms, the pseudo-contradictions of matter v. mind, body v. soul, but also self v. not self. Moreover, all such pseudo-contradictions (individual v. social, sensation v. response, parasite v. host, and etc.) are resolved as scale thick, self-similar examples of semiotic transaction wherein degeneration or habituation on one scale of life allows for generative or novel interaction on another.

Me, Myself, and Semiotic Function: Finding the “I” in Biology Ostdiek, G. Biosemiotics (2016). doi:10.1007/s12304-016-9268-1

complex complexity. Dionisio

[...] thinking in terms of dyadic causality in hierarchical concentric systems and expanding the methods of systems biology to ecosystem level; or the extension of signal transduction to “social signal transduction”; or the “horizontal expansion” of neural networks and neural correlates implied in social and cultural neuroscience e in general the kind of integration that is implied or implemented by hierarchical modules and first-order emergence, as opposed to some sort of embedded heterarchy e may be leading to the possibility of reproducing mistakes in scientific tautologies that are based on a single monocontexture for mapping these complex processes [...] neglecting the scalar increase of semiotic freedom, subjectivity, cognition/volition and consciousness.

Towards a heterarchical approach to biology and cognition. Bruni LE, Giorgi F Prog Biophys Mol Biol. 119(3):481-92. doi: 10.1016/j.pbiomolbio.2015.07.005.

complex complexity. Dionisio

It is widely assumed in developmental biology and bioengineering that optimal understanding and control of complex living systems follows from models of molecular events. The success of reductionism has overshadowed attempts at top-down models and control policies in biological systems. However, other fields, including physics, engineering and neuroscience, have successfully used the explanations and models at higher levels of organization, including least-action principles in physics and control-theoretic models in computational neuroscience. Exploiting the dynamic regulation of pattern formation in embryogenesis and regeneration requires new approaches to understand how cells cooperate towards large-scale anatomical goal states. Here, we argue that top-down models of pattern homeostasis serve as proof of principle for extending the current paradigm beyond emergence and molecule-level rules. We define top-down control in a biological context, discuss the examples of how cognitive neuroscience and physics exploit these strategies, and illustrate areas in which they may offer significant advantages as complements to the mainstream paradigm. By targeting system controls at multiple levels of organization and demystifying goal-directed (cybernetic) processes, top-down strategies represent a roadmap for using the deep insights of other fields for transformative advances in regenerative medicine and systems bioengineering.

Top-down models in biology: explanation and control of complex living systems above the molecular level. Pezzulo G, Levin M J R Soc Interface. 13(124). pii: 20160555. DOI: 10.1098/rsif.2016.0555

complex complexity. Dionisio

Leaves and other lateral organs arise from a stem cell population called the shoot apical meristem (SAM). The bypass1 (bps1) mutant of Arabidopsis (Arabidopsis thaliana) produces a root-sourced compound (the bps signal) that moves to the shoot and is sufficient to arrest growth of a wild-type shoot; however, the mechanism of growth arrest is not understood. [...] the bps signal pathway has the potential for long-distance regulation through modification of CK signaling and altering gene expression. Long-distance signaling in plants is necessary for both normal development and to coordinate physiological responses. Signaling between roots and shoots is especially important for coordinating stress perception (e.g. water availability and nutrient deficiencies) with growth. Whether the bps signal is the compound produced by a drought-treated root, however, awaits a deeper understanding of the full set of responses to the bps signal and biochemical identification of this enigmatic molecule.

The Mobile bypass Signal Arrests Shoot Growth by Disrupting Shoot Apical Meristem Maintenance, Cytokinin Signaling, and WUS Transcription Factor Expression Dong-Keun Lee, David L. Parrott, Emma Adhikari, Nisa Fraser, and Leslie E. Sieburth Plant Physiol. 171(3): 2178–2190. doi: 10.1104/pp.16.00474

complex complexity. Dionisio

... Dionisio

[...] a complete set of annotated genes offers a starting point for a detailed characterization of gene functions, biochemical and regulatory pathways, or quantitative trait loci. Genes are the nodes in a biological network, which offers valuable insights into protein complexes, regulatory interactions, and metabolic processes that determine the physiological and biochemical properties of a cell, an organ or an organism [...] We believe these pointers will help the next generation of plant scientists to assess the quality of new genome sequences in a transparent and balanced manner and to formulate a standard for delivering better plant genome sequences, which are the templates for new biological discoveries.

Are We There Yet? Reliably Estimating the Completeness of Plant Genome Sequences Elisabeth Veeckman, Tom Ruttink and Klaas Vandepoele Plant Cell. 28(8): 1759–1768. doi: 10.1105/tpc.16.00349

work in progress. complex complexity. Dionisio

EF-P maintains coupling of translation and transcription by decreasing ribosome stalling at polyproline motifs. Other regulators that facilitate ribosome translocation through roadblocks to prevent premature transcription termination upon uncoupling remain to be identified. Our results implicate a universally conserved EF-P as one of these factors, with others to be discovered. Extensive experimentation guided by bioinformatics is now necessary to identify the degree to which potentially EF-P-altered transcription termination sites contribute globally to gene expression.

Maintenance of Transcription-Translation Coupling by Elongation Factor P Sara Elgamal, Irina Artsimovitch and Michael Ibba mBio. 7(5): e01373-16. doi: 10.1128/mBio.01373-16

Complex complexity. Dionisio

DNA-dependent multisubunit RNA polymerase (RNAP) is the key enzyme of gene expression and a target of regulation in all kingdoms of life. It is a complex multifunctional molecular machine which, unlike other DNA-binding proteins, engages in extensive and dynamic interactions (both specific and nonspecific) with DNA, and maintains them over a distance. These interactions are controlled by DNA sequences, DNA topology, and a host of regulatory factors. The last 15 years saw a remarkable progress in our understanding of the structure-function relationship of bacterial RNAP thanks to the advances in structural studies of this enzyme. It is hoped that in the near future, structural studies will continue to reveal fine details of transcription, especially of the events during formation of RPc, scrunching of RPinit and termination processes.

Bacterial RNA Polymerase-DNA Interaction-The Driving Force of Gene Expression and the Target for Drug Action. Lee J, Borukhov S Front Mol Biosci. 3:73. DOI: 10.3389/fmolb.2016.00073

Complex complexity. Dionisio

Light and temperature are two particularly important environmental cues for plant survival. Carbon and nitrogen are two essential macronutrients required for plant growth and development, and cellular carbon and nitrogen metabolism must be tightly coordinated. Nitrogen is one of the essential macronutrients required for plant growth and development. Nitrogen is not only a constituent of key cell molecules, such as nucleic acids, ATP, amino acids, chlorophyll, and several plant hormones, but is also the pivotal regulator of numerous biological processes, including amino acid metabolism, protein synthesis, and carbon metabolism Most of the down-regulated genes were involved in the sugar and amino acid metabolism, while most of the up-regulated genes were involved in the photosynthesis, sugar, and amino acid metabolism.

A Natural Light/Dark Cycle Regulation of Carbon-Nitrogen Metabolism and Gene Expression in Rice Shoots. Li H, Liang Z, Ding G, Shi L, Xu F, Cai H Front Plant Sci. 7:1318. doi: 10.3389/fpls.2016.01318.

Complex complexity. Dionisio

Codon usage bias is a universal feature of all genomes, but its in vivo biological functions in animal systems are not clear. Most amino acids are encoded by two to six synonymous codons. Preferential use of certain synonymous codons, a phenomenon called codon usage bias, was found in all genomes [...] These results suggest a universal mechanism in eukaryotes that uses a codon usage “code” within genetic codons to regulate co-translational protein folding. Synonymous codon mutations have been associated with many human diseases with unknown mechanisms.

Codon usage affects the structure and function of the Drosophila circadian clock protein PERIOD. Fu J, Murphy KA, Zhou M, Li YH, Lam VH, Tabuloc CA, Chiu JC, Liu Y Genes Dev. 30(15):1761-75. doi: 10.1101/gad.281030.116.

Complex complexity. Dionisio

Hematopoietic stem cells give rise to all blood cells in a differentiation process that involves widespread epigenome remodeling. All blood cells originate from hematopoietic stem cells (HSCs), which represent the apex of a differentiation cascade of progenitor cell types that gives rise to billions of new cells every day. The observed patterns of multi-lineage differentiation among MLPs and CLPs may reflect an underappreciated level of epigenetic plasticity in human hematopoietic differentiation [...] Given the medical relevance [...] and technical feasibility [...] of using DNA methylation as a clinical biomarker, it is expected that detailed DNA methylation analysis of immunodeficiencies, cardiovascular diseases, and blood cell malignancies will help advance precision medicine.

DNA Methylation Dynamics of Human Hematopoietic Stem Cell Differentiation. Farlik M1, Halbritter F1, Müller F2, Choudry FA3, Ebert P2, Klughammer J1, Farrow S3, Santoro A4, Ciaurro V4, Mathur A5, Uppal R5, Stunnenberg HG6, Ouwehand WH7, Laurenti E8, Lengauer T9, Frontini M10, Bock C11 Cell Stem Cell. 19(6):808-822. doi: 10.1016/j.stem.2016.10.019.

Complex complexity. Dionisio

[...] the question of how WUS expressions is centered and restricted within the SAM, becomes a key question in studying the stem cell homeostasis in the SAM. [...] the model makes specific predictions that can be utilized to design experiments to test the model hypothesis and to further clarify underlying mechanism of gene expression patterning within the SAM. [...] regulation of the CK receptor AHK4, through a reaction-diffusion mechanism can plausibly account for an array of observed phenomena regarding WUS patterning and thus providing one possible answer to the question of how the organizing center is centered.

Centering the Organizing Center in the Arabidopsis thaliana Shoot Apical Meristem by a Combination of Cytokinin Signaling and Self-Organization Milad Adibi,1,¤a* Saiko Yoshida,2,¤b Dolf Weijers,2 and Christian Fleck PLoS One. 11(2): e0147830. doi: 10.1371/journal.pone.0147830

Complex complexity. Dionisio

[...] patterning in SAM occurs at the level of CK reception and signaling. [...] the interplay between CK signaling, WUS/CLV feedback loop and boundary signals can account for positioning of the WUS expression, and provides directions for further experimental investigation.

Centering the Organizing Center in the Arabidopsis thaliana Shoot Apical Meristem by a Combination of Cytokinin Signaling and Self-Organization Milad Adibi,1,¤a* Saiko Yoshida,2,¤b Dolf Weijers,2 and Christian Fleck PLoS One. 11(2): e0147830. doi: 10.1371/journal.pone.0147830

Complex complexity. Dionisio

Plants have the ability to continously generate new organs by maintaining populations of stem cells throught their lives. The shoot apical meristem (SAM) provides a stable environment for the maintenance of stem cells. All cells inside the SAM divide, yet boundaries and patterns are maintained. Experimental evidence indicates that patterning is independent of cell lineage, thus a dynamic self-regulatory mechanism is required. A pivotal role in the organization of the SAM is played by the WUSCHEL gene (WUS). An important question in this regard is that how WUS expression is positioned in the SAM via a cell-lineage independent signaling mechanism.

Centering the Organizing Center in the Arabidopsis thaliana Shoot Apical Meristem by a Combination of Cytokinin Signaling and Self-Organization Milad Adibi,1,¤a* Saiko Yoshida,2,¤b Dolf Weijers,2 and Christian Fleck PLoS One. 11(2): e0147830. doi: 10.1371/journal.pone.0147830

Complex complexity. Dionisio

How molecular patterning scales to organ size is highly debated in developmental biology. [...] the deformation of the tissue transposes meristem geometry into an instructive scaling and positional input for the apical plant stem cell niche. As opposed to the classical homeostatic view on the SAM domains, this result shows a built-in adaptability of the stem cell pool to changes in tissue size. [...] as the live image acquisition and processing steadily improve, it should be possible within the next few years to test this hypothesis using single cell resolution time courses, encompassing the meristematic tissue and the precise morphological changes associated with flower development (including the cryptic bract and multiple stages of flower development). [...] the cytokinin-degrading CKXs enzymes are expressed in the SAM and procambium and affect WUS expression and meristem size (31). CKXs are also induced by cytokinin signaling (32). Whether their role in the meristem is to reinforce the robustness of WUS expression to cytokinin fluctuations via this negative feedback or to have a defining role on WUS expression remains to be fully assessed. The next major challenge is to understand how gene regulation interplays with mechanics and tissue geometry to balance the generation of new tissue and the control of the stem cell niche.

An epidermis-driven mechanism positions and scales stem cell niches in plants Jérémy Gruel,1 Benoit Landrein,1,2,* Paul Tarr,3,* Christoph Schuster,1 Yassin Refahi,1,2 Arun Sampathkumar,3 Olivier Hamant,2 Elliot M. Meyerowitz,1,3,4 and Henrik Jönsson Sci Adv. 2(1): e1500989. doi: 10.1126/sciadv.1500989

[Emphasis added] Complex complexity. Dionisio

#2279 follow-up

see paper referenced @1715-1723 starting here:

https://uncommondescent.com/intelligent-design/mystery-at-the-heart-of-life/#comment-613319

Dionisio

The scientific method itself cannot be reduced to mass and energy. Neither can language, translation, coding and decoding, mathematics, logic theory, programming, symbol systems, the integration of circuits, computation, categorizations, results tabulation, the drawing and discussion of conclusions. The prevailing Kuhnian paradigm rut of philosophic physicalism is obstructing scientific progress, biology in particular. There is more to life than chemistry. All known life is cybernetic. Control is choice-contingent and formal, not physicodynamic.

Is Life Unique? David L. Abel Life 2(1), 106-134; doi:10.3390/life2010106 http://www.mdpi.com/2075-1729/2/1/106/htm

Complex complexity. Dionisio

Axon ensheathment by specialized glial cells is an important process for fast propagation of action potentials. The rapid electrical conduction along myelinated axons is mainly due to its saltatory nature characterized by the accumulation of ion channels at the nodes of Ranvier. However, how these ion channels are transported and anchored along axons is not fully understood. Molecular analysis of ndrg4 mutants shows that expression of snap25 and nsf are sharply decreased, revealing a role of ndrg4 in controlling vesicle exocytosis. This uncovers a previously unknown function of ndrg4 in regulating vesicle docking and nodes of Ranvier organization, at least through its ability to finely tune the expression of the t-SNARE/NSF machinery.

Neuronal Ndrg4 Is Essential for Nodes of Ranvier Organization in Zebrafish Laura Fontenas, Flavia De Santis, Vincenzo Di Donato, Cindy Degerny, Béatrice Chambraud, Filippo Del Bene, Marcel Tawk http://dx.doi.org/10.1371/journal.pgen.1006459 PLOS Genetics

Complex complexity. Dionisio

Understanding their physiological roles and the factors that induce the switch to a pathological role are important when developing novel therapeutic strategies. However, much still remains to be discovered, since we have just scratched the surface of the enigma called “extracellular vesicle”.

Focus on Extracellular Vesicles: Introducing the Next Small Big Thing. Kalra H, Drummen GP, Mathivanan S Int J Mol Sci. 17(2):170. doi: 10.3390/ijms17020170.

Work in progress... stay tuned. Complex complexity. Dionisio

Intercellular communication was long thought to be regulated exclusively through direct contact between cells or via release of soluble molecules that transmit the signal by binding to a suitable receptor on the target cell, and/or via uptake into that cell. With the discovery of small secreted vesicular structures that contain complex cargo, both in their lumen and the lipid membrane that surrounds them, a new frontier of signal transduction was discovered.

Focus on Extracellular Vesicles: Introducing the Next Small Big Thing. Kalra H, Drummen GP, Mathivanan S Int J Mol Sci. 17(2):170. doi: 10.3390/ijms17020170.

a new frontier of signal transduction was discovered.? Another frontier? Oh, no! :) Complex complexity. Dionisio

Discovery of a nutrient-based conditionality is novel in the deflagellation pathway and it is yet to be determined whether this phenotype is related to gametogenesis. [...] ADF4 remains unidentified. More genes remain to be discovered in the deflagellation pathway of Chlamydomonas, genes potentially also involved in the premitotic release of centrosomes. While our screen and subsequent mapping and complementation identified several interesting new genes to investigate, a future screen of ts lethal mutant strains could uncover important genes involved in both deflagellation and mitotic progression.

A Forward Genetic Screen and Whole Genome Sequencing Identify Deflagellation Defective Mutants in Chlamydomonas, Including Assignment of ADF1 as a TRP Channel. Hilton LK, Meili F, Buckoll PD, Rodriguez-Pike JC, Choutka CP, Kirschner JA, Warner F, Lethan M, Garces FA, Qi J, Quarmby LM G3 (Bethesda). 6(10):3409-3418. doi: 10.1534/g3.116.034264.

Work in progress... stay tuned. Complex complexity. :) Dionisio

With rare exception, ciliated cells entering mitosis lose their cilia, thereby freeing basal bodies to serve as centrosomes in the formation of high-fidelity mitotic spindles. Cilia can be lost by shedding or disassembly, but either way, it appears that the final release may be via a coordinated severing of the nine axonemal outer doublet microtubules linking the basal body to the ciliary transition zone. Little is known about the mechanism or regulation of this important process. We report identification of ADF1, discovery of at least four new deflagellation loci, and identification of flagellar protein FAP16 as a player in the signaling pathway.

A Forward Genetic Screen and Whole Genome Sequencing Identify Deflagellation Defective Mutants in Chlamydomonas, Including Assignment of ADF1 as a TRP Channel. Hilton LK, Meili F, Buckoll PD, Rodriguez-Pike JC, Choutka CP, Kirschner JA, Warner F, Lethan M, Garces FA, Qi J, Quarmby LM G3 (Bethesda). 6(10):3409-3418. doi: 10.1534/g3.116.034264.

Complex complexity. :) Dionisio

One critical and perhaps overlooked aspect of the cilium is its dynamic nature: the protein composition changes constantly, the membrane is renewed, cilia length is changing…even the entire cilium can be shed and regenerated! The finding that the cilium shed EVs adds another layer of complexity to this essential organelle. Many exciting new areas in this emerging new field of ciliary EVs await exploration. The best is yet to come.

Ciliary Extracellular Vesicles: Txt Msg Organelles. Wang J, Barr MM Cell Mol Neurobiol. ;36(3):449-57. doi: 10.1007/s10571-016-0345-4.

[emphasis added] overlooked? Why? another layer of complexity? Another one? Oh, no! :) The best is yet to come. Duh! We know that! :) Complex complexity Dionisio

Cilia are sensory organelles that protrude from cell surfaces to monitor the surrounding environment. In addition to its role as sensory receiver, the cilium also releases extracellular vesicles (EVs). Until the 21st century, both cilia and EVs were ignored as vestigial or cellular junk. As research interest in these two organelles continues to gain momentum, we envision a new field of cell biology emerging.

Ciliary Extracellular Vesicles: Txt Msg Organelles. Wang J, Barr MM Cell Mol Neurobiol. ;36(3):449-57. doi: 10.1007/s10571-016-0345-4.

[emphasis added] a new field of cell biology? Another one? :) Complex complexity Dionisio

[...] moving forward to better understanding the co?regulation of the cell cycle and gene expression will necessitate utilizing techniques for high temporal and spatial resolution of cell cycle kinetics [...] [...] our proposed model of cell cycle gated transcriptional regulation brings focus back to the functional role of morphogens as cell cycle regulators, and proposes a specific and testable mechanism by which morphogens, in their roles as growth factors (how they were originally discovered), determine cell fate (based on more recent studies of pattern formation). Our goal in writing this treatise is to challenge the scientific community to use the power of strong inference (Platt 1964) to consider alternative hypotheses for the mechanisms of pattern formation.

The relationship between growth and pattern formation. Bryant SV, Gardiner DM Regeneration (Oxf). 3(2):103-22. doi: 10.1002/reg2.55.

Complex complexity Dionisio

The emergence, over developmental time, of the pattern and form of the embryo from the fertilized egg is a topic that has engaged the interest of biologists from the earliest days of modern embryology [...] It is evident that this process involves both growth and pattern formation, but the functional relationship between these processes is as yet unclear. Ultimately, we need to understand how cells use gene products to work together to create an embryo, or to regenerate a leg, in order to track backwards to understand the role that specific molecules and genes play in enabling the relevant cellular behaviors.

The relationship between growth and pattern formation. Bryant SV, Gardiner DM Regeneration (Oxf). 3(2):103-22. doi: 10.1002/reg2.55.

Complex complexity Dionisio

Successful development depends on the creation of spatial gradients of transcription factors within developing fields, and images of graded distributions of gene products populate the pages of developmental biology journals. Therefore the challenge is to understand how the graded levels of intracellular transcription factors are generated across fields of cells. The model of cell cycle gated transcriptional regulation brings focus back to the functional role of morphogens as cell cycle regulators, and proposes a specific and testable mechanism by which morphogens, in their roles as growth factors (how they were originally discovered), also determine cell fate.

The relationship between growth and pattern formation. Bryant SV, Gardiner DM Regeneration (Oxf). 3(2):103-22. doi: 10.1002/reg2.55.

Complex complexity Dionisio

Mathematics is often used to model biological systems. The precise characterization of these phenomena will require a more careful analysis of the kinetics of ductal morphogenesis. In its current state, our model has some limitations. The first is that the current model only allows for changes in histology (cellular number and arrangements) not gross morphology (increased branching). A second limitation is that the parameters were evaluated as averages and assumed to be constant over time, while variations in these values could change the predicted elongation rate and may account for the natural variation in growth rates.

A Geometrically-Constrained Mathematical Model of Mammary Gland Ductal Elongation Reveals Novel Cellular Dynamics within the Terminal End Bud. Paine I1,2, Chauviere A3, Landua J1, Sreekumar A2, Cristini V4,5,6,7, Rosen J2, Lewis MT PLoS Comput Biol. 12(4):e1004839. doi: 10.1371/journal.pcbi.1004839.

Complex complexity affects the accuracy of models applied to biology. Dionisio

E26 transformation-specific (Ets) family of transcription factors are characterized by the presence of Ets-DNA binding domain and have been found to be highly involved in hematopoiesis and various tissue differentiation. With improved proteomics and gene editing tools that are now available, therefore, future studies which elucidate the role of ESE-1 during embryonic development will provide not only better insights into ESE-1 function in specific cell differentiation pathways, but also its interactions with other Ets family members. In addition, understanding how epithelium-specific Ets factors contribute to normal embryonic development by, for example, global gene expression analysis in systemic knockdown study (Atabakhsh et al., 2012), will help us to better understand how they take part in disorders and abnormalities which share signaling pathways and gene clusters involved in embryogenesis, such as cancer. This may open new opportunities to tackle aberrant cell differentiation or repair mechanisms that pose barriers to effective treatment, while building on our current body of knowledge on how multi-member protein families function collectively.

ESE-1 in Early Development: Approaches for the Future. Lee CM, Wu J, Xia Y, Hu J Front Cell Dev Biol. 4:73. doi: 10.3389/fcell.2016.00073.

Complex complexity Dionisio

Sortilin has been shown to bind multiple ligands, and to have physiological functions beyond the nervous system. Possible roles for sortilin in the development of the embryo have not been examined. Whether this is due to redundancy of sortilin in thyroid gland function, or a question of experimental circumstances remain to be discovered. It is our hope that this structural characterization will encourage new studies of the functions of sortilin and SorCS2 in organ development.

Spatiotemporal patterns of sortilin and SorCS2 localization during organ development. Boggild S, Molgaard S, Glerup S, Nyengaard JR BMC Cell Biol. 17:8. doi: 10.1186/s12860-016-0085-9.

Complex complexity. Dionisio

Importantly, the transcriptional programs regulating the expression of specific GSL glycosyltransferases, their physical interactions and sub-Golgi compartmentalization, as well as the accessibility to their substrates are parameters that we still have not completely unravelled. […] we have little clue of how GSL synthesis is controlled. Future studies focused on the regulation of GSL metabolism, should provide a more systematic view on the GSL role in signalling and organism pathophysiology. […] a comprehensive picture of the impact of GSL composition on cell signalling and transcriptional regulation is lacking. […] only a modest number of GSLs have been studied in any real detail, thus leaving the understanding of the specific roles of most GSLs in driving differentiation processes to future research.

Glycosphingolipid–Protein Interaction in Signal Transduction Domenico Russo, Seetharaman Parashuraman and Giovanni D’Angelo Int J Mol Sci. 17(10): 1732. doi: 10.3390/ijms17101732

Complex complexity. Dionisio

[…] there are still many aspects to be clarified regarding how protein binding specificity is conferred by parameters such as the length of the acyl chains of the ceramide, the degree of unsaturation and how these features can specifically modulate signal transduction. The combination of all these parameters yields a further level of complexity, which constitute an additional information reservoir being perceived by direct protein interactors, and involved in the GSL-dependent fine tuning of cell signalling.

Glycosphingolipid–Protein Interaction in Signal Transduction Domenico Russo, Seetharaman Parashuraman and Giovanni D’Angelo Int J Mol Sci. 17(10): 1732. doi: 10.3390/ijms17101732

Complex complexity. Dionisio

[…] the extent of GSL involvement in cell regulation is not yet fully addressed. […] more effort is required to systematically identify new GSDs in the whole proteome, and to learn about their biochemical features. […] to date it is unknown how many GSD types exist, and how they are structured. […] further bioinformatics and biochemical studies are required to understand the role of GSL-glycan moieties in GSL–protein interactions. […] structural and dynamics data on GSD/GSL complexes are required to understand how each sugar residue interfaces with the surrounding amino acid counterpart. […] it will be possible in a near future to systematically reveal GSL–protein interactions.

Glycosphingolipid–Protein Interaction in Signal Transduction Domenico Russo, Seetharaman Parashuraman and Giovanni D’Angelo Int J Mol Sci. 17(10): 1732. doi: 10.3390/ijms17101732

Complex complexity. Dionisio

[...] although GSDs have been recognized to bind GSL-glycan portions with different affinities, the basic principles accounting for specificity of these interactions are still far from being understood. As a consequence, future developments in the field will probably derive from solving the following issues. To date, the rules determining how the information contained in GSL “words” is read are not understood. [...] we lack an estimation of the fraction of the proteome that interacts with specific GSLs and of protein domains/motifs involved in these interactions.

Glycosphingolipid–Protein Interaction in Signal Transduction Domenico Russo, Seetharaman Parashuraman and Giovanni D’Angelo Int J Mol Sci. 17(10): 1732. doi: 10.3390/ijms17101732

Complex complexity. Dionisio

[...] brain-enriched gangliosides, probably by their regulatory function on signalling, modulate neuronal function and contribute to neuronal development by influencing the epigenetic state of the cell. This regulatory layer adds to known mechanisms of tissue patterning such as morphogen gradients that induce the differentiation of specific cell types in a distinct spatial order.

Glycosphingolipid–Protein Interaction in Signal Transduction Domenico Russo, Seetharaman Parashuraman and Giovanni D’Angelo Int J Mol Sci. 17(10): 1732. doi: 10.3390/ijms17101732

Complex complexity. Dionisio

[...] the GSL composition of cells changes during differentiation, as a direct consequence of a change in the expression of specific GSL synthesizing enzymes. The transcriptional programmes responsible for these changes are unknown [...]

Glycosphingolipid–Protein Interaction in Signal Transduction Domenico Russo, Seetharaman Parashuraman and Giovanni D’Angelo Int J Mol Sci. 17(10): 1732. doi: 10.3390/ijms17101732

Complex complexity. Dionisio

GSLs constitute a regulatory layer acting orthogonally to the ligand–receptor–transducers module, which allows the dynamic fine-tuning of intracellular signalling. Vertebrates possess a vast repertoire of GSLs, which differ according to the sugar composition, the anomeric linkages of the glycosidic bonds, and to the extent of branching of their glycans. GSLs regulate cellular signalling pathways by interacting with components of the signal transduction machinery (i.e., hormones, receptors and, intracellular transducers).

Glycosphingolipid–Protein Interaction in Signal Transduction Domenico Russo, Seetharaman Parashuraman and Giovanni D’Angelo Int J Mol Sci. 17(10): 1732. doi: 10.3390/ijms17101732

Complex complexity. Dionisio

Glycosphingolipids (GSLs) are a class of ceramide-based glycolipids essential for embryo development in mammals. The synthesis of specific GSLs depends on the expression of distinctive sets of GSL synthesizing enzymes that is tightly regulated during development. [...] the mechanistic details of these GSL–protein interactions are often poorly understood [...] [...] the basic principles by which GSL-glycans are specifically perceived by GSDs are unknown.

Glycosphingolipid–Protein Interaction in Signal Transduction Domenico Russo, Seetharaman Parashuraman and Giovanni D’Angelo Int J Mol Sci. 17(10): 1732. doi: 10.3390/ijms17101732

Complex complexity. Dionisio

Both Petri nets and differential equations are important modeling tools for biological processes. In biology, a gradient is a graded change in concentration of specific signaling molecules, called morphogens, through a group of cells. The morphogens get produced by a cell or group of cells, called the source, and emanate from there spreading throughout the tissue. At the same time molecules get degraded in the tissue. This simultaneous production and degradation establishes a slope in concentration levels, known as the morphogen gradient. Cells in the tissue sense the morphogen concentration in their direct surroundings and respond by adopting a specific behavior. In this way morphogens have a direct effect on cell development and differentiation and are therefore of the utmost importance. For this reason, a model which furthers our understanding and analysis of the process, both from an operational as well as a denotational perspective, is of great use to the field of biology.

Modeling biological gradient formation: combining partial differential equations and Petri nets Laura M. F. Bertens, Jetty Kleijn, Sander C. Hille, Monika Heiner, Maciej Koutny and Fons J. Verbeek Nat Comput. 15(4): 665–675. doi: 10.1007/s11047-015-9531-4

Complex complexity. The authors of this paper should have consulted professor L. M. of the U. of T. in Canada who could have told them how exactly the morphogen gradients form. :) Dionisio

The brain enables animals to behaviorally adapt in order to survive in a complex and dynamic environment, but how reward-oriented behaviors are achieved and computed by its underlying neural circuitry is an open question. The BG have a parallel pathway structure suitable for conveying action commands, with both action promotion and suppression built in. [...] some PD symptoms could result from a dysfunctional D1 pathway, whereas the D2 pathway would still be functionally adequate although itself also affected by the reduced dopamine level.

Functional Relevance of Different Basal Ganglia Pathways Investigated in a Spiking Model with Reward Dependent Plasticity. Berthet P, Lindahl M, Tully PJ, Hellgren-Kotaleski J, Lansner A Front Neural Circuits. 10:53. doi: 10.3389/fncir.2016.00053.

Dionisio

When dealing with more complex reactions, such as reactions involving several components and several steps, our approach allows to recognize the various basic ‘devices’ at work and to build the whole circuitry in a cascade fashion so to figure out how the equivalent ‘electronic circuit’ effectively processes information as the reaction goes by. In particular, a suitable combination of the elementary bricks described above leads to the construction of (bio-)logic chemical gates [...] [...] efforts are still needed to enlarge this scheme in order to apply to general out-of-equilibrium regimes (for instance with time-dependent field variations).

Complete integrability of information processing by biochemical reactions Elena Agliari, Adriano Barra, Lorenzo Dello Schiavo and Antonio Moro Sci Rep. 6: 36314. doi: 10.1038/srep36314

[emphasis added] Complex complexity. :) Dionisio

Statistical mechanics provides an effective framework to investigate information processing in biochemical reactions. [...] how the thermodynamics of biochemical reactions spontaneously[?] encodes information processing. [?] These results stem from investigations scattered over different fields of biological research involving, for instance, inter-cellular and intra-cellular signalling, enzymatic cycles, ribo and toggle switches, ultra-sensitive mechanisms, DNA-computing, transcriptional and regulatory networks, and more.

Complete integrability of information processing by biochemical reactions Elena Agliari, Adriano Barra, Lorenzo Dello Schiavo and Antonio Moro Sci Rep. 6: 36314. doi: 10.1038/srep36314

[emphasis added] Complex complexity. :) Dionisio

MAP theory has the potential to provide a powerful framework to explore and understand the role of noise and dynamics in cell state transitions during normal development and also in other situations such as artificial directed reprogramming experiments. More generally, our results emphasise that stochastic fluctuations in gene expression can influence the dynamics and outcome of gene regulatory networks and highlight the importance of developing the mathematical tools to explore these aspects of developmental patterning.

Intrinsic Noise Profoundly Alters the Dynamics and Steady State of Morphogen-Controlled Bistable Genetic Switches. Perez-Carrasco R1, Guerrero P1, Briscoe J2, Page KM PLoS Comput Biol. 12(10):e1005154. doi: 10.1371/journal.pcbi.1005154.

Dionisio

A practical feature of MAP theory is that it can be extended to larger networks comprising several genes and to full kinetic reaction schemes, that include, for example, the dynamics of mRNA production and decay and discrete promoter states as well as more detailed description of the expression bursts [...]. This would offer insight not only into simple binary decisions, such as that described in this study, but also provide a way to study transitions in more complex and realistic models of cell development

Intrinsic Noise Profoundly Alters the Dynamics and Steady State of Morphogen-Controlled Bistable Genetic Switches. Perez-Carrasco R1, Guerrero P1, Briscoe J2, Page KM PLoS Comput Biol. 12(10):e1005154. doi: 10.1371/journal.pcbi.1005154.

Dionisio

Observing coordinated changes in gene expression that matched MAP predictions would support the validity of the MAP approach and allow key parameters of the biological system to be estimated. Experimental corroboration of gene expression dynamics characteristic of those predicted by the MAP would provide insight into the mechanisms controlling cell decisions and greatly strengthen the evidence underpinning the use of dynamical systems theory to model these developmental events.

Intrinsic Noise Profoundly Alters the Dynamics and Steady State of Morphogen-Controlled Bistable Genetic Switches. Perez-Carrasco R1, Guerrero P1, Briscoe J2, Page KM PLoS Comput Biol. 12(10):e1005154. doi: 10.1371/journal.pcbi.1005154.

Dionisio

A transcriptional mechanism capable of the analogue to digital conversion necessary to transform the continuous morphogen gradient into distinct domains of gene expression is the so-called genetic toggle switch. This sub-network, present in many biological contexts, consists of cross-repression between sets of transcriptional determinants that are expressed mutually exclusively in alternative cell identities.

Intrinsic Noise Profoundly Alters the Dynamics and Steady State of Morphogen-Controlled Bistable Genetic Switches. Perez-Carrasco R1, Guerrero P1, Briscoe J2, Page KM PLoS Comput Biol. 12(10):e1005154. doi: 10.1371/journal.pcbi.1005154.

Dionisio

The bistable switch, a common regulatory sub-network, is found in many biological processes. It consists of cross-repressing components that generate a switch-like transition between two possible states. In developing tissues, bistable switches, created by cross-repressing transcriptional determinants, are often controlled by gradients of secreted signalling molecules—morphogens. These provide a mechanism to convert a morphogen gradient into stripes of gene expression that determine the arrangement of distinct cell types.

Intrinsic Noise Profoundly Alters the Dynamics and Steady State of Morphogen-Controlled Bistable Genetic Switches. Perez-Carrasco R1, Guerrero P1, Briscoe J2, Page KM PLoS Comput Biol. 12(10):e1005154. doi: 10.1371/journal.pcbi.1005154.

Dionisio

During tissue development, patterns of gene expression determine the spatial arrangement of cell types. In many cases, gradients of secreted signalling molecules-morphogens-guide this process by controlling downstream transcriptional networks. A mechanism commonly used in these networks to convert the continuous information provided by the gradient into discrete transitions between adjacent cell types is the genetic toggle switch, composed of cross-repressing transcriptional determinants.

Intrinsic Noise Profoundly Alters the Dynamics and Steady State of Morphogen-Controlled Bistable Genetic Switches. Perez-Carrasco R1, Guerrero P1, Briscoe J2, Page KM PLoS Comput Biol. 12(10):e1005154. doi: 10.1371/journal.pcbi.1005154.

Dionisio

[...] the tonsils contribute to first line immunity against foreign pathogens in the upper aero-digestive tract [...] [...] the risk of deep neck infection is significantly increased among patients who have undergone a tonsillectomy. Additional research is needed to explore the possible mechanisms behind these findings.

Tonsillectomy and the Risk for Deep Neck Infection—A Nationwide Cohort Study Ying-Piao Wang,1,2,3 Mao-Che Wang,2,4 Hung-Ching Lin,1,3 Kuo-Sheng Lee,1,3 and Pesus Chou PLoS One. 10(4): e0117535. doi: 10.1371/journal.pone.0117535

Dionisio

The human palatine tonsils and the nasopharyngeal tonsil were considered the defense mechanism against ingested or inhaled foreign pathogens. The current findings suggest that the tubal tonsils possess abilities of active transportation of foreign antigens, and will act as inductive and effector sites in the mucosal immune system. Our results also indicated a significant difference in roles of immune responses among individual tonsillar organs, suggesting functional sub-compartmentalization.

Functions of tonsils in the mucosal immune system of the upper respiratory tract using a novel animal model, Suncus murinus. Suzumoto M1, Hotomi M, Fujihara K, Tamura S, Kuki K, Tohya K, Kimura M, Yamanaka N Acta Otolaryngol. 126(11):1164-70. DOI: 10.1080/00016480600681593

Dionisio

The role of the human appendix is still not clearly identified. Recent literature shows that the human appendix might be regarded as a part of the immune system because many immunoglobulin-producing cells can be detected in normal appendix mucosa. Therefore, due to the change of immune function after removing the human appendix, people with appendectomy are found to be associated with increased risk of pulmonary tuberculosis, colorectal cancer, rheumatoid arthritis, and ischemic heart disease. More research is needed to examine issues related to the pathogenesis of appendectomy associated with pyogenic liver abscess.

Appendectomy correlates with increased risk of pyogenic liver abscess A population-based cohort study in Taiwan Kuan-Fu Liao, MD, MS,a,b Shih-Wei Lai, MD,c,d Cheng-Li Lin, MS,c,e and Sou-Hsin Chien, MDa Medicine (Baltimore). 95(26): e4015. doi: 10.1097/MD.0000000000004015

Dionisio

The mechanism between the relationship with an appendectomy and subsequent disease still remains unknown. [...] female subjects who undergo an appendectomy have a higher risk of RA than comparison female subjects. The vermiform appendix is part of gut-associated lymphoid tissue (GALT) which may be considered an immune organ in a natural environment. Previous studies showed that changes in immune function after an appendectomy may be associated with a variety of diseases such as coeliac disease, ulcerative colitis, Crohn’s disease, Clostridium difficile infection, acute myocardial infraction, and pulmonary tuberculosis. Some evidence has shown that the appendix may be associated with substantial lymphatic tissue which is thought to play a specific role in immune function.

An Appendectomy Increases the Risk of Rheumatoid Arthritis: A Five-Year Follow-Up Study Ya-Mei Tzeng,#1 Li-Ting Kao,2 Senyeong Kao,2 Herng-Ching Lin,3 Ming-Chieh Tsai,#4 and Cha-Ze Lee PLoS One. 10(5): e0126816. doi: 10.1371/journal.pone.0126816

Dionisio

[...] the risk of gallstones was significantly higher for patients within 5 years after an appendectomy. The specific pathway linking an appendectomy to gallstone formation, especially in women, deserves attention and further study. Future more extensive investigations possibly collecting laboratory investigations in longitudinal follow-up study design with larger sample sizes are warranted to further ascertain the link between appendectomy and its consequent risks on gallstones. [...] the appendix is recognized as an essential component of mammalian mucosal immune function, particularly B-lymphocyte-mediated immune responses and extrathymically derived T-lymphocytes. As one of the guardians of the internal body from the hostile external environment being removed after an appendectomy, the "safe house" for commensal bacteria is damaged. Impaired immunity may facilitate proliferation of pathogens which induce regional infectious diseases, such as Crohn’s disease. Further clinical or basic studies are needed to elucidate whether gallstones are consequences or comorbidities of appendicitis/an appendectomy.

Increased Risk of Clinically Significant Gallstones following an Appendectomy: A Five-Year Follow-Up Study Shiu-Dong Chung,#1,2,3 Chung-Chien Huang,#4 Herng-Ching Lin,#3,4 Ming-Chieh Tsai,5 and Chao-Hung Chen PLoS One. 11(10): e0165829. doi: 10.1371/journal.pone.0165829

[emphasis added] Dionisio

The real function of the human appendix has long been argued. Although it might not be considered vital, recent studies have observed an association between removal of the appendix and GI tract diseases, such as an elevated risk for Crohn’s disease and a reduced risk for ulcerative colitis. In a population-based study, increased risks of malignancy in digestive systems, such as colorectal cancer, were found following an appendectomy. Moreover, the incidence of gall bladder cancer increased 2-fold among patients who underwent an appendectomy.

Increased Risk of Clinically Significant Gallstones following an Appendectomy: A Five-Year Follow-Up Study Shiu-Dong Chung,#1,2,3 Chung-Chien Huang,#4 Herng-Ching Lin,#3,4 Ming-Chieh Tsai,5 and Chao-Hung Chen PLoS One. 11(10): e0165829. doi: 10.1371/journal.pone.0165829

Dionisio

Findings suggest that the appendix is well-suited to serve as a “safe house” for biofilm formation to preserve and protect commensal bacteria needed in the colon. More evidence has accumulated associating an appendectomy with chronic inflammatory disorders of the gastrointestinal (GI) tract closer to the appendix, such as ulcerative colitis and Crohn’s disease. Cancer risks following an appendectomy were also observed in GI tract systems including colon cancer and the reproductive system including prostate cancer

Increased Risk of Clinically Significant Gallstones following an Appendectomy: A Five-Year Follow-Up Study Shiu-Dong Chung,#1,2,3 Chung-Chien Huang,#4 Herng-Ching Lin,#3,4 Ming-Chieh Tsai,5 and Chao-Hung Chen PLoS One. 11(10): e0165829. doi: 10.1371/journal.pone.0165829

Dionisio

Although the vermiform appendix is commonly considered a vestigial organ, adverse health consequences after an appendectomy have garnered increasing attention. We found an increased risk of a subsequent gallstone diagnosis within 5 years after an appendectomy. Although the vermiform appendix in humans is commonly considered a vestigial organ, a certain immune function is believed to be involved based on its association with substantial lymphatic tissues.

Increased Risk of Clinically Significant Gallstones following an Appendectomy: A Five-Year Follow-Up Study Shiu-Dong Chung,#1,2,3 Chung-Chien Huang,#4 Herng-Ching Lin,#3,4 Ming-Chieh Tsai,5 and Chao-Hung Chen PLoS One. 11(10): e0165829. doi: 10.1371/journal.pone.0165829

Dionisio

The gut microbiome is being more widely recognized for its association with positive health outcomes, including those distant to the gastrointestinal system. As the types of prebiotics available diversify, so too will our understanding of the range of microbes able to degrade them, and the extent to which body sites can be impacted by their consumption. The human colon harbours 1011–1012 live microorganisms per gram that, along with those in the small intestine, comprise the gut microbiota. In healthy individuals, this vast community acts symbiotically with the host to improve intestinal integrity, metabolism, and compete against pathogenic organisms. More human clinical trials are needed, particularly longitudinal, that have the power to observe subtle changes over the duration of ingestion, as well as carefully controlled animal studies to explain how these effects occur. Given the success of prebiotics in the attenuation of many diseases and improvement of health at distant sites, these food-grade saccharides are becoming key components of a health-promoting diet.

Distant Site Effects of Ingested Prebiotics Stephanie Collins and Gregor Reid Nutrients. 8(9): 523. doi: 10.3390/nu8090523

Dionisio

Optimal nutrition early in life is exceptionally important when rapid brain development occurs. In human infants, breast milk is recognized as the optimal form of nutrition due to its many roles in supporting infant growth and development. Some human milk bioactives thought to exert beneficial effects on developing brain such as docosahexaenoic acid (DHA), milk fat globule membrane (MFGM), and lactoferrin have been individually studied, but knowledge of their combined impact is lacking. It is well understood that neuroanatomical development does not progress uniformly across all regions and pathways and that differential maturation contributes to differential development of cognitive capacities. [...] a combination of bioactive ingredients in early life diet can influence structural brain development.

Early life diet containing prebiotics and bioactive whey protein fractions increased dendritic spine density of rat hippocampal neurons. Waworuntu RV, Hanania T, Boikess SR, Rex CS, Berg BM Int J Dev Neurosci. 55:28-33. doi: 10.1016/j.ijdevneu.2016.09.001.

Dionisio

Microorganisms exhibit a wide range of environmental adaptations and lifestyles encoded by their genomes. The genetic code alone only scratches the surface of complexity in the biological network of a living cell.

Protein Languages Differ Depending on Microorganism Lifestyle Joseph J. Grzymski1,* and Adam G. Marsh PLoS One. 9(5): e96910. doi: 10.1371/journal.pone.0096910

Complex complexity Dionisio

Neurons are highly compartmentalized cells with functionally distinct cytoplasmic/membrane domains (dendrites, axons, and somas), [...] Local mRNA translation mediates the adaptive responses of axons to extrinsic signals [...] [...] intricate regulation of compartment-specific mRNA translation in mammalian CNS axons supports the formation and maintenance of neural circuits in vivo. [...] local protein synthesis regulates synaptic transmission and axon maintenance.

Dynamic Axonal Translation in Developing and Mature Visual Circuits Toshiaki Shigeoka,1,4 Hosung Jung,2,4,5,? Jane Jung,2 Benita Turner-Bridger,1 Jiyeon Ohk,2 Julie Qiaojin Lin,1 Paul S. Amieux,3 and Christine E. Holt1 Cell. 166(1): 181–192. doi: 10.1016/j.cell.2016.05.029

Complex complexity Dionisio

The spinal cord integrates and relays somatosensory input, leading to complex motor responses. Research over the past couple of decades has identified transcription factor networks that function during development to define and instruct the generation of diverse neuronal populations within the spinal cord. A number of studies have now started to connect these developmentally defined populations with their roles in somatosensory circuits. Here, we review our current understanding of how neuronal diversity in the dorsal spinal cord is generated and we discuss the logic underlying how these neurons form the basis of somatosensory circuits.

Making sense out of spinal cord somatosensory development. Lai HC, Seal RP, Johnson JE Development 143: 3434-3448; doi: 10.1242/dev.139592

Complex complexity. Dionisio

More than a passive effector of gene expression, mRNA translation (protein synthesis) by the ribosome is a rapidly tunable and dynamic molecular mechanism. [...] our understanding of regulation of the ribosome and mRNA translation during normal brain development is only in its early stages. mRNA translation is emerging as a key driver of the rapid and timed regulation of spatiotemporal gene expression in the developing nervous system, including the neocortex. Understanding the multivariate control of mRNA translation by ribosomal complex specificity will be critical to reveal the intricate mechanisms of normal brain development and pathologies of neurodevelopmental disorders.

The frontier of RNA metamorphosis and ribosome signature in neocortical development. Kraushar ML, Popovitchenko T, Volk NL, Rasin MR Int J Dev Neurosci. pii: S0736-5748(16)30004-1. doi: 10.1016/j.ijdevneu.2016.02.003.

Complex complexity. Dionisio

Surprisingly, we did not observe any NOGGIN induction in [...] This suggests important differences in the inductive rules between vertebrates, and will require further investigations [...] Surprisingly, we found in our system that NOGGIN was critical in positioning fate domains over a wide range of density in our human gastruloids, which strongly suggests a role for NOGGIN in positioning the primitive streak and mesendodermal populations during early human gastrulation. How activators and inhibitors spread between epithelial cells is obscure.

A Balance between Secreted Inhibitors and Edge Sensing Controls Gastruloid Self-Organization. Etoc F, Metzger J, Ruzo A, Kirst C, Yoney A, Ozair MZ, Brivanlou AH, Siggia ED Dev Cell. 39(3):302-315. doi: 10.1016/j.devcel.2016.09.016. http://www.cell.com/developmental-cell/pdf/S1534-5807(16)30638-4.pdf http://www.cell.com/cms/attachment/2072728012/2068550133/mmc2.pdf

Complex complexity. Dionisio

In some instances, mathematics beyond the usual gene-by-gene differential equations is required to tie together qualitative facts that are intrinsic to development Thus, if one hopes to explain morphogenesis in engineering terms that can be used in a predictive way to guide regenerative medicine, some astute phenomenological descriptions of subprocesses are necessary.

A Balance between Secreted Inhibitors and Edge Sensing Controls Gastruloid Self-Organization. Etoc F, Metzger J, Ruzo A, Kirst C, Yoney A, Ozair MZ, Brivanlou AH, Siggia ED Dev Cell. 39(3):302-315. doi: 10.1016/j.devcel.2016.09.016. http://www.cell.com/developmental-cell/pdf/S1534-5807(16)30638-4.pdf http://www.cell.com/cms/attachment/2072728012/2068550133/mmc2.pdf

Complex complexity. Dionisio

The earliest aspects of human embryogenesis remain mysterious. Our knowledge about morphogen/inhibitor induction is very limited in mammals. The gastrulating embryo is a remarkable example of a self-organizing system: from a seemingly homogeneous epiblast layer, cells are allocated into the three germ layers as the body plan unfolds. There is a complex interplay between geometry and signaling.

A Balance between Secreted Inhibitors and Edge Sensing Controls Gastruloid Self-Organization. Etoc F, Metzger J, Ruzo A, Kirst C, Yoney A, Ozair MZ, Brivanlou AH, Siggia ED Dev Cell. 39(3):302-315. doi: 10.1016/j.devcel.2016.09.016. http://www.cell.com/developmental-cell/pdf/S1534-5807(16)30638-4.pdf http://www.cell.com/cms/attachment/2072728012/2068550133/mmc2.pdf

Complex complexity. Dionisio

[...] investigators are now frequently observing that the complexity of structural order emerging in cultures of PPSCs and MPSCs can be astonishing. Whether a blastocyst possesses specific patterning information for axis formation and positioning/shaping of a PS [...] and how it is encoded is still a matter of debate among embryologists.

Self-Organization of Stem Cell Colonies and of Early Mammalian Embryos: Recent Experiments Shed New Light on the Role of Autonomy vs. External Instructions in Basic Body Plan Development. Denker HW Cells 5(4), 39; doi:10.3390/cells5040039

Complex complexity Dionisio

One of the lessons already learned from these studies is a reconciliation of Turing?driven mechanisms and Wolpertian positional information as it is clear that the former drives the emergence of localised signalling sources that, when stabilised, act as references for patterning: positional information is a result of genetically encoded self?assembly. There are more [lessons] to come.

Organoids and the genetically encoded self-assembly of embryonic stem cells David A. Turner, Peter Baillie-Johnson and Alfonso Martinez Arias Bioessays. 38(2): 181–191. doi: 10.1002/bies.201500111

There are more [lessons] to come? Work in progress... stay tuned. Complex complexity. Dionisio

[...] the interface between genetically encoded self?assembled organoids with designer bioengineering promises much, but the harvesting of this interaction will bring about an interesting reassessment of developmental biology, more focused on molecular mechanisms than on patterns.

Organoids and the genetically encoded self-assembly of embryonic stem cells David A. Turner, Peter Baillie-Johnson and Alfonso Martinez Arias Bioessays. 38(2): 181–191. doi: 10.1002/bies.201500111

interesting reassessment of developmental biology? Will this be in the biology textbooks soon? Complex complexity. Dionisio

There might be surprises ahead as the molecular mechanisms underlying the generation of organoids might be different from those mediating the corresponding organs in vivo. The organoids in their own way represent a new challenge to the molecular systems that underlie pattern formation and we might find that although the final structures are very similar to those produced in embryos, their paths are different.

Organoids and the genetically encoded self?assembly of embryonic stem cells David A. Turner, Peter Baillie?Johnson and Alfonso Martinez Arias Bioessays. 38(2): 181–191. doi: 10.1002/bies.201500111

There might be surprises ahead? more surprises? a new challenge ? another one? Complex complexity :) Dionisio

Embryonic development transforms a single celled zygote into a collection of multicellular tissues and organs arranged into structures we call organisms. A key element in this transformation is the ordered generation of cellular diversity which depends on the progressive allocation of cells to specific fates and their self?assembly into three dimensional structures according to emergent rules encoded in those fates. This process depends on programs encoded in, and decoded by, signaling and transcriptional networks.

Organoids and the genetically encoded self?assembly of embryonic stem cells David A. Turner, Peter Baillie?Johnson and Alfonso Martinez Arias Bioessays. 38(2): 181–191. doi: 10.1002/bies.201500111

Complex complexity Dionisio

Understanding the mechanisms of early embryonic patterning and the timely allocation of specific cells to embryonic regions and fates as well as their development into tissues and organs, is a fundamental problem in Developmental Biology. [...] the events underlying the development of these systems are not purely linked to “self?organization,” as often suggested, but rather to a process of genetically encoded self?assembly where genetic programs encode and control the emergence of biological structures.

Organoids and the genetically encoded self?assembly of embryonic stem cells David A. Turner, Peter Baillie?Johnson and Alfonso Martinez Arias Bioessays. 38(2): 181–191. doi: 10.1002/bies.201500111

Complex complexity Dionisio

[...] axons, migrating cells and cells in developmental fields interpret secreted guidance cues and signaling proteins that encode positional information in the form of chemogradient distributions that are stored in the ECM. [...] proteins that have been observed between signal producing and receiving cells are cytoneme-associated and are neither extracellular nor ECM-bound. [...] the cytonemes that mediate Dpp and FGF signaling contact the ECM directly in ways that involve both integrins and specific HSPG interactions.

Cells must express components of the planar cell polarity system and extracellular matrix to support cytonemes Hai Huang and Thomas B Kornberg eLife. 5: e18979. doi: 10.7554/eLife.18979

Complex complexity. Dionisio

The language of development has a small vocabulary of signaling proteins that consists in part of Fibroblast growth factor (FGF) and Bone morphogenic proteins such as Drosophila Decapentaplegic (Dpp). This language may be used in most or all metazoan organs.

Cells must express components of the planar cell polarity system and extracellular matrix to support cytonemes Hai Huang and Thomas B Kornberg eLife. 5: e18979. doi: 10.7554/eLife.18979

How is that same development language used within different contexts? What controls that? Dionisio

The embryos of animals develop in a controlled manner that ensures that their tissues and organs form properly and at the right time. These processes depend on molecules called morphogens that are distributed throughout the embryo in specific ways and that are dispersed via extensions that protrude from the surfaces of cells. These extensions, called cytonemes, transport the morphogens across the distances that separate cells and transfer these molecules to target cells via direct contact. [...] the extracellular space is organized and regulated [...] [...] the extracellular matrix is essential for developmental signaling. Future challenges include understanding how the layers of the extracellular matrix form and how information is encoded in these layers for the cytonemes to decipher as they navigate to their targets.

Cells must express components of the planar cell polarity system and extracellular matrix to support cytonemes Hai Huang and Thomas B Kornberg eLife. 5: e18979. doi: 10.7554/eLife.18979

organized and regulated? how? More layers of information? More control levels? How do the cytonemes detect and decipher the encoded information? Complex complexity. :) Dionisio

[...] an exchange of morphogens alone by diffusion seems highly unlikely. Instead, due to flexibility of mesenchymal cell projections including tunneling nanotubes, it is probable that most of morphogens are transported this path at the right time, punctual site, and dosed amount. Whether microvesicles are involved in the transport of morphogens within the renal stem/progenitor cell niche has to be explored.

Special Morphological Features at the Interface of the Renal Stem/Progenitor Cell Niche Force to Reinvestigate Transport of Morphogens During Nephron Induction Will W. Minuth* and Lucia Denk Biores Open Access. 5(1): 49–60. doi: 10.1089/biores.2015.0039

They were wrong.... again? Oh, well. What else is new? Complex complexity. :) Dionisio

The transport of morphogens within the renal stem/progenitor cell niche was in the past more simplified described than it really seems to be. Previously it was assumed that mesenchymal and epithelial cells in the renal stem/progenitor cell niche have an intimate contact and that the reciprocal transport of morphogens during induction of a nephron is based exclusively on diffusion. However, recent morphological findings illustrate that mesenchymal and epithelial cell bodies are separated by a striking interface consisting of textural extracellular matrix.

Special Morphological Features at the Interface of the Renal Stem/Progenitor Cell Niche Force to Reinvestigate Transport of Morphogens During Nephron Induction Will W. Minuth* and Lucia Denk Biores Open Access. 5(1): 49–60. doi: 10.1089/biores.2015.0039

Oh, well. What else is new? Complex complexity. Dionisio

[...] it was presupposed that all morphogens are transported by diffusion. However, earlier and actual literature including present morphological data contradict the general assumption that all involved morphogens are transported by diffusion between mesenchymal and epithelial cells.

Special Morphological Features at the Interface of the Renal Stem/Progenitor Cell Niche Force to Reinvestigate Transport of Morphogens During Nephron Induction Will W. Minuth* and Lucia Denk Biores Open Access. 5(1): 49–60. doi: 10.1089/biores.2015.0039

What did they base that wrong presupposition on? A 7-year-old child would have figured out that diffusion alone would not do the work in many cases. Where is the humility in science? Where are the open-minded researchers? Complex complexity. Dionisio

Formation of a nephron depends on reciprocal signaling of different morphogens between epithelial and mesenchymal cells within the renal stem/progenitor cell niche. Previously, it has been surmised that a close proximity exists between both involved cell types and that morphogens are transported between them by diffusion. However, actual morphological data illustrate that mesenchymal and epithelial stem/progenitor cell bodies are separated by a striking interface.

Special Morphological Features at the Interface of the Renal Stem/Progenitor Cell Niche Force to Reinvestigate Transport of Morphogens During Nephron Induction Will W. Minuth* and Lucia Denk Biores Open Access. 5(1): 49–60. doi: 10.1089/biores.2015.0039

Complex complexity. Dionisio

gpuccio @2215: [referring to paper referenced @2214]

Are there really people who believe that two identical twins, if they possessed the same information, would have only one mind? Has human stupidity really got to that point?

The text "it is generally accepted that..." leaves open the possibility that some people may not accept it. The meaning of that part of the text did not hit me until you brought it up. Good catch! Thank you. Sorry, but unfortunately the answer to your questions might be very discouraging, perhaps even scary. Dionisio

The physico-chemical processes occurring inside cells are under the computational control of genetic (DNA) and epigenetic (internal structural) programming. [...] scant attention has been paid to [...] the molecular biological interpreters that give phenotypic meaning to the sequence information that is quite faithfully replicated during cellular reproduction. The near universality and age of the mapping from nucleotide triplets to amino acids embedded in the functionality of the protein synthetic machinery speaks to the early development of a system of coding which is still extant in every living organism. The early phylogeny of the amino acyl-tRNA synthetase enzymes is discussed in such terms, leading to the conclusion that the observed optimality of the genetic code is a natural outcome of the processes of self-organization that produced it.

The generation of meaningful information in molecular systems Peter R. Wills DOI: 10.1098/rsta.2015.0066 Philosophical Transactions of the Royal Society A: Mathematical, Physical & Engineering Sciences

This paper includes some pseudoscientific statements that may be ignored. Dionisio

Dioniso: "For example, it is generally accepted that identical twins have distinct minds despite exactly the same blueprints for their construction." Are there really people who believe that two identical twins, if they possessed the same information, would have only one mind? Has human stupidity really got to that point? gpuccio

Science periodically experiences a discovery of a whole new area of investigation. Two minds identical in terms of the initial design are typically considered to be different if they possess different information. For example, it is generally accepted that identical twins have distinct minds despite exactly the same blueprints for their construction.

The Space of Possible Mind Designs Roman Yampolskiy DOI: 10.1007/978-3-319-21365-1_23 In book: Artificial General Intelligence, pp.218-227

Did anybody say "design"? :) Dionisio

Importins and exportins influence gene expression by enabling nucleocytoplasmic shuttling of transcription factors. Although importins/exportins are known to regulate spatiotemporal kinetics of NF-?B and other transcription factors governing innate immunity, the mechanistic details of these interactions have not been elucidated and mathematically modelled. Deciphering complex interactions of innate immune responses would thus require specific mechanistic models of regulation of these three transcription factors. By including interactions involving importin-? and exportin we bring the modelling of spatiotemporal kinetics of transcription factors to a more mechanistic level.

Importins promote high-frequency NF-?B oscillations increasing information channel capacity. Korwek Z, Tudelska K, Na??cz-Jawecki P, Czerkies M, Prus W, Markiewicz J, Kocha?czyk M, Lipniacki T Biol Direct. 11(1):61. DOI: 10.1186/s13062-016-0164-z

Dionisio

Eukaryotic transcription factors in the NF-?B family are central components of an extensive genetic network that activates cellular responses to inflammation and to a host of other external stressors. This network consists of feedback loops that involve the inhibitor I?B?, numerous downstream functional targets, and still more numerous binding sites that do not appear to be directly functional. Under steady stimulation, the regulatory network of NF-?B becomes oscillatory, and temporal patterns of NF-?B pulses appear to govern the patterns of downstream gene expression needed for immune response. Understanding how the information from external stress passes to oscillatory signals and is then ultimately relayed to gene expression is a general issue in systems biology. The regulatory network based on the transcription factor NF-?B has a broad range of influence in eukaryotic cells, which includes orchestrating immune response to inflammation, apoptosis, proliferation, differentiation and many more activities.

Molecular stripping, targets and decoys as modulators of oscillations in the NF-?B/I?B?/DNA genetic network Zhipeng Wang, Davit A. Potoyan, and Peter G. Wolynes J R Soc Interface. 13(122): 20160606. doi: 10.1098/rsif.2016.0606

Complex complexity. Dionisio

Biological systems use a variety of mechanisms to deal with the uncertain nature of their external and internal environments. Two of the most common motifs employed for this purpose are the incoherent feedforward (IFF) and feedback (FB) topologies. [...] the effectiveness and preference of one motif over the other lies mostly in the practical implementation details and not in their structural properties. [...] the combined circuit has an effective gain that is greater than the sum or product of the gains of the individual components. [...] FB and IFF architectures, though at first glance can appear very different, can be considered as two sides of the same coin. The main differences between the two lie in the ability to adapt to dynamic input fluctuations and the biological constrains in their implementations.

Implementation Considerations, Not Topological Differences, Are the Main Determinants of Noise Suppression Properties in Feedback and Incoherent Feedforward Circuits Gentian Buzi and Mustafa Khammash* Teresa M. Przytycka, Editor PLoS Comput Biol. 12(6): e1004958. doi: 10.1371/journal.pcbi.1004958

Complex complexity. :) Dionisio

The regulation of mRNA degradation is a critical step in the gene expression process. [...] codon optimality is a major determinant of mRNA stability in Saccharomyces cerevisiae [...] [...] the association between codon optimality and mRNA stability may be a broadly conserved phenomenon. Determining relative contributions from direct mechanistic links and selective pressures will be a key step to a fuller understanding of mRNA stability control.

Analysis of the association between codon optimality and mRNA stability in Schizosaccharomyces pombe. Harigaya Y, Parker R BMC Genomics. 17(1):895. DOI: 10.1186/s12864-016-3237-6

Dionisio

Accumulating evidence indicates that the capacity to integrate information in the brain is a prerequisite for consciousness. Integrated Information Theory (IIT) of consciousness attracts scientists who investigate consciousness owing to its explanatory and predictive powers for understanding the neural properties of consciousness. Although its neurobiological basis remains unclear, consciousness may be related to certain aspects of information processing [...] An unanswered question is how integrated information should be practically calculated taking account of the both directions of information flow, using an empirical distribution. An unresolved difficulty that impedes practical calculation of integrated information is how to partition a system. One way to work around this difficulty would be to develop optimization algorithms to quickly find a partition that well approximates the MIP. Besides the practical problem of finding the MIP, there remains a theoretical problem of how to compare integrated information across different partitions. It is unclear whether there is a reasonable theoretical foundation that adjudicates the best normalization scheme. [...] it is unclear if the normalization factor, which is proposed for systems whose states are represented by discrete variables, is appropriate for systems whose states are represented by continuous variables. Further investigations are required to resolve the practical and theoretical issues related to the MIP. [...] more research is required to determine whether such an approach is a valid method to define global interactions [...]

Measuring Integrated Information from the Decoding Perspective. Oizumi M, Amari S, Yanagawa T, Fujii N, Tsuchiya N PLoS Comput Biol. 12(1):e1004654. doi: 10.1371/journal.pcbi.1004654

Dionisio

A quest for a systems-level neuroscientific basis of anesthetic-induced loss and return of consciousness has been in the forefront of research for the past 2 decades. Recent advances toward the discovery of underlying mechanisms have been achieved using experimental electrophysiology, multichannel electroencephalography, magnetoencephalography, and functional magnetic resonance imaging. By the careful dosing of various volatile and IV anesthetic agents to the level of behavioral unresponsiveness, both specific and common changes in functional and effective connectivity across large-scale brain networks have been discovered and interpreted in the context of how the synthesis of neural information might be affected during anesthesia. The results of most investigations to date converge toward the conclusion that a common neural correlate of anesthetic-induced unresponsiveness is a consistent depression or functional disconnection of lateral frontoparietal networks, which are thought to be critical for consciousness of the environment. A reduction in the repertoire of brain states may contribute to the anesthetic disruption of large-scale information integration leading to unconsciousness. In future investigations, a systematic delineation of connectivity changes with multiple anesthetics using the same experimental design, and the same analytical method will be desirable. The critical neural events that account for the transition between responsive and unresponsive states should be assessed at similar anesthetic doses just below and above the loss or return of responsiveness. There will also be a need to identify a robust, sensitive, and reliable measure of information transfer. Ultimately, finding a behavior-independent measure of subjective experience that can track covert cognition in unresponsive subjects and a delineation of causal factors versus correlated events will be essential to understand the neuronal basis of human consciousness and unconsciousness.

Disconnecting Consciousness: Is There a Common Anesthetic End Point? Hudetz AG, Mashour GA. Anesth Analg. 123(5):1228-1240. DOI: 10.1213/ANE.0000000000001353

Dionisio

Please note that the paper referenced @2206 was previously referenced @2199, but some of the quoted text is different. Dionisio

Although many influential high-profile studies on consciousness have been published over the last 25 years, it is not clear how much of this research is directly relevant for understanding the neural basis of conscious experience [...] [...] although there are theories of consciousness that have made it to standard neuroscience textbooks, the puzzle of consciousness persists and the need for focused interdisciplinary attacks on the problem is as timely as ever. [...] given the accelerating pace of technical improvements it is necessary that the cognitive neuroscience community steps up the game too and asks: how can our experimental paradigms specifically target the neural basis of consciousness?

Still wanted—the mechanisms of consciousness! Jaan Aru, and Talis Bachmann Front Psychol. 6: 5. doi: 10.3389/fpsyg.2015.00005

Dionisio

The field of stoichiogenomics aims at understanding the influence of nutrient limitations on the elemental composition of the genome, transcriptome, and proteome. The 20 amino acids and the 4?nt differ in the number of nutrients they contain, such as nitrogen (N). Thus, N limitation shall theoretically select for changes in the composition of proteins or RNAs through preferential use of N-poor amino acids or nucleotides, which will decrease the N-budget of an organism. While these N-saving mechanisms have been evidenced in microorganisms, they remain controversial in multicellular eukaryotes. The absence of stoichiogenomic signal despite strong N limitation within a powerful phylogenetic framework casts doubt on the existence of stoichiogenomic mechanisms in metazoans.

No Evidence That Nitrogen Limitation Influences the Elemental Composition of Isopod Transcriptomes and Proteomes. Francois CM, Duret L, Simon L, Mermillod-Blondin F, Malard F, Konecny-Dupré L, Planel R, Penel S, Douady CJ, Lefébure T Mol Biol Evol. 33(10):2605-20. doi: 10.1093/molbev/msw131

Does this relate to the paper referenced @2204? Complex complexity. Work in progress... stay tuned. :) Dionisio

Genomes are composed of long strings of nucleotide monomers (A, C, G and T) that are either scavenged from the organism’s environment or built from metabolic precursors. [...] differential nitrogen availability, due to differences in host environment and metabolic inputs, contributes to changes in codon bias and genome composition. Specifically, adaptation to low nitrogen availability results in reduced nitrogen content in nucleotide sequences. These results reveal a previously hidden relationship between cellular metabolism and genome evolution and provide new insight into how genome sequence evolution can be influenced by adaptation to different diets.

Dietary nitrogen alters codon bias and genome composition in parasitic microorganisms Emily A. Seward and Steven Kelly Genome Biology201617:226 DOI: 10.1186/s13059-016-1087-9

Is this about flexible/robust built-in adaptation mechanisms in the biological systems associated with their micro-evolution? Complex complexity. :) Dionisio

[...] phagocytes and crq are important actors regulating the interaction between a host and its microbiome. [...] depending on the microbe, humoral and cellular immune responses can act at distinct stages of infection. In this context, phagocytosis acts as a main defense mechanism against pathogens that may escape AMPs or modulate their production. [...] plasmatocytes, Crq, and phagocytosis are all key factors in the immune response, and that losing crq induces a state of chronic immune induction. The ability of a host to control microbes decreases with age, a phenomenon called immune senescence. The causes of immune senescence remain elusive, but the loss of immune cells with age and a decline in their ability to phagocytose have been suggested. [...] Crq is essential in development and aging to protect against environmental microbes. Further characterization of the crq mutation in Drosophila will provide an interesting conceptual framework to understand auto-inflammatory diseases and their repercussions on immune homeostasis and host health.

The Drosophila CD36 Homologue croquemort Is Required to Maintain Immune and Gut Homeostasis during Development and Aging Aurélien Guillou, Katia Troha, Hui Wang, Nathalie C. Franc, and Nicolas Buchon Mary O'Riordan, Editor PLoS Pathog. 12(10): e1005961. doi: 10.1371/journal.ppat.1005961

Complex complexity. Work in progress… stay tuned. :) Dionisio

Mounting appropriate immune responses against pathogens is critical for the survival of all animals. Mechanisms to both eliminate microbes and resolve infection by returning the immune system to basal activity are necessary to maintain an adequate and balanced immune response. Alterations in these responses can lead to immune deficiency or auto-inflammation. Yet, to date, how these mechanisms are coordinated upon infection remains unclear.

The Drosophila CD36 Homologue croquemort Is Required to Maintain Immune and Gut Homeostasis during Development and Aging Aurélien Guillou, Katia Troha, Hui Wang, Nathalie C. Franc, and Nicolas Buchon Mary O'Riordan, Editor PLoS Pathog. 12(10): e1005961. doi: 10.1371/journal.ppat.1005961

Complex complexity. Work in progress… stay tuned. :) Dionisio

Phagocytosis is an ancient mechanism central to both tissue homeostasis and immune defense. Both the identity of the receptors that mediate bacterial phagocytosis and the nature of the interactions between phagocytosis and other defense mechanisms remain elusive. [...] Crq plays a key role in maintaining immune and organismal homeostasis.

The Drosophila CD36 Homologue croquemort Is Required to Maintain Immune and Gut Homeostasis during Development and Aging Aurélien Guillou, Katia Troha, Hui Wang, Nathalie C. Franc, and Nicolas Buchon Mary O'Riordan, Editor PLoS Pathog. 12(10): e1005961. doi: 10.1371/journal.ppat.1005961

Complex complexity. Work in progress… stay tuned. :) Dionisio

Like any other field, the field of consciousness research benefits from a careful distinction between the concepts involved. [...] the field of consciousness research will benefit from an integrated view of evidence from various experimental and neuroscientific paradigms [...] Future research on consciousness will also benefit from careful distinction of the exact roles of different frontal lobe areas [...]

Commentary: Is the Frontal Lobe Involved in Conscious Perception? Marnix Naber,* and Jan Brascamp Front Psychol. 6: 1736. doi: 10.3389/fpsyg.2015.01736

Dionisio

[...] although there are theories of consciousness that have made it to standard neuroscience textbooks, the puzzle of consciousness persists and the need for focused interdisciplinary attacks on the problem is as timely as ever. It might be that for understanding the NCC we need more advanced tools for measuring and controlling neural processes. However, it is important to note that such sophisticated tools will not be sufficient for closing in on the mechanisms of consciousness [...]

Still wanted—the mechanisms of consciousness! Jaan Aru1,* and Talis Bachmann Front Psychol. 6: 5. doi: 10.3389/fpsyg.2015.00005

Dionisio

Phenomenal consciousness is currently the target of a booming neuroscientific research program, which intends to find the neural correlates of consciousness (NCCs). [...] it is not obvious what makes something fall under the term “NCC.” The neuroscience of consciousness searching for NCC2.0s can in principle progress like any other science: by competing in the game of predictive fit.

A Deeper Look at the “Neural Correlate of Consciousness” Sascha Benjamin Fink Front Psychol. 7: 1044. doi: 10.3389/fpsyg.2016.01044

Dionisio

One of the most mysterious phenomena in science is the nature of conscious experience. Due to its subjective nature, a reductionist approach is having a hard time in addressing some fundamental questions about consciousness. The material basis of subjective conscious phenomena remains one of the most difficult scientific questions.

Using category theory to assess the relationship between consciousness and integrated information theory. Tsuchiya N, Taguchi S, Saigo H Neurosci Res. 107:1-7. doi: 10.1016/j.neures.2015.12.007. http://www.sciencedirect.com/science/article/pii/S0168010215002989

Complex complexity. Work in progress… stay tuned. :) Dionisio

[...] any attempt to deal with hierarchical multi-scales using conventional techniques is doomed to failure no matter how much data we collect. This makes the application of conventional mathematics to an overall view of life extremely difficult. Many biological phenomena do not have adequate mathematical representations. This is because living systems are deploying logic and semiotics beyond our conception of mathematics into the domain of computation, which is on its part much richer than the standard Turing machine paradigm. [...] the development of a unified research framework in biomathematics and biocomputation to explore the relationship between morphogenesis and the development, evolution and degeneration of brain functions across multiple layers, domains and perspectives.

Integral Biomathics reloaded: 2015 Plamen L. Simeonov, Ron Cottam http://dx.doi.org/10.1016/j.pbiomolbio.2015.10.001 Progress in Biophysics and Molecular Biology Volume 119, Issue 3, Pages 728–733 Integral Biomathics: Life Sciences, Mathematics, and Phenomenological Philosophy

Complex complexity. Work in progress… stay tuned. :) Dionisio

The objective of a biology-driven mathematics pursued by Integral Biomathics is indeed an appraisal of the second-order types of nested logic in place of the first-order logic with which most standard mathematicians are familiar. Today theoretical biologists are intensifying their efforts to overcome reductionism in order to comprehend the reality of life.

Integral Biomathics reloaded: 2015 Plamen L. Simeonov, Ron Cottam http://dx.doi.org/10.1016/j.pbiomolbio.2015.10.001 Progress in Biophysics and Molecular Biology Volume 119, Issue 3, Pages 728–733 Integral Biomathics: Life Sciences, Mathematics, and Phenomenological Philosophy

Complex complexity. Work in progress… stay tuned. :) Dionisio

Many biological phenomena do not have adequate mathematical representations. This is because living systems use structures that are not yet grasped by our present conceptions of mathematics and computation. In particular they are circularly organized and they use recursions. Mathematics at the present time deals only superficially with circular organization or the consequences of recursion. We just have not yet found a way to adequately deal with such matters!

Integral Biomathics reloaded: 2015 Plamen L. Simeonov, Ron Cottam http://dx.doi.org/10.1016/j.pbiomolbio.2015.10.001 Progress in Biophysics and Molecular Biology Volume 119, Issue 3, Pages 728–733 Integral Biomathics: Life Sciences, Mathematics, and Phenomenological Philosophy

Complex complexity. Work in progress... stay tuned. :) Dionisio

@2192: "...an ingenious invention of nature..." Wow! nature is really smart! Maybe a Nobel Prize should be awarded to nature too? :) BTW, how did nature come up with such an ingenious invention? How did it develop it? How did it test it? How did it implement it? Dionisio

Wrapping DNA around protein beads, to form so-called nucleosomes, is an ingenious invention of nature allowing the condensation of an enormous amount of genomic information into a tiny package. [...] the chromatin provides an extra layer of control over gene expression. This control is exerted through a plethora of chemical modifications of the histones and the DNA, so-called epigenetic marks, which alter chromatin structure and provide specific recognition sites for regulatory factors. The relationship between chromatin modifications and gene expression is a hen-and-egg problem. It is further complicated by the fact that multiple chromatin modifications can occur in the same locus and that the same modification can have different roles at different sites of a locus. We are far from understanding the causal relationship between transcriptional activity and chromatin marking. [...] in order to fully understand the molecular mechanisms that control the timing of the floral meristem, a combination of tissue- or cell type-specific analyses with genome-wide and computational approaches will be necessary in the future. FLC must be the single most-studied gene that is epigenetically regulated, and the diversity and complexity of the regulatory pathways culminating in its control are astounding.

Chromatin and Epigenetics Anna Amtmann Hong Ma Doris Wagner Plant Physiol. 168(4): 1185–1188. doi: 10.1104/pp.15.01023 PMCID: PMC4528774 Focus on Chromatin/Epigenetics

Dionisio

Although the presence of RNA modifications such as the 5’ cap structure and internal N6-methyladenosine (m6A) in mRNAs has been known for decades (Desrosiers et al. 1974; Perry and Kelley 1974; Dubin and Taylor 1975; Shatkin 1976), the flood gates have only just been opened for a new wave of research describing other modifications and their impact on gene regulation. The four base constituents of RNA are modified by over 100 different RNA modifications. This additional complexity of RNA is essential for basic functions, such as gene regulation and translation. While the RNA modifying ‘writers’ have been investigated in plants, studies on potential ‘erasers’ and ‘readers’ are lacking. Further research is needed to elucidate the mechanisms and functional roles of mRNA modifications such as alternative splicing, and stress responses.

Deciphering the epitranscriptome: A green perspective. Burgess A1,2, David R1,2, Searle IR J Integr Plant Biol. 58(10):822-835. doi: 10.1111/jipb.12483.

Dionisio

Despite the observational association studies’ aim to increase our understanding of the environmental impact on phenotype development, the underlying mechanisms linking subtle methylation changes to an eventual phenotype remained unaddressed. We are now starting to gain insight into the function and relevance of such small changes in methylation from genes, such as NR3C1. The emerging approach, combining both NGS and single cell technology, will allow a far more in depth analysis of this phenomenon and its importance overall as well as on the single-cell level. The recognition and appreciation of the functional significance of such small differences in methylation highlights the importance of unaddressed EWAS questions, particularly in identifying the correct confounding variables. Being able to control for different sources of variability has become more important in order to ensure the small changes observed are genuine biological differences and to be able to subsequently interpret them.

DNA methylation: conducting the orchestra from exposure to phenotype? Fleur A. D. Leenen1, 2, Claude P. Muller1, 2 and Jonathan D. Turner1 Clinical Epigenetics The official journal of the Clinical Epigenetics Society DOI: 10.1186/s13148-016-0256-8

Work in progress... stay tuned. Complex complexity. Dionisio

The classical view that only the protein coding regions of the genome are transcribed into RNA is rapidly changing, and it is widely accepted that non-protein-coding intergenic regions are pervasively transcribed into distinct transcripts, which constitute a large fraction of transcriptional output at least in terms of species, if not quantity [1] and [2]. […] many of the lncRNAs are not essential for life, and instead they play modulatory roles or are required in particular tissues under certain conditions. It will be important for future studies to identify the precise environment or molecular context wherein lncRNAs execute their essential biological functions.

Lessons from reverse-genetic studies of lncRNAs http://dx.doi.org/10.1016/j.bbagrm.2015.06.011 Shinichi Nakagaw Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms Volume 1859, Issue 1, Pages 177–183 SI: Clues to long noncoding RNA taxonomy

Dionisio

The central dogma of biology states that genetic information hard-wired into DNA is transcribed into RNA and subsequently translated into proteins. However, for several decades, scientists have noted the existence and studied the function of RNAs that are not translated, formally known as noncoding RNAs (ncRNAs) It is known that more than 70% of mammalian genomes are transcribed, yet the vast majority of transcripts do not code for proteins. Are these noncoding transcripts merely transcriptional noise, or do they serve a biological purpose? While the number of mammalian genes is quite close to that of simpler invertebrates, mammals are far more complex animals, and it is the vast difference in the number of lncRNAs which could explain such surprising differences in complexity Some ncRNAs may not have measurable functions under experimental conditions, but could become functional under environmental stress […] […] with the emergence of new tools—especially those in the field of phenotype assessment and genome editing—to study ncRNA functions in cells, researchers will be able to advance knowledge of this family of transcripts.

Discovery and functional analysis of lncRNAs: Methodologies to investigate an uncharacterized transcriptome ? • Kaori Kashi, Lindsey Henderson, Alessandro Bonetti, Piero Carninci • http://dx.doi.org/10.1016/j.bbagrm.2015.10.010 • Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms • Volume 1859, Issue 1, Pages 3–15 • SI: Clues to long noncoding RNA taxonomy

Dionisio

A remarkable feature of the adult brain is its plasticity in response to experience. It is evident that the coordination and synchronicity of biochemical processes related to RNA metabolism, including its modification, editing and structural variation, bidirectionally contribute to the language and internal dialog of the cell and are critically important for driving experience-dependent plasticity in the brain and adaptive behavior. However, it is also clear that much more work is needed in this area Although it has been studied for many years, RNA localization within neurons remains a frontier for investigation in the context of the adult brain and experience-dependent plasticity. Determining how a cell organizes its molecular components is one of the great remaining challenges in neuroscience.

Evolving insights into RNA modifications and their functional diversity in the brain. Nainar S1, Marshall PR2,3, Tyler CR2,3, Spitale RC1, Bredy TW Nat Neurosci. 19(10):1292-8. doi: 10.1038/nn.4378.

Dionisio

[…] differential gene expression sets up different cell fates and the major developmental axes of the early embryo. Knowledge of genomic, transcriptomic, proteomic, and metabolomic processes paves the way to understanding how differential gene expression establishes cell heterogeneity during normal development and disease states.

High-Sensitivity Mass Spectrometry for Probing Gene Translation in Single Embryonic Cells in the Early Frog (Xenopus) Embryo Camille Lombard-Banek,1 Sally A. Moody,2 and Peter Nemes1 Front Cell Dev Biol. 4: 100. doi: 10.3389/fcell.2016.00100

Dionisio

Lymphatic vessels have historically been viewed as passive conduits for fluid and immune cells, but this perspective is increasingly being revised as new functions of lymphatic vessels are revealed. [...] we still lack an adequate understanding of the organ- and vessel-type-specific molecular differences of endothelium, how they contribute to specific functions of lymphatic vessels, and how the establishment and maintenance of these features are regulated

Heterogeneity in the lymphatic vascular system and its origin Maria H. Ulvmar and Taija Mäkinen Cardiovasc Res. 111(4): 310–321. doi: 10.1093/cvr/cvw175

Dionisio

Memory and Learning Gene Linked to Obesity http://www.genengnews.com/gen-news-highlights/memory-and-learning-gene-linked-to-obesity/81253350

The CNS contributes to obesity and metabolic disease; however, the underlying neurobiological pathways remain to be fully established. [...] the neural pathways that actively respond to HFD feeding and mediate adiposity under overnutrition remain incompletely characterized. Although it is clear that the CNS participates in the biological responses to obesogenic conditions, the detailed neurobiological pathways remain unclear. [...] neuronal Rap1 is a major regulator of leptin sensitivity and acts as a mediator of leptin resistance in obesity. One of the most important questions arising from this study concerns how overnutrition leads to the activation of Rap1 in the CNS.

Neuronal Rap1 Regulates Energy Balance, Glucose Homeostasis, and Leptin Actions. Kaneko K, Xu P, Cordonier EL, Chen SS, Ng A, Xu Y, Morozov A, Fukuda M Cell Rep. 16(11):3003-15. doi: 10.1016/j.celrep.2016.08.039.

Dionisio

Despite the substantial knowledge on the pathological features, the mechanism initiating or leading to the development of AD remains poorly understood. Neurodegenerative diseases are complex disorders where various cell types are involved in the overall pathology. Regeneration in such diseases, the causes of which are not fully elucidated, may seem a far dream; however, findings in model organisms may herald a promise for advancement toward cellular therapies. The field requires novel approaches and new model organisms to tackle the hurdles of reverting neuronal death, preventing synaptic degeneration, ameliorating cognitive decline, and inducing the plasticity of neural stem/progenitor cells.

Neural stem/progenitor cells in Alzheimer’s disease Gizem Tincer,a,b Violeta Mashkaryan,a,b Prabesh Bhattarai,a,b and Caghan Kizila,b Yale J Biol Med. 89(1): 23–35.

Dionisio

Zebrafish, as a valuable reductionist model, thus, could help us to directly address the role of individual factors on stem cells and distinguish the positive and negative inflammatory cues, which could be tested in mammalian systems to find candidates for clinical trials. This understanding may help designing regenerative therapies in neurodegenerative environment of human brains by tweaking the inflammatory milieu and its players, such as IL4.

IL4/STAT6 Signaling Activates Neural Stem Cell Proliferation and Neurogenesis upon Amyloid-?42 Aggregation in Adult Zebrafish Brain. Bhattarai P1, Thomas AK2, Cosacak MI1, Papadimitriou C1, Mashkaryan V1, Froc C3, Reinhardt S4, Kurth T4, Dahl A4, Zhang Y2, Kizil C5 Cell Rep. 17(4):941-948. doi: 10.1016/j.celrep.2016.09.075.

Dionisio

Two Proteins Identified That Offer New Hope for Alzheimer’s Patients http://www.genengnews.com/gen-news-highlights/two-proteins-identified-that-offer-new-hope-for-alzheimer-s-patients/81253348 Dionisio

Sloppy work detected. I apologize for unacceptable errors that have been made when posting research paper references. Using tools like Zotero, which detects repeated entries of the same paper, one can find unintended redundancies. However, sometimes I have skipped that important procedure and may have posted paper references without ensuring duplicate instances of the same quoted text. Please, note that in some cases the same paper is referenced in more than one post, but the quoted text is different in each sub-post. That is done intentionally for various reasons. Either to save the post in order to avoid losing it for technical issues that may arise at that moment, or just to reduce the amount of quoted text within a single post, thus making it a little easier to read it. In those intentional cases the posts should appear together, on the same date, one after another. However if the same paper is found referenced in more than one post, but on distant dates, and the quoted text coincides (at least partially) then that could be a mistake. For example, just noticed the article:

Actomyosin ring driven cytokinesis in budding yeast Franz Meitinger, Saravanan Palani doi:10.1016/j.semcdb.2016.01.043 Seminars in Cell & Developmental Biology Volume 53, Pages 19–27 Cytokinetic ring construction and constriction Fibroblast Growth factor signalling

appears referenced twice in this thread but on distant dates: July 3 and September 20 of this year. That's obviously a mistake resulting from not having set the necessary controls and also because I wasn't careful enough to ensure this kind of mistake doesn't happen. Now, all that said, I noticed a kind-of funny thing associated with this embarrassing mistake I made: the quoted text is not quite the same. That seems to indicate that on each separate occasion different parts of the text were selected for the posted quotes. A small portion of the quoted text coincides, but the rest are different. That may tell us that the given paper is really juicy. :)

July 3, 2016 at 2:28 pm Cytokinesis is the final process in the cell cycle that physically divides one cell into two. […] cytokinesis is driven by a contractile actomyosin ring (AMR) and the simultaneous formation of a primary septum, which serves as template for cell wall deposition. AMR assembly, constriction, primary septum formation and cell wall deposition are successive processes and tightly coupled to cell cycle progression to ensure the correct distribution of genetic material and cell organelles among the two rising cells prior to cell division. The role of the AMR in cytokinesis and the molecular mechanisms that drive AMR constriction and septation are the focus of current research. […] cells have […] robust systems that ensure high fidelity in coordinating cell division processes. Research over the last two decades has identified essential components of the cell division machinery as well as their complex interactions throughout the cell cycle. Structural information, investigations into the molecular mechanisms and of key and regulatory components have given insight into how the AMR drives cytokinesis. However, we do not completely understand the basic mechanisms that drive and coordinate AMR constriction and septum formation. A future milestone in the field will be to establish an in vitro system that is able to simulate in vivo characteristics of the cell division machinery. This would allow one to investigate the underlying mechanisms in a fully tunable manner. In vivo evidence has demonstrated that the formation of extracellular matrix and the involved membrane associated proteins might be essential for the function of the AMR and even for its assembly. The implementation of these aspects in an in vitro system will be challenging.

September 20, 2016 at 1:27 am […] we do not completely understand the basic mechanisms that drive and coordinate AMR constriction and septum formation. The role of the AMR in cytokinesis and the molecular mechanisms that drive AMR constriction and septation are the focus of current research. […] how budding yeast cells orchestrate the multitude of molecular mechanisms that control AMR driven cytokinesis in a spatio-temporal manner to achieve an error free cell division. [?] […] the function of the AMR is optimized to meet the special requirements of the particular organism/cell type. […] the complex network of interactions between the plasma membrane and the AMR could form redundancy to provide a certain amount of robustness to the system. How the actin cables are organized in budding yeast is unknown and comparative studies have not been performed to date. How Mlc2 contributes to AMR constriction is not currently understood. The motor domain of Myo1, the regulatory myosin light chain Mlc2 and actin dynamics clearly contribute to AMR constriction. The molecular mechanism of the latter two and which role the primary septum plays remains to be fully elucidated. It is unclear why the AMR breaks in Inn1 or Chs2 deficient mutants that cannot form a primary septum […] […] efficient AMR constriction and primary septum formation are interdependent. Whether Rho1 directly regulates cell cleavage is not known. Rho1 is in addition to its function in AMR assembly the major regulator of secondary septum formation. This requires sequential Rho1 activation and inhibition steps in a spatiotemporal manner to allow the successive formation of the AMR and secondary septum and subsequent cell separation.

Please, post a comment with a warning about another duplicate case (quoted text overlap) that you may encounter here. Simply indicate the post numbers so I can review them. Thank you. I'll try hard to prevent this from happening again. Dionisio

#2170 addendum butifnot October 9, 2016 at 3:01 am Dionisio

For survival and growth, bacteria move in liquid environment by rotating a long filamentous organelle, the flagellum. The bacterial flagellum is a huge extracellular assembly composed of more than 20,000 subunits of about 30 different proteins. Most of the component proteins are translocated into the central channel of the growing flagellum via the flagellar protein export apparatus driven by proton motive force and ATP hydrolysis, and go through the channel to the growing tip for their assembly.

Insight into the flagella type III export revealed by the complex structure of the type III ATPase and its regulator Katsumi Imada,a,1,2 Tohru Minamino,b,1 Yumiko Uchida,a Miki Kinoshita,a,b and Keiichi Namba Proc Natl Acad Sci U S A. 113(13): 3633–3638. doi: 10.1073/pnas.1524025113 PMCID: PMC4822572 Microbiology

Dionisio

[...] the structure of the complex between FlgN and its substrates is not known [...] When it is time for FliD to be exported, FliT binds and escorts FliD to the membrane for its export and the assembly of the filament-capping structure.

Proc Natl Acad Sci U S A. 113(35):9798-803. doi: 10.1073/pnas.1607845113. Recognition and targeting mechanisms by chaperones in flagellum assembly and operation. Khanra N1, Rossi P1, Economou A2, Kalodimos CG3.

How does it determine when it's time to act? Dionisio

The classical paradigm states that the structure of a protein is related to its function. However, it has been shown that at least 30% of the human genome has no specific structure, including the whole gene or part of it, and that these regions generally bind to other proteins or DNA [...] IDPs behave very differently than globular proteins, leading to a complex regulation of the mechanism of protein-protein recognition by changes in protein conformation. Our results are in agreement with previous experimental studies, allowing a clear picture of how p53 is regulated by phosphorylation and giving new insights into how post-translational modifications can regulate the function of IDPs.

Phosphorylation Regulates the Bound Structure of an Intrinsically Disordered Protein: The p53-TAZ2 Case. Ithuralde RE, Turjanski AG PLoS One. 11(1):e0144284. doi: 10.1371/journal.pone.0144284.

Dionisio

Post-translational modifications (PTMs) produce significant changes in the structural properties of intrinsically disordered proteins (IDPs) by affecting their energy landscapes. PTMs can induce a range of effects, from local stabilization or destabilization of transient secondary structure to global disorder-to-order transitions, potentially driving complete state changes between intrinsically disordered and folded states or dispersed monomeric and phase-separated states.

Modulation of Intrinsically Disordered Protein Function by Post-translational Modifications. Bah A, Forman-Kay JD. J Biol Chem. 291(13):6696-705. doi: 10.1074/jbc.R115.695056.

Dionisio

Biologically active but floppy proteins represent a new reality of modern protein science. These intrinsically disordered proteins (IDPs) and hybrid proteins containing ordered and intrinsically disordered protein regions (IDPRs) constitute a noticeable part of any given proteome. Functionally, they complement ordered proteins, and their conformational flexibility and structural plasticity allow them to perform impossible tricks and be engaged in biological activities that are inaccessible to well folded proteins with their unique structures. [...] despite their simplified amino acid sequences, IDPs/IDPRs are complex entities often resembling chaotic systems, are structurally and functionally heterogeneous, and can be considered an important part of the structure-function continuum. Furthermore, IDPs/IDPRs are everywhere, and are ubiquitously engaged in various interactions characterized by a wide spectrum of binding scenarios and an even wider spectrum of structural and functional outputs.

Dancing Protein Clouds: The Strange Biology and Chaotic Physics of Intrinsically Disordered Proteins. Uversky VN1. J Biol Chem. 291(13):6681-8. doi: 10.1074/jbc.R115.685859.

Dionisio

The process of DNA segregation is a crucial stage of the bacterial cell cycle and it depends on the precise coordination with other cellular events. [...] pSM19035 and TP228 despite sharing the same type Ib partitioning system employ distinct segregation mechanisms. [...] which event occurs first? If ParR assembly into a super-helical structure occurs first, then the macromolecular complex may recruit parC. Otherwise, the centromere might function as a scaffold for ParR oligomerization. TubY seems to be a regulator protein that modulates TubZ assembly (Oliva et al., 2012) and also acts as a transcriptional activator (Ge et al., 2014b) but the exact molecular mechanisms remain elusive. It is still common for new partitioning systems to be discovered in plasmids, phages, and on chromosomes. Together with a growing body of molecular insights these will help to broaden our understanding of DNA trafficking during bacterial cell division and in particular how DNA is attached to the CBP during segrosome formation and then to the motor protein through the segrosome.

Segrosome Complex Formation during DNA Trafficking in Bacterial Cell Division María A. Oliva Front Mol Biosci. 3: 51. doi: 10.3389/fmolb.2016.00051

Dionisio

gpuccio: Thank you for writing such an encouraging and supportive message, which has additional value because it comes from someone who has unambiguously promoted the fascinating concept of biological controlling procedures and has demonstrated genuine passion for keeping biology research truthful and humble. I've learned much from your insightful articles and commentaries. I look forward to reading more of your interesting OPs in the days ahead. I know you're serious about what you write, hence it takes time to produce a valuable article on such a complex topic as the controlling procedures underlying the multilevel regulatory networks and signaling pathways orchestrated within the marvelous biological systems we observe. Please, keep working on it and delight us with another juicy article to discuss. I'm also working intensively on gathering as much information as I can and will try to share the most interesting ones with the serious readers in this site. This is also a humbling learning experience for me. Dionisio

Dionisio: Your contributions on this thread are one of the best things happening at UD! Please, go on with your wonderful work. :) gpuccio

#2169 addendum Pindi September 1, 2016 at 9:41 pm Pindi September 2, 2016 at 2:34 am Both posts were about irrelevant issues unrelated to science. Dionisio

Here are some (not all) participants in this thread: bornagain77 December 21, 2014 at 10:34 am bornagain77 December 21, 2014 at 1:14 pm bornagain77 December 21, 2014 at 1:15 pm bornagain77 December 23, 2014 at 9:19 pm bornagain77 December 24, 2014 at 6:20 pm bornagain77 June 21, 2015 at 7:50 am bornagain77 June 21, 2015 at 7:51 am bornagain77 June 21, 2015 at 7:52 am bornagain77 July 3, 2015 at 12:54 pm Axel December 21, 2014 at 12:20 pm Axel January 7, 2015 at 8:43 am Seversky December 21, 2014 at 1:01 pm Seversky December 23, 2014 at 7:48 pm Seversky December 24, 2014 at 5:36 pm Seversky December 24, 2014 at 5:50 pm mahuna December 21, 2014 at 3:33 pm PeterJ December 23, 2014 at 1:04 am Quest January 1, 2015 at 9:38 am AVS January 7, 2015 at 2:19 pm AVS January 7, 2015 at 3:09 pm AVS January 7, 2015 at 4:01 pm AVS January 7, 2015 at 4:15 pm Joe January 7, 2015 at 7:32 pm gpuccio January 7, 2015 at 6:22 am gpuccio January 7, 2015 at 6:28 am gpuccio January 8, 2015 at 6:31 am gpuccio February 14, 2015 at 6:40 am gpuccio October 31, 2015 at 1:03 am gpuccio October 31, 2015 at 4:16 am gpuccio November 17, 2015 at 7:12 am gpuccio November 17, 2015 at 10:26 am gpuccio November 29, 2015 at 6:13 am gpuccio December 2, 2015 at 5:38 am gpuccio December 2, 2015 at 10:43 am gpuccio December 16, 2015 at 6:39 am gpuccio July 14, 2016 at 2:41 am gpuccio July 14, 2016 at 8:32 am gpuccio October 1, 2016 at 1:44 am gpuccio October 5, 2016 at 3:26 pm William J Murray February 14, 2015 at 5:45 am Upright BiPed December 16, 2015 at 9:50 am Upright BiPed December 16, 2015 at 2:04 pm Dionisio

Defining the molecular nature of these interactions continues to be an essential step toward the understanding of these intriguing DNA binding proteins.

ParB Partition Proteins: Complex Formation and Spreading at Bacterial and Plasmid Centromeres Barbara E. Funnell Front Mol Biosci. 3: 44. doi: 10.3389/fmolb.2016.00044

Dionisio

A large segment of the proteome consists of disordered regions, yet in most cases, little is known about their mechanisms and functions. What are the roles of protein disorder in cell biology, and how do intrinsically disordered proteins function?

Cell. 166(5):1074-7. doi: 10.1016/j.cell.2016.08.012. Illuminating the Dark Proteome.

Dionisio

Large Tumors Destroyed by Innate/Adaptive Immunotherapy Combo http://www.genengnews.com/gen-news-highlights/large-tumors-destroyed-by-innate-adaptive-immunotherapy-combo/81253360

Dionisio

These clinical data together with the preclinical studies in this report support further clinical investigation of poxvirus-based active immunotherapy with immune checkpoint blockade to address the high unmet need for cancer patients who do not respond to immune checkpoint blockade alone.

Poxvirus-Based Active Immunotherapy with PD-1 and LAG-3 Dual Immune Checkpoint Inhibition Overcomes Compensatory Immune Regulation, Yielding Complete Tumor Regression in Mice. Foy SP1, Sennino B1, dela Cruz T1, Cote JJ1, Gordon EJ1, Kemp F1, Xavier V1, Franzusoff A1, Rountree RB1, Mandl SJ1. PLoS One. 11(2):e0150084. doi: 10.1371/journal.pone.0150084.

Dionisio

Checkpoint blockade with antibodies specific for cytotoxic T lymphocyte-associated protein (CTLA)-4 or programmed cell death 1 (PDCD1; also known as PD-1) elicits durable tumor regression in metastatic cancer, but these dramatic responses are confined to a minority of patients. This suboptimal outcome is probably due in part to the complex network of immunosuppressive pathways present in advanced tumors, which are unlikely to be overcome by intervention at a single signaling checkpoint. These results demonstrate the capacity of an elicited endogenous immune response to destroy large, established tumors and elucidate essential characteristics of combination immunotherapies that are capable of curing a majority of tumors in experimental settings typically viewed as intractable.

Eradication of large established tumors in mice by combination immunotherapy that engages innate and adaptive immune responses. Moynihan KD1,2,3, Opel CF1,4, Szeto GL1,2,3, Tzeng A1,2, Zhu EF1,4, Engreitz JM5,6, Williams RT7, Rakhra K1, Zhang MH1, Rothschilds AM1,2, Kumari S1, Kelly RL1,2, Kwan BH1,2, Abraham W1, Hu K2, Mehta NK1,2, Kauke MJ1,4, Suh H1, Cochran JR8,9,10, Lauffenburger DA1,2,3, Wittrup KD1,2,4, Irvine DJ Nat Med. 2016 doi: 10.1038/nm.42

Dionisio

The three stop codons UAA, UAG, and UGA signal the termination of mRNA translation. As a result of a mechanism that is not adequately understood, they are normally used with unequal frequencies. In highly expressed genes stop codon usage is compositionally and structurally consistent with highly efficient translation termination signals. The causes of the uneven use of synonymous codons, named codon usage bias or codon bias, are not yet fully understood. The strong relationship between stop codon identity and base context of the proximal 3’-UTR can be explained by a common structural function related with the efficiency of translation termination, or with functional activities connected with processes involving mRNA metabolism.

Selective forces and mutational biases drive stop codon usage in the human genome: a comparison with sense codon usage Edoardo Trotta BMC Genomics. 17: 366. doi: 10.1186/s12864-016-2692-4

Dionisio

Understanding the regulatory mechanisms controlling how DNA is converted to RNA, which is then translated into protein sequences, is a key challenge in molecular biology. [...] prokaryotes and single-cell eukaryotes can actively regulate protein expression levels by adjusting codon usage and tRNA anticodon abundance [...] Whether codon usage is used to fine-tune levels of protein translation in mammals is actively debated. [...] the rate at which a protein can be synthesized from an mRNA is influenced by the relationship between tRNA anticodon abundance and codon frequency within the mRNA. [...] orphan codons that lack a corresponding tRNA are decoded using non-canonical pairing between codons and anticodons, commonly referred to as wobble base pairing [...] [...] the extent to which each codon is translated by a specific tRNA via wobble base pairing differs between species [...] [...] the mammalian genome is better optimized for complex transcriptional and post-transcriptional regulation [...] [...] prokaryotes and mammals differ in the extent to which translational efficiency and codon biases are relied upon as a regulatory mechanism.

Codon-Driven Translational Efficiency Is Stable across Diverse Mammalian Cell States Konrad L. M. Rudolph,#1 Bianca M. Schmitt,#2 Diego Villar,2 Robert J. White,3 John C. Marioni,1,2,4,* Claudia Kutter,2,5,* and Duncan T. Odom2,4,* Nicolas Galtier, Editor PLoS Genet. 12(5): e1006024. doi: 10.1371/journal.pgen.1006024

Dionisio

Whether codon usage fine-tunes mRNA translation in mammals remains controversial, with recent papers suggesting that production of proteins in specific Gene Ontological (GO) pathways can be regulated by actively modifying the codon and anticodon pools in different cellular conditions. GC variation across the mammalian genome is most likely a result of the interplay between genome repair and gene duplication mechanisms, rather than selective pressures caused by codon-driven translational rates. Consequently, codon usage differences in mammalian transcriptomes are most easily explained by well-understood mutational biases acting on the underlying genome.

Codon-Driven Translational Efficiency Is Stable across Diverse Mammalian Cell States Konrad L. M. Rudolph,#1 Bianca M. Schmitt,#2 Diego Villar,2 Robert J. White,3 John C. Marioni,1,2,4,* Claudia Kutter,2,5,* and Duncan T. Odom2,4,* Nicolas Galtier, Editor PLoS Genet. 12(5): e1006024. doi: 10.1371/journal.pgen.1006024

Dionisio

The expression of a gene is a tightly regulated process and is exerted by a myriad of different mechanisms. [...] mRNA modifications are a powerful mechanism to post-transcriptionally regulate gene expression. Regulation of gene expression is a complex multistep process. The synthesis of a functional protein is subject to several layers of regulation, starting from the synthesis of various transcription factors up to the correct assembly of the nascent protein by chaperones. [...] the site-specific incorporation of modified RNA nucleotides into coding regions of mRNAs revealed astonishingly versatile effects on protein synthesis depending not only on the type of the RNA modification but also on the codon position [...] [...] it is of utmost importance to elucidate all mechanisms behind. [...] many aspects of mRNA modifications are still far from being completely understood. Elucidating the regulation of mRNA modifications and their cellular functions will open up a completely new way in understanding gene regulation on the level of RNA.

mRNA modifications: Dynamic regulators of gene expression? Thomas Philipp Hoernes, Alexander Hüttenhofer, and Matthias David Erlacher RNA Biol. 13(9): 760–765. doi: 10.1080/15476286.2016.1203504

Dionisio

The different triplets encoding the same amino acid, termed as synonymous codons, are not equally abundant in a genome. It is likely that the order of the nucleotides in the triplet codon is also perhaps involved in the phenomenon of codon usage bias in organisms. [...] our study indicates a vital role of the nucleotide sequence of the triplet in selection as OCs in bacteria [...] More research on codon–anticodon pairing during translation is likely to provide empirical evidence in favour of the role of codon–anticodon interaction on the selection of OCs.

Discrepancy among the synonymous codons with respect to their selection as optimal codon in bacteria Siddhartha Sankar Satapathy,1 Bhesh Raj Powdel,2 Alak Kumar Buragohain,3,4 and Suvendra Kumar Ray3,* DNA Res. 23(5): 441–449. doi: 10.1093/dnares/dsw027

Dionisio

Recent evidence provides strong support for the idea that cells use tRNA to dynamically regulate gene expression in response to stress. [...] reprogrammed tRNAs are involved in the selective translation of proteins from families of genes in which there is a second genetic code, in the form of a biased use of degenerate codons. The identification of stress-induced changes in tRNA modification, codon-biased translation, and MoTTs supports the idea that cells use distinct translational programs during stress responses. As a corollary to translational up-regulation of stress response proteins, it is likely that stress-induced changes in tRNA modification will cause significant down-regulation in the translation groups of codon-biased transcripts, as an efficient means to shut down specific activities as the cell alters phenotype to survive the stress. Ongoing studies will test these models and other features of the translational control of cell stress response. [...] tools will yield important new insights into the role of translational elongation in cell stress response.

Codon-biased translation can be regulated by wobble-base tRNA modification systems during cellular stress responses Lauren Endres,1 Peter C Dedon,2,3,* and Thomas J Begley1,4,* RNA Biol. 12(6): 603–614. doi: 10.1080/15476286.2015.1031947

Dionisio

[...] the mechanism by which amino acids activate Vps34 remained unclear. It is not clear how LRS regulation of Vps34-PLD can be reconciled with the reported LRS regulation of Rag [...] [...] it is possible that other factors may be involved in amino acid-sensing and/or signal transduction by LRS in the cytosol, which warrant future investigations.

Leucyl-tRNA synthetase activates Vps34 in amino acid-sensing mTORC1 signaling Mee-Sup Yoon,1,2,†* Kook Son,1,† Edwin Arauz,1 Jung Min Han,3,4 Sunghoon Kim,5 and Jie Chen Cell Rep. 16(6): 1510–1517. doi: 10.1016/j.celrep.2016.07.008

Dionisio

While such global translational repression was observed many decades ago, its functional significance remains unknown. [...] it is unclear whether IRES-dependent translation represents a general mechanism of translational regulation during mitosis, and whether such IRES-dependent translational activation represents, a minor, or the dominant mechanism of gene-specific translational regulation during mitosis. [...] translational regulation can enhance the efficiency of post-translational protein inhibition, which may represent a more general function for translational repression. [...] together these studies provide a complete overview of translational regulation during the cell cycle.

Regulation of mRNA translation during mitosis Marvin E Tanenbaum,1 Noam Stern-Ginossar,1,2,3 Jonathan S Weissman,1,2,3 and Ronald D Vale1,* eLife. 4: e07957. doi: 10.7554/eLife.07957

Dionisio

Passage through mitosis is driven by precisely-timed changes in transcriptional regulation and protein degradation. However, the importance of translational regulation during mitosis remains poorly understood. [...] it is not clear whether regulation of translation is involved in control of the cell division. These findings uncover a new role for the control of protein production in regulating the cell cycle. The next challenge will be to find out whether suppression of translation is also used in other biological systems where proteins need to be rapidly inactivated.

Regulation of mRNA translation during mitosis Marvin E Tanenbaum,1 Noam Stern-Ginossar,1,2,3 Jonathan S Weissman,1,2,3 and Ronald D Vale1,* eLife. 4: e07957. doi: 10.7554/eLife.07957

Dionisio

Translation is an essential step in gene expression. The reasons for this phenomenon are at present unclear. It could be that these switches are regulated. In the future, it will be interesting to analyze mRNAs regulated at the translational level. Future studies will be thus required to understand the functions of the DYNC1H1 translation factories. In the future, it will be interesting to determine whether these correspond to translation factories or to sites of accumulation of untranslated mRNA, as in the case of P-bodies. It would also be interesting to determine whether the accumulation of mRNAs in foci is linked to a specific transport pathway that may help to deliver them when and where they are needed.

Visualization of single endogenous polysomes reveals the dynamics of translation in live human cells. Pichon X1, Bastide A2, Safieddine A2, Chouaib R2, Samacoits A3, Basyuk E2, Peter M2, Mueller F3, Bertrand E1. J Cell Biol. 214(6):769-81. doi: 10.1083/jcb.201605024.

Dionisio

Translation is under tight spatial and temporal controls to ensure protein production in the right time and place in cells.

Real-Time Imaging of Translation on Single mRNA Transcripts in Live Cells. Wang C, Han B1, Zhou R, Zhuang X Cell. 165(4):990-1001. doi: 10.1016/j.cell.2016.04.040.

Dionisio

Translation is the fundamental biological process converting mRNA information into proteins. [...] the translation of localized mRNA in living cells remains poorly understood [...] Further development will be needed to study translation of endogenous genes. This technology provides a tool with which to address the spatiotemporal translation mechanism of single mRNAs in living cells.

Translation dynamics of single mRNAs in live cells and neurons Bin Wu, Carolina Eliscovich, Young J. Yoon and Robert H. Singer Science. 352(6292): 1430–1435. doi: 10.1126/science.aaf1084

Dionisio

Future studies using the SunTag approach will illuminate the range of variation on endogenous mRNAs. As tracking of single molecules by fluorescence microscopy gets more attainable, three-color studies tracking a transcript, its translation, and trans factors will lead to great insight into the function and timing of trans factors in regulating translation. [...] there is wide variability within and between mRNA populations. Whether this variability is stochastic or represents differential regulation among the individual mRNAs remains to be seen.

A beacon in the cytoplasm: Tracking translation of single mRNAs. Pingali HV, Hilliker AK. J Cell Biol. 214(6):649-52. doi: 10.1083/jcb.201608075.

Complex complexity. Dionisio

While our data reveal an important role of the LIC in Hook3-mediated dynein motility, a number of questions remain unanswered. Many of these important questions can be addressed through structural and functional studies of multiple types of cargo adaptor proteins interacting with dynein and dynactin.

Assembly and activation of dynein-dynactin by the cargo adaptor protein Hook3. Schroeder CM, Vale RD. J Cell Biol. 214(3):309-18. doi: 10.1083/jcb.201604002.

Dionisio

Taken together, huge progress has been made in our understanding of the basic dynein motor mechanism. The field is currently approaching the “next frontier” which is how this basic mechanism is influenced by important dynein motor regulators like Nudel/Lis1 or the dynactin complex so that dynein motor activity can be exactly shaped according to the biological function.

Review: Structure and mechanism of the dynein motor ATPase Section Editor: Alfred Wittinghofer Helgo Schmidt 1 and Andrew P. Carter Biopolymers. 105(8): 557–567. doi: 10.1002/bip.22856

The next frontier? More questions? Work in progress... stay tuned. Complex complexity. Dionisio

Dyneins are multiprotein complexes that move cargo along microtubules in the minus end direction. The largest individual component of the dynein complex is the heavy chain. [...] it has been largely enigmatic how ATP?hydrolysis in the AAA+ ring causes these rearrangements. The past five years have seen a surge of high resolution information on the dynein motor domain that finally allowed unprecedented insights into this important open question. [...] there are still a number of important open questions. Crystal and electron microscopy structures at higher resolution are needed to answer these questions.

Review: Structure and mechanism of the dynein motor ATPase Section Editor: Alfred Wittinghofer Helgo Schmidt 1 and Andrew P. Carter Biopolymers. 105(8): 557–567. doi: 10.1002/bip.22856

Dionisio

The ability of eukaryotic cells to position and distribute organelles appropriately is a general characteristic of cellular organization. Yet, the mechanisms underlying such distribution in a cell remain elusive.

Active diffusion and microtubule-based transport oppose myosin forces to position organelles in cells Congping Lin,1,2,* Martin Schuster,1,* Sofia Cunha Guimaraes,1,† Peter Ashwin,2 Michael Schrader,1 Jeremy Metz,1 Christian Hacker,1 Sarah Jane Gurr,1 and Gero Steinberg Nat Commun. 2016; 7: 11814. doi: 10.1038/ncomms11814

Dionisio

Even distribution of peroxisomes (POs) and lipid droplets (LDs) is critical to their role in lipid and reactive oxygen species homeostasis. How even distribution is achieved remains elusive, but diffusive motion and directed motility may play a role.

Active diffusion and microtubule-based transport oppose myosin forces to position organelles in cells Congping Lin,1,2,* Martin Schuster,1,* Sofia Cunha Guimaraes,1,† Peter Ashwin,2 Michael Schrader,1 Jeremy Metz,1 Christian Hacker,1 Sarah Jane Gurr,1 and Gero Steinberg Nat Commun. 2016; 7: 11814. doi: 10.1038/ncomms11814

Dionisio

Eukaryotic cells use microtubule-based intracellular transport for the delivery of many subcellular cargos, including organelles. The canonical view of organelle transport is that organelles directly recruit molecular motors via cargo-specific adaptors. In contrast with this view, we show here that peroxisomes move by hitchhiking on early endosomes, an organelle that directly recruits the transport machinery. These results present a new mechanism of microtubule-based organelle transport in which peroxisomes hitchhike on early endosomes and identify PxdA as the novel linker protein required for this coupling. Exciting future directions include determining whether hitchhiking is broadly conserved outside of fungi, identifying the linkers required for other cargos to hitchhike on EEs, and determining the mechanisms that initiate and terminate hitchhiking.

Peroxisomes move by hitchhiking on early endosomes using the novel linker protein PxdA John Salogiannis,1 Martin J. Egan,1 and Samara L. Reck-Peterson J Cell Biol. 212(3): 289–296. doi: 10.1083/jcb.201512020

Complex complexity. Dionisio

Bni1 was found to be ubiquitylated in a large-scale proteomic study (KOLAWA et al. 2013), although the E3 ubiquitin-ligase(s) involved is unknown. [...] further work will be required to assess the possible involvement of Dma proteins in ubiquitylation of formins or formin regulators. Additional mechanisms, besides binding to Rho GTPases, are necessary for complete formin activation in vitro [...] [...] we speculate that Dma-dependent ubiquitylation might impact a novel regulatory input to formin regulation that is unlinked to the ones described to date [...] In summary, our data uncover a potentially novel level of regulation of formin activation that adds up to its overwhelming complexity. Considering the critical role of formins in a variety of diverse cellular processes, such as cell polarity, cell migration, cytokinesis, spindle positioning and cytokinesis it not surprising that formins are subject to elaborate and multilayered controls.

Control of Formin Distribution and Actin Cable Assembly by the E3 Ubiquitin Ligases Dma1 and Dma2. Juanes MA, Piatti S. Genetics. 204(1):205-20. doi: 10.1534/genetics.116.189258.

Complex complexity. Emphasis added. Dionisio

The last 20 years have witnessed a blooming of papers addressing the mechanisms that regulate cytokinesis. In spite of cutting-edge technologies that have considerably improved the resolution of cytokinetic events and the enormous efforts by researchers in the field, many important questions await an answer [...] One major obstacle to the progress of our knowledge in this field is the redundancy and intertwinings of cytokinetic pathways and proteins involved, which often makes the contribution of each hard to assess. Nevertheless, we can therefore expect in the years to come exciting discoveries that will shed light on such a fascinating and intricate process providing, hopefully, a complete and detailed picture of cytokinesis.

The final cut: cell polarity meets cytokinesis at the bud neck in S. cerevisiae Maria Angeles Juanes and Simonetta Piatti Cell Mol Life Sci. 2016; 73: 3115–3136. doi: 10.1007/s00018-016-2220-3

There yet? Work in progress... stay tuned. Complex complexity (on steroids). :) Dionisio

Dpp-Omb signaling unidirectionally restricts the Iro-C expression domain in the wing discs. Different cell affinities specified by asymmetric Omb and Iro-C activities are necessary for H/N fold initiation and progression [...] the folding cells not only subdivide tissues but also provide positional information as well as initiate or organize the tissue metamorphosis. Whether the H/N fold possesses the later function remains to be determined.

Complementary expression of optomotor-blind and the Iroquois complex promotes fold formation to separate wing notum and hinge territories Dan Wang, Lingyun Li, Juan Lu, Suning Liu, Jie Shen DOI: http://dx.doi.org/10.1016/j.ydbio.2016.05.020 Developmental Biology Volume 416, Issue 1, Pages 225–234

Complex complexity. Dionisio

Animal morphogenesis requires folds or clefts to separate populations of cells which are often associated with different cell affinities. In the Drosophila wing imaginal disc, the regional expression of the Iroquois complex (Iro-C) in the notum leads to the formation of the hinge/notum (H/N) fold that separates the wing hinge and notum territories. Although Decapentaplegic (Dpp) signaling has been revealed as essential for the hinge/notum subdivision through the restriction of Iro-C toward the notum region, the mechanism by which the H/N border develops into a fold is unknown. [...] omb and Iro-C not only are complementarily expressed but also cooperate to promote H/N fold formation.

Complementary expression of optomotor-blind and the Iroquois complex promotes fold formation to separate wing notum and hinge territories Dan Wang, Lingyun Li, Juan Lu, Suning Liu, Jie Shen DOI: http://dx.doi.org/10.1016/j.ydbio.2016.05.020 Developmental Biology Volume 416, Issue 1, Pages 225–234

Reverse-engineering complex complexity? :) Dionisio

Further study is needed to better understand how the pre-neurula expression of Ascl1 functions as a transactivator and promotes neurogenesis. More studies are needed in future to unravel the function of the multifaceted cell fate regulator Ascl1. It remains unclear whether or how much Ascl1 protein is maternally stored. ASCL1 is a dual function gene essential for early embryonic cell fate specification.

A novel role for Ascl1 in the regulation of mesendoderm formation via HDAC-dependent antagonism of VegT Li Gao,1,* Xuechen Zhu,1,* Geng Chen,1 Xin Ma,2 Yan Zhang,1 Aftab A. Khand,1 Huijuan Shi,1 Fei Gu,1 Hao Lin,1 Yuemeng Chen,3 Haiyan Zhang,1 Lei He,1 and Qinghua Tao Development. 143(3): 492–503. doi: 10.1242/dev.126292

Dionisio

As the activity of neurons can be ever more precisely controlled with genetically targeted optical strategies (18), biological and technical challenges remain that make these approaches still unsafe for applications in human disease. Kim et al. (9) provide an important first effort to determine the parameters for safe and behaviorally relevant electrical activation of neurons in primary somatosensory cortex.

Making sense: Determining the parameter space of electrical brain stimulation Dona K. Murphey Proc Natl Acad Sci U S A. 112(49): 15012–15013. doi: 10.1073/pnas.1520704112 PMCID: PMC4679050 Neuroscience, Engineering

Emphasis added. Let's keep in mind that none of this deals with the actual will associated with the given command, movement or sensor impulses they refer to in this paper. In the case of the command/motor impulses, they're most probably similar for both voluntary and involuntary movements. The possible reasoning preceding the command/motor impulses is in and by itself a different class of informational process. Dionisio

Intracortical microstimulation of the somatosensory cortex offers the potential for creating a sensory neuroprosthesis to restore tactile sensation. Whereas animal studies have suggested that both cutaneous and proprioceptive percepts can be evoked using this approach, the perceptual quality of the stimuli cannot be measured in these experiments. We show that microstimulation within the hand area of the somatosensory cortex of a person with long-term spinal cord injury evokes tactile sensations perceived as originating from locations on the hand and that cortical stimulation sites are organized according to expected somatotopic principles. Many of these percepts exhibit naturalistic characteristics (including feelings of pressure), can be evoked at low stimulation amplitudes, and remain stable for months. Further, modulating the stimulus amplitude grades the perceptual intensity of the stimuli, suggesting that intracortical microstimulation could be used to convey information about the contact location and pressure necessary to perform dexterous hand movements associated with object manipulation.

Intracortical microstimulation of human somatosensory cortex Sharlene N. Flesher, Jennifer L. Collinger, Stephen T. Foldes, Jeffrey M. Weiss, John E. Downey, Elizabeth C. Tyler-Kabara, Sliman J. Bensmaia, Andrew B. Schwartz, Michael L. Boninger and Robert A. Gaunt Science Translational Medicine DOI: 10.1126/scitranslmed.aaf8083

Dionisio

The electrophysiological effect of cortical microstimulation has been shown to be restricted to a volume tens of micrometers in diameter (17), consistent with the size of a visual cortical column. However, the cell type-specific populations of neurons activated with this kind of stimulation remain unknown.

Making sense: Determining the parameter space of electrical brain stimulation Dona K. Murphey Proc Natl Acad Sci U S A. 112(49): 15012–15013. doi: 10.1073/pnas.1520704112 PMCID: PMC4679050 Neuroscience, Engineering

This paper contains pseudoscientific statements based on unproven presuppositions. The above quoted text shows that fundamental issues remain unresolved. Dionisio

Ultimately, by enabling neural circuits to be both recorded and manipulated with the spatial and temporal precision on which they operate during behavior, this approach should yield new insights into the nature of the neural code.

All-Optical Interrogation of Neural Circuits Valentina Emiliani,Adam E. Cohen, Karl Deisseroth and Michael Häusser J Neurosci. 35(41): 13917–13926. doi: 10.1523/JNEUROSCI.2916-15.2015

Dionisio

A brain-computer interface (BCI) system transforms neural activity into control signals for external devices in real time. A BCI user needs to learn to generate specific cortical activity patterns to control external devices effectively. We call this process BCI learning, and it often requires significant effort and time. Therefore, it is important to study this process and develop novel and efficient approaches to accelerate BCI learning.

Brain computer interface learning for systems based on electrocorticography and intracortical microelectrode arrays. Hiremath SV1, Chen W2, Wang W3, Foldes S4, Yang Y5, Tyler-Kabara EC6, Collinger JL7, Boninger ML8. Front Integr Neurosci. ;9:40. doi: 10.3389/fnint.2015.00040.

Dionisio

During the last two decades, considerable progress has been made in the studies of brain-computer interfaces (BCIs)--devices in which motor signals from the brain are registered by multi-electrode arrays and transformed into commands for articial actuators such as cursors and robotic devices. This review is focused on one problem. Voluntary motor control is based on neurophysiological processes which depend heavily on the afferent innervation of skin, muscles and joints. Thus, invasive BCI has to be based on a bidirectional system in which motor control signals are registered by multi-channel micro-electrodes implanted in motor areas, while tactile, proprioceptive and other useful signals are transported back to the brain through spatial-temporal patterns of intracortical microstimulation (ICMS) delivered to sensory areas. In general, the studies of invasive BCIs have advanced in several directions. The progress of BCIs with articial sensory feedback will not only help patients, but will also expand knowledge base in the field of human cortical functions.

Fiziol Cheloveka. 2016 Jan-Feb;42(1):128-36. [Artificial Feedback for Invasive Brain-Computer Interfaces]. [Article in Russian] Badakva AM, Miller NV, Zobova LN.

Dionisio

Brain-machine interfaces (BMI) translate neuronal activity of the brain into signals driving an external effector or affecting internal body parts and functions. Current techniques allow to interface electric neuronal activity in vivo ranging from intracellular potentials over extracellular action potentials (APs) up to local field potentials (LFPs). The general aim is to record APs and LFPs. BMI performance is still far from natural. As electrodes may be used for stimulation and recording; stimulation could be adapted to ongoing brain activity to improve efficacy. [...] the great opportunity offered by invasive BMIs thus lies in accurate control [...] Prostheses will be controlled using high-dimensional BMI output signals (Wodlinger et al., 2015) while at the same time BMI input signals, obtained from skin prostheses (Kim et al., 2014) during interaction with the environment, will be transmitted to cortical sensory areas. Providing such information may remain far off evoking natural percepts but the brain will learn to make use of such artificial input channels. It is now crucial to overcome current challenges of invasive BMIs: better understanding of the “neuronal code,” [...] Benefits derivable from such advances, especially regarding increased information transfer rates, biocompatibility, and long-term signal stability (Chao et al., 2010) over years, are being investigated and might be decisive for the development of future BMIs.

Invasive vs. Non-Invasive Neuronal Signals for Brain-Machine Interfaces: Will One Prevail? Stephan Waldert* Front Neurosci. 10: 295. doi: 10.3389/fnins.2016.00295

Dionisio

Oops! pushed the wrong button? #2030 got posted twice? Sorry, my mistake. Dionisio

The circadian clock involves relatively few elements, thus it is the least heterogeneous and the most precise. […] CD means that a substrate is transformed/activated only in the presence of particular chemicals (e.g. ions, small molecules) and only under specific conditions (e.g. membrane depolarization). […] all biochemical processes in all neurons involve gene expression/translation mechanisms […] […] many brain regions have neurons with large dendritic arbors, both suggestive of exquisite CD, and supportive of timing, such as striatum, hippocampus, and cerebellum, though it is unclear that they would have to be extensive to support scalar timing.

Curr Opin Behav Sci. ;8:207-213. Clocks within Clocks: Timing by Coincidence Detection. Buhusi CV1, Oprisan SA2, Buhusi M1.

Complex complexity. :) Dionisio

The circadian clock involves relatively few elements, thus it is the least heterogeneous and the most precise. […] CD means that a substrate is transformed/activated only in the presence of particular chemicals (e.g. ions, small molecules) and only under specific conditions (e.g. membrane depolarization). […] all biochemical processes in all neurons involve gene expression/translation mechanisms […] […] many brain regions have neurons with large dendritic arbors, both suggestive of exquisite CD, and supportive of timing, such as striatum, hippocampus, and cerebellum, though it is unclear that they would have to be extensive to support scalar timing.

Curr Opin Behav Sci. ;8:207-213. Clocks within Clocks: Timing by Coincidence Detection. Buhusi CV1, Oprisan SA2, Buhusi M1.

Dionisio

In mammals, the suprachiasmatic nucleus (SCN) contains a central clock that synchronizes daily (i.e., 24-h) rhythms in physiology and behavior. SCN neurons are cell-autonomous oscillators that act synchronously to produce a coherent circadian rhythm. In addition, the SCN helps regulate seasonal rhythmicity. Photic information is perceived by the SCN and transmitted to the pineal gland, where it regulates melatonin production. Within the SCN, adaptations to changing photoperiod are reflected in changes in neurotransmitters and clock gene expression, resulting in waveform changes in rhythmic electrical activity, a major output of the SCN. Efferent pathways regulate the seasonal timing of breeding and hibernation. In humans, seasonal physiology and behavioral rhythms are also present, and the human SCN has seasonally rhythmic neurotransmitter levels and morphology. In summary, the SCN perceives and encodes changes in day length and drives seasonal changes in downstream pathways and structures in order to adapt to the changing seasons.

The suprachiasmatic nuclei as a seasonal clock. Coomans CP, Ramkisoensing A, Meijer JH. Front Neuroendocrinol. 37:29-42. doi: 10.1016/j.yfrne.2014.11.002.

Dionisio

sensory regulation of circadian photoentrainment is complex, with multiple processing steps that are not all well understood A more complex question is how cones contribute to circadian photoentrainment. The extent to which this represents the role of cones in other mammals is still unclear. [...] detailed comparative studies of how cones and colour influence mammalian circadian photoentrainment are urgently required. In the future, a better understanding of the sensory control of the circadian clock in humans and animals (especially the impact of colour) should allow us to design more healthy environments that support optimal circadian alignment.

Using light to tell the time of day: sensory coding in the mammalian circadian visual network. Brown TM J Exp Biol. 219(Pt 12):1779-92. doi: 10.1242/jeb.132167.

Dionisio

Circadian clocks are a near-ubiquitous feature of biology, allowing organisms to optimise their physiology to make the most efficient use of resources and adjust behaviour to maximise survival over the solar day. To fulfil this role, circadian clocks require information about time in the external world. This is most reliably obtained by measuring the pronounced changes in illumination associated with the earth's rotation. In mammals, these changes are exclusively detected in the retina and are relayed by direct and indirect neural pathways to the master circadian clock in the hypothalamic suprachiasmatic nuclei. Recent work reveals a surprising level of complexity in this sensory control of the circadian system, including the participation of multiple photoreceptive pathways conveying distinct aspects of visual and/or time-of-day information.

Using light to tell the time of day: sensory coding in the mammalian circadian visual network. Brown TM J Exp Biol. 219(Pt 12):1779-92. doi: 10.1242/jeb.132167.

Emphasis added. "surprising level of complexity"? Why surprising? What's so surprising about it? Complex complexity on steroids. :) Dionisio

The suprachiasmatic nucleus (SCN) of the anterior hypothalamus is the master circadian clock that coordinates daily rhythms in behavior and physiology in mammals. Like other hypothalamic nuclei, the SCN displays an impressive array of distinct cell types characterized by differences in neurotransmitter and neuropeptide expression. Individual SCN neurons and glia are able to display self-sustained circadian rhythms in cellular function that are regulated at the molecular level by a 24h transcriptional-translational feedback loop. Remarkably, SCN cells are able to harmonize with one another to sustain coherent rhythms at the tissue level. Mechanisms of cellular communication in the SCN network are not completely understood, but recent progress has provided insight into the functional roles of several SCN signaling factors. Despite recent progress, our understanding of SCN circuitry and coupling is far from complete. Further work is needed to map SCN circuitry fully and define the signaling mechanisms that allow for collective timekeeping in the SCN network.

Collective timekeeping among cells of the master circadian clock. Evans JA J Endocrinol. 230(1):R27-49. doi: 10.1530/JOE-16-0054.

There yet? :) Emphasis added. Work in progress... stay tuned. Complex complexity (on steroids). Dionisio

The suprachiasmatic nucleus (SCN) is a network of neural oscillators that program daily rhythms in mammalian behavior and physiology. Over the last decade much has been learned about how SCN clock neurons coordinate together in time and space to form a cohesive population. Despite this insight, much remains unknown about how SCN neurons communicate with one another to produce emergent properties of the network. Future studies that pair analytical behavioral assays with modern neuroscience techniques have the potential to provide deeper insight into SCN circuit mechanisms.

In synch but not in step: Circadian clock circuits regulating plasticity in daily rhythms. Evans JA, Gorman MR. Neuroscience. 320:259-80. doi: 10.1016/j.neuroscience.2016.01.072.

Emphasis added. Work in progress... stay tuned. Complex complexity (on steroids). :) Dionisio

Improved understanding of the mechanisms by which circadian rhythm disruption accelerates pathologies allow for discovery of diagnostic biomarkers and future targets for drug development. In the era of personalized medicine, the dimension of time needs to be brought into the equation within translational research and clinical medicine. To reach these goals, it is crucial to develop multicenter, multidiscipline collaborations between basic and translational scientists in the fields of circadian biology, GI/liver, and metabolic disorders. [...] we first need to address many as yet unanswered questions on (1) different sources of melatonin in the GI tract, (2) the role of melatonin in normal and pathophysiology of the GI tract, and (3) the dynamic, rhythm, and downstream signaling of melatonin in the GI tract.

Circadian Rhythms in Gastrointestinal Health and Diseases. Bishehsari F, Levi F, Turek FW, Keshavarzian A. Gastroenterology. 151(3):e1-5. doi: 10.1053/j.gastro.2016.07.036.

Dionisio

[...] knowledge of the circadian system and its behavior in cultured cells, together with cell lines that differentially express the AhR, provide unique, yet underutilized opportunities to study the interaction between circadian rhythms and AhR signaling. The dietary component curcumin, a natural phenol found in spices, and resveratrol, a natural phenol found in red wine, along with synthetic compounds CH-223191, 6,2,4-trimethoxyflavone, and GNF351, have been reported as AhR antagonists. It is becoming more evident that multiple mechanisms of AhR activation and downstream interaction with circadian rhythms and metabolism exist, but not all AhR-dependent consequences can be explained through dioxin response element (DRE)-dependent mechanisms. Understanding the variety of mechanisms by which AhR exerts its effects on metabolism may reveal new targets of interest for the conservation of homeostasis and reinforces the significance of AhR in clock disruption and metabolic disorder.

Role of Aryl Hydrocarbon Receptor in Circadian Clock Disruption and Metabolic Dysfunction. Jaeger C, Tischkau SA Environ Health Insights. 10:133-41. doi: 10.4137/EHI.S38343.

Work in progress... stay tuned. Complex complexity. Dionisio

AhR is widely expressed throughout the body. Peripheral AhR activation and interaction with circadian signaling in metabolic tissues such as liver, adipose, and muscle has the potential to alter metabolism, but further studies are required to elucidate their detailed mechanisms.

Role of Aryl Hydrocarbon Receptor in Circadian Clock Disruption and Metabolic Dysfunction. Jaeger C, Tischkau SA Environ Health Insights. 10:133-41. doi: 10.4137/EHI.S38343.

Dionisio

The prevalence of metabolic syndrome, a clustering of three or more risk factors that include abdominal obesity, increased blood pressure, and high levels of glucose, triglycerides, and high-density lipoproteins, has reached dangerous and costly levels worldwide. Increases in morbidity and mortality result from a combination of factors that promote altered glucose metabolism, insulin resistance, and metabolic dysfunction. Although diet and exercise are commonly touted as important determinants in the development of metabolic dysfunction, other environmental factors, including circadian clock disruption and activation of the aryl hydrocarbon receptor (AhR) by dietary or other environmental sources, must also be considered. Understanding the variety of AhR-dependent mechanisms, including its interactions with the circadian timing system that promote metabolic dysfunction, reveals new targets of interest for maintenance of healthy metabolism.

Role of Aryl Hydrocarbon Receptor in Circadian Clock Disruption and Metabolic Dysfunction. Jaeger C, Tischkau SA Environ Health Insights. 10:133-41. doi: 10.4137/EHI.S38343.

Dionisio

Further mechanistic molecular studies are needed to understand the role of AHR regulating self-renewal responses of tissue-resident stem cells niches or whether AHR participates in self-renewal by promoting release of factors by the stem cells themselves. Further studies need to consider whether stem cells may be regulated by AHR ligands via alternative binding pockets which may in turn lead to binding to alternative AHR responsive elements and regulation of different gene promoters. [...] further studies using molecular tools may provide information about the specific players involved.

The Aryl Hydrocarbon Receptor Relays Metabolic Signals to Promote Cellular Regeneration Fanny L. Casado Stem Cells Int. 2016; 2016: 4389802. doi: 10.1155/2016/4389802

Complex complexity. Dionisio

[...] formation of apical projections is under the control of mechanisms involved in establishment and maintenance of epithelial cell polarity. [...] further investigations are required to identify additional components or polarity regulator/s that act in conjunction with the two Lgls in formation of apical microridges.

aPKC regulates apical localization of Lgl to restrict elongation of microridges in developing zebrafish epidermis Renuka Raman,1 Indraneel Damle,1 Rahul Rote,1,* Shamik Banerjee,1,2 Chaitanya Dingare,1,† and Mahendra Sonawane Nat Commun. 7: 11643. doi: 10.1038/ncomms11643

Dionisio

Biological phenomena, such as development, are complex dynamic processes. They cannot be reduced to the characteristics of their components and need to be described by interactions within multiple hierarchical levels comprising a system. [...] temporally co-ordinated signals from numerous effector pathways define the divergent cell fates. [...] it is not clear whether de- and redifferentiation operate as a bidirectional process or which elements predominate during these transitions [...] [...] the underlying gene regulatory mechanisms are still not understood well enough to inform the design process. Future experimental systems must be designed in concert with mathematical models to integrate the complex biomechanical and biochemical signalling4

A systems biology approach to defining regulatory mechanisms for cartilage and tendon cell phenotypes. Mueller AJ1, Tew SR1,2, Vasieva O3, Clegg PD1,2, Canty-Laird EG Sci Rep. 6:33956. doi: 10.1038/srep33956.

Dionisio

[...] excellent progress has been made in elucidating both the signaling pathways and the transcriptional regulatory networks that control [...] Mechanical signals [...] have also been shown to be important regulators of both chondrocyte proliferation and bone morphology. However, the details regarding how these various signals modulate either the expression and/or activity of the relevant transcription factors is only beginning to be explored. Such a detailed molecular understanding will be necessary to fully comprehend how either the initiation of chondrogenesis or growth plate expansion is regulated with such precision during vertebrate development.

A pathway to bone: signaling molecules and transcription factors involved in chondrocyte development and maturation Elena Kozhemyakina,1 Andrew B. Lassar,1,* and Elazar Zelzer2 Development. 142(5): 817–831. doi: 10.1242/dev.105536

There yet? Nope, but we're just missing the details. Not a big deal, is it? :) Complex complexity. :) Dionisio

The parameters that dictate whether a hypertrophic chondrocyte will either undergo apoptosis or initiate the osteogenic differentation program and survive in the bone matrix are not yet understood. It is not clear what controls these strikingly different responses to Fgf18 signaling at differing stages of growth plate development.

A pathway to bone: signaling molecules and transcription factors involved in chondrocyte development and maturation Elena Kozhemyakina,1 Andrew B. Lassar,1,* and Elazar Zelzer2 Development. 142(5): 817–831. doi: 10.1242/dev.105536

There yet? Nope, but we're just missing the details. Not a big deal, is it? :) Complex complexity. :) Dionisio

Endochondral ossification consists of successive steps of chondrocyte differentiation, including mesenchymal condensation, differentiation of chondrocytes, and hypertrophy followed by mineralization and ossification. [...] Cdc42 is involved not in osteogenesis but in chondrogenesis in which the BMP2/Cdc42/Pak/p38/Smad signaling module promotes mesenchymal condensation and the TGF-?/Cdc42/Pak/Akt/Sox9 signaling module facilitates chondrogenic differentiation.

Signaling Cascades Governing Cdc42-Mediated Chondrogenic Differentiation and Mensenchymal Condensation. Wang JR1, Wang CJ2, Xu CY1, Wu XK1, Hong D2, Shi W1, Gong Y1, Chen HX3, Long F4, Wu XM5. Genetics. 202(3):1055-69. doi: 10.1534/genetics.115.180109.

Complex complexity. :) Dionisio

butifnot @2112: Thank you for the interesting comments. Dionisio

Future directions will be aimed at acquiring a deeper mechanistic understanding of the roles of FGF signaling in development and in adult tissues with a goal of understanding how these pathways become reactivated during injury response and cancer. [...] it remains unclear whether polymorphisms result in gain- or loss-of-function.

The Fibroblast Growth Factor signaling pathway David M Ornitz and Nobuyuki Itoh Wiley Interdiscip Rev Dev Biol. 4(3): 215–266. doi: 10.1002/wdev.176

Dionisio

Fascinating Dionisio. I am particularly interested in electric fields as a mechanism of coordination/control/signaling/ etc etc. Maybe a global field as well as superposed fields. Also, I remember reading of some research which began as an investigation of why two isomers were so vastly different in effect one being highly toxic and the other benign. The investigator noticed that the toxic one was opaque to uv wavelengths and went on to develop the idea that intra/inter cellular communication occurred with uv light emissions of single to several photon intensity. With experiments of biological communication being stopped by uv-opaque separation. The coordination, and control, and meta-information processing, that has been unknown, unaddressed, undiscovered, makes most of what has been ascertained trivial by comparison. Seems like much of DNA is ingredients and the recipe is going to blow our minds. butifnot

The fact that cells are being constantly displaced from the distal mesenchyme by an intrinsically timed programme of proliferation thus provides a robust mechanism by which a precise gradient of positional values can become established [...] [...] an intrinsic cell cycle clock, sustained by AER signalling, is part of the timing mechanism that specifies the positional values of the zeugopod and autopod. [...] it is unclear how the specification of positional values relates to the final limb anatomy [...] [...] it is tempting to speculate that a link between this process of self-organization and cell adhesion exists. The possibility that permissive AER signals increase over time, which has never been demonstrated, cannot be excluded and requires further investigation. A fundamental issue is whether extrinsic signals or an intrinsic timer re-specifies missing positional values during limb regeneration. [...] an emerging theme is that both signal and time-based mechanisms operate together during embryogenesis. Whether timing in other patterning systems is an intrinsic property remains largely undetermined.

An intrinsic timer specifies distal structures of the vertebrate limb Patricia Saiz-Lopez,1,* Kavitha Chinnaiya,2,* Victor M. Campa,1 Irene Delgado,1,† Maria A. Ros,a,1,3 and Matthew Towers Nat Commun. 6: 8108. doi: 10.1038/ncomms9108

Dionisio

An enigmatic problem in developmental biology is how the positional values along the proximo-distal axis (that is, humerus to digits) of the vertebrate limb are specified. Although this has been a topic of intense investigation, a consensus model has not been reached. [...] the positional values of the zeugopod and autopod are progressively specified in an intrinsically timed manner.

An intrinsic timer specifies distal structures of the vertebrate limb Patricia Saiz-Lopez,1,* Kavitha Chinnaiya,2,* Victor M. Campa,1 Irene Delgado,1,† Maria A. Ros,a,1,3 and Matthew Towers Nat Commun. 6: 8108. doi: 10.1038/ncomms9108

Complex complexity. Dionisio

How the positional values along the proximo-distal axis (stylopod-zeugopod-autopod) of the limb are specified is intensely debated. Early work suggested that cells intrinsically change their proximo-distal positional values by measuring time. Recently, however, it is suggested that instructive extrinsic signals from the trunk and apical ectodermal ridge specify the stylopod and zeugopod/autopod, respectively. [...] the zeugopod and autopod are specified by an intrinsic timing mechanism. [...] distal mesenchyme cells intrinsically time Hoxa13 expression, cell cycle parameters and the duration of the overlying apical ectodermal ridge. [...] cell affinities intrinsically change in the distal mesenchyme [leading to] a gradient of positional values along the proximo-distal axis. [they propose] a complete model in which a switch from extrinsic signalling to intrinsic timing patterns the vertebrate limb.

An intrinsic timer specifies distal structures of the vertebrate limb Patricia Saiz-Lopez,1,* Kavitha Chinnaiya,2,* Victor M. Campa,1 Irene Delgado,1,† Maria A. Ros,a,1,3 and Matthew Towers Nat Commun. 6: 8108. doi: 10.1038/ncomms9108

Dionisio

A future challenge will be to see if similar retinoic acid gradients and noise control occur in other tissues, and if the noise has any positive role to play in development. Morphogens are long-range signals thought to induce different cell behaviors in a concentration-dependent manner, but how such graded signals can be established in the face of noise and how they specify sharp boundaries of target gene expression remain unclear.

Noise modulation in retinoic acid signaling sharpens segmental boundaries of gene expression in the embryonic zebrafish hindbrain. Sosnik J1,2,3, Zheng L2,4, Rackauckas CV2,4, Digman M1,2,5, Gratton E1,2,5, Nie Q1,2,4, Schilling TF1,2. Elife. 5:e14034. doi: 10.7554/eLife.14034.

Dionisio

Morphogen gradients induce sharply defined domains of gene expression in a concentration-dependent manner, yet how cells interpret these signals in the face of spatial and temporal noise remains unclear. [...] RA forms a noisy gradient during critical stages of hindbrain patterning and that cells use distinct intracellular binding proteins to attenuate noise in RA levels. Increasing noise disrupts sharpening of rhombomere boundaries and proper patterning of the hindbrain. These findings reveal novel cellular mechanisms of noise regulation, which are likely to play important roles in other aspects of physiology and disease.

Noise modulation in retinoic acid signaling sharpens segmental boundaries of gene expression in the embryonic zebrafish hindbrain. Sosnik J1,2,3, Zheng L2,4, Rackauckas CV2,4, Digman M1,2,5, Gratton E1,2,5, Nie Q1,2,4, Schilling TF1,2. Elife. 5:e14034. doi: 10.7554/eLife.14034.

Dionisio

#2104 error correction: Where it reads "shy?" it should read "why?" instead. Sorry for this mistake. I wasn't careful enough. Should review the text before posting it. My fault. Dionisio

Morphogens were originally defined as secreted signaling molecules that diffuse from local sources to form concentration gradients, which specify multiple cell fates. More recently morphogen gradients have been shown to incorporate a range of mechanisms including short-range signal activation, transcriptional/translational feedback, and temporal windows of target gene induction. Many critical cell-cell signals implicated in both embryonic development and disease, such as Wnt, fibroblast growth factor (Fgf), hedgehog (Hh), transforming growth factor beta (TGFb), and retinoic acid (RA), are thought to act as morphogens, but key information on signal propagation and ligand distribution has been lacking for most. The zebrafish provides unique advantages for genetics and imaging to address gradients during early embryonic stages when morphogens help establish major body axes. This has been particularly informative for RA, where RA response elements (RAREs) driving fluorescent reporters as well as Fluorescence Resonance Energy Transfer (FRET) reporters of receptor binding have provided evidence for gradients, as well as regulatory mechanisms that attenuate noise and enhance gradient robustness in vivo.

Visualizing retinoic acid morphogen gradients. Schilling TF, Sosnik J, Nie Q Methods Cell Biol. 133:139-63. doi: 10.1016/bs.mcb.2016.03.003.

Just ask professor L.M. of the U of T in Canada. :) But make sure to ask only honest questions, whatever that means. :) Complex complexity. :) Dionisio

[...] there must be other molecules and mechanisms in the embryo that refine and shape the Nodal morphogen gradient. [...] one possible mechanism to shape the gradient is transient binding of Nodal proteins to immobilized diffusion regulators [...] Another potential mechanism for gradient formation is rapid clearance of molecules during diffusion [...] [...] cells selectively destroy Nodal ligands by recognizing the lysosome-targeting signal, since the ligands have to be internalized. [...] the Nodal gradient is dependent upon diffusion, binding, and degradation of the morphogen. [...] some aspects of the system have not been taken into account in our simulations. It will be interesting to determine how Oep/Cripto co-receptors and Lefty shape the active signaling gradient. It is not known if the ECM or HSPGs play a role in modulating the Nodal morphogen gradient [...] [...] in addition to hindered diffusion via binding to the receptors and inhibitors, the differential stability of Nodal ligands play key roles in shaping the Nodal gradient and activity range. [...] diffusion, extracellular interactions i.e., Nodal-receptor binding, Nodal-Lefty inhibitor binding, and selective ligand destruction collectively shape and refine the Nodal morphogen gradient.

Extracellular interactions and ligand degradation shape the nodal morphogen gradient Yin Wang, Xi Wang, Thorsten Wohland and Karuna Sampath eLife. 2016; 5: e13879. doi: 10.7554/eLife.13879

ECM: extracellular matrix HSPGs: heparan sulphate proteoglycans Do the conclusions of this research paper mean that all the previous hype about Turing and diffusion related to the morphogen gradient formation was premature? Are we ever going to see more humility in scientific research? Why did it take them so long to realize that diffusion alone could not explain the whole enchilada? A child could have figured that out much faster, by simply asking the humble "how?" and "shy?" questions right from the start. Why can't scientists approach research with that sense of wonder, with open mind, thinking out of pre-established boxes, beyond biased preconceived standards? Just ask professor L.M. of the U of T in Canada. :) But make sure to ask only honest questions, whatever that means. :) Complex complexity. :) Dionisio

In contrast to the differential diffusion model, a recent study suggested that a temporal signal activation window created by microRNA-430 (miRNA-430) delays translation of the Nodal antagonist Lefty to determine the dimensions of Nodal signaling in the gastrula [...] [...] it is unclear how the proposed temporal activation window might be converted into a spatial Nodal gradient Some studies have suggested that in addition to diffusion, the gradient of a morphogen is related to the rate of ligand clearance or stability [...] How the lysosome-targeting region regulates Nodal clearance and how it influences the Nodal morphogen gradient was not known. [...] diffusivity alone is insufficient to generate the Nodal morphogen gradient. [...] in order to generate and maintain a robust Nodal morphogen gradient, ligand clearance by degradation is balanced against the binding and release of Nodal ligands with the receptor and inhibitors.

Extracellular interactions and ligand degradation shape the nodal morphogen gradient Yin Wang, Xi Wang, Thorsten Wohland and Karuna Sampath eLife. 2016; 5: e13879. doi: 10.7554/eLife.13879

Does this mean that all the hype about Turing and diffusion related to the morphogen gradient formation was premature? Are we ever going to see more humility in scientific research papers? Just ask professor L.M. of the U of T in Canada. :) But make sure to ask only honest questions, whatever that means. :) Complex complexity. :) Dionisio

[...] until now it was not fully clear how the well-known morphogen called Nodal moves in live zebrafish as they develop. [...] in addition to Nodal diffusing and binding to receiving cells, one of the most important factors determining how far and quickly Nodal moves is its inactivation and destruction. [...] diffusivity, extra-cellular interactions, and selective ligand destruction collectively shape the Nodal morphogen gradient. [...] future experiments will aim to examine these molecules and their interactions when they are produced at their normal locations in the animal over time.

Extracellular interactions and ligand degradation shape the nodal morphogen gradient Yin Wang, Xi Wang, Thorsten Wohland and Karuna Sampath eLife. 2016; 5: e13879. doi: 10.7554/eLife.13879

Just ask professor L.M. of the U of T in Canada. :) Dionisio

How morphogen gradients are formed is not fully understood. Studies in many organisms have suggested three major mechanisms to establish morphogen gradients: 1) diffusion, 2) transcytosis and 3) via cytonemes Nodal proteins, which belong to the TGF-? family of signaling proteins, play critical roles in vertebrate development [...] [...] the Nodal morphogen gradient has been proposed to be established by simple diffusion [...] How Nodal diffusion is hindered, and to what extent it shapes the Nodal gradient is unclear.

Extracellular interactions and ligand degradation shape the nodal morphogen gradient Yin Wang, Xi Wang, Thorsten Wohland and Karuna Sampath eLife. 2016; 5: e13879. doi: 10.7554/eLife.13879

Just ask professor L.M. of the U of T in Canada. :) Dionisio

The correct distribution and activity of secreted signaling proteins called morphogens is required for many developmental processes. Nodal morphogens play critical roles in embryonic axis formation in many organisms. Models proposed to generate the Nodal gradient include diffusivity, ligand processing, and a temporal activation window. But how the Nodal morphogen gradient forms in vivo remains unclear.

Extracellular interactions and ligand degradation shape the nodal morphogen gradient Yin Wang, Xi Wang, Thorsten Wohland and Karuna Sampath eLife. 2016; 5: e13879. doi: 10.7554/eLife.13879

Just ask professor L.M. of the U of T in Canada. :) Dionisio

Pressing questions remain unanswered, and there is a glaring need for human studies addressing these. Recent studies have also begun exploring how clock gene SNPs may influence responses to dietary interventions [...], and ultimately knowledge of circadian system gene variants may also help inform personalized nutrition. There are also several non-essential dietary compounds consistently shown to influence the circadian system. Further research is needed to see if such compounds might be useful in humans, however. If they are, what are the best times to consume them to maximise their impact, and what are the dose-response and phase-response curves of these compounds? Continuing collaboration between chronobiologists and nutritionists will further clarify interactions between nutrition and the circadian system, and ultimately has the potential to reduce the prevalence and burden of chronic diseases.

Nutrition and the Circadian System Gregory D M Potter,1 Janet E Cade,2 Peter J Grant,3 and Laura J Hardie Br J Nutr. 116(3): 434–442. doi: 10.1017/S0007114516002117

SNP: single-nucleotide polymorphisms TRF: time-of-day-restricted feeding Dionisio

The human circadian system anticipates and adapts to daily environmental changes to optimise behaviour according to time of day and temporally partition incompatible physiological processes. At the helm of this system is a master clock in the suprachiasmatic nuclei (SCN) of the anterior hypothalamus. An appreciation of the circadian system has many implications for nutritional science and may ultimately help reduce the burden of chronic diseases.

Nutrition and the Circadian System Gregory D M Potter,1 Janet E Cade,2 Peter J Grant,3 and Laura J Hardie Br J Nutr. 116(3): 434–442. doi: 10.1017/S0007114516002117

Dionisio

Feeding behavior, metabolism and circadian clocks are interlinked. Calorie restriction (CR) is a feeding paradigm known to extend longevity CR recruits biological clocks as a natural mechanism of metabolic optimization under conditions of limited energy resources. Future study focused on the effects of CR in circadian clock mutants will help to clarify connections between clock and CR.

Calorie restriction regulates circadian clock gene expression through BMAL1 dependent and independent mechanisms Sonal A. Patel,1 Nikkhil Velingkaar,1 Kuldeep Makwana,1 Amol Chaudhari,1 and Roman Kondratova,1 Sci Rep. 6: 25970. doi: 10.1038/srep25970

Dionisio

A series of fascinating discoveries in the field of circadian rhythms have revealed the direct implication of the clock in the maintenance of cellular homeostasis. [...] the circadian transcriptional landscape seems highly complex as it implicates dynamic changes in nuclear organization [...] Understanding how the nuclear landscape integrates metabolic cues and shapes the transcriptional output will be of great importance. Unravelling the mechanisms leading to metabolic syndromes is critical because it may expose key molecular players in the circadian control of glucose or lipid homeostasis.

Chromatin landscape and circadian dynamics: Spatial and temporal organization of clock transcription Lorena Aguilar-Arnal and Paolo Sassone-Corsi Proc Natl Acad Sci U S A. 112(22): 6863–6870. doi: 10.1073/pnas.1411264111 PMCID: PMC4460512 Cell Biology

Dionisio

An additional regulatory layer is achieved through noncoding RNAs. Further investigations are necessary to decipher the functional characteristics of these oscillatory noncoding RNAs and how they impact circadian transcription. The extent of the influence that chromatin topological organization has on the circadian transcriptome needs to be determined. Further research is necessary to decipher the impact of one carbon metabolism in the circadian transcriptome. The coordination and integration of metabolic pathways within the circadian epigenome appear intricate. To which extent genome topology senses circadian metabolism remains to be explored.

Chromatin landscape and circadian dynamics: Spatial and temporal organization of clock transcription Lorena Aguilar-Arnal and Paolo Sassone-Corsi Proc Natl Acad Sci U S A. 112(22): 6863–6870. doi: 10.1073/pnas.1411264111 PMCID: PMC4460512 Cell Biology

Dionisio

The circadian clock is an endogenous timekeeper present in almost all life forms. [...] the clock system is not driven by external “zeitgebers” (a German word that means time-giver), but it is rather synchronized or entrained by zeitgebers every day to adjust to the 24-h period. [...] the circadian clock generates an internal biological rhythm that synchronizes and adapts to the changing environment. In mammals, the master clock resides in the suprachiasmatic nucleus (SCN) of the hypothalamus, which receives external light information from the retina through the retinohypothalamic tract. The mechanisms involved in the communication between the SCN and the periphery remain poorly explored although they are thought to be complex and multilayered.

Chromatin landscape and circadian dynamics: Spatial and temporal organization of clock transcription Lorena Aguilar-Arnal and Paolo Sassone-Corsi Proc Natl Acad Sci U S A. 112(22): 6863–6870. doi: 10.1073/pnas.1411264111 PMCID: PMC4460512 Cell Biology

Dionisio

Circadian rhythms drive the temporal organization of a wide variety of physiological and behavioral functions in ?24-h cycles. This control is achieved through a complex program of gene expression. Deciphering the molecular mechanisms that connect the circadian clock machinery with the nuclear landscape will reveal yet unexplored pathways that link cellular metabolism to epigenetic control.

Chromatin landscape and circadian dynamics: Spatial and temporal organization of clock transcription Lorena Aguilar-Arnal and Paolo Sassone-Corsi Proc Natl Acad Sci U S A. 112(22): 6863–6870. doi: 10.1073/pnas.1411264111 PMCID: PMC4460512 Cell Biology

Dionisio

The mammalian circadian system is organized as a hierarchy of oscillators, with the master pacemaker located in the suprachiasmatic nucleus (SCN) of the hypothalamus. Circadian oscillators are present in almost all tissues of an organism, and the SCN orchestrates their coordinated function. The control that the circadian clock exerts on cellular metabolism is complex and multilayered, yet numerous underlying molecular mechanisms are being unraveled. [...] the circadian clock, a well-coordinated transcription-translation feedback system that orchestrates and integrates gene expression, protein stability and metabolite production to keep correct time. The extent of metabolic influence on clock function needs further investigation. The decoding of the language that links nutrients and metabolites to the circadian clock will be important to decipher how mis-regulation of circadian rhythms leads to chronic diseases such as obesity and diabetes.

Chromatin Dynamics of Circadian Transcription Lorena Aguilar-Arnal and Paolo Sassone-Corsi Curr Mol Biol Rep. 1(1): 1–9. doi: 10.1007/s40610-015-0001-7

Complex complexity on steroids. :) Dionisio

The mammalian circadian system is organized as a hierarchy of oscillators, with the master pacemaker located in the suprachiasmatic nucleus (SCN) of the hypothalamus. Circadian oscillators are present in almost all tissues of an organism, and the SCN orchestrates their coordinated function.

Chromatin Dynamics of Circadian Transcription Lorena Aguilar-Arnal and Paolo Sassone-Corsi Curr Mol Biol Rep. 1(1): 1–9. doi: 10.1007/s40610-015-0001-7

Dionisio

The molecular circadian clock orchestrates the daily cyclical expression of thousands of genes. Unraveling the molecular aspects of such interplays is likely to reveal new therapeutic strategies towards the treatment of metabolic disorders.

Chromatin Dynamics of Circadian Transcription Lorena Aguilar-Arnal and Paolo Sassone-Corsi Curr Mol Biol Rep. 1(1): 1–9. doi: 10.1007/s40610-015-0001-7

Complex complexity. :) Dionisio

The circadian clock has a profound effect on gene regulation, controlling rhythmic transcript accumulation for up to half of expressed genes in eukaryotes. Evidence also exists for clock control of mRNA translation, but the extent and mechanisms for this regulation are not known. [...] clock control of eEF-2 activity promotes rhythmic translation of specific mRNAs.

Circadian clock regulation of mRNA translation through eukaryotic elongation factor eEF-2. Caster SZ, Castillo K, Sachs MS, Bell-Pedersen D. Proc Natl Acad Sci U S A. 113(34):9605-10. doi: 10.1073/pnas.1525268113.

Dionisio

Future studies that determine targets and functions of these noncoding RNAs on a genome scale will need to be incorporated. How the constraints on the cost of gene expression constrain other biological circuits such as feedback loops, enzymatic activities, proportional regulation of promoter activities in coexpression networks, or transcriptional networks that are involved in cyclical gene expression still needs to be investigated. Future studies that empirically calculate these parameters over time can ultimately be incorporated into this model to determine total energy use and whether cycling genes contribute to an energy saving mechanism. Future experiments that empirically measure the energetic properties of all of these processes on a genome-wide basis will contribute to our overall knowledge of cycling gene energy usage.

Cycling transcriptional networks optimize energy utilization on a genome scale Guang-Zhong Wang,1 Stephanie L. Hickey,1 Lei Shi,2 Hung-Chung Huang,1,4 Prachi Nakashe,1 Nobuya Koike,1,5 Benjamin P. Tu,2 Joseph S. Takahashi,1,3,* and Genevieve Konopka Cell Rep. 2015 Dec 1; 13(9): 1868–1880. doi: 10.1016/j.celrep.2015.10.043

Dionisio

Genes expressing circadian RNA rhythms are enriched for metabolic pathways, however, the adaptive significance of cyclic gene expression remains unclear. [...] rhythmic gene expression optimizes the metabolic cost of global gene expression [...] If a protein is not needed at a particular time, its production is shut down. [...] cellular processes that consume energy in the cell that may play a part in cycling gene expressions [...] [:]

[1] the transport of mRNA and protein outside of the nucleus, [2] protein folding and misfolding [...] , [3] alternative splicing [4] DNA repair

[...] this needs to be investigated further especially with regards to translational efficiency [...]

Cycling transcriptional networks optimize energy utilization on a genome scale Guang-Zhong Wang,1 Stephanie L. Hickey,1 Lei Shi,2 Hung-Chung Huang,1,4 Prachi Nakashe,1 Nobuya Koike,1,5 Benjamin P. Tu,2 Joseph S. Takahashi,1,3,* and Genevieve Konopka Cell Rep. 2015 Dec 1; 13(9): 1868–1880. doi: 10.1016/j.celrep.2015.10.043

Dionisio

The spindle assembly checkpoint (SAC) is a key mechanism to regulate the timing of mitosis and ensure that chromosomes are correctly segregated to daughter cells. The recruitment of the Mad1 and Mad2 proteins to the kinetochore is normally necessary for SAC activation. This recruitment is coordinated by the SAC kinase Mps1, which phosphorylates residues at the kinetochore to facilitate binding of Bub1, Bub3,

Synthetic Physical Interactions Map Kinetochore-Checkpoint Activation Regions Guðjón Ólafsson and Peter H. Thorpe G3 (Bethesda). 6(8): 2531–2542. doi: 10.1534/g3.116.031930

Complex complexity. Dionisio

@2077 error correction: professor L.M. of the U of T in Canada did not write (explicitly) that he knew exactly how morphogen gradients form, as it was incorrectly stated @2077. professor L.M. of the U of T in Canada just answered a simple 'yes/no' question affirmatively. A copy of that brief exchange of comments with professor L.M. of the U of T in Canada is available upon request. At some point professor L.M. of the U of T in Canada stated that he won't discuss with me because I don't ask honest questions, whatever that means. I was looking forward to a serious discussion where I could benefit from the professor's knowledge of biology, but he decided to quit. Let's hope that professor L.M. of the U of T in Canada will reconsider his decision and will come back to continue our serious polite discussion on the most interesting biology related issues. Dionisio

[...] the microtubule-binding properties of the Ska complex may primarily aid in coordinating PP1 recruitment to, or activity at, kinetochores. [...] recruitment is a critical function of the Ska complex for opposing mitotic kinases that destabilize kinetochore-microtubule attachment and that signal the spindle checkpoint. [...] the Ska complex may integrate chromosome alignment at metaphase with full recruitment of PP1, thus opposing spindle checkpoint kinases signaling and promoting the metaphase-anaphase transition.

The human SKA complex drives the metaphase-anaphase cell cycle transition by recruiting protein phosphatase 1 to kinetochores Sushama Sivakumar,1,2,3 Pawe? ? Janczyk,4 Qianhui Qu,2,3 Chad A Brautigam,5 P Todd Stukenberg,4,* Hongtao Yu,2,3,* and Gary J Gorbsky eLife. 5: e12902. doi: 10.7554/eLife.12902

Complex complexity. :) Dionisio

The next few years of research will impart various degrees of nuances and answers to these and many other intriguing yet unresolved questions and promise to be an exciting time for mitosis investigators.

How the SAC gets the axe: Integrating kinetochore microtubule attachments with spindle assembly checkpoint signaling Shivangi Agarwal and Dileep Varma Bioarchitecture. 5(1-2): 1–12. doi: 10.1080/19490992.2015.1090669

Dionisio

[...] there exist important yet unanswered questions that remain tantalizing areas for further research in attachment responsive SAC activity. Some of these questions include: ( a ) what is the precise molecular link between the Ndc80 complex, the key kMT attachment pivot and SAC activity? ( b ) what is the direct or indirect role of the KMN network in SAC silencing in the absence of dynein/dynactin motor machinery? ( c ) does the “Constitutive centromere-associated network” (CCAN) have any role in distinguishing attached vs unattached kinetochores and regulating the SAC?

How the SAC gets the axe: Integrating kinetochore microtubule attachments with spindle assembly checkpoint signaling Shivangi Agarwal and Dileep Varma Bioarchitecture. 5(1-2): 1–12. doi: 10.1080/19490992.2015.1090669

Dionisio

Precise knowledge of how kMT attachments trigger the removal of SAC components from kinetochores or how the checkpoint proteins feedback in to the attachment machinery remains elusive. Our understanding of the integration and coordination between kMT attachment and SAC signaling is still very primitive, and definitely warrants extensive deliberation. [...] the exact nature of SAC signaling is poorly understood [...] How such a mechanical sensory signal is transduced into a biochemical signaling cascade remains enigmatic [...]

How the SAC gets the axe: Integrating kinetochore microtubule attachments with spindle assembly checkpoint signaling Shivangi Agarwal and Dileep Varma Bioarchitecture. 5(1-2): 1–12. doi: 10.1080/19490992.2015.1090669

Dionisio

[...] it is tempting to speculate that there are classes of MAPs that use defined sets of binding motifs and therefore compete with each other for MT real estate (40). This will be an important area for future cryo-EM–based structural studies.

Near-atomic cryo-EM structure of PRC1 bound to the microtubule Elizabeth H. Kellogg,a,b,1 Stuart Howes,c,1,2 Shih-Chieh Ti,d Erney Ramírez-Aportela,e Tarun M. Kapoor,d Pablo Chacón,e and Eva Nogales Proc Natl Acad Sci U S A. 113(34): 9430–9439. doi: 10.1073/pnas.1609903113 PMCID: PMC5003279 Inaugural Article Biophysics and Computational Biology

Dionisio

Protein folding has been described as both exceedingly complex and remarkably simple We anticipate that this work will open up new avenues for addressing poorly understood aspects of protein-folding kinetics, including the molecular mechanisms of cotranslational and chaperone-assisted folding.

Structure-Based Prediction of Protein-Folding Transition Paths William M. Jacobs, Eugene I. Shakhnovich DOI: http://dx.doi.org/10.1016/j.bpj.2016.06.031 Biophysical Journal Volume 111, Issue Pages 925–936

Dionisio

gpuccio @2076: Yes, agree it's a very interesting paper, which proves the amazing power of the magic combination of RM+HGT+NS+T+... that has produced such an astonishing complex complexity! :) Dionisio

There must be something we do not know. Something has been missed or overlooked [...] [...] nothing we put together approaches the complexity that exists in the live cell. [...] even our best simulations and cartoons have an incomplete picture of the environment [...] [...] we do not even know what is in the cell. [...] the strong interactions we thought we understood are not correct [...]

The Dark Matter of Biology Jennifer L. Ross Biophysical Journal Volume 111, Issue 5, Pages 909–916 Biophysical Perspective http://dx.doi.org/10.1016/j.bpj.2016.07.037

There yet? :) The author of this paper should have asked professor L.M. of the U of T in Canada, who wrote in this very blog that he knew exactly how morphogen gradients form! :) Dionisio

Dionisio: "The Dark Matter of Biology" Great paper! Here is some special treasure from it:

Cells are like tiny computers. They receive inputs, they perform calculations, and they respond. The calculations they perform are done within signaling networks written in the language of PTMs of proteins. These proteins have already been translated and folded (to the extent that they are folded) using a more basic genetic code written in the DNA of the organism. Using the computer analogy, the genetic code, written in DNA, acts like the operating system of the cell. The operating system is important for directing the underlying activities for creation of hardware (proteins), but it does not inform us about how the proteins talk to each other and interact. The signaling code, written in PTMs, is like a software program, also called applications, or ‘‘apps’’ for short. Previous reviews have used the description of a code to envision the posttranslational states of tubulin’s carboxy-terminal tail (54–56). However, the code for the apps is probably not a simple one-to-one cipher. Rather, the PTM code is likely combinatorial, statistical, and complex in nature. Further, different codes can be written, erased, and rewritten on the same proteins repeatedly, adding complexity over time and space.

gpuccio

The dark matter of biology is likely to have multiple, vital roles to regulate signaling, rates of reactions, water structure and viscosity, crowding, and other cellular activities. We need to create new tools to image, detect, and understand these dark-matter species if we are to truly understand fundamental physical principles of biology.

The Dark Matter of Biology Jennifer L. Ross Biophysical Journal Volume 111, Issue 5, Pages 909–916 Biophysical Perspective http://dx.doi.org/10.1016/j.bpj.2016.07.037

Complex complexity. :) Dionisio

The inside of the cell is full of important, yet invisible species of molecules and proteins that interact weakly but couple together to have huge and important effects in many biological processes. Such “dark matter” inside cells remains mostly hidden, because our tools were developed to investigate strongly interacting species and folded proteins.

The Dark Matter of Biology Jennifer L. Ross Biophysical Journal Volume 111, Issue 5, Pages 909–916 Biophysical Perspective http://dx.doi.org/10.1016/j.bpj.2016.07.037

Dionisio

[...] little is known about the molecular mechanisms that distinguish diapause from non-diapause in this important mosquito species. [...] we know little about how mosquitoes are able translate complex environmental signals into the developmental switch that evokes the complex hormonal and physiological traits that comprise the diapause syndrome. It is our hope that a more comprehensive investigation of the functional roles of the genes described in this study, along with an expansion to additional time points, will result in a clearer understanding of the intriguing diapause phenotype.

Comparative Transcriptomics Reveals Key Gene Expression Differences between Diapausing and Non-Diapausing Adults of Culex pipiens David S. Kang,1 Michael A. Cotten,1 David L. Denlinger,2 and Cheolho Sim PLoS One. 2016; 11(4): e0154892. doi: 10.1371/journal.pone.0154892

Dionisio

Maternal factors play essential roles in coordinating embryonic cell fates in time and space. More studies are needed in future to unravel the function of the multifaceted cell fate regulator Ascl1. Further study is needed to better understand how the pre-neurula expression of Ascl1 functions as a transactivator and promotes neurogenesis. It remains unclear whether or how much Ascl1 protein is maternally stored.

A novel role for Ascl1 in the regulation of mesendoderm formation via HDAC-dependent antagonism of VegT Li Gao,1,* Xuechen Zhu,1,* Geng Chen,1 Xin Ma,2 Yan Zhang,1 Aftab A. Khand,1 Huijuan Shi,1 Fei Gu,1 Hao Lin,1 Yuemeng Chen,3 Haiyan Zhang,1 Lei He,1 and Qinghua Tao Development. 143(3): 492–503. doi: 10.1242/dev.126292

Dionisio

Nutrition and lifestyle, known to modulate aging process and age-related diseases, might also affect telomerase activity. [...] what we eat, how we eat and how much we eat, together with lifestyle significantly, can affect our telomerase/telomere system with a great impact on healthspan. “Similes cum similibus curantur” and in nature is still hidden the secret of healthy and long life whereas telomerase could represent the distinctive target. Many mechanisms and pathways underlie nutrition, lifestyle and longevity including telomere length modulation.

Nutrition and lifestyle in healthy aging: the telomerase challenge Virginia Boccardi,1 Giuseppe Paolisso,2 and Patrizia Mecocci1 Aging (Albany NY). ; 8(1): 12–15. doi: 10.18632/aging.100886

Dionisio

Further studies will probably reveal other wound?induced factors required to decide whether the regeneration initiation program should continue, and if so which tissues should be replaced. Non?genetic cues, such as reactive oxygen species and calcium, are generically released upon injury in a number of organisms [...] whether and how they may contribute to regeneration initiation through interactions with positional cues remains an open question. Planarians can regenerate after virtually all amputation scenarios. This requires a robust system that instructs stem cells to correctly replace missing tissues.

Go ahead, grow a head! A planarian's guide to anterior regeneration. Owlarn S, Bartscherer K. Regeneration (Oxf). ;3(3):139-55. doi: 10.1002/reg2.56. eCollection 2016.

Complex complexity. :) Dionisio

The planarian regeneration field is at an extremely exciting place, poised to contribute to our understanding of physiological networks in pattern formation [...] Much more work is needed to unify bioelectric and biochemical signaling. In particular, bi?directional regulatory loops between specific chemical pathways, chromatin state, and spatial voltage distributions need to be characterized. Physiological networks also need to start being incorporated into the advanced modeling platforms, which heretofore largely focus on gene regulatory networks and biochemical gradients [...] [...] it is unclear currently which of the many phenotypes exhibited in the literature are in fact permanent, or what mechanisms mediate the permanence. In planaria, ventral nerve cord integrity synergizes with GJC to determine whether a head forms at a wound (Oviedo et al. 2010); this interaction is currently not understood but is probably a gateway to understanding the relationship between neural and non?neural bioelectric signaling in pattern control. One of the major areas for future development, in addition to specific techniques and datasets, is advances in conceptual integration of molecular data and algorithmic understanding of the regenerating body as a computational distributed system [...]

Physiological controls of large-scale patterning in planarian regeneration: a molecular and computational perspective on growth and form. Durant F, Lobo D, Hammelman J, Levin M Regeneration (Oxf). 3(2):78-102. doi: 10.1002/reg2.54.

Dionisio

Top-down models may facilitate altering encoded goal states (e.g., target morphologies), bypassing the complexity explosion currently facing regenerative medicine’s attempts to control complex shape by tweaking molecules. [...] a better understanding of the bioelectric code may allow optogenetic or similar methods to rewrite the target morphology in vivo, inducing cells to build desired patterns as a kind of universal constructor. Interestingly, this effort may also pay off in the reverse direction, shedding light on the semantics of bioelectric states in the brain. However, cybernetic strategies are applicable to top-down regulation via any mechanism, not only bioelectricity, and can readily be explored in the context of biomechanical forces, gene regulatory networks, etc. For example, an area to be investigated is the application of active inference models to gene-regulatory networks and protein interaction networks, attempting to analyze their dynamics as an information-processing structure. Computer engineering and neuroscience serve as proofs-of-principle that efficient control of complex systems can be pursued with top-down models of goal-directed activity. Concepts such as feedback control and goal-seeking algorithms must also be included in training courses that nowadays focus principally on differential equations for gradients and network analysis, omitting complementary perspectives from computer science and engineering despite the ubiquitous calls for a deeper integration across disciplines.

Re-Membering the Body: applications of computational neuroscience to the top-down control of regeneration of limbs and other complex organs G. Pezzuloa and M. Levin Integr Biol (Camb). 7(12): 1487–1517. doi: 10.1039/c5ib00221d

Complex complexity. Dionisio

Directed cell migration is a complex process that involves front-rear polarization, characterized by cell adhesion and cytoskeleton-based protrusion, retraction, and contraction of either a single cell or a cell collective. Single cell polarization depends on a variety of mechanochemical signals including external adhesive cues, substrate stiffness, and confinement. In cell ensembles, coordinated polarization of migrating tissues results not only from the application of traction forces on the extracellular matrix but also from the transmission of mechanical stress through intercellular junctions.

Front-Rear Polarization by Mechanical Cues: From Single Cells to Tissues. Ladoux B1, Mège RM2, Trepat X3. Trends Cell Biol. 26(6):420-33. doi: 10.1016/j.tcb.2016.02.002

Complex complexity. :) Dionisio

Further understanding will require a more profound insight into active and passive properties of actomyosin as well as intermediate and MT networks at various time and length scales. It will also require a more precise determination of force transmission at cell–cell contacts and its regulation by ECM mechanical properties and cell matrix adhesion. There is also an urgent need to progress in the molecular understanding of cellular and subcellular methanol sensing at cell-cell and cell-matrix contacts and on instructive biochemical cues mobilized at the various scales. Clearly, we are at early ages of the understanding of this multistate polarization by mechanical cues. This is, however, a crucial bottleneck in understanding cell and tissue polarization in 2D layers and 3D matrices in reconstituted tissues as well as in understanding the general principles underlying morphogenetic movements.

Front-Rear Polarization by Mechanical Cues: From Single Cells to Tissues. Ladoux B1, Mège RM2, Trepat X3. Trends Cell Biol. 26(6):420-33. doi: 10.1016/j.tcb.2016.02.002

Work in progress... stay tuned. :) Dionisio

[...] it is not clear why, in a given cell population, cells can exhibit different migration behaviors despite using the same machinery and being subjected to the same pro-migration cues. What we do know about the mechanisms that govern cell migration only serves to underscore the complexity of the system, particularly in cases where there is more than one input signal.

Tuning cell migration: contractility as an integrator of intracellular signals from multiple cues Francois Bordeleau1 and Cynthia A. Reinhart-Kinga Version 1. F1000Res 5: F1000 Faculty Rev-1819. doi: 10.12688/f1000research.7884.1

Complex complexity. Emphasis mine. Dionisio

There has been immense progress in our understanding of the factors driving cell migration in both two-dimensional and three-dimensional microenvironments over the years. However, it is becoming increasingly evident that even though most cells share many of the same signaling molecules, they rarely respond in the same way to migration cues. To add to the complexity, cells are generally exposed to multiple cues simultaneously, in the form of growth factors and/or physical cues from the matrix. Understanding the mechanisms that modulate the intracellular signals triggered by multiple cues remains a challenge.

Tuning cell migration: contractility as an integrator of intracellular signals from multiple cues Francois Bordeleau1 and Cynthia A. Reinhart-Kinga Version 1. F1000Res 5: F1000 Faculty Rev-1819. doi: 10.12688/f1000research.7884.1

Complex complexity. Emphasis mine. Dionisio

Further experiments are also needed to answer a number of other questions. [...] we cannot help but wonder how many similar structures have been missed in the cells of other organisms and therefore are still waiting to be discovered.

Cellular fingers take hold Yukiko M Yamashita eLife. 2016; 5: e19405. doi: 10.7554/eLife.19405

Dionisio

[...] the direction in which the invagination forms is under the control of the same signaling pathway that controls planar cell polarity. Confirming that the invagination does indeed anchor the centrosome will require further study, in particular to identify the molecular components that govern how the invagination forms.

Cellular fingers take hold Yukiko M Yamashita eLife. 2016; 5: e19405. doi: 10.7554/eLife.19405

Dionisio

Cells in textbooks tend to have simple shapes, with surfaces that merely separate the contents of the cell from the outside world. However, this is far from the truth.

Cellular fingers take hold Yukiko M Yamashita eLife. 2016; 5: e19405. doi: 10.7554/eLife.19405

this is far from the truth? Does that mean that biology textbooks are not telling the truth? Dionisio

Invaginations in the membranes of embryonic cells appear to orient cell division in sea squirts.

Cellular fingers take hold Yukiko M Yamashita eLife. 2016; 5: e19405. doi: 10.7554/eLife.19405

Dionisio

Development of the air sac primordium requires components of the PCP system Dpp and FGF signaling requires Prickle and Van Gogh The constitution of the ECM is dependent on prickle and Van Gogh Dpp signaling depends on dally but FGF signaling depends on dlp Cytonemes navigate in a stratified ECM Cytoneme-mediated signaling requires integrin function

Cells must express components of the planar cell polarity system and extracellular matrix to support cytonemes. Huang H1, Kornberg TB Elife. ;5. pii: e18979. doi: 10.7554/eLife.18979.

Dionisio

gpuccio: Glad to see your insightful comments here again! Thank you! What you stated @2054 is highly interesting indeed. That's a very good observation. Yes, agree with you that the referred paper definitely seems like a research jewel. Please, keep reviewing the references and let us know if you spot another 'juicy' paper here. Since professor L.M. of the U. of T. in Canada decided not to share his profound knowledge about how exactly morphogenesis occurs, I have no option but to search the available literature myself. :) But this is not easy for me at all. It would have been much nicer to have someone explain this complex complexity to the rest of us, right? But he said I don't ask honest questions, whatever that means. :) That's why I appreciate so much your very insightful comments on the referenced papers. Dionisio

[...] secreted signaling proteins and signaling protein receptors are not distributed in the extracellular environment and are not bound to the ECM, but rather that the cytonemes that mediate Dpp and FGF signaling contact the ECM directly in ways that involve both integrins and specific HSPG interactions.

Cells must express components of the planar cell polarity system and extracellular matrix to support cytonemes. Huang H1, Kornberg TB Elife. ;5. pii: e18979. doi: 10.7554/eLife.18979.

Complex complexity. Dionisio

[...] the extracellular space is organized and regulated [...] [...] the extracellular matrix is essential for developmental signaling. [...] it is not known whether the cells between the producing and receiving cells (henceforth called 'intermediate cells') also contribute to cytoneme-mediated signaling.

Cells must express components of the planar cell polarity system and extracellular matrix to support cytonemes. Huang H1, Kornberg TB Elife. ;5. pii: e18979. doi: 10.7554/eLife.18979.

Dionisio

The language of development has a small vocabulary of signaling proteins that consists in part of Fibroblast growth factor (FGF) and Bone morphogenic proteins such as Drosophila Decapentaplegic (Dpp). This language may be used in most or all metazoan organs.

Cells must express components of the planar cell polarity system and extracellular matrix to support cytonemes. Huang H1, Kornberg TB Elife. ;5. pii: e18979. doi: 10.7554/eLife.18979.

Did anybody say language ? Another language ? Wasn't the language in the genome? How many languages do the biological systems speak? Are they multilingual? Complex complexity. :) Emphasis mine. Dionisio

Dionisio: Thank you for your continuing work! You really point to important and very interesting papers from the literature. :) I was specially impressed by this one: "Physiological inputs regulate species-specific anatomy during embryogenesis and regeneration" The idea that similar electro-biological levels of control could be responsible for both cellular development in metazoa and information processing in the brain is new and stimulating. And the idea that epigenetic information can be stored as some electrical pattern in cells and tissues is really promising. I repost here the abstract, in case someone else can be interested:

A key problem in evolutionary developmental biology is identifying the sources of instructive information that determine species-specific anatomical pattern. Understanding the inputs to large scale morphology is also crucial for efforts to manipulate pattern formation in regenerative medicine and synthetic bioengineering. Recent studies have revealed a physiological system of communication among cells that regulates pattern during embryogenesis and regeneration in vertebrate and invertebrate models. Somatic tissues form networks using the same ion channels, electrical synapses, and neurotransmitter mechanisms exploited by the brain for information processing. Experimental manipulation of these circuits was recently shown to override genome default patterning outcomes, resulting in head shapes resembling those of other species in planaria and Xenopus. The ability to drastically alter macroscopic anatomy to that of other extant species, despite a wild-type genomic sequence, suggests exciting new approaches to the understanding and control of patterning. Here, we review these results and discuss hypotheses regarding nongenomic systems of instructive information that determine biological growth and form.

gpuccio

Future challenges include understanding how the layers of the extracellular matrix form and how information is encoded in these layers for the cytonemes to decipher as they navigate to their targets.

Cells must express components of the planar cell polarity system and extracellular matrix to support cytonemes. Huang H1, Kornberg TB Elife. ;5. pii: e18979. doi: 10.7554/eLife.18979.

Dionisio

The embryos of animals develop in a controlled manner that ensures that their tissues and organs form properly and at the right time. These processes depend on molecules called morphogens that are distributed throughout the embryo in specific ways and that are dispersed via extensions that protrude from the surfaces of cells. These extensions, called cytonemes, transport the morphogens across the distances that separate cells and transfer these molecules to target cells via direct contact. However, it was not known how cytonemes navigate to their targets. [...] cytonemes interact directly and specifically with proteins in the stratified ECM.

Cells must express components of the planar cell polarity system and extracellular matrix to support cytonemes. Huang H1, Kornberg TB Elife. ;5. pii: e18979. doi: 10.7554/eLife.18979.

Dionisio

[...] why are the zones arranged as concentric spheres? One answer may be that this has the potential to maximize the likelihood of diffused products arriving at their targets.

Functional Zonation of the Adult Mammalian Adrenal Cortex Gavin P. Vinson Front Neurosci. 2016; 10: 238. doi: 10.3389/fnins.2016.00238

Wow! Nature is so smart! :) Dionisio

[...] it more and more appears that the functions of the gland should be viewed as an integrated whole, greater than the sum of its component parts. The nature and significance of the zonation of the mammalian adrenal cortex has attracted considerable interest during the fifteen decades following the first description of its three main zones, zona glomerulosa, zona fasciculata, and zona reticularis, by Arnold (1866). Like the human body itself, the function of the adrenal gland is an integrated whole, much greater than the sum of its parts. We should aim to think of it that way.

Functional Zonation of the Adult Mammalian Adrenal Cortex Gavin P. Vinson Front Neurosci. 2016; 10: 238. doi: 10.3389/fnins.2016.00238

Dionisio

The standard model of adrenocortical zonation holds that the three main zones, glomerulosa, fasciculata, and reticularis each have a distinct function, producing mineralocorticoids (in fact just aldosterone), glucocorticoids, and androgens respectively. Recent progress in understanding the development of the gland and the distribution of steroidogenic enzymes, trophic hormone receptors, and other factors suggests that this model needs refinement.

Functional Zonation of the Adult Mammalian Adrenal Cortex Gavin P. Vinson Front Neurosci. 2016; 10: 238. doi: 10.3389/fnins.2016.00238

Dionisio

Morphogens are long-range signals thought to induce different cell behaviors in a concentration-dependent manner, but how such graded signals can be established in the face of noise and how they specify sharp boundaries of target gene expression remain unclear. [...] RA gradient persists during gastrulation and establishment of rhombomeres. [...] the fluctuations in RA levels that we observed in embryos are clearly biological in origin. [...] cells actively control the magnitude of noise in a signaling molecule in a multicellular system in vivo. [...] it seems likely that cells possess mechanisms to limit this noise propagation.

Noise modulation in retinoic acid signaling sharpens segmental boundaries of gene expression in the embryonic zebrafish hindbrain Julian Sosnik,1,2,3 Likun Zheng,2,4 Christopher V Rackauckas,2,4 Michelle Digman,1,2,5 Enrico Gratton,1,2,5 Qing Nie,1,2,4 and Thomas F Schilling eLife. 2016; 5: e14034. doi: 10.7554/eLife.14034

Dionisio

Morphogen gradients induce sharply defined domains of gene expression in a concentration-dependent manner, yet how cells interpret these signals in the face of spatial and temporal noise remains unclear. Animal cells need to be able to communicate with each other so that they can work together in tissues and organs. To do so, cells release signaling molecules that can move around within a tissue and be detected by receptors on other cells. A future challenge will be to see if similar retinoic acid gradients and noise control occur in other tissues, and if the noise has any positive role to play in development.

Noise modulation in retinoic acid signaling sharpens segmental boundaries of gene expression in the embryonic zebrafish hindbrain Julian Sosnik,1,2,3 Likun Zheng,2,4 Christopher V Rackauckas,2,4 Michelle Digman,1,2,5 Enrico Gratton,1,2,5 Qing Nie,1,2,4 and Thomas F Schilling eLife. 2016; 5: e14034. doi: 10.7554/eLife.14034

Dionisio

[...] it is possible that factors produced by other species living within a host organism's body can serve as an additional input to the organism's pattern by editing or altering its endogenous bioelectrical circuits This adds a layer of complexity to the typical “evo-devo” story [...] The list of the molecular signals that propagate through physiological networks is likely to grow rapidly in the following years. However, several players (current, calcium, neurotransmitters) are already implicated. The molecular and algorithmic analogies between how somatic tissues and the brain utilize these same components are a fertile area for novel inquiry, and remain to be tested in specific contexts.

Physiological inputs regulate species-specific anatomy during embryogenesis and regeneration Kelly G. Sullivan,† Maya Emmons-Bell,† and Michael Levin Commun Integr Biol. 9(4): e1192733. doi: 10.1080/19420889.2016.1192733

Dionisio

[...] the DNA specifies the hardware (the complement of channels, neurotransmitters, and GJ proteins), while the resulting bioelectric activity of these circuits (with spontaneous symmetry-breaking, self-organization, and other complex dynamics) is the software.

Physiological inputs regulate species-specific anatomy during embryogenesis and regeneration Kelly G. Sullivan,† Maya Emmons-Bell,† and Michael Levin Commun Integr Biol. 9(4): e1192733. doi: 10.1080/19420889.2016.1192733

How did we get that software? Dionisio

[...] bioelectric networks facilitate robustness of physiological states and the patterning they regulate (via negative feedback loops and long-range state sensing). Morphogenetic functions guided by bioelectric circuits are also robust to mutation in channels and their transcriptional regulation. bioelectric states as control points tend to be powerful “master regulators”, allowing the initiation of self-limiting patterning modules as subroutines from a low information content input (trigger); this is due to the existence of positive feedback loops, which sustain and amplify bioelectric states once a threshold has been surpassed by a transient bioelectric stimulus (exploited also by action potentials in brain circuits).

Physiological inputs regulate species-specific anatomy during embryogenesis and regeneration Kelly G. Sullivan,† Maya Emmons-Bell,† and Michael Levin Commun Integr Biol. 9(4): e1192733. doi: 10.1080/19420889.2016.1192733

Dionisio

The functional signaling properties of physiological networks are determined by the electrical activity, not the mere presence or absence of specific molecules. This implies a departure from the standard molecular biological paradigm, where cell state is thought to be derivable by proteomic and transcriptomic profiling. Bioelectric information can only be read out in the living state (not in fixed, biochemically-analyzed tissue).

Physiological inputs regulate species-specific anatomy during embryogenesis and regeneration Kelly G. Sullivan,† Maya Emmons-Bell,† and Michael Levin Commun Integr Biol. 9(4): e1192733. doi: 10.1080/19420889.2016.1192733

Dionisio

[...] bioelectric circuits have their own unique and complex dynamics that derive from the fact that ion channels and GJs determine cell voltage but are also themselves regulated by voltage gradients. These feedback loops and the resulting electric circuit state transitions over time are not predictable from the rules governing genetic sequence, transcriptional networks, or chromatin state53 because channels and GJs open and close post-translationally, implementing functional signaling that is invisible to profiling at transcriptional or translational levels.

Physiological inputs regulate species-specific anatomy during embryogenesis and regeneration Kelly G. Sullivan,† Maya Emmons-Bell,† and Michael Levin Commun Integr Biol. 9(4): e1192733. doi: 10.1080/19420889.2016.1192733

Dionisio

Biological patterning is at the nexus of most of the important problems facing basic biology and biomedicine. Understanding the instructive signals that ensure self-assembly and maintenance of complex 3-dimensional morphology is crucial for basic evolutionary and developmental biology. How do cells, all derived from the same fertilized egg (the original stem cell) and bearing the same DNA, become not only differentiated into distinct cell types, but arranged into stereotypical spatial patterns with no external guidance? This question is at the center of understanding evolutionary change because development is what links genetics (upon which mutation acts) with form and function (upon which selection operates).

Physiological inputs regulate species-specific anatomy during embryogenesis and regeneration Kelly G. Sullivan,† Maya Emmons-Bell,† and Michael Levin Commun Integr Biol. 9(4): e1192733. doi: 10.1080/19420889.2016.1192733

Dionisio

A key problem in evolutionary developmental biology is identifying the sources of instructive information that determine species-specific anatomical pattern. Understanding the inputs to large-scale morphology is also crucial for efforts to manipulate pattern formation in regenerative medicine and synthetic bioengineering. Recent studies have revealed a physiological system of communication among cells that regulates pattern during embryogenesis and regeneration in vertebrate and invertebrate models. Somatic tissues form networks using the same ion channels, electrical synapses, and neurotransmitter mechanisms exploited by the brain for information-processing. Experimental manipulation of these circuits was recently shown to override genome default patterning outcomes, resulting in head shapes resembling those of other species in planaria and Xenopus. The ability to drastically alter macroscopic anatomy to that of other extant species, despite a wild-type genomic sequence, suggests exciting new approaches to the understanding and control of patterning. Here, we review these results and discuss hypotheses regarding non-genomic systems of instructive information that determine biological growth and form.

Physiological inputs regulate species-specific anatomy during embryogenesis and regeneration Kelly G. Sullivan,† Maya Emmons-Bell,† and Michael Levin Commun Integr Biol. 9(4): e1192733. doi: 10.1080/19420889.2016.1192733

Dionisio

The temporal components of different sensory, motor, cognitive and learning tasks often require different levels of accuracy, precision, flexibility (e.g. the time it takes to ‘reset’ a clock between tasks) and complexity (e.g. simple intervals or complex patterns). Whether or not STP and intrinsic dynamics of recurrent circuits account for timing in the subsecond range remains an open question. [...] the mechanisms underlying the diverse forms of temporal processing the brain performs remain to be elucidated [...]

Timing as an intrinsic property of neural networks: evidence from in vivo and in vitro experiments Anubhuti Goel and Dean V. Buonomano Philos Trans R Soc Lond B Biol Sci. 369(1637): 20120460. doi: 10.1098/rstb.2012.0460

Dionisio

[...] the human brain is exquisitely capable of processing temporal information and generating temporal patterns. Indeed, the sophistication of temporal processing is well illustrated by the observation that humans can reduce communication to a purely temporal code, as occurs when people communicate using Morse code. Despite the obvious importance of temporal processing to communication, learning, cognition, and sensory and motor processing, even the most basic mechanisms of how animals discriminate simple intervals or generate timed responses remains unknown.

Timing as an intrinsic property of neural networks: evidence from in vivo and in vitro experiments Anubhuti Goel and Dean V. Buonomano Philos Trans R Soc Lond B Biol Sci. 369(1637): 20120460. doi: 10.1098/rstb.2012.0460

Dionisio

The discrimination and production of temporal patterns on the scale of hundreds of milliseconds are critical to sensory and motor processing. Indeed, most complex behaviours, such as speech comprehension and production, would be impossible in the absence of sophisticated timing mechanisms. Despite the importance of timing to human learning and cognition, little is known about the underlying mechanisms, in particular whether timing relies on specialized dedicated circuits and mechanisms or on general and intrinsic properties of neurons and neural circuits.

Timing as an intrinsic property of neural networks: evidence from in vivo and in vitro experiments Anubhuti Goel and Dean V. Buonomano Philos Trans R Soc Lond B Biol Sci. 369(1637): 20120460. doi: 10.1098/rstb.2012.0460

Dionisio

Eukaryotic genomes are organized into chromatin, a higher?order structure comprising histones and DNA. Dynamic assembly of nucleosomes is essential for the control of DNA?templated processes such as replication, DNA damage repair, and gene regulation [...] [...] oligomerization of isolated Nap1 and Nap1–histone complexes occurs under physiological conditions in vitro and in vivo [...] The physiological role of such oligomerization has remained unclear. Future studies need to experimentally demonstrate the role of the NLS and how defective oligomerization or histone loading interferes with the yNap1 functional cycle. The transport of histones into or out of the nucleus is an essential step in chromatin assembly and the masking and unmasking of NLS sequences, as a function of histone binding and oligomerization may be a mechanism for regulating subcellular localization of yNAP1 and histones.

Structural evidence for Nap1?dependent H2A–H2B deposition and nucleosome assembly Carmen Aguilar?Gurrieri, Amédé Larabi, Vinesh Vinayachandran, Nisha A Patel, Kuangyu Yen, Rohit Reja, Ima?O Ebong, Guy Schoehn, Carol V Robinson, B Franklin Pugh, ? View ORCID ProfileDaniel Panne DOI 10.15252/embj.201694105 The EMBO Journal 35, 1465-1482

Dionisio

What determines whether a TF depends on the chromatin context of its target genes or whether it is able to initiate a remodeling process that will reshape the epigenetic landscape, making it permissive for gene expression? Is this the prerogative of a specific class of TFs, the “pioneer factors,” or can many TFs do this depending on expression level and interactions with other factors? How are chromatin-modifying enzymes, with PRC2 as a prime example, targeted to their genomic locations?

Chromatin Control of Developmental Dynamics and Plasticity Matteo Perino, Gert Jan C. Veenstra DOI: http://dx.doi.org/10.1016/j.devcel.2016.08.004 Volume 38, Issue 6, p610–620 Developmental Cell

Dionisio

How are the influences of signaling and germ layer specification integrated with the cell-autonomous influences of maternal factors and specific signals embedded within the DNA sequence of regulatory regions to direct chromatin state and the developmental program? With what temporal dynamics and mechanistic hierarchy does this happen, and how are cellular competence and potency balanced with the need for commitment and epigenetic stability of cell fate? What does cell-fate specification and determination mean at the level of chromatin state of genes involved in different developmental programs?

Chromatin Control of Developmental Dynamics and Plasticity Matteo Perino, Gert Jan C. Veenstra DOI: http://dx.doi.org/10.1016/j.devcel.2016.08.004 Volume 38, Issue 6, p610–620 Developmental Cell

Dionisio

Multicellular animals owe their complexity to their capacity to produce and maintain a multitude of different cell types that share virtually the same genomic DNA. Such complexity requires tight regulation of gene expression to unambiguously specify and constrain the developmental paths taken by cells in the embryo. It will be important to address a number of remaining questions. Studies in recent years have made exciting inroads into these questions, and much progress is expected in addressing the outstanding questions in years to come. [...] integration of these powerful techniques, alongside synergistic approaches combining developmental and computational biology, will provide insight into the profound questions associated with the multiple levels of complexity of the developing embryo, from egg to organism.

Chromatin Control of Developmental Dynamics and Plasticity Matteo Perino, Gert Jan C. Veenstra DOI: http://dx.doi.org/10.1016/j.devcel.2016.08.004 Volume 38, Issue 6, p610–620 Developmental Cell

Dionisio

It would be interesting to know whether the non-BMP-activated HSCs in the FL are also controlled by Hh/VEGF signaling, and an appropriate culture system should be developed to test this. Whether the increase in AGM explant HSCs is due to the expansion and shift in BMP-activation status of existing HSCs, or the new generation of HSCs (non-BMP-activated), or both, remains unclear. It will be interesting in future studies to examine these cells and the early hematopoietic tissues in the context of BMP, as well as Hh signaling through fate-mapping approaches.

BMP and Hedgehog Regulate Distinct AGM Hematopoietic Stem Cells Ex Vivo Mihaela Crisan,1,2 Parham Solaimani Kartalaei,1,3 Alex Neagu,1 Sofia Karkanpouna,1 Tomoko Yamada-Inagawa,1 Caterina Purini,1 Chris S. Vink,1,3 Reinier van der Linden,1 Wilfred van Ijcken,4 Susana M. Chuva de Sousa Lopes,5 Rui Monteiro,6 Christine Mummery,5 and Elaine Dzierzak1, Stem Cell Reports. 6(3): 383–395. doi: 10.1016/j.stemcr.2016.01.016

Dionisio

Hematopoietic stem cells (HSC), the self-renewing cells of the adult blood differentiation hierarchy, are generated during embryonic stages. The first HSCs are produced in the aorta-gonad-mesonephros (AGM) region of the embryo through endothelial to a hematopoietic transition. BMP4 and Hedgehog affect their production and expansion, but it is unknown whether they act to affect the same HSCs.

BMP and Hedgehog Regulate Distinct AGM Hematopoietic Stem Cells Ex Vivo Mihaela Crisan,1,2 Parham Solaimani Kartalaei,1,3 Alex Neagu,1 Sofia Karkanpouna,1 Tomoko Yamada-Inagawa,1 Caterina Purini,1 Chris S. Vink,1,3 Reinier van der Linden,1 Wilfred van Ijcken,4 Susana M. Chuva de Sousa Lopes,5 Rui Monteiro,6 Christine Mummery,5 and Elaine Dzierzak1, Stem Cell Reports. 6(3): 383–395. doi: 10.1016/j.stemcr.2016.01.016

Dionisio

SNPs associated with disease susceptibility often reside in enhancer clusters, or super-enhancers. Constituents of these enhancer clusters cooperate to regulate target genes and often extend beyond the linkage disequilibrium (LD) blocks containing risk SNPs identified in genome-wide association studies (GWAS). We identified 'outside variants', defined as SNPs in weak LD with GWAS risk SNPs that physically interact with risk SNPs as part of a target gene's regulatory circuitry. These outside variants further explain variation in target gene expression beyond that explained by GWAS-associated SNPs. Additionally, the clinical risk associated with GWAS SNPs is considerably modified by the genotype of outside variants. Collectively, these findings suggest a potential model in which outside variants and GWAS SNPs that physically interact in 3D chromatin collude to influence target transcript levels as well as clinical risk. This model offers an additional hypothesis for the source of missing heritability for complex traits.

Modeling disease risk through analysis of physical interactions between genetic variants within chromatin regulatory circuitry. Corradin O1,2, Cohen AJ1, Luppino JM1, Bayles IM1, Schumacher FR3, Scacheri PC1 Nat Genet. doi: 10.1038/ng.3674

Complex complexity. :) Dionisio

Regeneration in the animal kingdom is one of the most fascinating problems that have allowed scientists to address many issues of fundamental importance in basic biology. However, we came to know that the regenerative capability may vary across different species. [...] it is imperative to study the underlying molecular basis of neurogenesis during CNS development in order to uncover the molecular signals that are adapted during adult neurogenesis. [...] it is important to identify the progenitors in the regenerating cord, so that their contribution to neurogenesis could be elucidated [...]

Regeneration of Zebrafish CNS: Adult Neurogenesis Sukla Ghosh * and Subhra Prakash Hui Neural Plast. 5815439. doi: 10.1155/2016/5815439

Dionisio

Embryogenesis is replete with transcription factor “codes” and networks working in concert to specify and differentiate various cell types. Prdm family members function in multi-protein transcription regulatory complexes that control diverse aspects of neural development—from the patterning of expression domains and cell specification to axonal projections and circuit formation. There are several gene families with important roles in early neural development. Prdm genes also have essential functions in CNS development, thereby placing the Prdm family alongside these other gene families as key regulators of neural development.

An emerging role for prdm family genes in dorsoventral patterning of the vertebrate nervous system Denise A. Zannino and Charles G. Sagerström Neural Dev. 10: 24. doi: 10.1186/s13064-015-0052-8

Dionisio

[...] many open questions remain. Some key pieces of data will be required before a complete model can be constructed. [...] researchers may not always be measuring what they think they are and this could hinder correct interpretation of the results. It is unknown exactly what the identity of these cells would be however. It seems likely that as yet undiscovered sources of complexity are hidden in what might at first appear to be a straightforward system [...] It is hoped that we are not too far away from working quantitative models which could allow the hoard of information currently available to be integrated into a functional, and predictive, overview.

Different Mechanisms Must Be Considered to Explain the Increase in Hippocampal Neural Precursor Cell Proliferation by Physical Activity. Overall RW1, Walker TL1, Fischer TJ1, Brandt MD2, Kempermann G1 Front Neurosci. 10:362. doi: 10.3389/fnins.2016.00362.

Dionisio

[...] improved models are required to account for the existing data and that such models will have to be instructive on the fundamental mechanisms involved in adult neural stem cell proliferation. That such apparently minor details in experimental methodology might lead to fundamentally different interpretations highlights the necessity for clear hypotheses to be generated to tease apart the complexity in this system. [...] regulation of cell death by physical activity remains an intriguing possibility [...] [...] more work is needed to comfortably incorporate this process into a global model of adult neurogenesis. Whether these quiescent progenitors would undergo only symmetric division or have some limited capacity for self-renewal is still not clear.

Different Mechanisms Must Be Considered to Explain the Increase in Hippocampal Neural Precursor Cell Proliferation by Physical Activity. Overall RW1, Walker TL1, Fischer TJ1, Brandt MD2, Kempermann G1 Front Neurosci. 10:362. doi: 10.3389/fnins.2016.00362.

Dionisio

[...] the parameters for most of these factors have not yet been reliably experimentally determined, making the construction of a useful model seemingly intractable. The result of this complexity is that, despite much work, the cellular mechanism by which physical activity causes increased precursor cell proliferation has still not been established. It will be necessary to establish a comprehensive mechanistic framework before more detailed and dynamic models can be attempted.

Different Mechanisms Must Be Considered to Explain the Increase in Hippocampal Neural Precursor Cell Proliferation by Physical Activity. Overall RW1, Walker TL1, Fischer TJ1, Brandt MD2, Kempermann G1 Front Neurosci. 10:362. doi: 10.3389/fnins.2016.00362.

Dionisio

The number of proliferating neural precursor cells in the adult hippocampus is strongly increased by physical activity. The mechanisms through which this behavioral stimulus induces cell proliferation, however, are not yet understood. In fact, even the mode of proliferation of the stem and progenitor cells is not exactly known. We must therefore consider other mechanisms by which physical activity leads to enhanced precursor cell proliferation.

Different Mechanisms Must Be Considered to Explain the Increase in Hippocampal Neural Precursor Cell Proliferation by Physical Activity. Overall RW1, Walker TL1, Fischer TJ1, Brandt MD2, Kempermann G1 Front Neurosci. 10:362. doi: 10.3389/fnins.2016.00362.

Dionisio

Moved to the third way thread Dionisio

The contractile structure driving invagination in the ectodermal placodes is topologically somewhat analogous to the contractile actin cables that drive invagination by apical constriction in epithelial monolayers, but on a vastly different scale: intercalation among cells rather than actin and myosin filaments. [...] the similarity, right down to the distribution of force-deformed nuclei, between tooth bud, hair follicle, and mammary gland primordia indicates that these ectodermal organs share the same mechanisms of physical morphogenesis.

Invagination of Ectodermal Placodes Is Driven by Cell Intercalation-Mediated Contraction of the Suprabasal Tissue Canopy Eleni Panousopoulou and Jeremy B. A. Green* PLoS Biol. 14(3): e1002405. doi: 10.1371/journal.pbio.1002405

Dionisio

Ectodermal organs such as teeth, hair follicles, and mammary glands begin their development as placodes. These are local epithelial thickenings that invaginate into mesenchymal space. There is currently little mechanistic understanding of the cellular processes driving the early morphogenesis of these organs and of why they lead to invagination rather than simple tissue thickening. [...] the physical events that lead placodes to invaginate are unclear. Epithelial bending, especially invagination, is a recurrent morphogenetic event in development, but our knowledge of the underlying cellular mechanisms is quite limited. Overall, our results describe the dynamic rearrangements that take place during tooth placode formation and suggest that similar processes occur in other organs that are formed by invagination of stratified placodes.

Invagination of Ectodermal Placodes Is Driven by Cell Intercalation-Mediated Contraction of the Suprabasal Tissue Canopy Eleni Panousopoulou and Jeremy B. A. Green* PLoS Biol. 14(3): e1002405. doi: 10.1371/journal.pbio.1002405

Dionisio

The mechanisms driving stratification and invagination are poorly understood. [...] FGF generates suprabasal tissue by asymmetric cell division, while Shh triggers cell rearrangement in this tissue to drive invagination all the way to bud formation. [...] cellular mechanisms that form placodes and buds are poorly described. [...] whether cells converge within, under or over the pre-existing epithelial layer has not been established, and the relationship of placode thickening to placode invagination is not clear. Remarkably, stratification and invagination could be separated according to signalling pathway: FGF signalling is necessary and sufficient for proliferation and stratification, whereas Shh is required for convergence, invagination and bud neck formation. Together, these resolve ectodermal placode formation and invagination into two simple morphogenetic elements.

Epithelial stratification and placode invagination are separable functions in early morphogenesis of the molar tooth Jingjing Li, Lemonia Chatzeli, Eleni Panousopoulou, Abigail S. Tucker, and Jeremy B. A. Green Development. 143(4): 670–681. doi: 10.1242/dev.130187

Dionisio

Clarifying the role of COOLAIR in monitoring long-term exposure to fluctuating temperatures experienced by plants during winter, and how this function has evolved during adaptation, will provide an important paradigm for lncRNA studies. Further COOLAIR studies, including motif deletion and compensatory mutations, will aid in interrogating structure-function relationships, including roles in temperature perception. Identifying COOLAIR in more species will allow more iterations of consensus secondary structure refinement.

COOLAIR Antisense RNAs Form Evolutionarily Conserved Elaborate Secondary Structures Emily J. Hawkes, Scott P. Hennelly, Irina V. Novikova, Judith A. Irwin, Caroline Dean, Karissa Y. Sanbonmatsu DOI: http://dx.doi.org/10.1016/j.celrep.2016.08.045 Cell Repost, Volume 16, Issue 12, p3087–3096

Dionisio

There is considerable debate about the functionality of long non-coding RNAs (lncRNAs). Lack of sequence conservation has been used to argue against functional relevance. Long non-coding RNAs (lncRNAs) have emerged as potentially important players in the epigenetic regulation of development and disease in many organisms.

COOLAIR Antisense RNAs Form Evolutionarily Conserved Elaborate Secondary Structures Emily J. Hawkes, Scott P. Hennelly, Irina V. Novikova, Judith A. Irwin, Caroline Dean, Karissa Y. Sanbonmatsu DOI: http://dx.doi.org/10.1016/j.celrep.2016.08.045 Cell Repost, Volume 16, Issue 12, p3087–3096

Dionisio

In mammals, the brain and spinal cord develop from a flat sheet of cells called the neural plate, which bends around to create a structure known as the neural tube. This bending process occurs through a complex sequence of cell shape changes. Future work is now needed to investigate the exact molecules targeted by PDK1 and the roles they play in disorders and diseases caused by a lack of the PTEN protein.

The tumor suppressor PTEN and the PDK1 kinase regulate formation of the columnar neural epithelium Joaquim Grego-Bessa,1† Joshua Bloomekatz,1‡ Pau Castel,2 Tatiana Omelchenko,3 José Baselga,2,4 and Kathryn V Anderson eLife. 5: e12034. doi: 10.7554/eLife.12034

Work in progress... stay tuned. :) Dionisio

Epithelial morphogenesis and stability are essential for normal development and organ homeostasis. [...] PTEN is required for stabilization of planar cell packing in the neural plate and for the formation of stable apical-basal microtubule arrays. [...] appropriate levels of membrane-associated PDPK1 are required for stabilization of apical junctions, which promotes cell elongation, during epithelial morphogenesis.

The tumor suppressor PTEN and the PDK1 kinase regulate formation of the columnar neural epithelium Joaquim Grego-Bessa,1† Joshua Bloomekatz,1‡ Pau Castel,2 Tatiana Omelchenko,3 José Baselga,2,4 and Kathryn V Anderson eLife. 5: e12034. doi: 10.7554/eLife.12034

Too little of this? Too much of that? Complex complexity. :) Dionisio

[...] negative regulation of tight junction formation involves other, as yet unrecognized players that control the activity of CFL1. [...] Cfl1 has a complex role in tumor progression: although increased CFL1 activity may promote metastasis, CFL1 also stabilizes epithelial integrity and therefore may help prevent invasion and metastasis.

Morphogenesis of the mouse neural plate depends on distinct roles of cofilin 1 in apical and basal epithelial domains Joaquim Grego-Bessa, Jeffrey Hildebrand, and Kathryn V. Anderson Development. 142(7): 1305–1314. doi: 10.1242/dev.115493

Complex complexity. Dionisio

[...] it is surprising that cofilin is required for the activation of actomyosin contraction [...] [...] the apical ring constriction that drives neural tube closure is also driven by cofilin-mediated actin depolymerization [...] [...] activation of the apical myosin motor depends on this cofilin-mediated actin depolymerization.

Morphogenesis of the mouse neural plate depends on distinct roles of cofilin 1 in apical and basal epithelial domains Joaquim Grego-Bessa, Jeffrey Hildebrand, and Kathryn V. Anderson Development. 142(7): 1305–1314. doi: 10.1242/dev.115493

surprising ? Why? :) Dionisio

CFL1 is enriched in both the apical and basal domains of neural epithelial cells and it has different roles in the two domains. [...] in the apical domain of the neural plate CFL1 is required for activation of cytoplasmic myosin, contraction of the apical actin ring and therefore for neural tube closure, whereas the basal activity of CFL1 prevents the basal formation of active actomyosin and tight junctions and helps maintain the basement membrane

Morphogenesis of the mouse neural plate depends on distinct roles of cofilin 1 in apical and basal epithelial domains Joaquim Grego-Bessa, Jeffrey Hildebrand, and Kathryn V. Anderson Development. 142(7): 1305–1314. doi: 10.1242/dev.115493

Same molecule with different context-dependent roles? Isn't that neat? :) Dionisio

Through highly orchestrated cell shape changes, including apical constriction, the neural plate folds and the dorsalmost cells join to create a closed tube. [...] cofilin 1 is required for the apical activation of actomyosin that is necessary for neural tube closure. [...] apically localized proteins switch cofilin from a basal inhibitor of actomyosin to an apical activator of actomyosin contractility.

Morphogenesis of the mouse neural plate depends on distinct roles of cofilin 1 in apical and basal epithelial domains Joaquim Grego-Bessa, Jeffrey Hildebrand, and Kathryn V. Anderson Development. 142(7): 1305–1314. doi: 10.1242/dev.115493

Emphasis mine. Dionisio

The genetic control of mammalian epithelial polarity and dynamics can be studied in vivo at cellular resolution during morphogenesis of the mouse neural tube. The mouse neural plate is a simple epithelium that is transformed into a columnar pseudostratified tube over the course of ?24?h. Apical F-actin is known to be important for neural tube closure, but the precise roles of actin dynamics in the neural epithelium are not known.

Morphogenesis of the mouse neural plate depends on distinct roles of cofilin 1 in apical and basal epithelial domains Joaquim Grego-Bessa, Jeffrey Hildebrand, and Kathryn V. Anderson Development. 142(7): 1305–1314. doi: 10.1242/dev.115493

Dionisio

It is tempting to speculate that the diverse functions of Alix may be primarily related to the capacity of this scaffold protein to directly interact with the actin cytroskeleton, thereby creating the most favourable setting for components of multiprotein complexes to assemble in a timely, spatial and dynamic manner and to target them to specific cellular microdomains.

Alix-mediated assembly of the actomyosin–tight junction polarity complex preserves epithelial polarity and epithelial barrier Yvan Campos,1 Xiaohui Qiu,1 Elida Gomero,1 Randall Wakefield,2 Linda Horner,2 Wojciech Brutkowski,3 Young-Goo Han,4 David Solecki,4 Sharon Frase,2 Antonella Bongiovanni,5 and Alessandra d'Azzo Nat Commun. 7: 11876. doi: 10.1038/ncomms11876

Dionisio

Maintenance of epithelial cell polarity and epithelial barrier relies on the spatial organization of the actin cytoskeleton and proper positioning/assembly of intercellular junctions. However, how these processes are regulated is poorly understood.

Alix-mediated assembly of the actomyosin–tight junction polarity complex preserves epithelial polarity and epithelial barrier Yvan Campos,1 Xiaohui Qiu,1 Elida Gomero,1 Randall Wakefield,2 Linda Horner,2 Wojciech Brutkowski,3 Young-Goo Han,4 David Solecki,4 Sharon Frase,2 Antonella Bongiovanni,5 and Alessandra d'Azzo Nat Commun. 7: 11876. doi: 10.1038/ncomms11876

Dionisio

[...] it is unknown how these point mutations compromise biochemically the L-BG synthesis or any additional function of Bgs1. Future studies are required that delve into the GS activity and the cell wall ultrastructure and composition of these mutants. [...] cooperation of Bgs1 and Pxl1 is required to maintain the other GS subunits in the division site. [...] how this is accomplished is still unknown. [...] a noteworthy hypothesis is that [...] might act as [...] which somehow would help to [...] and this could trigger [...] which would ultimately promote [...]

Fission yeast septation Juan C. G. Cortés,a Mariona Ramos,a Masako Osumi,b,c Pilar Pérez,a and Juan Carlos Ribas Commun Integr Biol. 9(4): e1189045. doi: 10.1080/19420889.2016.1189045

[...] a noteworthy hypothesis is that [...] might act as [...] which somehow would help to [...] and this could trigger [...] which would ultimately promote [...] Very precise and accurate description of what's going on. :) Dionisio

[...] we do not completely understand the basic mechanisms that drive and coordinate AMR constriction and septum formation. The role of the AMR in cytokinesis and the molecular mechanisms that drive AMR constriction and septation are the focus of current research. [...] how budding yeast cells orchestrate the multitude of molecular mechanisms that control AMR driven cytokinesis in a spatio-temporal manner to achieve an error free cell division. [?] [...] the function of the AMR is optimized to meet the special requirements of the particular organism/cell type. [...] the complex network of interactions between the plasma membrane and the AMR could form redundancy to provide a certain amount of robustness to the system. How the actin cables are organized in budding yeast is unknown and comparative studies have not been performed to date. How Mlc2 contributes to AMR constriction is not currently understood. The motor domain of Myo1, the regulatory myosin light chain Mlc2 and actin dynamics clearly contribute to AMR constriction. The molecular mechanism of the latter two and which role the primary septum plays remains to be fully elucidated. It is unclear why the AMR breaks in Inn1 or Chs2 deficient mutants that cannot form a primary septum [...] [...] efficient AMR constriction and primary septum formation are interdependent. Whether Rho1 directly regulates cell cleavage is not known. Rho1 is in addition to its function in AMR assembly the major regulator of secondary septum formation. This requires sequential Rho1 activation and inhibition steps in a spatio-temporal manner to allow the successive formation of the AMR and secondary septum and subsequent cell separation.

Actomyosin ring driven cytokinesis in budding yeast Franz Meitingera, Saravanan Palani http://dx.doi.org/10.1016/j.semcdb.2016.01.043 Seminars in Cell & Developmental Biology Volume 53, Pages 19–27 Cytokinetic ring construction and constriction Fibroblast Growth factor signalling

Complex complexity. :) Dionisio

Cleavage furrow formation during cell division requires a highly conserved set of cytoskeletal and membrane-trafficking proteins [...] The cell division cycle is accompanied by drastic changes in cell shape that necessitate dynamic interplay between the membrane and actin cytoskeleton [...] It is possible that opposing activities of F-BAR proteins Synd and Cip4 with respect to Dia are in a balance, and future experiments can test whether this function plays a role in limiting the growth of pseudocleavage furrows. Further experiments combining protein interactions and deduction of the biophysical nature of Synd-Pnut-actin association with the plasma membrane will elucidate the molecular mechanism that makes Synd an important component of pseudocleavage furrow-extension or contractile-ring assembly at large.

Syndapin promotes pseudocleavage furrow formation by actin organization in the syncytial Drosophila embryo Aparna Sherlekar and Richa Rikhy* Mol Biol Cell. 27(13): 2064–2079. doi: 10.1091/mbc.E15-09-0656

Dionisio

Rng10 and Rga7 also have independent functions during cell division and polarized growth, which will be further investigated in the future. Rga7 localization depends on Rng10 and they work together to regulate conserved glucan synthases for successful septum formation and cell integrity during cell division. It will be interesting to elucidate how Rng10 interacts with Rga7

Roles of the novel coiled-coil protein Rng10 in septum formation during fission yeast cytokinesis. Liu Y1, Lee IJ1, Sun M2, Lower CA1, Runge KW3, Ma J2, Wu JQ4. Mol Biol Cell. 27(16):2528-41. doi: 10.1091/mbc.E16-03-0156.

Dionisio

Cytokinesis segregates chromosomes, cytoplasm, and organelles into the two daughter cells during the cell-division cycle. The later stages of cytokinesis are still poorly understood.

Roles of the novel coiled-coil protein Rng10 in septum formation during fission yeast cytokinesis. Liu Y1, Lee IJ1, Sun M2, Lower CA1, Runge KW3, Ma J2, Wu JQ4. Mol Biol Cell. 27(16):2528-41. doi: 10.1091/mbc.E16-03-0156.

Dionisio

Differentiation waves are reasonably robust, in that they can accommodate variations in cell numbers, cell size, embryo size, and a wide range of temperature and other environmental fluctuations, including the hand of the experimenter, i.e., in multicell tissues they are traversing. [...] the cybernetic embryo has become a testable hypothesis. By thinking of the embryo in terms of differentiation waves that have goals in the cybernetic sense, we have a theory of how the embryo builds itself that is experimentally testable. The model only requires we accept the cell state splitter as the organelle of differentiation.

The organelle of differentiation in embryos: the cell state splitter Natalie K. Gordon and Richard Gordon Theor Biol Med Model. 2016; 13: 11. doi: 10.1186/s12976-016-0037-2

Dionisio

The result is a bifurcating cybernetic system, which we represent as a differentiation tree. One nuance is that some waves go through more than one tissue, perhaps providing some global coordination. The cell state splitters triggered by these waves, representable by the differentiation code, result in the right kinds of cells in an organism in the right place, at the right time.

The organelle of differentiation in embryos: the cell state splitter Natalie K. Gordon and Richard Gordon Theor Biol Med Model. 2016; 13: 11. doi: 10.1186/s12976-016-0037-2

Dionisio

We are beginning to compare the differentiation trees of various organisms across widely different phyla. We expect to find some larger unifying structure of differentiation trees, perhaps illuminating the evolution of differentiation.

The organelle of differentiation in embryos: the cell state splitter Natalie K. Gordon and Richard Gordon Theor Biol Med Model. 2016; 13: 11. doi: 10.1186/s12976-016-0037-2

Let's keep watching this to see how far they get. Dionisio

There are numerous problems with the morphogen gradient model. Many doubts about the functioning or existence of these so-called “morphogen” gradients have been raised, with alternatives and elaborations, and transport mechanisms other than diffusion being proposed. The force driving this alternating pattern has not yet been documented [...] The precise cytoskeletal signal remains to be found [...] We now have another explanation for so-called “morphogen” gradients. This gradient is merely a temporary epiphenomenon, a byproduct of differentiation wave activity. It is plausible that there are differences between early versus late developmental cell state splitter signal events.

The organelle of differentiation in embryos: the cell state splitter Natalie K. Gordon and Richard Gordon Theor Biol Med Model. 2016; 13: 11. doi: 10.1186/s12976-016-0037-2

Dionisio

That all of these interactions between genetically identical cells should somehow work themselves out in the creation of many distinct microenvironments, all in the right place at the right time, is about as plausible as having a musically untrained crowd of chattering people suddenly switch their cacophony to four part harmony and perform Mozart’s complete Ave Verum Corpus.

The organelle of differentiation in embryos: the cell state splitter Natalie K. Gordon and Richard Gordon Theor Biol Med Model. 2016; 13: 11. doi: 10.1186/s12976-016-0037-2

Beautifully said! A very clear description of the given scenario. Dionisio

Multicellular organisms are made of 4D spatiotemporal arrays of different cell types. The identity and function of any individual cell is defined and presumably determined by the specific complement of proteins and RNA that the cell contains. Proteins and RNA are encoded in the genome. While each cell has a complete copy of the whole genome, each cell uses only a portion of the total gene products encoded in it. The mechanism by which this process of differentiation of the one-cell embryo (i.e., the fertilized egg) into more than 3.72×1013 cells of up to 7000 cell types is accomplished over space and time is the central puzzle of embryology.

The organelle of differentiation in embryos: the cell state splitter Natalie K. Gordon and Richard Gordon Theor Biol Med Model. 2016; 13: 11. doi: 10.1186/s12976-016-0037-2

Dionisio

During differentiation, EBs contain a temporally-shifting mixture of various cell lineages, each with its own gene expression profile, signaling characteristics, and lineage history. Additional experiments with combinations of Wnt3 and CHIR are needed to further validate the route of regulation. Adding selective fluorescence markers for earlier or later stages of differentiation and single-cell mRNA analysis can extend the spatio-temporal depiction of expression trend and improve the clock accuracy, providing a better insight into whole EB inter-related processes.

Integrated live imaging and molecular profiling of embryoid bodies reveals a synchronized progression of early differentiation Jonathan Boxman,1,* Naor Sagy,1,* Sirisha Achanta,2 Rajanikanth Vadigepalli,a,2 and Iftach Nachman Sci Rep. 2016; 6: 31623. doi: 10.1038/srep31623

Dionisio

The coordinated progression of different cell lineages is essential for the formation of functional tissues and organs. Embryonic stem cells can be aggregated into embryoid bodies (EBs), which have the potential to differentiate to a diverse population of adult specialized cells. The differentiation of EBs into cells of the three germ layers, even in the absence of externally added directive signals, indicates that the required signals for these processes can autonomously build up within each EB. How these signals interact to coordinate the growth and relative composition of multiple lineages is not fully characterized.

Integrated live imaging and molecular profiling of embryoid bodies reveals a synchronized progression of early differentiation Jonathan Boxman,1,* Naor Sagy,1,* Sirisha Achanta,2 Rajanikanth Vadigepalli,a,2 and Iftach Nachman Sci Rep. 2016; 6: 31623. doi: 10.1038/srep31623

Dionisio

Embryonic stem cells can spontaneously differentiate into cell types of all germ layers within embryoid bodies (EBs) in a highly variable manner. Whether there exists an intrinsic differentiation program common to all EBs is unknown.

Integrated live imaging and molecular profiling of embryoid bodies reveals a synchronized progression of early differentiation Jonathan Boxman,1,* Naor Sagy,1,* Sirisha Achanta,2 Rajanikanth Vadigepalli,a,2 and Iftach Nachman Sci Rep. 2016; 6: 31623. doi: 10.1038/srep31623

Dionisio

The red-green system samples the visual world at a lower resolution than the achromatic system. [...] the nervous system represents these two pieces of information with separate pathways that emerge as early as the photoreceptor synapse: one chiefly concerned with high-resolution achromatic vision and a second, lower-resolution color system.

The elementary representation of spatial and color vision in the human retina Ramkumar Sabesan1,*,†,‡, Brian P. Schmidt2,†, William S. Tuten1 and Austin Roorda1 Science Advances Vol. 2, no. 9, e1600797 DOI: 10.1126/sciadv.1600797

Dionisio

A single photoreceptor is sensitive to both the intensity and the wavelength of light falling on it and, therefore, confounds brightness and color signals. Our visual system ultimately constructs a representation of the external world from the output of the photoreceptor mosaic in which color and achromatic contrast are divorced. How, and which, postreceptoral neural pathways recover and segregate this multiplexed information from individual receptors remains unresolved.

The elementary representation of spatial and color vision in the human retina Ramkumar Sabesan1,*,†,‡, Brian P. Schmidt2,†, William S. Tuten1 and Austin Roorda1 Science Advances Vol. 2, no. 9, e1600797 DOI: 10.1126/sciadv.1600797

Dionisio

The retina is the most accessible element of the central nervous system for linking behavior to the activity of isolated neurons. [...] the nervous system encodes high-resolution achromatic information and lower-resolution color signals in separate pathways that emerge as early as the first synapse.

The elementary representation of spatial and color vision in the human retina Ramkumar Sabesan1,*,†,‡, Brian P. Schmidt2,†, William S. Tuten1 and Austin Roorda1 Science Advances Vol. 2, no. 9, e1600797 DOI: 10.1126/sciadv.1600797

Dionisio

[...] diffusion, extracellular interactions i.e., Nodal-receptor binding, Nodal-Lefty inhibitor binding, and selective ligand destruction collectively shape and refine the Nodal morphogen gradient.

Extracellular interactions and ligand degradation shape the nodal morphogen gradient Yin Wang,1,2,† Xi Wang,3,† Thorsten Wohland,2,3,* and Karuna Sampath eLife. 2016; 5: e13879. doi: 10.7554/eLife.13879

Dionisio

The correct distribution and activity of secreted signaling proteins called morphogens is required for many developmental processes. Nodal morphogens play critical roles in embryonic axis formation in many organisms. Models proposed to generate the Nodal gradient include diffusivity, ligand processing, and a temporal activation window. But how the Nodal morphogen gradient forms in vivo remains unclear.

Extracellular interactions and ligand degradation shape the nodal morphogen gradient Yin Wang,1,2,† Xi Wang,3,† Thorsten Wohland,2,3,* and Karuna Sampath eLife. 2016; 5: e13879. doi: 10.7554/eLife.13879

Professor L.M. of the U. of T. in Canada claimed to know exactly how morphogen gradients form. The authors of this paper should consult with professor L.M. Dionisio

"The complexity builds in robustness. Robustness is important in enabling organisms to resist unfavorable changes in their environments or genomes." Denis Noble http://www.thebestschools.org/dialogues/evolution-denis-noble-interview/ Dionisio

At first, it was just a premonitory tremor: the piecing together of a rudimentary whole human genome in 2001. Then, just two years later, came an earth-shaking eruption: the completion of the Human Genome Project. This explosive event rocked the molecular genetics landscape and released bioscientific forces that to this day show no signs of abating. Ceaseless flows of academic brainstorming and commercial innovation are reshaping old fields and creating new ones, ultimately spreading fertility to downstream disciplines such as epigenetics and epigenomics.

GEN News Awaken Dormant DNA, Epigenetically Epigenetics Isn’t Limited to Studying Marks on Chromatin Rob Ranulph Jones http://www.genengnews.com/gen-articles/awaken-dormant-dna-epigenetically/5818/

Dionisio

Circulating Biomarkers: A Complex Space with Multiple Parts The topic of circulating biomarkers includes markers as simple as glucose or cholesterol as well as protein biomarkers such as C-reactive protein (CRP), circulating cell-free DNA (cfDNA), or circulating RNA. In newer cases, it also includes genes such as BCRA1, KRAS, and others. Recently, the field has expanded to include circulating tumor cells (CTCs) and exosomes or extracellular vesicles (EVs).

Trends in Various Segments of the Circulating Biomarkers Space Circulating Biomarkers: A Complex Space with Multiple Parts Gary Oosta, Ph.D., Enal Razvi, Ph.D. http://www.genengnews.com/insight-and-intelligence/trends-in-various-segments-of-the-circulating-biomarkers-space/77900736/

Dionisio

When cells get together, they have a curious way of breaking bread. They take bites out of each other, by means of a process called bidirectional trans-endocytosis. Then they go their separate ways, moving as needed to form or repair the body’s tissues. Although cells have long been known to tear themselves away from each other, the etiquette of the process has been unclear. What codes of behavior do cells observe when they regulate contact-mediated repulsion?

GEN News Cells Take Call, Then Eat and Run http://www.genengnews.com/gen-news-highlights/cells-take-call-then-eat-and-run/81253179/

Dionisio

Researchers at MIT say they have deciphered the structure of one type of long noncoding RNA (lncRNA) and used that information to figure out how it interacts with a cellular protein to control the development of heart muscle cells. This is one of first studies to link the structure of lncRNAs to their function. "Emerging data points to fundamental roles for many of these molecules in development and disease, so we believe that determining the structure of lncRNAs is critical for understanding how they function," says Laurie Boyer, Ph.D. Learning more about how lncRNAs control cell differentiation could offer a new approach to developing drugs for patients whose hearts have been damaged by cardiovascular disease, aging, or cancer.

GEN News MIT Team Shows How lncRNA Works http://www.genengnews.com/gen-news-highlights/mit-team-shows-how-lncrna-works/81253184/

Dionisio

@1978-1983: This Fgfr2 seems like a very 'sexy' protein, doesn't it? :) Dionisio

The endodermal and ectodermal domains of Fgfr2 play distinct roles in urethral tubulogenesis; however, in both tissue compartments Fgfr2 controls epithelial cell proliferation, stratification and adhesion. Coordination of these cellular processes in the urethral epithelium and the overlying surface ectoderm is required both for synchronous development and for structural integrity of the developing urethral tube and prepuce.

Tissue-specific roles of Fgfr2 in development of the external genitalia Marissa L. Gredler,1 Ashley W. Seifert,1,* and Martin J. Cohn Development. 142(12): 2203–2212. doi: 10.1242/dev.119891

Complex complexity. Dionisio

Together, these data raise the intriguing possibility that Fgfr2 in the genital tubercle epithelia drives epithelial maturation by coupling proliferation with cellular morphogenesis. An important but poorly understood feature of sexually dimorphic external genital development is internalization of the male urethra [...] [...] urethral tubulogenesis and internalization are interdependent processes that each require Fgfr2.

Tissue-specific roles of Fgfr2 in development of the external genitalia Marissa L. Gredler,1 Ashley W. Seifert,1,* and Martin J. Cohn Development. 142(12): 2203–2212. doi: 10.1242/dev.119891

Complex complexity. Dionisio

[...] the cells are able to sense increases in mechanical force [...] [...] normal ventrolateral preputial development requires strong epithelial integrity at the ectodermal-endodermal boundary. [...] this axis along the ventral midline of the genital tubercle acts as a scaffold around which the preputial swellings eventually fuse. Coordinated cell shape changes mediate tubulogenesis of many organs [...] Cytoskeletal reorganizations underlie cell shape changes, require cell adhesion and occur in a cell-cycle-dependent manner [...]

Tissue-specific roles of Fgfr2 in development of the external genitalia Marissa L. Gredler,1 Ashley W. Seifert,1,* and Martin J. Cohn Development. 142(12): 2203–2212. doi: 10.1242/dev.119891

Complex complexity. Dionisio

In both the urethral and the surface epithelia of the genital tubercle, Fgfr2 promotes proliferation by mediating the G1/S cell cycle transition and is required for adhesion and morphological maturation of basal epithelial cells. [...] structural integrity of the ectodermal-endodermal boundary at the ventral midline integrates these morphogenetic events and is regulated by Fgf signaling. Fgfr2 mediates the same cellular processes in both the endoderm and the ectoderm of the developing genital tubercle.

Tissue-specific roles of Fgfr2 in development of the external genitalia Marissa L. Gredler,1 Ashley W. Seifert,1,* and Martin J. Cohn Development. 142(12): 2203–2212. doi: 10.1242/dev.119891

Complex complexity. Dionisio

[...] Fgfr2 acts as a link between hormonal and genetic regulation of external genital development. [...] urethral tubulogenesis, prepuce morphogenesis, and sexually dimorphic patterning of the urethra are three crucial processes in external genital development that are controlled by independent regions of Fgfr2 activity. [...] Fgfr2 activity in the endoderm mediates urethral epithelial maturation, whereas ectodermal Fgfr2 is required for formation of the prepuce.

Tissue-specific roles of Fgfr2 in development of the external genitalia Marissa L. Gredler,1 Ashley W. Seifert,1,* and Martin J. Cohn Development. 142(12): 2203–2212. doi: 10.1242/dev.119891

Dionisio

Tubular morphogenesis (tubulogenesis) is essential for normal embryonic development [...] A variety of mechanisms can drive tube formation, such as the wrapping mechanism of neurulation, budding of the salivary and mammary glands, and the delamination/migration process of bile duct development [...] External genital development involves a series of budding and fusion events. [...] urethral tubulogenesis involves multiple morphogenetic processes, including evagination of the cloacal wall to form the bilaminar plate, epithelial stratification and maturation, and remodeling of the plate to form the lumen of the tube.

Tissue-specific roles of Fgfr2 in development of the external genitalia Marissa L. Gredler,1 Ashley W. Seifert,1,* and Martin J. Cohn Development. 142(12): 2203–2212. doi: 10.1242/dev.119891

Dionisio

[...] discovering the identity of the deubiquitylase that removes H3 ubiquitylation may provide key insight into the dynamics of DNA methylation regulation at the level of histone ubiquitylation. [...] direct evidence of USP7 catalyzed deubiquitylation of H3 is lacking. We speculate that epigenetic mechanisms of multivalency and allostery are more widespread and add additional layers of complexity, specificity, and connectivity to chromatin recognition, modification patterning, and genome regulation.

Hemi-methylated DNA regulates DNA methylation inheritance through allosteric activation of H3 ubiquitylation by UHRF1. Harrison JS1,2, Cornett EM3, Goldfarb D4, DaRosa PA5, Li ZM6, Yan F7, Dickson BM3, Guo AH1, Cantu DV1, Kaustov L8, Brown PJ8, Arrowsmith CH8, Erie DA9, Major MB4,7, Klevit RE5, Krajewski K1, Kuhlman B1,2, Strahl BD1,2, Rothbart SB3. DOI: http://dx.doi.org/10.7554/eLife.17101 eLife 2016;5:e17101

This is not any god-of-the-gaps. This is just complex complexity. :) Unending revelation of the ultimate reality. Dionisio

[...] it is intriguing to speculate that UHRF1 functions to provide a nucleation event for DNMT1 recruitment to chromatin. Future studies mapping the genome-wide distribution of UHRF1-directed H3 ubiquitylation in relation to DNA methylation patterning will clarify the relationship between UHRF1 and DNMT1 activities. How might HeDNA binding alter the substrate preference of UHRF1 directed ubiquitylation? Determining the active conformation of UHRF1 will be an important step in further understanding the regulation imparted by HeDNA.

Hemi-methylated DNA regulates DNA methylation inheritance through allosteric activation of H3 ubiquitylation by UHRF1. Harrison JS1,2, Cornett EM3, Goldfarb D4, DaRosa PA5, Li ZM6, Yan F7, Dickson BM3, Guo AH1, Cantu DV1, Kaustov L8, Brown PJ8, Arrowsmith CH8, Erie DA9, Major MB4,7, Klevit RE5, Krajewski K1, Kuhlman B1,2, Strahl BD1,2, Rothbart SB3. DOI: http://dx.doi.org/10.7554/eLife.17101 eLife 2016;5:e17101

This is not any god-of-the-gaps. This is just complex complexity. :) Unending revelation of the ultimate reality. Dionisio

[...] it remains to be seen whether uncoupling UHRF1 from HeDNA recognition changes its residence genome-wide [...] coordinated recognition of H3 and DNA, independent of HeDNA discrimination, drives chromatin interaction. Further studies are necessary to examine the biological consequence of different patterns of H3 ubiquitylation by UHRF1 and their relationship to pre-existing histone PTM signatures.

Hemi-methylated DNA regulates DNA methylation inheritance through allosteric activation of H3 ubiquitylation by UHRF1. Harrison JS1,2, Cornett EM3, Goldfarb D4, DaRosa PA5, Li ZM6, Yan F7, Dickson BM3, Guo AH1, Cantu DV1, Kaustov L8, Brown PJ8, Arrowsmith CH8, Erie DA9, Major MB4,7, Klevit RE5, Krajewski K1, Kuhlman B1,2, Strahl BD1,2, Rothbart SB3. DOI: http://dx.doi.org/10.7554/eLife.17101 eLife 2016;5:e17101

This is not any god-of-the-gaps. This is just complex complexity. :) Unending revelation of the ultimate reality. Dionisio

The epigenetic inheritance of DNA methylation requires UHRF1, a histone- and DNA-binding RING E3 ubiquitin ligase that recruits DNMT1 to sites of newly replicated DNA through ubiquitylation of histone H3. UHRF1 binds DNA with selectivity towards hemi-methylated CpGs (HeDNA); however, the contribution of HeDNA sensing to UHRF1 function remains elusive.

Hemi-methylated DNA regulates DNA methylation inheritance through allosteric activation of H3 ubiquitylation by UHRF1 Joseph S Harrison, Evan M Cornett, Dennis Goldfarb, Paul A DaRosa, Zimeng M Li, Feng Yan, Bradley M Dickson, Angela H Guo, Daniel V Cantu, Lilia Kaustov, Peter J Brown, Cheryl H Arrowsmith, Dorothy A Erie, Michael B Major, Rachel E Klevit, Krzysztof Krajewski, Brian Kuhlman, Brian D Strahl, Scott B Rothbart DOI: http://dx.doi.org/10.7554/eLife.17101 eLife 2016;5:e17101

Dionisio

MBD2 is an integral part of the NuRD complex with many unanswered questions regarding its molecular and biological functions. In order to address these questions, it is essential to unravel the complexities of different isoforms of MBD2 in association with NuRD. Future investigations into MBD2 functions may have important implications for the study of pluripotency, immunity, and cancer, in addition to revealing insights into broader epigenetic mechanisms.

Emerging Molecular and Biological Functions of MBD2, a Reader of DNA Methylation Kathleen H. Wood and Zhaolan Zhou Front Genet. 7: 93. doi: 10.3389/fgene.2016.00093

This is not god-of-the-gaps. This is just complex complexity. :) Unending revelation of the ultimate reality. Dionisio

One study determined that most NuRD complexes in mammalian cells contain MBD3 rather than MBD2 (Zhang et al., 1999), but the dynamics of these interactions in vivo have not been fully determined. Additional biochemical evidence is necessary to determine if misregulation of NuRD activity occurs upon loss of MBD2 in the brain. The different isoforms of MBD2 introduce further complications into models of MBD2/NuRD function.

Emerging Molecular and Biological Functions of MBD2, a Reader of DNA Methylation Kathleen H. Wood and Zhaolan Zhou Front Genet. 7: 93. doi: 10.3389/fgene.2016.00093

This is not god-of-the-gaps. This is just complex complexity. :) Unending revelation of the ultimate reality. Dionisio

There are also many unanswered questions regarding the in vivo dynamics of the NuRD complex and MBD2 or MBD3. The spatiotemporal expression patterns of MBD2 and MBD3 raise further questions about NuRD formation and function, particularly in adult tissues where MBD3 is nearly undetectable but MBD2 is highly expressed [...] it remains to be determined why loss of MBD3, even conditionally in specific tissues, has severe phenotypic consequences, while constitutive loss of MBD2 has only mild effects [...]

Emerging Molecular and Biological Functions of MBD2, a Reader of DNA Methylation Kathleen H. Wood and Zhaolan Zhou Front Genet. 7: 93. doi: 10.3389/fgene.2016.00093

Dionisio

An essential goal of the MBD protein field that remains unresolved is defining the specific functions of these proteins in a biologically relevant context. [...] these questions are challenging to resolve because it is experimentally difficult to distinguish between functions that are MBD2-specific rather than mediated by the NuRD complex as a whole, while the role of MBD3 must also be considered. [...] each MBD protein has distinct loss-of-function phenotypes, spatiotemporal expression patterns, DNA binding properties, and protein complex interactions [...] It is not clear if these other binding partners represent specific, NuRD-independent functions of MBD2, or if they serve to mediate the interactions between MBD2 and NuRD.

Emerging Molecular and Biological Functions of MBD2, a Reader of DNA Methylation Kathleen H. Wood and Zhaolan Zhou Front Genet. 7: 93. doi: 10.3389/fgene.2016.00093

Dionisio

It is currently unknown if these pathways are also affected by loss of MBD2. These complexities indicate that identification and manipulation of specific therapeutic pathways targeted via MBD2 will be challenging. Because MBD2 appears to have variable or context specific effects on tumorigenesis, significant further investigations into the molecular mechanisms of MBD2 function must be undertaken to identify potential therapeutic targets associated with these functions.

Emerging Molecular and Biological Functions of MBD2, a Reader of DNA Methylation Kathleen H. Wood and Zhaolan Zhou Front Genet. 7: 93. doi: 10.3389/fgene.2016.00093

Dionisio

GR signaling has widespread, systemic effects related to stress, metabolism and inflammation [...], but it is unknown if loss of MBD2 affects these signaling mechanisms outside the hippocampus. [...] a genetic interaction between Mbd2 and Mbd3 argues that MBD3 cannot fully compensate for the loss of MBD2 [...] and further studies are needed to resolve this question. [...] considerable effort is required to fully understand the complexities of MBD2 function in immunity at the cellular and systemic levels.

Emerging Molecular and Biological Functions of MBD2, a Reader of DNA Methylation Kathleen H. Wood and Zhaolan Zhou Front Genet. 7: 93. doi: 10.3389/fgene.2016.00093

Dionisio

[...] the mechanisms of MBD2/NuRD recruitment and distribution on chromatin remain to be further investigated. [...] the dynamics and biological consequences of NuRD formation with either MBD2 or MBD3 are unclear, particularly in vivo in the cellular context. The highly complex network of diverse neuronal subtypes each have distinct epigenomic and transcriptional profiles [...]

Emerging Molecular and Biological Functions of MBD2, a Reader of DNA Methylation Kathleen H. Wood and Zhaolan Zhou Front Genet. 7: 93. doi: 10.3389/fgene.2016.00093

Dionisio

It is not clear if these interactions represent additional NuRD-independent functions of MBD2, or if they only serve to mediate MBD2-NuRD interactions. Further work is necessary to resolve the many remaining questions surrounding the mechanisms of MBD2 function both in association with and independent of the NuRD complex. It is currently unclear what proportion of cellular MBD2 is localized at these sites, as opposed to methylation-dense regions of the genome.

Emerging Molecular and Biological Functions of MBD2, a Reader of DNA Methylation Kathleen H. Wood and Zhaolan Zhou Front Genet. 7: 93. doi: 10.3389/fgene.2016.00093

Dionisio

Despite many biochemical and genetic studies on the MBD proteins, the precise functions of these proteins in vivo are yet to be fully investigated. Further work is required to determine the dynamics of MBD2, MBD3, and NuRD recruitment to chromatin, and how MBD2 may function within and independently of NuRD. It is unknown if PRMT chromatin-modifying activity is affected by MBD2 interactions.

Emerging Molecular and Biological Functions of MBD2, a Reader of DNA Methylation Kathleen H. Wood and Zhaolan Zhou Front Genet. 7: 93. doi: 10.3389/fgene.2016.00093

Dionisio

[...] recent advances have revealed a complex role for DNA methylation in regards to its dynamic turnover, cell type-specific distribution patterns, and effect on transcriptional regulation. [...] the mechanisms that direct the interpretation of these patterns to affect specific gene expression programs have yet to be fully determined. It is critical to gain further understanding of the mechanisms of DNA methylation in transcriptional regulation [...]

Emerging Molecular and Biological Functions of MBD2, a Reader of DNA Methylation Kathleen H. Wood and Zhaolan Zhou Front Genet. 7: 93. doi: 10.3389/fgene.2016.00093

Dionisio

DNA methylation is an epigenetic mark that is essential for many biological processes [...] Methylation is usually associated with transcriptional silencing, but new research has challenged this model. How DNA methylation patterns are interpreted into different functional output remains poorly understood.

Emerging Molecular and Biological Functions of MBD2, a Reader of DNA Methylation Kathleen H. Wood and Zhaolan Zhou Front Genet. 7: 93. doi: 10.3389/fgene.2016.00093

Dionisio

[...] the gene regulatory potential of Pax6 may be determined by its partners and in this specific case, Sox2 occupancy drives it more towards a transcription activating role. [...] genes that are required to be immediately switched on or off during differentiation of NPs may in some way benefit from being targeted by both Pax6 and Sox2. Pax6-driven gene regulatory program functions to ensure the unidirectionality towards neuronal differentiation.

Mapping gene regulatory circuitry of Pax6 during neurogenesis Sudhir Thakurela,1,5 Neha Tiwari,2,5 Sandra Schick,1 Angela Garding,1 Robert Ivanek,3 Benedikt Berninger,2,4 and Vijay K Tiwari1,* Cell Discov. 2: 15045. . doi: 10.1038/celldisc.2015.45

Dionisio

Pax6 is a highly conserved transcription factor among vertebrates and is important in various aspects of the central nervous system development. However, the gene regulatory circuitry of Pax6 underlying these functions remains elusive. During mammalian brain development, Pax6 is expressed in a specific spatiotemporal manner and is restricted to mainly neuronal tissues. Pax6 regulates the gene-expression program at multiple levels to ensure proper execution of the neurogenic program, and at the same time ensures the unidirectionality of neuronal differentiation.

Mapping gene regulatory circuitry of Pax6 during neurogenesis Sudhir Thakurela,1,5 Neha Tiwari,2,5 Sandra Schick,1 Angela Garding,1 Robert Ivanek,3 Benedikt Berninger,2,4 and Vijay K Tiwari1,* Cell Discov. 2: 15045. . doi: 10.1038/celldisc.2015.45

Dionisio

The complex structure of the mammalian cortex depends on the precise control of the polarization and migration of neural cells. It will be interesting to test in the future how Rapgef2 acts in conjunction with C3G to regulate neuronal differentiation. [...] the Rap1 GEF C3G is required in multipolar neurons for the MTB transition by promoting the formation of an axon and a leading process.

C3G/Rapgef1 Is Required in Multipolar Neurons for the Transition to a Bipolar Morphology during Cortical Development Bhavin Shah,1,4 Daniela Lutter,1 Magdalena L. Bochenek,2,¤ Katsuhiro Kato,2 Yaroslav Tsytsyura,3 Natalia Glyvuk,3 Akira Sakakibara,5 Jürgen Klingauf,3 Ralf H. Adams,2,4 and Andreas W. Püschel PLoS One. 11(4): e0154174. doi: 10.1371/journal.pone.0154174

Dionisio

Many levels of regulation exist that control the release, reception, and interpretation of the hedgehog signal. The discoveries made while investigating the molecular and cellular basis of the hedgehog signalling pathway have revealed novel and unpredicted mechanisms. [...] presenting one pathway in isolation does not give a true picture of cell processes in the context of a developing embryo or an adult tissue. During cellular response, input from other environmental cues and signals must be integrated,[...] [...] there is evidence for a multi-layered, complex system regulating this important signalling pathway.

Regulation of Hedgehog Signalling Inside and Outside the Cell Simon A. Ramsbottom1,* and Mary E. Pownall J Dev Biol. 4(3): 23. doi: 10.3390/jdb4030023

Dionisio

The onset of puberty is regulated by a small population of hypothalamic gonadotropin-releasing hormone (GnRH) neurons, which secrete GnRH decapeptide to the hypophyseal portal system. Unlike other neuroendocrine cell types that reside in the hypothalamus, GnRH neurons are born outside the CNS in the frontonasal area. The early events that lead to GnRH neuron specification and the origin of their progenitors in the olfactory pit are currently poorly understood. GnRH neuron specification occurs under explicit spatiotemporal conditions [...] Future studies are required to further characterize the neuroendocrine properties of these GnRH-expressing cells.

Development of Gonadotropin-Releasing Hormone-Secreting Neurons from Human Pluripotent Stem Cells Carina Lund,1 Kristiina Pulli,1 Venkatram Yellapragada,1 Paolo Giacobini,3,4 Karolina Lundin,5 Sanna Vuoristo,1 Timo Tuuri,5 Parinya Noisa,6,7,8 and Taneli Raivio Stem Cell Reports. 7(2): 149–157. doi: 10.1016/j.stemcr.2016.06.007

Dionisio

During vertebrate development, successive phases of embryonic and fetal myogenesis leads to formation and growth of skeletal muscles [...] Understanding regulation of myogenic progression from MPCs to muscle stem cells is central to building a comprehensive model of satellite cell function. [...] understanding the molecular signals that control and regulate the muscle stem cell population is essential to identify new therapeutic strategies for muscle diseases.

Gene Expression Profiling of Muscle Stem Cells Identifies Novel Regulators of Postnatal Myogenesis Sonia Alonso-Martin,1,2,3,*† Anne Rochat,1 Despoina Mademtzoglou,1,2,3 Jessica Morais,1 Aurélien de Reyniès,4 Frédéric Auradé,5 Ted Hung-Tse Chang,1,† Peter S. Zammit,6 and Frédéric Relaix Front Cell Dev Biol. 2016; 4: 58. doi: 10.3389/fcell.2016.00058

Dionisio

Bacterial HEMK2 homologs initially had been proposed to be involved in heme biogenesis or to function as adenine DNA methyltransferase. Later it was shown that this family of enzymes has protein glutamine methyltransferase activity, and they methylate the glutamine residue in the GGQ motif of ribosomal translation termination factors. The murine HEMK2 enzyme methylates Gln(185) of the eukaryotic translation termination factor eRF1. [...] further investigation will be required to understand the function of HEMK2-mediated methylation in proteins other than eRF1.

Substrate Specificity of the HEMK2 Protein Glutamine Methyltransferase and Identification of Novel Substrates. Kusevic D1, Kudithipudi S1, Jeltsch A2. J Biol Chem. 291(12):6124-33. doi: 10.1074/jbc.M115.711952

Dionisio

While the oxygen-dependent reversal of lysine N?-methylation is well established, the existence of bona fide N?-methylarginine demethylases (RDMs) is controversial. Post-translational modifications, which vastly increase the size of the functional proteome, play central roles in numerous cellular processes, including enzyme catalysis, protein–protein interactions and gene regulation. Now that enzymes that have RDM activity have been conclusively identified, efforts can focus on the demonstration of their biological relevance. [...] we are not yet able to conclusively determine RDM activity in cells [...]

Arginine demethylation is catalysed by a subset of JmjC histone lysine demethylases Louise J. Walport,1 Richard J. Hopkinson,1 Rasheduzzaman Chowdhury,1 Rachel Schiller,1 Wei Ge,1 Akane Kawamura,1,2 and Christopher J. Schofield Nat Commun. 7: 11974. doi: 10.1038/ncomms11974

Dionisio

Pindi @1948:

No, it’s not that a big a deal.

There are so many interesting biology research papers referenced in this thread but you write a single comment on something totally unrelated that you yourself deem "not that a big a deal"? Are you ok? :) Dionisio

Pindi @1948:

No, it’s not that a big a deal.

Is you original habitat close to the beautiful Norwegian fjords? :) Dionisio

Pindi @1948:

No, it’s not that a big a deal.

Aren't your comment and questions you posted @1946 important to you? Dionisio

Pindi @1948:

No, it’s not that a big a deal.

Don't you want to know the answer to the questions you posted @1946? Dionisio

Pindi @1948:

No, it’s not that a big a deal.

Then why did you write your comment @1946? What for? Can you tell? Dionisio

Pindi @1946:

I noticed you saying in another thread that talking to atheists was like talking to a wall.

Please, would you mind quoting the text and providing the link to the post you copied it from? Thank you. Dionisio

No, it's not that a big a deal. Pindi

Pindi: Can you provide the link to the post where you read that? Thank you. Dionisio

Dionisio, I noticed you saying in another thread that talking to atheists was like talking to a wall. Is that what you are doing here? Are you ok? Pindi

Our studies add a new dimension of information to the organization and plasticity of CENP-A chromatin [...] Our results also raise several questions that can be addressed in future studies. Whether a common RNA acts globally to control CEN chromatin at all chromosomes, or whether array-specific transcripts (SM McNulty and BA Sullivan, unpublished data) are linked to chromosome-specific CEN chromatin dynamics, however, remains to be explored.

Inheritance of the CENP-A chromatin domain is spatially and temporally constrained at human centromeres Justyne E. Ross, Kaitlin Stimpson Woodlief, and Beth A. Sullivan Epigenetics Chromatin. 9: 20. doi: 10.1186/s13072-016-0071-7

Dionisio

It is more likely that the maintenance of the CENP-A domain involves multiple players that work synergistically—heterochromatin and associated proteins to limit the size of the CEN chromatin domain, HJURP to bring pre-assembled CENP-A/H4 to the correct centromere region that has been licensed in telophase by Mis18 [35], incorporation of placeholder H3.3 during S phase by ATRX, DAXX, or other chaperones, modification of CENP-A, and/or methylation of H3K4/K36 to direct new CENP-A loading [16, 39]. Dissecting the hierarchy of such a complex pathway is a key area that remains to be explored in the context of CEN domain placement and maintenance on individual chromosomes.

Inheritance of the CENP-A chromatin domain is spatially and temporally constrained at human centromeres Justyne E. Ross, Kaitlin Stimpson Woodlief, and Beth A. Sullivan Epigenetics Chromatin. 9: 20. doi: 10.1186/s13072-016-0071-7

Emphasis mine. Dionisio

Cells responding to signals need to be able to distinguish these signals from random fluctuations (i.e., noise) [...] Morphogens are long-range signals thought to induce different cell behaviors in a concentration-dependent manner, but how such graded signals can be established in the face of noise and how they specify sharp boundaries of target gene expression remain unclear. A future challenge will be to see if similar retinoic acid gradients and noise control occur in other tissues, and if the noise has any positive role to play in development.

Noise modulation in retinoic acid signaling sharpens segmental boundaries of gene expression in the embryonic zebrafish hindbrain Julian Sosnik,1,2,3 Likun Zheng,2,4 Christopher V Rackauckas,2,4 Michelle Digman,1,2,5 Enrico Gratton,1,2,5 Qing Nie,1,2,4 and Thomas F Schilling eLife. 5: e14034. doi: 10.7554/eLife.14034

Dionisio

Animal cells need to be able to communicate with each other so that they can work together in tissues and organs. To do so, cells release signaling molecules that can move around within a tissue and be detected by receptors on other cells. Morphogen gradients induce sharply defined domains of gene expression in a concentration-dependent manner, yet how cells interpret these signals in the face of spatial and temporal noise remains unclear. These findings reveal novel cellular mechanisms of noise regulation, which are likely to play important roles [...]

Noise modulation in retinoic acid signaling sharpens segmental boundaries of gene expression in the embryonic zebrafish hindbrain Julian Sosnik,1,2,3 Likun Zheng,2,4 Christopher V Rackauckas,2,4 Michelle Digman,1,2,5 Enrico Gratton,1,2,5 Qing Nie,1,2,4 and Thomas F Schilling eLife. 5: e14034. doi: 10.7554/eLife.14034

Dionisio

[...] presenting one pathway in isolation does not give a true picture of cell processes in the context of a developing embryo or an adult tissue. During cellular response, input from other environmental cues and signals must be integrated, some of which can enhance the effect of Shh—such as the effect of Notch, which up-regulates SMO activity [...] In addition, other signals can change the way a cell responds to Shh [...] These other pathways also include multiple levels of regulation that will also impact Shh signalling. Taken together with the mechanisms described, there is evidence for a multi-layered, complex system regulating this important signalling pathway.

Regulation of Hedgehog Signalling Inside and Outside the Cell Simon A. Ramsbottom1,* and Mary E. Pownall J Dev Biol. 4(3): 23. doi: 10.3390/jdb4030023

Complex complexity. :) Dionisio

New technologies (e.g. CRISPR/Cas9) will permit the manipulation of regulatory sequences in the native locus, which should allow rapid progress in understanding how patterning information is integrated. Alongside these experimental objectives, improved models and simulations will undoubtedly be important and necessitate improved quantification of the components of the systems. This includes not only measuring the number of molecules of key TFs but also measurements of protein-DNA interactions and rates of transcription and translation of target genes. Models that simplify and abstract aspects of a system will help provide an intuitive understanding of its operation, whereas increasingly complex simulations will result in more realistic models and a means to interpret more and diverse forms of data. Together, therefore, our comparison of patterning in the Drosophila blastoderm and the vertebrate neural tube suggests a unified framework for morphogen-mediated pattern formation and establishes a research agenda that will likely take us through further revisions of this fascinating problem.

Morphogen rules: design principles of gradient-mediated embryo patterning James Briscoe, Stephen Small Development 142: 3996-4009; doi: 10.1242/dev.129452

Work in progress... stay tuned. :) Dionisio

[...] the mechanisms identified in the gap gene and neural tube networks represent general principles for morphogen interpretation Despite much progress, many questions remain. Elucidating the components and operation of the transcriptional networks continues and, for many tissues, the relative importance of the spatial or temporal component of gradients needs to be determined. How opposing gradients cross-talk and are integrated into networks is poorly understood.

Morphogen rules: design principles of gradient-mediated embryo patterning James Briscoe, Stephen Small Development 142: 3996-4009; doi: 10.1242/dev.129452

Would someone kindly notify the authors of the referenced paper that they should have consulted this with Professor L.M. o the U. of T. in Canada, who claimed in this site that he knows exactly how morphogen gradients are formed? :) Dionisio

A systematic survey of morphogen-regulated networks comprising three TFs identified six distinct classes of network design that generated striped gene expression [...] Each of these used a different dynamical mechanism to interpret the morphogen but all relied on cross-regulatory interactions between the TFs.

Morphogen rules: design principles of gradient-mediated embryo patterning James Briscoe, Stephen Small Development 142: 3996-4009; doi: 10.1242/dev.129452

Dionisio

[...] positional information is not a static measure but a process that arises from the dynamics of interactions within the network. [...] there is no mechanistic difference between spatial and temporal patterning: both spatial gradients and temporal changes in morphogen input can produce similar gene expression patterns. [...] boundary precision and size scaling are built into the system. The system is robust to fluctuations in the morphogen signal and provides an effective memory when morphogen signal declines, which offers an explanation for the striking ‘canalization’ of pattern formation in many developing tissues.

Morphogen rules: design principles of gradient-mediated embryo patterning James Briscoe, Stephen Small Development 142: 3996-4009; doi: 10.1242/dev.129452

Dionisio

The Drosophila blastoderm and the vertebrate neural tube are archetypal examples of morphogen-patterned tissues that create precise spatial patterns of different cell types. In both tissues, pattern formation is dependent on molecular gradients that emanate from opposite poles. Despite [...] differences in time scales, cell biology and molecular players, both tissues exhibit striking similarities in the regulatory systems that establish gene expression patterns that foreshadow the arrangement of cell types. First, signaling gradients establish initial conditions that polarize the tissue, but there is no strict correspondence between specific morphogen thresholds and boundary positions. Second, gradients initiate transcriptional networks that integrate broadly distributed activators and localized repressors to generate patterns of gene expression. Third, the correct positioning of boundaries depends on the temporal and spatial dynamics of the transcriptional networks. These similarities reveal design principles that are likely to be broadly applicable to morphogen-patterned tissues.

Morphogen rules: design principles of gradient-mediated embryo patterning James Briscoe, Stephen Small Development 142: 3996-4009; doi: 10.1242/dev.129452

Did anybody say 'design'? :) Dionisio

The model organism Drosophila melanogaster has been used extensively to study the various facets of host-microbe interaction and defence mechanisms. Aside from the discovery of several highly conserved mechanisms regulating the complex networks that underlie the innate immune system of the fly [1], the complex interplay between the host animal and its associated microbiota has been attracting rising attention In light of the relative simplicity of its microbiome compared to the complexity and species richness found in mammals [14], the fly is a highly useful model organism for the study of host-microbe interactions. Little is known, however, about the influence of epigenetic processes on gut and microbiome homeostasis in Drosophila and mammals, respectively. [...] why bacterial titres as well as the relative levels of some minor taxa become more similar between mutant and wild-type flies at later stages of age is not known to date. Further studies are needed to examine if CHD1 might actually affect the physiological age of the gut.

Impact of the Chromatin Remodeling Factor CHD1 on Gut Microbiome Composition of Drosophila melanogaster Johanna Sebald,#1 Michaela Willi,#2 Ines Schoberleitner,#1 Anne Krogsdam,2,3 Dorothea Orth-Höller,4 Zlatko Trajanoski,2 and Alexandra Lusser PLoS One. 11(4): e0153476. doi: 10.1371/journal.pone.0153476

Dionisio

The use of Next Generation Sequencing (NGS) for the analysis of complex microbial communities has increased dramatically in recent years. Reasons for this include a continual decrease in cost and an ever greater appreciation of the ability of NGS to more comprehensively characterise microbial communities than traditional culture based methods. Rapid advancements in sequencing technologies along with falling costs present widespread opportunities for microbiome studies across a vast and diverse array of environments. These impressive technological developments have been accompanied by a considerable growth in the number of methodological variables, including sampling, storage, DNA extraction, primer pairs, sequencing technology, chemistry version, read length, insert size, and analysis pipelines, amongst others. This increase in variability threatens to compromise both the reproducibility and the comparability of studies conducted.

Comparing Apples and Oranges?: Next Generation Sequencing and Its Impact on Microbiome Analysis. Clooney AG1,2,3, Fouhy F4,3, Sleator RD2,3, O' Driscoll A5,3, Stanton C4,3, Cotter PD4,3, Claesson MJ1,3. PLoS One. 11(2):e0148028. doi: 10.1371/journal.pone.0148028.

Dionisio

The microbiome is formed from the ecological communities of microorganisms that dominate the living world. Bacteria can now be identified through the use of next generation sequencing applied at several levels. Shotgun sequencing of all bacteria in a sample delivers knowledge of all the genes present. High-throughput sequencing of PCR-amplified taxonomic markers (like the 16S rRNA gene) has enabled a new level of analysis of complex bacterial communities known as microbiomes. Many tools exist to quantify and compare abundance levels or microbial composition of communities in different conditions. The sequencing reads have to be denoised and assigned to the closest taxa from a reference database.

Bioconductor workflow for microbiome data analysis: from raw reads to community analyses. Callahan BJ1, Sankaran K1, Fukuyama JA1, McMurdie PJ2, Holmes SP1. F1000Res. 5:1492. doi: 10.12688/f1000research.8986.1.

Dionisio

In recent years, scientists and funding organizations alike have come to realize that in order to successfully tackle the challenges of the field, close collaboration between various disciplines, e.g. statistics, molecular biology, genetics, and computer science, is of paramount importance 2, 6, 7. Development of free/libre open source software is usually done by a community of people with an interest in the tool. For scientific software, however, this is less often the case. Most scientific software is written by only a few authors, often a student working on a thesis. Once the paper describing the tool has been published, the tool is no longer developed further and is left to its own device.

The GenABEL Project for statistical genomics Lennart C. Karssen,a,1,2 Cornelia M. van Duijn,2 and Yurii S. Aulchenkob,1,3,4, Version 1. F1000Res. 5: 914. doi: 10.12688/f1000research.8733.1

Dionisio

The field of statistical (gen-)omics lies at the heart of current research into the genetic aetiology of (human) disease and personalized or precision medicine 1. Genome-wide association studies (GWAS), genotype imputation and next-generation sequencing (NGS) are just a few of the techniques used in this field that is driven by increasingly larger data sets 2, 3. With the advent of polyphenotype analysis as is now customary in e.g. lipidomics and metabolomics, the issues of dealing with big data have become imminent 4, 5.

The GenABEL Project for statistical genomics Lennart C. Karssen,a,1,2 Cornelia M. van Duijn,2 and Yurii S. Aulchenkob,1,3,4, Version 1. F1000Res. 5: 914. doi: 10.12688/f1000research.8733.1

Dionisio

Biobanks have been heralded as essential tools for translating biomedical research into practice, driving precision medicine to improve pathways for global healthcare treatment and services. Many nations have established specific governance systems to facilitate research and to address the complex ethical, legal and social challenges that they present, but this has not lead to uniformity across the world. Despite significant progress in responding to the ethical, legal and social implications of biobanking, operational, sustainability and funding challenges continue to emerge. No coherent strategy has yet been identified for addressing them. This has brought into question the overall viability and usefulness of biobanks in light of the significant resources required to keep them running.

Has the biobank bubble burst? Withstanding the challenges for sustainable biobanking in the digital era. Chalmers D1, Nicol D2, Kaye J3, Bell J3, Campbell AV4, Ho CW4, Kato K5, Minari J5, Ho CH6, Mitchell C3, Molnár-Gábor F7, Otlowski M2, Thiel D8, Fullerton SM9, Whitton T2. BMC Med Ethics. 17(1):39. doi: 10.1186/s12910-016-0124-2.

Dionisio

[...] biological research generating high volumes of data is distributed across many labs — highlighting the need to share resources. Much of the construction in big-data biology is virtual, focused on cloud computing — in which data and software are situated in huge, off-site centres that users can access on demand, so that they do not need to buy their own hardware and maintain it on site. Labs that do have their own hardware can supplement it with the cloud and use both as needed. They can create virtual spaces for data, software and results that anyone can access, or they can lock the spaces up behind a firewall so that only a select group of collaborators can get to them. Clouds are a solution, but they also throw up fresh challenges. Ironically, their proliferation can cause a bottleneck if data end up parked on several clouds and thus still need to be moved to be shared. And using clouds means entrusting valuable data to a distant service provider who may be subject to power outages or other disruptions. Most researchers tend to download remote data to local hardware for analysis. The alternative is to use the cloud for both data storage and computing. If the data are on a cloud, researchers can harness both the computing power and the tools that they need online, without the need to move data and software [...] Data transfer with fasp is hundreds of times quicker than methods using the normal Internet protocol [...] Data mountains and analysis are altering the way science progresses, and breeding biologists who get neither their feet nor their hands wet. Big data in biology add to the possibilities for scientists, [...] because data sit “under-analysed in databases all over the world”.

Biology: The big challenges of big data Vivien Marx Nature 498, 255–260 doi:10.1038/498255a

Dionisio

A number of different mechanisms are likely to regulate the distribution of these binding sites, including the biosynthesis of the HS chains, the localization of core proteins in membrane microdomains and the interactions of the polysaccharide chains with endogenous HS-binding proteins. The high multiplicity of interactions, both between proteins and polysaccharide and between the polysaccharide-binding proteins themselves [...] is likely to produce a dynamic network of interlinked molecules. This would then be responsible for the long-range (supramolecular) structure of the pericellular matrix, which determines its spatial binding capabilities for individual proteins. [...] although extracellular matrix in cartilage is specialized, in other tissues, an analogous situation may exist, where pericellular, extracellular and basement membrane matrices may exhibit different types of supramolecular structure and consequently have different functions.

Selectivity in glycosaminoglycan binding dictates the distribution and diffusion of fibroblast growth factors in the pericellular matrix Changye Sun,1 Marco Marcello,2 Yong Li,1 David Mason,2 Raphaël Lévy,1 and David G. Fernig Open Biol. 6(3): 150277. doi: 10.1098/rsob.150277

Dionisio

[...] it would be interesting to address a potential role for Noggin4 in blocking signalosome formation and/or function. It would be interesting to verify whether Noggin4, like Frzb, is also unable to antagonise Wnt3a activity.

Noggin4 is a long-range inhibitor of Wnt8 signalling that regulates head development in Xenopus laevis Fedor M. Eroshkin,1,* Alexey M. Nesterenko,b,1,2,* Alexander V. Borodulin,1 Natalia Yu. Martynova,1 Galina V. Ermakova,1 Fatima K. Gyoeva,3 Eugeny E. Orlov,1 Alexey A. Belogurov,1 Konstantin A. Lukyanov,1 Andrey V. Bayramov,c,1 and Andrey G. Zaraiskya,1 Sci Rep. 6: 23049. doi: 10.1038/srep23049

Dionisio

[...] there must be other molecules and mechanisms in the embryo that refine and shape the Nodal morphogen gradient. [...] diffusion, extracellular interactions i.e., Nodal-receptor binding, Nodal-Lefty inhibitor binding, and selective ligand destruction collectively shape and refine the Nodal morphogen gradient. It will be interesting to determine how Oep/Cripto co-receptors and Lefty shape the active signaling gradient. It is not known if the ECM or HSPGs play a role in modulating the Nodal morphogen gradient [...] [...] some aspects of the system have not been taken into account in our simulations. [...] simulations have not taken into consideration cell divisions or binding to other factors that could influence the gradient.

Extracellular interactions and ligand degradation shape the nodal morphogen gradient Yin Wang,1,2,† Xi Wang,3,† Thorsten Wohland,2,3,* and Karuna Sampath1,* eLife. 5: e13879. doi: 10.7554/eLife.13879

Dionisio

At the molecular and structural levels, further analyses are clearly needed to fully understand the implication of these parts of Reelin, as well as of the other RRs that have not been characterized so far. It will be interesting to characterize the full-length Reelin structurally, alone, and bound to its canonical receptors. Another fascinating element is the significance of the proteolysis of Reelin. [...] the dynamic regulation of these events is not well understood and it should be an area of intense research. A precise profiling of Reelin degradation over time will be necessary to understand Reelin function in health and disease. [...] it is likely that, in vivo, Reelin is further degraded into smaller fragments that can have currently unrecognized activities. Remarkably, because Erk1/2 activation is not mediated by the canonical signal transduction pathway, a non-canonical pathway that works during brain development must exist [...]

Structural Insights into Reelin Function: Present and Future Fanomezana M. Ranaivoson,1,2 Sventja von Daake,1,2 and Davide Comoletti1, Front Cell Neurosci. 10: 137. doi: 10.3389/fncel.2016.00137

Dionisio

Although specific molecular and physiological mechanisms remain to be further elucidated, these findings indicate that Reelin has the potential to modulate synaptic activity and thus affect memory formation in the adult and aging brain. [...] Reelin promotes the maturation of spines by regulating the NMDA receptor (NMDAR) subunit composition via an unidentified mechanism [...] [...] Dab1/SFK signaling is required for the molecular identity of this dendritic compartment, which regulates the processing of information in hippocampal circuits [...]

New Insights into Reelin-Mediated Signaling Pathways Gum Hwa Lee1,* and Gabriella D’Arcangelo Front Cell Neurosci. 10: 122. doi: 10.3389/fncel.2016.00122

Dionisio

The discovery of the canonical linear lipoprotein receptor/Dab1-dependent Reelin signaling cascade has enabled us to decipher many of the cellular and molecular mechanisms underlying Reelin’s multiple functions in the developing and adult brain, and is now one of the best-characterized signaling pathways involved in shaping the developing brain [...] [...] even for well-established Reelin targets, many open questions regarding their exact functional relevance remain, [...] The biological functions of non-canonical Reelin signaling cascades, as outlined in detail above, are even less well defined and require further investigation. [...] interactions of hitherto unknown significance, [...] might turn out to be of physiological significance and hint to as yet unknown or poorly defined functions of Reeling [...]

Canonical and Non-canonical Reelin Signaling Hans H. Bock* and Petra May Front Cell Neurosci. 10: 166. doi: 10.3389/fncel.2016.00166

Dionisio

Cul5-containing ubiquitin ligases regulate a variety of signaling pathways by targeting particular substrates for proteasomal degradation or competing for protein–protein interactions. However, many Cul5-containing ubiquitin ligases remain to be studied, and a complete list of substrates or binding proteins of Cul5 is not available. Certain viruses target Elongin C-interacting Cul5 (and in some cases Cul2) for hijacking, although the cause remains undetermined. Studies focusing on Elongin C might shed light on the physiological functions of Cul5.

The role of cullin 5-containing ubiquitin ligases Fumihiko Okumura, Akiko Joo-Okumura, Kunio Nakatsukasa, and Takumi Kamura Cell Div. 11: 1. doi: 10.1186/s13008-016-0016-3

Dionisio

[...] molecular pieces, identified from molecular genetics and in vivo electroporation, begin to take shape. However, the spatio-temporal regulation of these cellular events remains unclear. Furthermore, the dynamic behavior of each endosome in migrating neurons in cortical slices remains to be observed. Continual technological advances in in vivo cell biology and related research fields will shed light on unsolved questions to help us better understand the whole picture of cerebral cortical development.

Cellullar insights into cerebral cortical development: focusing on the locomotion mode of neuronal migration Takeshi Kawauch Front Cell Neurosci. 9: 394. doi: 10.3389/fncel.2015.00394

Dionisio

To summarize, we have identified a novel regulation of microridge formation by antagonistic interactions between aPKC and Lgl. Importantly, we have identified the significance of Lgl removal from the apical domain by aPKC in vertebrate epithelial cells. Our analyses presented here suggest that formation of apical projections is under the control of mechanisms involved in establishment and maintenance of epithelial cell polarity. [...] further investigations are required to identify additional components or polarity regulator/s that act in conjunction with the two Lgls in formation of apical microridges.

aPKC regulates apical localization of Lgl to restrict elongation of microridges in developing zebrafish epidermi Renuka Raman,1 Indraneel Damle,1 Rahul Rote,1,* Shamik Banerjee,1,2 Chaitanya Dingare,1,† and Mahendra Sonawanea,1 Nat Commun. 7: 11643. doi: 10.1038/ncomms11643

Dionisio

The spindle- and kinetochore-associated (Ska) complex is essential for normal anaphase onset in mitosis. The C-terminal domain (CTD) of Ska1 binds microtubules and was proposed to facilitate kinetochore movement on depolymerizing spindle microtubules. Microtubule binding by Ska, rather than acting in force production for chromosome movement, may instead serve to promote PP1 recruitment to kinetochores fully attached to spindle microtubules at metaphase.

The human SKA complex drives the metaphase-anaphase cell cycle transition by recruiting protein phosphatase 1 to kinetochores. Sivakumar S1,2,3, Janczyk P?4, Qu Q2,3, Brautigam CA5, Stukenberg PT4, Yu H2,3, Gorbsky GJ Elife. 5. pii: e12902. doi: 10.7554/eLife.12902

Dionisio

The spindle assembly checkpoint (SAC) is a key mechanism to regulate the timing of mitosis and ensure that chromosomes are correctly segregated to daughter cells. The recruitment of the Mad1 and Mad2 proteins to the kinetochore is normally necessary for SAC activation. This recruitment is coordinated by the SAC kinase Mps1, which phosphorylates residues at the kinetochore to facilitate binding of Bub1, Bub3, Mad1, and Mad2. There is evidence that the essential function of Mps1 is to direct recruitment of Mad1/2.

Synthetic Physical Interactions Map Kinetochore-Checkpoint Activation Regions Guðjón Ólafsson and Peter H. Thorpe G3 (Bethesda). 6(8): 2531–2542. doi: 10.1534/g3.116.031930

Dionisio

In the future, a deeper dissection of the molecular mechanisms governing these functional distinctions would significantly advance our understanding of mitotic progression. There however remains the possibility that LIC2-dynein could mediate kinetochore BubR1 removal by alternative mechanisms as well, which would be interesting to explore. This aspect of cytoplasmic dynein-dependent kinetochore Zw10 dynamics could be interesting to explore in the future.

Dynein Light Intermediate Chain 2 Facilitates the Metaphase to Anaphase Transition by Inactivating the Spindle Assembly Checkpoint Sagar P. Mahale,1,2 Amit Sharma,1,2 and Sivaram V. S. Mylavarapu1,2,* PLoS One. 11(7): e0159646. doi: 10.1371/journal.pone.0159646

Dionisio

The process of mitosis involves the attachment of chromosomes to a protein scaffold, called the mitotic spindle, via large protein complexes called kinetochores [...]. Throughout mitosis, the kinetochores, and hence the chromosomes, execute a highly complex stochastic motion culminating in the segregation of the genetic material to the two daughter cells.

KiT: a MATLAB package for kinetochore tracking Jonathan W. Armond,1,2,* Elina Vladimirou,1 Andrew D. McAinsh,1 and Nigel J. Burroughs Bioinformatics. 32(12): 1917–1919. doi: 10.1093/bioinformatics/btw087

Dionisio

During mitosis, chromosomes are attached to the mitotic spindle via large protein complexes called kinetochores. The motion of kinetochores throughout mitosis is intricate and automated quantitative tracking of their motion has already revealed many surprising facets of their behaviour.

KiT: a MATLAB package for kinetochore tracking Jonathan W. Armond,1,2,* Elina Vladimirou,1 Andrew D. McAinsh,1 and Nigel J. Burroughs Bioinformatics. 32(12): 1917–1919. doi: 10.1093/bioinformatics/btw087

Dionisio

Kinetochores are multi-protein complexes that mediate the physical coupling of sister chromatids to spindle microtubule bundles (called kinetochore (K)-fibres) from respective poles. [...] how is kinetochore directional switching regulated to generate the observed pseudo-periodic oscillations incorporating both LIDS and TIDS choreographies, with TIDS being inhibited relative to LIDS. [...] how is this switching accomplished under low spring tension, that rarely, if ever, achieves a kinetochore stall. [...] what changes in the spindle explain the increase in trajectory stochasticity and the PEF with distance from the centre of the metaphase plate. Future work is needed to tie down the biochemical and mechanical processes that underpin these behaviours.

Inferring the Forces Controlling Metaphase Kinetochore Oscillations by Reverse Engineering System Dynamics. Armond JW1, Harry EF2, McAinsh AD3, Burroughs NJ1. PLoS Comput Biol. ;11(11):e1004607. doi: 10.1371/journal.pcbi.1004607

Dionisio

A closure operator defining an information system is a very general concept, which can be used to define geometric, topological, logical, and algebraic structures. The invariance of the description of information is here identical with the invariance of the closure space with respect to transformations preserving its structure. Now, when the toolkit for the study of the transformations of information systems and their invariants is ready, the next task is to apply it to the analysis of more specific instances of information.

Invariance as a Tool for Ontology of Information Marcin J. Schroeder Information 7(1), 11; doi:10.3390/info7010011

Dionisio

Cell engineering has brought us tantalizingly close to the goal of deriving patient-specific hematopoietic stem cells (HSCs). While directed differentiation and transcription factor-mediated conversion strategies have generated progenitor cells with multilineage potential, to date, therapy-grade engineered HSCs remain elusive due to insufficient long-term self-renewal and inadequate differentiated progeny functionality. A cross-species approach involving zebrafish and mammalian systems offers complementary methodologies to improve understanding of native HSCs. Here, we discuss the role of conserved developmental timing processes in vertebrate hematopoiesis, highlighting how identification and manipulation of stage-specific factors that specify HSC developmental state must be harnessed to engineer HSCs for therapy.

Engineering Hematopoietic Stem Cells: Lessons from Development. Rowe RG1, Mandelbaum J1, Zon LI2, Daley GQ3. Cell Stem Cell. 18(6):707-20. doi: 10.1016/j.stem.2016.05.016.

Dionisio

[...] it is possible that spatial segregation of co-operating and spatial overlap of antagonizing factors may also be important for adjustment of HSC development in vivo. How exactly HSC maturation dynamics depend on overlapping concentrations of factors requires further analysis. [...] it is currently unclear whether any factors become expressed in a polarized manner within the reaggregates and as such, whether polarization is also a pre-requisite for HSC maturation. The distinction between these two scenarios will require further investigation.

Inductive interactions mediated by interplay of asymmetric signalling underlie development of adult haematopoietic stem cells Céline Souilhol,1 Christèle Gonneau,1 Javier G. Lendinez,1 Antoniana Batsivari,1 Stanislav Rybtsov,1 Heather Wilson,1 Lucia Morgado-Palacin,1 David Hills,1 Samir Taoudi,2,3,4 Jennifer Antonchuk,5 Suling Zhao,1 and Alexander Medvinsky Nat Commun. 2016; 7: 10784. doi: 10.1038/ncomms10784

Dionisio

BMP4 signalling is a key factor involved during differentiation of ventral mesoderm and its further specification into haematopoietic cells. [...] downregulation of BMP signalling is functionally important for HSC development in the embryo. [...] all three signalling pathways studied can cooperate for HSC development [...] [...] the interplay of Shh and BMP pathways is broadly involved in development. [...] the feed-forward loop Shh?Noggin/Noggin?Shh is also involved in HSC development in vivo.

Inductive interactions mediated by interplay of asymmetric signalling underlie development of adult haematopoietic stem cells Céline Souilhol,1 Christèle Gonneau,1 Javier G. Lendinez,1 Antoniana Batsivari,1 Stanislav Rybtsov,1 Heather Wilson,1 Lucia Morgado-Palacin,1 David Hills,1 Samir Taoudi,2,3,4 Jennifer Antonchuk,5 Suling Zhao,1 and Alexander Medvinsky Nat Commun. 2016; 7: 10784. doi: 10.1038/ncomms10784

Dionisio

[...] HSC development in the embryo involves stage-dependent interactions between dorsal, ventral and lateral domains of the AGM region, mediated at least partly by the interplay of SCF, Shh, BMP4 and Noggin. Further detailed analysis will be required to better understand the complexity of the AGM signalling landscape in which HSC development takes place.

Inductive interactions mediated by interplay of asymmetric signalling underlie development of adult haematopoietic stem cells Céline Souilhol,1 Christèle Gonneau,1 Javier G. Lendinez,1 Antoniana Batsivari,1 Stanislav Rybtsov,1 Heather Wilson,1 Lucia Morgado-Palacin,1 David Hills,1 Samir Taoudi,2,3,4 Jennifer Antonchuk,5 Suling Zhao,1 and Alexander Medvinsky Nat Commun. 2016; 7: 10784. doi: 10.1038/ncomms10784

Dionisio

The centrosome is a key component of the cell is involved in the processes of cell division, cell motility, intracellular transport, organization of the microtubules (MT) network and the production of cilia and flagella. The peculiarity of this organelle is that its boundaries are not clearly defined, the centrioles at the center of the centrosome are surrounded by electron dense pericentriolar material, the size and protein composition of this centrosome component experiences significant transformation during the cell cycle. [...] within the centrosome different proteins occupy different areas corresponding to: MT nucleation region (defined as gamma-tubulin-stained area), regulatory region (defined as kinase pEg2-stained area) and motor proteins region (kinesin-like motor XlEg5-stained area). The boundary of pEg2 is near 1.3 times greater while XlEg5 is 3.0 times greater than that of gamma-tubulin. Thus, the size of the centrosome, determined according to the structural electron microscopy (EM) analysis (about 1 µm) corresponds to the regulatory proteins area, but the actual functional centrosome size defined at the motor proteins region, is more than twice the size.

Where are the limits of the centrosome? Irina B. Alieva? & Rustem E. Uzbekov BioArchitecture ? Volume 6, 2016 - Issue 3 ?http://dx.doi.org/10.1080/19490992.2016.1168957

Dionisio

During the cell cycle, centrosomes duplicate only once in a highly spatiotemporally regulated manner that is controlled by many proteins described in the present work. Perturbation of these regulatory mechanisms can affect the proper execution of the various processes and result in the formation of abnormal centrosomes In the future, further detailed characterization of centrosome regulation during the cell cycle could provide promising targets for cancer therapy.

Regulation of the centrosome cycle Hiroki Fujita, Yuki Yoshino & Natsuko Chiba ?http://dx.doi.org/10.1080/23723556.2015.1075643 Molecular & Cellular Oncology ? Volume 3, 2016 - Issue 2

Dionisio

Centrosomes are the microtubule organizing centers (MTOCs) of most animal cells and play a critical role in mitotic spindle orientation. The centrosome consists of a pair of centrioles, namely mother and daughter centrioles, embedded in the pericentriolar matrix (PCM).

Regulation of the centrosome cycle Hiroki Fujita, Yuki Yoshino & Natsuko Chiba ?http://dx.doi.org/10.1080/23723556.2015.1075643 Molecular & Cellular Oncology ? Volume 3, 2016 - Issue 2

Dionisio

The centrosome, consisting of mother and daughter centrioles surrounded by the pericentriolar matrix (PCM), functions primarily as a microtubule organizing center (MTOC) in most animal cells. In dividing cells the centrosome duplicates once per cell cycle and its number and structure are highly regulated during each cell cycle to organize an effective bipolar spindle in the mitotic phase.

Regulation of the centrosome cycle Hiroki Fujita, Yuki Yoshino & Natsuko Chiba ?http://dx.doi.org/10.1080/23723556.2015.1075643 Molecular & Cellular Oncology ? Volume 3, 2016 - Issue 2

Dionisio

Future work will be needed to investigate how this protein cascade fits into the bigger picture of centriole assembly and how it is connected to the very early steps of procentriole formation. Centriole-to-centrosome conversion follows a strict timetable, and it has been suggested that Plk1 (Polo-like kinase 1) plays an important role in regulating the process in human cells. [...] unraveling the potential roles of Polo/Plk1 in regulating these interactions will be an intriguing topic for future study.

How the newborn centriole becomes a mother Jingyan Fu & David Glover http://dx.doi.org/10.1080/15384101.2016.1164566 Cell Cycle ? Volume 15, 2016 - Issue 12 Page 1521-1522

Dionisio

Interestingly, the daughter centriole can neither duplicate itself nor nucleate pericentriolar material (PCM), a cloud of proteins that enhances the microtubule nucleating ability of the centrosome, until the centriole has passed through mitosis. Understanding centriole to centrosome conversion requires knowledge of the centriolar components that are loaded during mitosis, how they are organized in space and the dependencies of their recruitment.

How the newborn centriole becomes a mother Jingyan Fu & David Glover http://dx.doi.org/10.1080/15384101.2016.1164566 Cell Cycle ? Volume 15, 2016 - Issue 12 Page 1521-1522

Dionisio

The centriole is a conserved organelle in most animal cells. It is built with numerous proteins including a 9-fold symmetrical microtubule wall. Centrioles usually exist in pairs and constitute the core of the centrosome, the major microtubule-organizing center of the cell.

How the newborn centriole becomes a mother Jingyan Fu & David Glover http://dx.doi.org/10.1080/15384101.2016.1164566 Cell Cycle ? Volume 15, 2016 - Issue 12 Page 1521-1522

Dionisio

Centriole-to-centrosome conversion takes place following a strict timetable during mitosis in which the mitotic kinase, Plk1, has been suggested to play an important role. It seems likely that the protein-protein interactions we describe can be further regulated by phosphorylation both in time and space to control the sequence of events. Unraveling the potential roles of Polo:Plk1 in regulating these interactions will be a fascinating topic for future study.

Conserved Molecular Interactions in Centriole-to-Centrosome Conversion Jingyan Fu,1,6 Zoltan Lipinszki,1,3 Hélène Rangone,1 Mingwei Min,1,4 Charlotte Mykura,1,5 Jennifer Chao-Chu,1 Sandra Schneider,1 Nikola S. Dzhindzhev,1 Marco Gottardo,2 Maria Giovanna Riparbelli,2 Giuliano Callaini,2 and David M. Glover Nat Cell Biol. 18(1): 87–99. doi: 10.1038/ncb3274

Dionisio

Centrioles are required to assemble centrosomes for cell division and cilia for motility and signaling. New centrioles assemble perpendicularly to pre-existing ones in G1-S and elongate throughout S and G2. Fully-elongated daughter centrioles are converted into centrosomes during mitosis to be able to duplicate and organize pericentriolar material in the next cell cycle. The molecular basis of this conversion from centriole to centrosome has remained mysterious. [...] centriole-to-centrosome conversion involves a cascade of interactions i [...]

Conserved Molecular Interactions in Centriole-to-Centrosome Conversion Jingyan Fu,1,6 Zoltan Lipinszki,1,3 Hélène Rangone,1 Mingwei Min,1,4 Charlotte Mykura,1,5 Jennifer Chao-Chu,1 Sandra Schneider,1 Nikola S. Dzhindzhev,1 Marco Gottardo,2 Maria Giovanna Riparbelli,2 Giuliano Callaini,2 and David M. Glover Nat Cell Biol. 18(1): 87–99. doi: 10.1038/ncb3274

Dionisio

[...] it is necessary to carefully examine which of these newly identified centriolar proteins are structural constituents of the centriole and which are accessory proteins, and what their structural and functional roles are in centriole assembly. It is foreseeable that many more structural characterizations on centriole assembly will be reported in the coming years, which, together with continuous advancements in functional and in vivo studies, will provide a more refined view of one of the most important and fascinating cellular structures that has captivated cell biologists for over a century.

Building a ninefold symmetrical barrel: structural dissections of centriole assembly Gang Dong Open Biol. 5(8): 150082. doi: 10.1098/rsob.150082

@1895: "[...] the underlying molecular mechanisms for centriole assembly had been a mystery—until recently." Does that mean it's not a mystery anymore? :) Dionisio

Recent studies using various techniques have identified many new centriolar components. It is likely that more centriole-associated proteins will be reported in the future. However, unlike the five core centriolar proteins, at least some of them are organism- or cell-specific.

Building a ninefold symmetrical barrel: structural dissections of centriole assembly Gang Dong Open Biol. 5(8): 150082. doi: 10.1098/rsob.150082

@1895: "[...] the underlying molecular mechanisms for centriole assembly had been a mystery—until recently." Does that mean it's not a mystery anymore? :) Dionisio

The field faces several challenges in this process including (i) to understand how centriole assembly is initiated, (ii) to uncover how centriole duplication is regulated by both kinases and phosphatases, (iii) to determine the high-resolution structures and the functional roles for those coiled-coil-containing centriolar proteins, and (iv) to precisely assign the relative positions and the interaction network of different centriolar proteins and their structural/functional roles.

Building a ninefold symmetrical barrel: structural dissections of centriole assembly Gang Dong Open Biol. 5(8): 150082. doi: 10.1098/rsob.150082

@1895: "[...] the underlying molecular mechanisms for centriole assembly had been a mystery—until recently." Does that mean it's not a mystery anymore? :) Dionisio

The recent progress in structural studies on centriolar components, with each of the five core components having been at least partially characterized, has greatly advanced our understanding of centriole assembly at the high-resolution level. However, further studies will be necessary to precisely determine their contributions, both physically and temporally, during centriole assembly, and to uncover their interplay with other newly identified constitutive or accessory centriolar proteins and each other.

Building a ninefold symmetrical barrel: structural dissections of centriole assembly Gang Dong Open Biol. 5(8): 150082. doi: 10.1098/rsob.150082

@1895: "[...] the underlying molecular mechanisms for centriole assembly had been a mystery—until recently." Does that mean it's not a mystery anymore? :) Dionisio

Centrioles are short microtubule-based organelles with a conserved ninefold symmetry. They are essential for both centrosome formation and cilium biogenesis in most eukaryotes. A core set of five centriolar proteins has been identified and their sequential recruitment to procentrioles has been established. However, structures at atomic resolution for most of the centriolar components were scarce, and the underlying molecular mechanisms for centriole assembly had been a mystery—until recently.

Building a ninefold symmetrical barrel: structural dissections of centriole assembly Gang Dong Open Biol. 5(8): 150082. doi: 10.1098/rsob.150082

Dionisio

In human cells, the basal body (BB) core comprises a ninefold microtubule-triplet cylindrical structure. Distal and subdistal appendages are located at the distal end of BB, where they play indispensable roles in cilium formation and function. [...] humans possess a complex arsenal of mechanisms to regulate the BB, although the idiosyncrasies between cell types that regulate these processes are unknown. [...] the centrosome-associated ciliary membrane functions in temporal control of ciliogenesis. BBs possess most of the characteristics of centrosomes, including the ability to organize the microtubule cytoskeleton. It appears that one of the major regulatory roles of BBs is coordination of several complicated trafficking pathways. [...] the mechanism of proteasome recruitment to the centrosome and/or BB is unknown. Essential efforts toward identification of additional mutations in centrosome/BBs that cause ciliopathies exponentially expand our current knowledge on centrosomes/BBs. This will both facilitate our understanding of these important structures [...] [...] the overlapping properties and functions of centrosomes and BBs, and the ability of both to perturb ciliogenesis when disrupted, make it difficult to discern the molecular mechanisms behind ciliopathies.

Human basal body basics Anastassiia Vertii, Hui-Fang Hung, Heidi Hehnly and Stephen Doxsey Celia 2016 5:13 DOI: 10.1186/s13630-016-0030-8

Dionisio

PCP proteins maintain planar polarity in many epithelial tissues and have been implicated in cilia development in vertebrate embryos. [...] in addition to cell polarity, PCP components control basal body organization and function. During development, embryonic cells often become oriented in the plane of the tissue, causing visibly polarized patterns [...] It remains to be investigated whether Wtip is directly involved in PCP. At present, the relationship between roles of Pk3 in basal body organization and PCP is unclear. Future studies are needed to further define mechanisms that involve Pk3 and regulate ciliogenesis and PCP.

Prickle3 synergizes with Wtip to regulate basal body organization and cilia growth Chih-Wen Chu,1 Olga Ossipova,1 Andriani Ioannou,1 and Sergei Y. Sokola Sci Rep.; 6: 24104. doi: 10.1038/srep24104

Dionisio

Further investigation of the potential "bright side" of ROS and mitochondrial respiration is necessary to target specific pathways, such as the mechanistic target of rapamycin, nicotinamidases, sirtuins, mRNA decoupling and protein expression, and Wnt signaling, that can impact oxidative stress-ROS mechanisms to extend lifespan and eliminate disease onset.

J Transl Sci. 2016;2(3):185-187. Epub 2016 Apr 28. The bright side of reactive oxygen species: lifespan extension without cellular demise. Maiese K1.

Dionisio

Neural Regen Res. 2016 Mar;11(3):372-85. doi: 10.4103/1673-5374.179032. Novel nervous and multi-system regenerative therapeutic strategies for diabetes mellitus with mTOR. Maiese K1.

Dionisio

Sci Rep. 2016 May 19;6:26149. doi: 10.1038/srep26149. Fructose, but not glucose, impairs insulin signaling in the three major insulin-sensitive tissues. Baena M1,2, Sangüesa G1,2, Dávalos A3, Latasa MJ3, Sala-Vila A4,5, Sánchez RM1,2,4, Roglans N1,2,4, Laguna JC1,2,4, Alegret M1,2

Dionisio

It is now clear that mTOR has a central role in coordinating the outcome of pathogen defense by modulating immunity mediated by lymphoid cells. However, many details of the host–pathogen interaction, and their implications, are still to be determined. [...] it is clear that there is still much to learn about utilizing the mTOR pathway for successful therapeutic intervention.

mTOR Regulation of Lymphoid Cells in Immunity to Pathogens Rachael Keating and Maureen Ann McGargill Front Immunol. 7: 180. doi: 10.3389/fimmu.2016.00180

Dionisio

Immunity to pathogens exists as a fine balance between promoting activation and expansion of effector cells, while simultaneously limiting normal and aberrant responses. These seemingly opposing functions are kept in check by immune regulators. The mechanistic target of rapamycin (mTOR) is a serine/threonine kinase that senses nutrient availability and, in turn, regulates cell metabolism, growth, and survival accordingly. mTOR plays a pivotal role in facilitating immune defense against invading pathogens by regulating the differentiation, activation, and effector functions of lymphoid cells. A thorough understanding of how mTOR impacts lymphoid cells in pathogen defense will provide the necessary base for developing therapeutic interventions for infectious diseases.

mTOR Regulation of Lymphoid Cells in Immunity to Pathogens Rachael Keating and Maureen Ann McGargill Front Immunol. 7: 180. doi: 10.3389/fimmu.2016.00180

Dionisio

Whether mTORC1 acts on TECs to influence these signal mechanisms to confer temporal control of ??T17 differentiation is unknown at present. [...] it is reasonable to speculate that gradual decreases of mTORC1 activity in TECs may contribute to thymic involution, and increases of mTORC1 activity might delay or prevent thymic involution. These hypotheses warrant further investigation. Immune cells undergo specific switches during development Mechanisms that enforce such temporal controls or developmental switch are unknown. An important question that remains to be addressed is how mTORC1 controls TEC development and function.

mTORC1 in Thymic Epithelial Cells Is Critical for Thymopoiesis, T-Cell Generation, and Temporal Control of ??T17 Development and TCR?/? Recombination Hong-Xia Wang, 1 , 2 Jinwook Shin, 1 Shang Wang, 1 , 3 Balachandra Gorentla, 1 Xingguang Lin, 1 , 3 Jimin Gao, 3 Yu-Rong Qiu, 2 ,* and Xiao-Ping Zhong PLoS Biol. 14(2): e1002370. doi: 10.1371/journal.pbio.1002370

Dionisio

At present, how proteins are transferred from thymocytes to TECs remains unknown, but the process is likely involved in multiple mechanisms. It would be interesting to determine whether thymic B cells may uniquely present immunoglobulin epitopes to prevent generation of B cell–reactive T cells. [...] the physiological importance of protein transfer from thymocytes to TECs remains to be illuminated [...]

Intercellular Protein Transfer from Thymocytes to Thymic Epithelial Cells Hong-Xia Wang,1,2 Yu-Rong Qiu,2,* and Xiao-Ping Zhong1, PLoS One. 11(3): e0152641. doi: 10.1371/journal.pone.0152641

Dionisio

Cell division is often perceived to be a symmetric process by which one cell gives rise to two identical daughter cells. Throughout development, however, cell division can produce two daughter cells with different protein content, cell size, and developmental potential, that ultimately adopt distinct fates in a process termed asymmetric cell division1. One of the salient characteristics of the adaptive immune systems is the ability of a single antigen-specific T cell to proliferate and to differentiate into two distinct classes of daughter cells in responding to microbial infection, namely the terminal effector cells that mediate acute protection and the memory cells that provide long-term protective immunity. [...] whether there exist metabolic programs that orchestrate asymmetric division in T cells and whether this process can be manipulated for therapeutic purposes remain incompletely understood.

Metabolic control of asyMYCtric division Mytrang H Do1,2 and Ming O Li1 Cell Research 26:863–864. doi:10.1038/cr.2016.60;

Dionisio

Additional positively acting selectors are likely to work at the nab DWME based on conservation of known binding sequences, but further work will be required to elucidate these more definitively. [...] a Nab cofactor function for the putative fly Egr1/2 ortholog encoded by the stripe gene has yet to be identified. We thus speculate that the above homeodomain-containing selectors (Ap, Dll, Hth) and other selectors (e.g., Sd and Vg) work via a mechanism that is different from the graded spatial (Notch/BMP) and temporal (Zld) patterning effectors. [...] the relationship between selector and pathway effector binding sites would be informed by a helically phased “regulatory reading frame” based on nucleosomal positioning.

Integration of Orthogonal Signaling by the Notch and Dpp Pathways in Drosophila. Stroebele E1, Erives A2. Genetics. 203(1):219-40. doi: 10.1534/genetics.116.186791.

Complex complexity Dionisio

Future studies, including quantitative studies and modelling, should give further insight into pathway interaction and coordination during tissue development by molecules such as Pent. The precise mechanism by which Pent internalises glypicans will be an interesting avenue of future research.

Pentagone internalises glypicans to fine-tune multiple signalling pathways Mark Norman,1 Robin Vuilleumier,2 Alexander Springhorn,2,3 Jennifer Gawlik,1,3 and George Pyrowolakis1,2 eLife. 5: e13301. doi: 10.7554/eLife.13301

Dionisio

Future work should address the influence of Pent on glypican organisation at the nanoscale, and also the type of membranes at which Tkv and Dally localise, questions that are challenging to answer using current methods. In order to fully understand the role of Pent in establishment of the long range Dpp gradient, we must first better understand how glypicans function in Dpp signalling and how Dpp is spread throughout the tissue.

Pentagone internalises glypicans to fine-tune multiple signalling pathways Mark Norman,1 Robin Vuilleumier,2 Alexander Springhorn,2,3 Jennifer Gawlik,1,3 and George Pyrowolakis1,2 eLife. 5: e13301. doi: 10.7554/eLife.13301

Dionisio

Tight regulation of signalling activity is crucial for proper tissue patterning and growth. Bone morphogenetic protein (BMP) signalling is required in a wide variety of processes across higher organisms, from the establishment of the dorso-ventral (DV) axis in insects to the maintenance of the mammalian gut [...] Many of the biological functions of BMP signalling require a high degree of spatial regulation [...]

Pentagone internalises glypicans to fine-tune multiple signalling pathways Mark Norman,1 Robin Vuilleumier,2 Alexander Springhorn,2,3 Jennifer Gawlik,1,3 and George Pyrowolakis1,2 eLife. 5: e13301. doi: 10.7554/eLife.13301

Dionisio

It is becoming increasingly clear that a small class of secreted molecules, called ‘morphogens’, serves as the architects that coordinate patterning and growth during development. Morphogens define organ function by generating a spatial pattern of differentiated cells and also modulate organ size and shape.

Coordination of patterning and growth by the morphogen DPP. Restrepo S1, Zartman JJ2, Basler K3. Curr Biol. ;24(6):R245-55. doi: 10.1016/j.cub.2014.01.055.

The above quoted text is inaccurate, because it gives the credits for coordinating and defining to important players in the story. Morphogens are just important components of the whole choreography which is orchestrated at a higher level. Things must be called by their names. As we say in Spanish: "Al pan pan y al vino vino" or also "un lugar para cada cosa y cada cosa en su lugar". :) Dionisio

The elegance of animal body plans derives from an intimate connection between function and form, which during organ formation is linked to patterning and growth. Yet, how patterning and growth are coordinated still remains largely a mystery. Here, we focus on recent publications that both enrich our view of DPP signaling but also highlight outstanding questions of how DPP coordinates patterning and growth during development.

Coordination of patterning and growth by the morphogen DPP. Restrepo S1, Zartman JJ2, Basler K3. Curr Biol. ;24(6):R245-55. doi: 10.1016/j.cub.2014.01.055.

Dionisio

In spite of numerous efforts, many aspects of DPP signaling, such as the dispersion mechanism, scaling properties, and the role of DPP in wing disc growth control, remain open. To solve these conundrums new and more precise quantitative tools need to be devised to observe and analyze morphogen dynamics and pathway activity. As we continue to “contemplate all things organic,” we still have much to learn about how morphogens such as DPP regulate form and function.

Coordination of patterning and growth by the morphogen DPP. Restrepo S1, Zartman JJ2, Basler K3. Curr Biol. ;24(6):R245-55. doi: 10.1016/j.cub.2014.01.055.

Dionisio

Feedback regulation of UL cortical neurons by DL neurons or other sources has been less extensively studied. The intriguing co-existence of so many mechanisms is in coping with the complexity of regulated sequential cortical neurogenesis and gliogenesis, and requires coordination and interactions with Notch, a master regulator of NPC cell fate. Regulatory mechanisms are hence likely to operate in parallel and it will be challenging to understand how they are integrated in vivo during development, and to harness their potential for regeneration.

Feedback regulation of apical progenitor fate by immature neurons through Wnt7–Celsr3–Fzd3 signalling Wei Wang,1,* Yves Jossin,1 Guoliang Chai,1 Wen-Hui Lien,2 Fadel Tissir,a,1,† and Andre M. Goffinetb,1, Nat Commun. 7: 10936. doi: 10.1038/ncomms10936

Complex complexity. :) Dionisio

Celsr3 and Fzd3, probably together with Linx, have key roles in axon guidance but their function in neurogenesis and the gliogenic switch was not previously recognized. Our results also raise the question of the cellular origin of Wnt7 factors in the telencephalic wall.

Feedback regulation of apical progenitor fate by immature neurons through Wnt7–Celsr3–Fzd3 signalling Wei Wang,1,* Yves Jossin,1 Guoliang Chai,1 Wen-Hui Lien,2 Fadel Tissir,a,1,† and Andre M. Goffinetb,1, Nat Commun. 7: 10936. doi: 10.1038/ncomms10936

Dionisio

Our results identify a previously uncharacterized feedback mechanism that regulates the timing of AP fate via Jag1/Notch signalling. The Wnt7/Celsr3/Fzd3 signal fosters expression of Jag1 in immature neurons, which activates Notch in APs and orchestrates their sequential production of deep and UL cortical neurons, followed by glial.

Feedback regulation of apical progenitor fate by immature neurons through Wnt7–Celsr3–Fzd3 signalling Wei Wang,1,* Yves Jossin,1 Guoliang Chai,1 Wen-Hui Lien,2 Fadel Tissir,a,1,† and Andre M. Goffinetb,1, Nat Commun. 7: 10936. doi: 10.1038/ncomms10936

Emphasis mine. Dionisio

Sequential generation of neurons and glial cells during development is critical for the wiring and function of the cerebral cortex. This process requires accurate coordination of neural progenitor cell (NPC) fate decisions, by NPC-autonomous mechanisms as well as by negative feedback from neurons. Despite significant progress, the mechanisms that regulate the switch between production of DL and UL neurons, and the neurogenic to gliogenic switch remain incompletely known.

Feedback regulation of apical progenitor fate by immature neurons through Wnt7–Celsr3–Fzd3 signalling Wei Wang,1,* Yves Jossin,1 Guoliang Chai,1 Wen-Hui Lien,2 Fadel Tissir,a,1,† and Andre M. Goffinetb,1, Nat Commun. 7: 10936. doi: 10.1038/ncomms10936

Dionisio

Animal organs undergo development not in isolation but in the context of global body axes that form in the early embryo. The process of planar cell polarity (PCP) allows organogenesis to occur with reference to these axes. Planar cell polarity (PCP) information is a critical determinant of organ morphogenesis. While PCP in bounded epithelial sheets is increasingly well understood, how PCP is organized in tubular and acinar tissues is not. That both contexts involve important roles for polarized microtubules and are controlled by related atypical cadherins raises the possibility of ancient links between the modes of epithelial PCP organization.

Symmetry Breaking in an Edgeless Epithelium by Fat2-Regulated Microtubule Polarity. Chen DY1, Lipari KR1, Dehghan Y1, Streichan SJ2, Bilder D3. Cell Rep15(6):1125-33. doi: 10.1016/j.celrep.2016.04.014.

Dionisio

Tissues in developing embryos exhibit complex and dynamic rearrangements that shape forming organs, limbs, and body axes. Directed migration, mediolateral intercalation, lumen formation, and other rearrangements influence the topology and topography of developing tissues. These collective cell behaviors are distinct phenomena but all involve the fine-grained control of cell polarity. These two very different model systems demonstrate important commonalities but also key differences in how cell polarity is controlled in tissue morphogenesis. Together, these systems raise important, broader questions on how the developmental control of cell polarity contributes to morphogenesis of diverse tissues across the metazoa.

Dynamics of cell polarity in tissue morphogenesis: a comparative view from Drosophila and Ciona Michael T. Veemana,1 and Jocelyn A. McDonald Version 1. F1000Res. 5: F1000 Faculty Rev-1084. doi: 10.12688/f1000research.8011.1

Emphasis mine. Dionisio

Epithelial tissues are polarized along two axes. In addition to apical-basal polarity they are often polarized within the plane of the epithelium, so-called Planar Cell Polarity (PCP). [...] because there is a mutual dependence among the core PCP factors for their localization, it is impossible to determine in vivo which of these represent direct effects. CK1 family members have many defined and distinct roles in both Wnt signaling branches, the canonical Wnt pathway and Wnt-PCP signaling, [...] It is likely that additional phosphorylation events are conserved from Drosophila to vertebrates [...] [...] it is conceivable that S120/122 phosphorylation itself represents a priming event for additional phosphorylations within the conserved cluster. It should be interesting to address such questions in primitive organisms, like hydra, that require Wnt-signaling [...] but have fewer isoforms of the respective genes. [...] it is possible that Fz may function downstream of Dco/CK1? to prevent dephosphorylation of Vang. [...] Fz induced Vang phosphorylation serves as a mechanism to produce or reinforce asymmetric localization of PCP components. Although Fz is required for this phosphorylation to occur, its exact role remains unclear. Our study provides important insight into the critical importance of the Vang N-terminus and reveals an associated conserved regulatory mechanism of PCP establishment. Strikingly, this mechanism is independent of Dsh, the cell-autonomous effector of Fz and likely acts upstream of the Dsh-Pk-Dgo mediated cell-autonomous feedback loops.

Frizzled-induced Van Gogh phosphorylation by CK1? promotes asymmetric localization of core PCP factors in Drosophila Lindsay K. Kelly, Jun Wu, Wang A. Yanfeng, and Marek Mlodzik Cell Rep. 16(2): 344–356. doi: 10.1016/j.celrep.2016.06.010

Emphasis mine. Dionisio

[...] the goal of computation in biology is not toward artificial, general purpose computing but toward enabling sense and response behaviors relevant to biological applications. This realization should motivate a more application driven, top-down approach in designing synthetic gene circuits to tackle real-world challenges.

Foundations and Emerging Paradigms for Computing in Living Cells Kevin C. Ma, Samuel D. Perli, Timothy K. Lu doi:10.1016/j.jmb.2016.02.018 Journal of Molecular Biology Volume 428, Issue 5, Part B, Pages 893–915 Engineering Tools and Prospects in Synthetic Biology http://www.sciencedirect.com/science/article/pii/S0022283616001340

Dionisio

A subset of systems biologists have focused in particular on studying network motifs which occur more often than expected and thus are thought to carry specific information-processing capabilities; for instance, depending on the particular configuration, the feed-forward loop (FFL) can act to create sign-sensitive delays or as a pulser [221] and [222]. Oscillatory behavior and its mathematical analysis are another domain of interest for systems-level biologists. Focus is given to not only the composition and description of the various submodules of an oscillator but also its emergent behavior, characterized by its metrics such as its robustness and periodicity

Foundations and Emerging Paradigms for Computing in Living Cells Kevin C. Ma, Samuel D. Perli, Timothy K. Lu doi:10.1016/j.jmb.2016.02.018 Journal of Molecular Biology Volume 428, Issue 5, Part B, Pages 893–915 Engineering Tools and Prospects in Synthetic Biology

Dionisio

Models incorporating circuit architecture and exploring alternate topologies often lead to novel insights into the robustness of natural biological networks [...]. Synthetic circuits can offer a means to test these models. In comparison to the synthetic version, the natural system exhibited greater variability in competence duration times, thought to be advantageous in an unpredictable environmental context [...] A better understanding of the effects of positive and negative feedback topologies can then, in turn, allows bioengineers to exert greater degrees of control over the shape of circuit transfer functions.

Foundations and Emerging Paradigms for Computing in Living Cells Kevin C. Ma, Samuel D. Perli, Timothy K. Lu doi:10.1016/j.jmb.2016.02.018 Journal of Molecular Biology Volume 428, Issue 5, Part B, Pages 893–915 Engineering Tools and Prospects in Synthetic Biology

Dionisio

The relationship between systems biology and synthetic biology has often been described as synergistic: insights from natural networks provide parts and modules for synthetic biologists and synthetic circuits, in turn, are built to rigorously test our models of natural systems. One area where this complementarity is most evident is in the investigation of biological networks, where the “forward-engineering” perspective of synthetic biologists has been both inspired by and a contributor to studies of natural motifs.

Foundations and Emerging Paradigms for Computing in Living Cells Kevin C. Ma, Samuel D. Perli, Timothy K. Lu doi:10.1016/j.jmb.2016.02.018 Journal of Molecular Biology Volume 428, Issue 5, Part B, Pages 893–915 Engineering Tools and Prospects in Synthetic Biology

Dionisio

Genetic circuits, composed of complex networks of interacting molecular machines, enable living systems to sense their dynamic environments, perform computation on the inputs, and formulate appropriate outputs. Biological systems operate in dynamic environmental contexts where they sense and respond to various forms of stimuli. Systems found in nature sometimes exhibit a surprising degree of modularity [...]

Foundations and Emerging Paradigms for Computing in Living Cells Kevin C. Ma, Samuel D. Perli, Timothy K. Lu doi:10.1016/j.jmb.2016.02.018 Journal of Molecular Biology Volume 428, Issue 5, Part B, Pages 893–915 Engineering Tools and Prospects in Synthetic Biology

Dionisio

[...] while the many successes of control design in synthetic biology show great promise for complementing and leveraging on-going efforts of parts characterization, discovery/invention and tuning, many unique challenges need to be overcome, which are likely to require new methods and theories.

Control theory meets synthetic biology. Del Vecchio D1, Dy AJ2, Qian Y3 J R Soc Interface. 13(120). pii: 20160380. doi: 10.1098/rsif.2016.0380

Dionisio

While a simple PI controller may be unsuitable in this case, an advanced model-based controller, such as MPC, combined with estimators may be more promising. However, this requires a trustworthy model of the cellular processes to be controlled, which are typically subject to substantial noise and uncertainty. More research is required to understand how to overcome these challenges.

Control theory meets synthetic biology. Del Vecchio D1, Dy AJ2, Qian Y3 J R Soc Interface. 13(120). pii: 20160380. doi: 10.1098/rsif.2016.0380

Dionisio

Further experimental and theoretical studies are required to determine the performance and trade-offs of these types of integral controllers and how the issue of dilution may be overcome. [...] identifying the structures of signalling systems that qualify as insulation devices still requires more research. Additional theoretical and experimental research is required to understand the robustness, stability and performance of these systems.

Control theory meets synthetic biology. Del Vecchio D1, Dy AJ2, Qian Y3 J R Soc Interface. 13(120). pii: 20160380. doi: 10.1098/rsif.2016.0380

Dionisio

The question of how repression of Nanog in TE is achieved mechanistically by the BAF155-BRG1-containing complex remains open. Although we know several of the key players that are involved in the establishment of pluripotent and extra-embryonic fates, there is still little information about how these mechanisms are coordinated in vivo. The challenge for the future will be to determine the precise molecular mechanisms that direct the differences in epigenetic programming in individual cells as the embryo progresses through its normal development.

The BAF chromatin remodelling complex is an epigenetic regulator of lineage specification in the early mouse embryo Maryna Panamarova,1,2 Andy Cox,1,2 Krzysztof B. Wicher,1,2 Richard Butler,1 Natalia Bulgakova,1,2,3 Shin Jeon,4 Barry Rosen,5 Rho H. Seong,4 William Skarnes,5 Gerald Crabtree,6 and Magdalena Zernicka-Goetz1 Development. 143(8): 1271–1283. doi: 10.1242/dev.131961

Dionisio

Finding steady states is one of the key problems in the analysis of Boolean network models of biological processes. [...] the hybrid approach will give us a better chance to tackle challenges in identifying steady states, which is still unsolved in general. Another direction of our future work is to extend our method to determine all attractors including cyclic attractors.

An Efficient Steady-State Analysis Method for Large Boolean Networks with High Maximum Node Connectivity Changki Hong,1 Jeewon Hwang,1 Kwang-Hyun Cho,2 and Insik Shin1,* PLoS One. 10(12): e0145734. doi: 10.1371/journal.pone.0145734

Work in progress... stay tuned. :) Complex complexity. Dionisio

Modeling of biological systems as a network of interacting components has received increasing attention in various areas, such as computational and systems biology since it allows to analyze biological phenomena systematically at various scales including molecular and cellular levels Boolean networks (BNs) have been widely used among various network models because BNs are relatively simple and efficient to model large networks.

An Efficient Steady-State Analysis Method for Large Boolean Networks with High Maximum Node Connectivity Changki Hong,1 Jeewon Hwang,1 Kwang-Hyun Cho,2 and Insik Shin1,* PLoS One. 10(12): e0145734. doi: 10.1371/journal.pone.0145734

Dionisio

[...] insights into intercalation will provide new understanding of related processes [...] [...] deeper understanding of how intercalation programmes are activated will be needed to fully realise their potential in treating human patients. As future work clarifies the detailed mechanisms underlying examples of radial and mediolateral intercalation, an even deeper appreciation of these fundamental cellular behaviours will emerge.

Cell Intercalation from top to bottom Elise Walck-Shannon1 and Jeff Hardin Nat Rev Mol Cell Biol. 15(1): 34–48. doi: 10.1038/nrm3723

Dionisio

It will be interesting to determine whether redundant mechanisms work alongside PCP signalling in these last examples, or whether other novel mechanisms control planar polarity in these contexts. It will be interesting to determine what advantages are afforded by specific mechanisms of mediolateral intercalation. Another key question is how intercalation programmes differ from related events, such as collective migration, that seem to predominate in certain elongating tissues during development. To what extent these two behaviours are part of a large meta-programme of ‘social migration’ remains to be clarified.

Cell Intercalation from top to bottom Elise Walck-Shannon1 and Jeff Hardin Nat Rev Mol Cell Biol. 15(1): 34–48. doi: 10.1038/nrm3723

Dionisio

Developmental biologists have been fascinated by how an embryo is able to generate its shape—through morphogenesis—for centuries. Successful development requires both proper fate specification and proper movements of cells, two processes that are often intricately interdependent. Cell intercalation is one of these movements, and crucially depends on highly directed exchanges between neighbouring cells, without a change in overall cell number. This can occur early in development, when the germ layers are organized during gastrulation, or later during organogenesis if a particular tissue requires an extended morphology [...]

Cell Intercalation from top to bottom Elise Walck-Shannon1 and Jeff Hardin Nat Rev Mol Cell Biol. 15(1): 34–48. doi: 10.1038/nrm3723

Dionisio

Animal development requires a carefully orchestrated cascade of cell fate specification events and cellular movements. A surprisingly small number of choreographed cellular behaviours are used repeatedly to shape the animal body plan.

Cell Intercalation from top to bottom Elise Walck-Shannon1 and Jeff Hardin Nat Rev Mol Cell Biol. 15(1): 34–48. doi: 10.1038/nrm3723

Dionisio

The D-wing and P-abd thus provide two additional signaling paradigms that can, going forward, be used for discovery of additional cell biological and signaling mechanisms important for PCP.

Prickle isoforms control the direction of tissue polarity by microtubule independent and dependent mechanisms Katherine A. Sharp1,2 and Jeffrey D. Axelrod1 Biol Open. 5(3): 229–236. doi: 10.1242/bio.016162

Dionisio

[...] a more definitive understanding of how Pk and Sple are altering tissue polarity in the D-wing will require a better understanding of the mechanism of any distal or margin derived directional signal. The mechanisms through which Pk and Sple not only control microtubule polarity but also interpret signals from this unknown cryptic source are not clear. Whether analogous binding occurs between Pk and Ft is unknown.

Prickle isoforms control the direction of tissue polarity by microtubule independent and dependent mechanisms Katherine A. Sharp1,2 and Jeffrey D. Axelrod1 Biol Open. 5(3): 229–236. doi: 10.1242/bio.016162

Dionisio

Planar cell polarity (PCP) is the alignment of cells within the plane of an epithelium orthogonal to the apicobasal axis. PCP signaling provides cells with spatial information that they use to determine the direction in which polarized structures grow or to direct cell migration during tissue remodeling

Prickle isoforms control the direction of tissue polarity by microtubule independent and dependent mechanisms Katherine A. Sharp1,2 and Jeffrey D. Axelrod1 Biol Open. 5(3): 229–236. doi: 10.1242/bio.016162

Dionisio

Planar cell polarity signaling directs the polarization of cells within the plane of many epithelia. The direction of polarity in the D-wing is therefore likely determined by a novel mechanism independent of microtubule polarity. In the P-abd, Prickle and Spiny-legs interpret at least two directional cues through a microtubule-polarity-independent mechanism.

Prickle isoforms control the direction of tissue polarity by microtubule independent and dependent mechanisms Katherine A. Sharp1,2 and Jeffrey D. Axelrod1 Biol Open. 5(3): 229–236. doi: 10.1242/bio.016162

Dionisio

The elegance of animal body plans derives from an intimate connection between function and form, which during organ formation is linked to patterning and growth. Yet, how patterning and growth are coordinated still remains largely a mystery.

Coordination of patterning and growth by the morphogen DPP. Restrepo S1, Zartman JJ2, Basler K3. Curr Biol. 24(6):R245-55. doi: 10.1016/j.cub.2014.01.055.

Did anybody say 'mystery'? :) The authors of this paper should have consulted with professor L.M. of the U. Of Toronto in Canada, who claimed in this site to know exactly how morphogen gradients are formed. :) Dionisio

[...] the combination of novel imaging approaches, advanced in vivo manipulations that go beyond simple loss of function genetics, and reductionist systems to isolate and reconstruct processes will be instrumental. Furthermore, the inclusion of more complex behaviors in modeling studies will help shed light into the ability of cells to decipher intricate in vivo environments.

NEW PARADIGMS IN THE ESTABLISHMENT AND MAINTENANCE OF GRADIENTS DURING DIRECTED CELL MIGRATION Ritankar Majumdar,1 Michael Sixt,2 and Carole A. Parent1 Curr Opin Cell Biol. 0: 33–40. doi: 10.1016/j.ceb.2014.05.010

Dionisio

[...] the spatial and temporal dynamics of gradient formation, propagation and interpretation remain largely unknown in physiological contexts.

NEW PARADIGMS IN THE ESTABLISHMENT AND MAINTENANCE OF GRADIENTS DURING DIRECTED CELL MIGRATION Ritankar Majumdar,1 Michael Sixt,2 and Carole A. Parent1 Curr Opin Cell Biol. 0: 33–40. doi: 10.1016/j.ceb.2014.05.010

Dionisio

As the direct detection of the guidance cue itself, especially if it is in a soluble phase, is usually difficult, the molecular complexity hidden behind the observed process is often underestimated. In many cases a whole set of amplification loops might be nested into a seemingly simple attractant system.

NEW PARADIGMS IN THE ESTABLISHMENT AND MAINTENANCE OF GRADIENTS DURING DIRECTED CELL MIGRATION Ritankar Majumdar,1 Michael Sixt,2 and Carole A. Parent1 Curr Opin Cell Biol. 0: 33–40. doi: 10.1016/j.ceb.2014.05.010

Dionisio

In vitro data have demonstrated that cells can migrate directionally in response to chemical or physical cues and modeling studies have provided important insight into the minimal requirements needed to mediate directed cell migration. But what cells actually do in complex living organisms is far less clear.

NEW PARADIGMS IN THE ESTABLISHMENT AND MAINTENANCE OF GRADIENTS DURING DIRECTED CELL MIGRATION Ritankar Majumdar,1 Michael Sixt,2 and Carole A. Parent1 Curr Opin Cell Biol. 0: 33–40. doi: 10.1016/j.ceb.2014.05.010

Dionisio

How such gradients present and act in the context of an organism is far less clear.

NEW PARADIGMS IN THE ESTABLISHMENT AND MAINTENANCE OF GRADIENTS DURING DIRECTED CELL MIGRATION Ritankar Majumdar,1 Michael Sixt,2 and Carole A. Parent1 Curr Opin Cell Biol. 0: 33–40. doi: 10.1016/j.ceb.2014.05.010

Dionisio

Initial signaling events triggered by the T cell receptor (TCR) after the specific engagement of antigenic peptide–MHC complexes (pMHC) occur in dynamic TCR microclusters organized at the periphery of the immunological synapse (IS). In order to formally demonstrate the existence of hysteresis, we will need models that enable us to reach maximal stimulation of primary T cells with physiological antigenic peptides and then be able to go down in the stimulation before re-testing the activation state of the signaling module (31). Acute perturbation of signaling components and the cell machinery (such as cytoskeleton and endosomal compartment) should inform about the key players and the dynamics controlling the ultrasensitive response. In this context, dynamic regulation of cofilin by slingshots is under further investigation in our group.

Ultrasensitivity in the Cofilin Signaling Module: A Mechanism for Tuning T Cell Responses Rocio Ramirez-Munoz,1 Patricia Castro-Sánchez,1 and Pedro Roda-Navarro Front Immunol. 7: 59. doi: 10.3389/fimmu.2016.00059

Dionisio

It is possible that the sustained, clustering-dependent increase in SH2 binding might be involved in regulating the duration of ERK activation. Another interesting possibility is that clustering-dependent recruitment is a mechanism to diversify the response kinetics upon receptor stimulation. [...] additional experiments will be required to determine the conditions where clustering will have significant effects on rates of downstream signaling, and to develop a robust theoretical framework to describe this effect. In the process of reconciling seemingly discordant results obtained by interrogating the same system with multiple methodologies, one can gain novel insights into the system not possible from studies dependent on a single methodology.

Time-resolved multimodal analysis of Src Homology 2 (SH2) domain binding in signaling by receptor tyrosine kinases Joshua A Jadwin,1,† Dongmyung Oh,2,† Timothy G Curran,3,4 Mari Ogiue-Ikeda,1 Lin Jia,1 Forest M White,3,4 Kazuya Machida,1 Ji Yu,2 and Bruce J Mayer eLife. 2016; 5: e11835. doi: 10.7554/eLife.11835

Dionisio

[...] quantitative modeling of the observed kinetics is not straightforward. [...] other unidentified factors may be at play here. Fully resolving this question clearly requires more elaborate quantitative models. Signal outputs are subject to multiple positive and negative feedback loops [...]

Time-resolved multimodal analysis of Src Homology 2 (SH2) domain binding in signaling by receptor tyrosine kinases Joshua A Jadwin,1,† Dongmyung Oh,2,† Timothy G Curran,3,4 Mari Ogiue-Ikeda,1 Lin Jia,1 Forest M White,3,4 Kazuya Machida,1 Ji Yu,2 and Bruce J Mayer eLife. 2016; 5: e11835. doi: 10.7554/eLife.11835

Dionisio

[...] spatio-temporal changes in phosphosite availability in response to signals, and their impact on recruitment of SH2-containing proteins in vivo, are not well understood. Individual cells in a multicellular organism must receive signals from the environment and from other cells, and adjust their behavior accordingly. Often these signals are received by receptor proteins, which span the cell membrane and thus provide a way for signals from outside the cell to cause changes inside the cell. [...] the apparent delay in total membrane binding observed in vivo is the result of changes in the kinetics as a result of clustering, and not an issue of binding site availability alone.

Time-resolved multimodal analysis of Src Homology 2 (SH2) domain binding in signaling by receptor tyrosine kinases Joshua A Jadwin,1,† Dongmyung Oh,2,† Timothy G Curran,3,4 Mari Ogiue-Ikeda,1 Lin Jia,1 Forest M White,3,4 Kazuya Machida,1 Ji Yu,2 and Bruce J Mayer eLife. 2016; 5: e11835. doi: 10.7554/eLife.11835

Dionisio

Switch-like, ultrasensitive responses– responses that resemble those of cooperative enzymes but are not necessarily generated by cooperativity–are widespread in signal transduction. [...] mechanisms for generating ultrasensitivity: zero-order ultrasensitivity; multistep ultrasensitivity; inhibitor ultrasensitivity; and positive feedback (or double negative feedback) loops. [...] how ultrasensitive components can be important for the functioning of more complex signaling circuits. Ultrasensitivity can allow the effective transmission of signals down a signaling cascade, can contribute to the generation of bistability by positive feedback, and can promote the production of biochemical oscillations in negative feedback loops.

Ultrasensitivity part III: cascades, bistable switches, and oscillators James E. Ferrell, Jr and Sang Hoon Ha Trends Biochem Sci. 39(12): 612–618. doi: 10.1016/j.tibs.2014.10.002

Dionisio

The term ‘sensitivity’ was used in the literature with ambiguity—it refers to both switch-likeness and timing of a response. The ambiguity is exacerbated by the fact that a regulation, whether feedback or not, can affect both aspects of sensitivity. The coupling also constitutes daunting difficulties in regulating complex biological processes such as organogenesis and cell cycle progression. From a design perspective, decoupling is certainly desired to make the regulation manageable.

Tunable ultrasensitivity: functional decoupling and biological insights Guanyu Wanga,1 and Mengshi Zhang1 Sci Rep. 6: 20345. doi: 10.1038/srep20345

Dionisio

Sensitivity has become a basic concept in biology, but much less is known about its tuning, probably because allosteric cooperativity, the best known mechanism of sensitivity, is determined by rigid conformations of interacting molecules and is thus difficult to tune. Sensitivity is important in biology—a cell often needs to make clear-cut decisions such as whether to commit apoptosis or which cell type to become.

Tunable ultrasensitivity: functional decoupling and biological insights Guanyu Wanga,1 and Mengshi Zhang1 Sci Rep. 6: 20345. doi: 10.1038/srep20345

Dionisio

BMP4 signalling is a key factor involved during differentiation of ventral mesoderm and its further specification into haematopoietic cells. [...] the interplay of Shh and BMP pathways is broadly involved in development. [...] the feed-forward loop Shh?Noggin/Noggin?Shh is also involved in HSC development in vivo. [...] the polarized secreted factors form complex fields of gradients in vivo, which define an effector zone for optimal HSC development in the dorsal aorta and lead to the ventrally shifted appearance of dHSCs. [...] it is possible that spatial segregation of co-operating and spatial overlap of antagonizing factors may also be important for adjustment of HSC development in vivo. How exactly HSC maturation dynamics depend on overlapping concentrations of factors requires further analysis. [...] it is currently unclear whether any factors become expressed in a polarized manner within the reaggregates and as such, whether polarization is also a pre-requisite for HSC maturation. The distinction between these two scenarios will require further investigation. [...] HSC development in the embryo involves stage-dependent interactions between dorsal, ventral and lateral domains of the AGM region, mediated at least partly by the interplay of SCF, Shh, BMP4 and Noggin. Further detailed analysis will be required to better understand the complexity of the AGM signalling landscape in which HSC development takes place.

Inductive interactions mediated by interplay of asymmetric signalling underlie development of adult haematopoietic stem cells Céline Souilhol,1 Christèle Gonneau,1 Javier G. Lendinez,1 Antoniana Batsivari,1 Stanislav Rybtsov,1 Heather Wilson,1 Lucia Morgado-Palacin,1 David Hills,1 Samir Taoudi,2,3,4 Jennifer Antonchuk,5 Suling Zhao,1 and Alexander Medvinsky Nat Commun. 7: 10784. doi: 10.1038/ncomms10784

Dionisio

The blood–brain barrier (BBB) is a biological firewall that carefully regulates the cerebral microenvironment by acting as a physical, metabolic and transport barrier. The transport mechanisms utilised by L-arginine are known but they are not fully understood for ADMA, particularly at the BBB. Which CAT isoform is responsible remains undetermined [...] [...] further research is needed to further confirm the membrane localization of CAT-1 in these cells. [...] ADMA may use additional transport mechanisms to enter the endothelial cell. both L-arginine and ADMA appear to use system y+ influx mechanisms to enter hCMEC/D3 BBB cells [...]

The transporter and permeability interactions of asymmetric dimethylarginine (ADMA) and L-arginine with the human blood–brain barrier in vitro Christopher P. Watsona, Evangelos Pazarentzosb, Mehmet Fidanboylua, Beatriz Padillaa, Rachel Browna, Sarah A. Thomasa, doi:10.1016/j.brainres.2016.07.026 Brain Research Volume 1648, Part A, Pages 232–242

Dionisio

The central nervous system (CNS) is a highly organised structure. Many signalling systems work in concert to ensure that neural stem cells are appropriately directed to generate progenitor cells, which in turn mature into functional cell types including projection neurons, interneurons, astrocytes, and oligodendrocytes.

Low Density Lipoprotein Receptor Related Proteins as Regulators of Neural Stem and Progenitor Cell Function Loic Auderset, 1 Lila M. Landowski, 1 , 2 Lisa Foa, 2 and Kaylene M. Young 1 Stem Cells Int. 2108495. doi: 10.1155/2016/2108495

Dionisio

LRP1 is expressed in the brain, yet it is unclear which central nervous system cell types express LRP1 during development and in adulthood. CNS glia are highly susceptible to regulation by LRP1 signalling, a possibility that has been largely unexplored to date. [...] the role of LRP1 in OPCs has not yet been investigated. [...] further investigation into the function of LRP1 in this cell type would be warranted. [...] how LRP1 differentially regulates these functions is far from understood.

Low Density Lipoprotein-Receptor Related Protein 1 Is Differentially Expressed by Neuronal and Glial Populations in the Developing and Mature Mouse Central Nervous System Loic Auderset, Carlie L. Cullen, and Kaylene M. Young* Elizabeth J Coulson, Editor PLoS One. 11(6): e0155878. doi: 10.1371/journal.pone.0155878

Dionisio

#1833 addendum For example kidney? All that bluffing is just nonsense pseudoscience hogwash. Provide valid step-by-step examples. Dionisio

This mode of directional drive more evidently manifests the might of nature’s arrow toward a thermodynamic equilibrium. Such self-propelling spatial expansion is much simpler and robust compared to the Turing mechanism, which depends on an excitable (albeit also uniform) medium to create patterns that are (transiently) far away from thermodynamic equilibrium. Whether it is also involved in pattern formation during development or [...]

Where to Go: Breaking the Symmetry in Cell Motility Sui Huang PLoS Biol.; 14(5): e1002463. doi: 10.1371/journal.pbio.1002463

This seems like a big "where's the beef?" type of bluff. Can't they show a theoretical hypothetical description of their idea applied to specific organogenesis morphogenesis cases? Dionisio

Cell migration in the “correct” direction is pivotal for many biological processes. Although most work is devoted to its molecular mechanisms, the cell’s preference for one direction over others, thus overcoming intrinsic random motility, epitomizes a profound principle that underlies all complex systems [...]

Where to Go: Breaking the Symmetry in Cell Motility Sui Huang PLoS Biol.; 14(5): e1002463. doi: 10.1371/journal.pbio.1002463

Dionisio

How opposing gradients cross-talk and are integrated into networks is poorly understood. [...] our comparison of patterning in the Drosophila blastoderm and the vertebrate neural tube suggests a unified framework for morphogen-mediated pattern formation and establishes a research agenda that will likely take us through further revisions of this fascinating problem.

Morphogen rules: design principles of gradient-mediated embryo patterning James Briscoe, Stephen Small Development 142: 3996-4009; doi: 10.1242/dev.129452

Dionisio

[...] the mechanisms identified in the gap gene and neural tube networks represent general principles for morphogen interpretation. Despite much progress, many questions remain. Elucidating the components and operation of the transcriptional networks continues and, for many tissues, the relative importance of the spatial or temporal component of gradients needs to be determined.

Morphogen rules: design principles of gradient-mediated embryo patterning James Briscoe, Stephen Small Development 142: 3996-4009; doi: 10.1242/dev.129452

Dionisio

[...] positional information is not a static measure but a process that arises from the dynamics of interactions within the network. [...] there is no mechanistic difference between spatial and temporal patterning [...] [...] boundary precision and size scaling are built into the system. The system is robust to fluctuations in the morphogen signal and provides an effective memory when morphogen signal declines, which offers an explanation for the striking ‘canalization’ of pattern formation in many developing tissues.

Morphogen rules: design principles of gradient-mediated embryo patterning James Briscoe, Stephen Small Development 142: 3996-4009; doi: 10.1242/dev.129452

Dionisio

[...] [ideas] have evolved over the years to accommodate changing facts and fashions [...]

Morphogen rules: design principles of gradient-mediated embryo patterning James Briscoe, Stephen Small Development 142: 3996-4009; doi: 10.1242/dev.129452

Yes, Darwinist ideas seem to evolve in order to account for new discoveries coming at increasing pace from research. But perhaps they have overstretched their capacity to adjust? Maybe that's why some scientists are looking for other ways to explain things? Dionisio

The Drosophila blastoderm and the vertebrate neural tube are archetypal examples of morphogen-patterned tissues that create precise spatial patterns of different cell types. In both tissues, pattern formation is dependent on molecular gradients that emanate from opposite poles. Despite distinct evolutionary origins and differences in time scales, cell biology and molecular players, both tissues exhibit striking similarities in the regulatory systems that establish gene expression patterns that foreshadow the arrangement of cell types. First, signaling gradients establish initial conditions that polarize the tissue, but there is no strict correspondence between specific morphogen thresholds and boundary positions. Second, gradients initiate transcriptional networks that integrate broadly distributed activators and localized repressors to generate patterns of gene expression. Third, the correct positioning of boundaries depends on the temporal and spatial dynamics of the transcriptional networks. These similarities reveal design principles that are likely to be broadly applicable to morphogen-patterned tissues

Morphogen rules: design principles of gradient-mediated embryo patterning James Briscoe, Stephen Small Development 142: 3996-4009; doi: 10.1242/dev.129452

Did anybody say 'design principles'? :) Emphasis mine. Dionisio

Further detailed investigations on the possible role of melatonin in in vitro plant propagation, propagation through cutting, grafting and vascular reunion, flower development, enhancing male to female ratio in vegetables (cucurbits), improvement of fruit setting, fruit development, parthenocarpy, fruit drop (a major issue in commercially important fruit crops like citrus, mango, guava, etc.), role in breaking seed and tuber dormancy, fruit quality (size, color, nutraceutical value), seed development, fruit ripening and senescence (to improve post-harvest life/shelf life of fruits, vegetables, and cut flowers) needs clarification.

Melatonin: Current Status and Future Perspectives in Plant Science. Nawaz MA1, Huang Y2, Bie Z2, Ahmed W3, Reiter RJ4, Niu M2, Hameed S2. Front Plant Sci. ;6:1230. doi: 10.3389/fpls.2015.01230.

Dionisio

Melatonin (N-acetyl-5-methoxytryptamine) is a ubiquitous molecule with pleiotropic actions in different organisms. It performs many important functions in human, animals, and plants; these range from regulating circadian rhythms in animals to controlling senescence in plants. The mechanisms of action of melatonin is not clearly understood in plants [...] [...] this aspect is a missing link in understanding the biological functions of melatonin and it requires the attention of plant scientists. Although melatonin is ubiquitously distributed in plants, it is not known whether all plant organs synthesize this indoleamine. Its mechanism of transport throughout the plant also must be explored.

Melatonin: Current Status and Future Perspectives in Plant Science. Nawaz MA1, Huang Y2, Bie Z2, Ahmed W3, Reiter RJ4, Niu M2, Hameed S2. Front Plant Sci. ;6:1230. doi: 10.3389/fpls.2015.01230.

Dionisio

MEL and 5HT are indoleamines first identified as neurotransmitter signaling molecules in mammals but are ubiquitous across all forms of life. [...] the analyses of MEL and 5HT induced and modulated responses indicate that it is more likely that 5HT and MEL function through modulation of calcium and ROS signaling cascades, modulation of gene expression and interaction with other PGRs mediated by specific receptors. [...] there are many questions still to be answered with regards to the roles MEL and 5HT in plant growth and development and the diverse mechanisms by which they are accomplished.

A new balancing act: The many roles of melatonin and serotonin in plant growth and development Lauren A E Erland,1 Susan J Murch,2 Russel J Reiter,3 and Praveen K Saxena Plant Signal Behav.; 10(11): e1096469. doi: 10.1080/15592324.2015.1096469

Dionisio

Melatonin and serotonin are indoleamines first identified as neurotransmitters in vertebrates; they have now been found to be ubiquitously present across all forms of life. Both melatonin and serotonin were discovered in plants several years after their discovery in mammals, but their presence has now been confirmed in almost all plant families. The mechanisms of action of melatonin and serotonin are still poorly defined.

A new balancing act: The many roles of melatonin and serotonin in plant growth and development Lauren A E Erland,1 Susan J Murch,2 Russel J Reiter,3 and Praveen K Saxena Plant Signal Behav.; 10(11): e1096469. doi: 10.1080/15592324.2015.1096469

Dionisio

We expect that the integration of the information from all these approaches will provide us with a complex regulatory map that not only shows the details of gene functions and interactions in the floral boundaries, but also directs us to further explore the novel molecular mechanisms underlining the boundary formation in flower development.

Molecular Mechanisms of Floral Boundary Formation in Arabidopsis. Yu H1,2, Huang T3. Int J Mol Sci. ;17(3):317. doi: 10.3390/ijms17030317.

Dionisio

[...] a number of the floral boundary regulators crosstalk with phytohormone pathways [...] Application of these molecular tools in boundary-specific assays will help elucidate the spatial and temporal regulation of phytohormone signaling in the boundary field and better understand how hormonal pathways and other boundary regulators are coordinated in the formation of floral boundaries.

Molecular Mechanisms of Floral Boundary Formation in Arabidopsis. Yu H1,2, Huang T3. Int J Mol Sci. ;17(3):317. doi: 10.3390/ijms17030317.

Dionisio

How these different types of regulators interact in floral boundary formation is one of the important questions that remain to be well understood. [...] common genes or pathways likely play pivotal roles in the floral organ boundaries and the relationships of these regulators can form a comprehensive network that explains the molecular mechanism of floral organ boundary formation.

Molecular Mechanisms of Floral Boundary Formation in Arabidopsis. Yu H1,2, Huang T3. Int J Mol Sci. ;17(3):317. doi: 10.3390/ijms17030317.

Dionisio

Boundary formation is a crucial developmental process in plant organogenesis. Boundaries separate cells with distinct identities and act as organizing centers to control the development of adjacent organs. Organ boundaries are groups of specialized cells with restricted growth that are crucial for the development of plants and animals. Boundaries delineate identities by separating distinct functional domains, such as the meristem and organ primordia or adjacent organs, and also function as organizing centers for the downstream signaling events to pattern the organs at later stages [...]

Molecular Mechanisms of Floral Boundary Formation in Arabidopsis. Yu H1,2, Huang T3. Int J Mol Sci. ;17(3):317. doi: 10.3390/ijms17030317.

Dionisio

Thidiazuron (N-phenyl-N'-1,2,3-thiadiazol-5-ylurea; TDZ) is an artificial plant growth regulator that is widely used in plant tissue culture. Protocorm-like bodies (PLBs) induced by TDZ serve as an efficient and rapid in vitro regeneration system in Rosa species. Despite this, the mechanism of PLB induction remains relatively unclear.

Thidiazuron Triggers Morphogenesis in Rosa canina L. Protocorm-Like Bodies by Changing Incipient Cell Fate. Kou Y1, Yuan C2, Zhao Q1, Liu G1, Nie J1, Ma Z1, Cheng C1, Teixeira da Silva JA3, Zhao L1. Front Plant Sci. ;7:557. doi: 10.3389/fpls.2016.00557.

Another case where the effects of chemicals artificially administered to plants are not well understood? Dionisio

Addressing these questions will bring us closer to understanding how polar auxin transport is both a robust system in some contexts but highly dynamic and versatile in others. Integrating these different regulatory modules into one unifying model will also be a challenge for the coming years that will certainly require multidisciplinary approaches ranging from structural biology to quantitative biochemistry and cell imaging as well as mathematical modeling.

Regulation of polar auxin transport by protein and lipid kinases. Armengot L1, Marquès-Bueno MM1, Jaillais Y2. J Exp Bot. 67(14):4015-37. doi: 10.1093/jxb/erw216.

Dionisio

Among the outstanding questions that remain unanswered are: How the differential phosphorylations of PIN proteins act either on their polarity or activity? How auxin and GOLVEN peptides are perceived to regulate PIN intracellular trafficking? What are the molecular steps, independent of transcription, between cytokinin perception and PIN polarity regulation? What are the proteins regulated by phosphoinositides that control PIN trafficking and polarity? How other environmental (e.g. halotropism (Galvan-Ampudia et al., 2013)) and developmental (e.g. GA signaling (Lofke et al., 2013; Willige et al., 2011)) regulatory cues coalesce in the regulation of PIN trafficking and activity?

Regulation of polar auxin transport by protein and lipid kinases. Armengot L1, Marquès-Bueno MM1, Jaillais Y2. J Exp Bot. 67(14):4015-37. doi: 10.1093/jxb/erw216.

Dionisio

The directional transport of auxin, known as polar auxin transport, allows asymmetric distribution of this hormone in different cells and tissues. This system creates local auxin maxima, minima and gradients that are instrumental in both organ initiation and shape determination. [...] it is clear that much still need to be addressed to understand each pathway [...]

Regulation of polar auxin transport by protein and lipid kinases. Armengot L1, Marquès-Bueno MM1, Jaillais Y2. J Exp Bot. 67(14):4015-37. doi: 10.1093/jxb/erw216.

Dionisio

[...] these proposals will likewise have to be re-evaluated in light of our findings. [...] this only pushes the patterning question back a level: how, then, are the patterns in perception or transport established? Another outstanding question is how low cytokinin signalling levels are maintained in the metaxylem position. [...] we cannot describe the factors which lead to one pole being favoured over the other in any given instance [...] A full understanding of this phenomenon is likely to require incorporating existing longitudinal and transverse auxin transport models into a three-dimensional model of the root.

Parsimonious Model of Vascular Patterning Links Transverse Hormone Fluxes to Lateral Root Initiation: Auxin Leads the Way, while Cytokinin Levels Out. el-Showk S1, Help-Rinta-Rahko H2, Blomster T2, Siligato R2, Marée AF3, Mähönen AP2, Grieneisen VA PLoS Comput Biol. 11(10):e1004450. doi: 10.1371/journal.pcbi.1004450.

Dionisio

This finding is reinforced by spatial-temporal considerations of hormone diffusion within the context of this system: in order to be informative on the transverse scale of the Arabidopsis stele (around 50?m), a gradient would need to have a characteristic length of roughly the same order [...] [...] our analysis raises questions and challenges regarding the mechanics and dynamics of cytokinin transport which must be further addressed by experiments and more modelling alike. It is therefore important when constructing verbal or conceptual models to consider constraints which are introduced by conflicting requirements at different spatial scales. Quantitative considerations can lead to different qualitative mechanisms for how patterning occurs.

Parsimonious Model of Vascular Patterning Links Transverse Hormone Fluxes to Lateral Root Initiation: Auxin Leads the Way, while Cytokinin Levels Out. el-Showk S1, Help-Rinta-Rahko H2, Blomster T2, Siligato R2, Marée AF3, Mähönen AP2, Grieneisen VA PLoS Comput Biol. 11(10):e1004450. doi: 10.1371/journal.pcbi.1004450.

Dionisio

[...] contrary phenotypes are observed in the root and leaf, suggesting that the picture may be more complex. [...] specific LAX genes may act in concert with AUX1 in different developmental contexts, amplifying and buffering the auxin pattern generated by the PIN transporters. [...] demonstrating the implausibility of an informative cytokinin gradient forming on this scale via diffusive processes (whether or not combined with apolar transport)[...]

Parsimonious Model of Vascular Patterning Links Transverse Hormone Fluxes to Lateral Root Initiation: Auxin Leads the Way, while Cytokinin Levels Out. el-Showk S1, Help-Rinta-Rahko H2, Blomster T2, Siligato R2, Marée AF3, Mähönen AP2, Grieneisen VA PLoS Comput Biol. 11(10):e1004450. doi: 10.1371/journal.pcbi.1004450.

Dionisio

[...] emerging methodologies will provide new mechanistic insights into how the advance, retraction, and turning of the growth cone vehicle can be orchestrated during axon guidance, and how these behaviors are organized downstream of extracellular cues. [...] +TIPs have emerged as molecular tour guides that can inform and direct these axonal behaviors, by modulating their interactions with both actin and MT cytoskeletons in response to signaling cascades. It is evident, then, that future works that expand the breadth and depth of +TIP identification, function, and regulation will be instrumental to our understanding of axon guidance behaviors.

TIPsy tour guides: how microtubule plus-end tracking proteins (+TIPs) facilitate axon guidance. Bearce EA1, Erdogan B1, Lowery LA1. Front Cell Neurosci. ;9:241. doi: 10.3389/fncel.2015.00241.

Dionisio

[...] we have described how numerous +TIPs are phosphorylated downstream of signaling molecules. However, it is clear that our current knowledge of these interactions is over-simplified. Determining how multiple signaling cascades and kinase activities can be integrated constructively to designate a +TIP’s localization and behavior may be considered an ultimate pursuit within the field.

TIPsy tour guides: how microtubule plus-end tracking proteins (+TIPs) facilitate axon guidance. Bearce EA1, Erdogan B1, Lowery LA1. Front Cell Neurosci. ;9:241. doi: 10.3389/fncel.2015.00241.

Dionisio

[...] kinesin-5 and kinesin-12 families have also shown commanding involvement in growth cone turning [...], though whether an EB interaction is involved in their localization in this context is not known. [...] CLIP-115 and CLIP-190 have been investigated in many shared examinations with CLIP-170 [...], but their individual roles in the growth cone are less well-clarified, and may emerge with time. As new +TIPs are frequently being established in a number of systems, it will be necessary to begin to not only consider their individual interactions in axon guidance, but also to examine their interplay with one another.

TIPsy tour guides: how microtubule plus-end tracking proteins (+TIPs) facilitate axon guidance. Bearce EA1, Erdogan B1, Lowery LA1. Front Cell Neurosci. ;9:241. doi: 10.3389/fncel.2015.00241.

Emphasis mine. Dionisio

The growth cone is able to correctly maneuver through a myriad of extracellular cues, leading its axon accurately through the developing nervous system, turning in response to attractive or repulsive stimuli, and halting when it has arrived at the correct destination. The mechanisms by which this responsive cytoskeletal machine is able to detect and then translate numerous guidance signals are largely unknown.

TIPsy tour guides: how microtubule plus-end tracking proteins (+TIPs) facilitate axon guidance. Bearce EA1, Erdogan B1, Lowery LA1. Front Cell Neurosci. ;9:241. doi: 10.3389/fncel.2015.00241.

Dionisio

The growth cone is a dynamic cytoskeletal vehicle, which drives the end of a developing axon. It serves to interpret and navigate through the complex landscape and guidance cues of the early nervous system. +TIPs accumulate at the dynamic ends of MTs, where they are well-positioned to encounter and respond to key signaling events downstream of guidance receptors, catalyzing immediate changes in microtubule stability and actin cross-talk, that facilitate both axonal outgrowth and turning events.

TIPsy tour guides: how microtubule plus-end tracking proteins (+TIPs) facilitate axon guidance. Bearce EA1, Erdogan B1, Lowery LA1. Front Cell Neurosci. ;9:241. doi: 10.3389/fncel.2015.00241.

Dionisio

The connectome can be envisioned as the “wiring of the CNS” but the “wires” are highly dynamics and plastic elements whose structure and functions are continuously modified by the network activity itself.

Morphogenetic and Histogenetic Roles of the Temporal-Spatial Organization of Cell Proliferation in the Vertebrate Corticogenesis as Revealed by Inter-specific Analyses of the Optic Tectum Cortex Development Melina Rapacioli,1 Verónica Palma,2 and Vladimir Flores Front Cell Neurosci. 10: 67. doi: 10.3389/fncel.2016.00067

Complex complexity. :) Dionisio

A fashionable idea that has generated a great expectation in the fields of the psychology, cognitive neurology, sociology and so on, is that the overall human behavior, including the consciousness with its emotional and moral components will be explained, in the not too distant future, in terms of the networking of the highest cortical areas and their corresponding subcortical centers.

Morphogenetic and Histogenetic Roles of the Temporal-Spatial Organization of Cell Proliferation in the Vertebrate Corticogenesis as Revealed by Inter-specific Analyses of the Optic Tectum Cortex Development Melina Rapacioli,1 Verónica Palma,2 and Vladimir Flores Front Cell Neurosci. 10: 67. doi: 10.3389/fncel.2016.00067

The peer-review publications should stand firmly against the consumption of any hallucinogenic drugs by the authors before their papers get published. :) BTW, is psychology a science? :) Dionisio

It is presumed that the modern neurosciences will accumulate enough information as to describe the human mind in terms of the function of interconnecting cortical and subcortical neuronal circuit networks. While this could be a long-range goal, a less ambitious objective could be the description of the behaviors of lower species in terms of defined patterns of activity of the above mentioned neuronal circuits.

Morphogenetic and Histogenetic Roles of the Temporal-Spatial Organization of Cell Proliferation in the Vertebrate Corticogenesis as Revealed by Inter-specific Analyses of the Optic Tectum Cortex Development Melina Rapacioli,1 Verónica Palma,2 and Vladimir Flores Front Cell Neurosci. 10: 67. doi: 10.3389/fncel.2016.00067

There yet? :) Dionisio

The central nervous system areas displaying the highest structural and functional complexity correspond to the so called cortices, i.e., concentric alternating neuronal and fibrous layers. Corticogenesis, i.e., the development of the cortical organization, depends on the temporal-spatial organization of several developmental events:

(a) the duration of the proliferative phase of the neuroepithelium, (b) the relative duration of symmetric (expansive) versus asymmetric (neuronogenic) sub phases, ? (c) the spatial organization of each kind of cell division, (e) the time of determination and cell cycle exit and (f) the time of onset of the post-mitotic neuronal migration and (g) the time of onset of the neuronal structural and functional differentiation.

The first five events depend on molecular mechanisms that perform a fine tuning of the proliferative activity. Changes in any of them significantly influence the cortical size or volume (tangential expansion and radial thickness), morphology, architecture and also impact on neuritogenesis and synaptogenesis affecting the cortical wiring.

Morphogenetic and Histogenetic Roles of the Temporal-Spatial Organization of Cell Proliferation in the Vertebrate Corticogenesis as Revealed by Inter-specific Analyses of the Optic Tectum Cortex Development Melina Rapacioli,1 Verónica Palma,2 and Vladimir Flores Front Cell Neurosci. 10: 67. doi: 10.3389/fncel.2016.00067

Is there (d) between (c) and (e)? :) Dionisio

Is there exchange and conversion from one complex to the next? For example, following CORVET recruitment to early endosomes, does the core remain and the other subunits are turned over while new ones recruited to build HOPS? Likewise, does GARP reach the recycling endosome and is converted there into EARP? Alternatively, individual complex assembly may occur on membranes according to demand. What can we make of the moonlighting functions of tether components? The action of Vps39 as a tether in organellar contact sites is very intriguing and it is conceivable that the cell reuses successful units in different contexts.

Membrane Tethering Complexes in the Endosomal System Anne Spang* Front Cell Dev Biol. 4: 35. doi: 10.3389/fcell.2016.00035

Dionisio

A lot of open questions remain; below are a few to consider. Do we know the identity of all tethers in the endosomal system? Likely not, In particular the function of the orphan CHEVI complex needs to be established and the missing interaction partners for both CHEVI and FERARI must be identified. Since it is likely that the individual subunits of the tethers are not forming very stable complexes in the cytoplasm, we may not be able to detect easily other complexes by biochemical means. Hence, we will also require help from genetics. The combination of both will be instrumental in elucidating the identity and function of additional tethers in the endosomal system and beyond.

Membrane Tethering Complexes in the Endosomal System Anne Spang* Front Cell Dev Biol. 4: 35. doi: 10.3389/fcell.2016.00035

Dionisio

[...] there are other tethering functions in the endosomal system as there are multiple pathways through which proteins can be delivered from endosomes to either the TGN or the plasma membrane. Furthermore, proteins that may be part of novel tethering complexes have been recently identified. Thus, it is likely that more tethering factors exist.

Membrane Tethering Complexes in the Endosomal System Anne Spang* Front Cell Dev Biol. 4: 35. doi: 10.3389/fcell.2016.00035

Dionisio

Here, we describe a new connexion between Nuf, an adaptor of Rab11-GTPase to the microtubule motor proteins in the recycling endosomes (RE) process, and aPKC, one of the main regulators of cell polarity. We demonstrate that aPKC phosphorylates Nuf, modifying Nuf subcellular distribution and, thus, RE delivery. We also show that aPKC’s apical recycling is maintained through Nuf-Rab11-RE. Thus, our results provide a novel link between cell polarity regulation and cellular traffic control.

Nuclear fallout provides a new link between aPKC and polarized cell trafficking. Calero-Cuenca FJ1, Espinosa-Vázquez JM1, Reina-Campos M2, Díaz-Meco MT2, Moscat J2, Sotillos S3. BMC Biol. ;14:32. doi: 10.1186/s12915-016-0253-6.

Complex complexity. :) Dionisio

Cells must be organized in different functional domains to maintain cell homeostasis and exert their functions. This is achieved through conserved proteins that polarize the cell or regulate directional trafficking of cellular vesicles. Both mechanisms must be coordinated but there is little information about their relationship.

Nuclear fallout provides a new link between aPKC and polarized cell trafficking. Calero-Cuenca FJ1, Espinosa-Vázquez JM1, Reina-Campos M2, Díaz-Meco MT2, Moscat J2, Sotillos S3. BMC Biol. ;14:32. doi: 10.1186/s12915-016-0253-6.

Dionisio

Cell polarity, essential for cell physiology and tissue coherence, emerges as a consequence of asymmetric localization of protein complexes and directional trafficking of cellular components. Although molecules required in both processes are well known their relationship is still poorly understood.

Nuclear fallout provides a new link between aPKC and polarized cell trafficking. Calero-Cuenca FJ1, Espinosa-Vázquez JM1, Reina-Campos M2, Díaz-Meco MT2, Moscat J2, Sotillos S3. BMC Biol. ;14:32. doi: 10.1186/s12915-016-0253-6.

Dionisio

Making correct cell fate decisions fundamentally contributes to both the developmental and homeostasis of complex tissue structures in multicellular organisms. The exact biological reason(s) for biased centrosome inheritance, and whether centrosome identity directly participates in the cell fate decision process, remains to be fully answered. Cell fate acquisition is determined by the unequal distribution of fate-determining protein complexes into daughter cells during mitosis. Coordinated links between cortical polarity and mitotic spindle orientation underlie the cell’s ability to generate asymmetric daughter fates. Continued efforts to define the molecular mechanisms of asymmetric cell division will further illuminate this fascinating biological process [...] Surely additional regulatory mechanisms remain to be discovered, including how cell polarity and spindle positioning are coordinated with the cell cycle.

Cell Fate Decision Making through Oriented Cell Division. Dewey EB1, Taylor DT1, Johnston CA1. J Dev Boil. 3(4):129-157 DOI: 10.3390/jdb3040129

Dionisio

The ability to dictate cell fate decisions is critical during animal development. Moreover, faithful execution of this process ensures proper tissue homeostasis throughout adulthood [...] [...] protein complexes control cell fate decisions across diverse tissues. Maintaining proper daughter cell inheritance patterns of these determinants during mitosis is therefore a fundamental step of the cell fate decision-making process.

Cell Fate Decision Making through Oriented Cell Division. Dewey EB1, Taylor DT1, Johnston CA1. J Dev Boil. 3(4):129-157 DOI: 10.3390/jdb3040129

Dionisio

[...] the modulation of the relative dynamics of SBD and NBD, observed by MD simulations on the ns scale and quantified by the centre of mass analysis, could effectively reflect the efficacy of the allosteric communication between the domains, as well as the modulation of the ATPase function of Hsp70.

An atomistic view of Hsp70 allosteric crosstalk: from the nucleotide to the substrate binding domain and back Federica Chiappori,1 Ivan Merelli,1 Luciano Milanesi,b,1 Giorgio Colombo,2 and Giulia Mora Sci Rep. 6: 23474. doi: 10.1038/srep23474

Dionisio

The Hsp70 is an allosterically regulated family of molecular chaperones. They consist of two structural domains, NBD and SBD, connected by a flexible linker. ATP hydrolysis at the NBD modulates substrate recognition at the SBD, while peptide binding at the SBD enhances ATP hydrolysis.

An atomistic view of Hsp70 allosteric crosstalk: from the nucleotide to the substrate binding domain and back Federica Chiappori,1 Ivan Merelli,1 Luciano Milanesi,b,1 Giorgio Colombo,2 and Giulia Mora Sci Rep. 6: 23474. doi: 10.1038/srep23474

Dionisio

[...] the details of the Hsp70-Hsp40 interaction remain elusive. [...] it is not clear how Hsp40s alone, or together with the substrate, influence allosteric signal transmission between the domains. It is not clear whether they alter, either alone or in cooperation with other cochaperones like nucleotide exchange factors, the interdomain communication in Hsp70s to facilitate transfer of the substrate to Hsp90 or to stabilize the Hsp70-substrate complex for timely release at the proteasome. [...] it is not known whether interdomain communication is subject to modulation by the post-translational modifications of Hsp70s that occur in eukaryotes

Insights into the molecular mechanism of allostery in Hsp70s. Mayer MP1, Kityk R1. Front Mol Biosci. ;2:58. doi: 10.3389/fmolb.2015.00058.

Merriam-Webster Dictionary Definition of allosteric: of, relating to, undergoing, or being a change in the shape and activity of a protein (as an enzyme) that results from combination with another substance at a point other than the chemically active site Dionisio

Hsp70s chaperone an amazing number and variety of cellular protein folding processes. Hsp70 is probably the most versatile of all chaperones, constituting a central hub of the cellular protein folding network. [...] the intricate mechanism of the Hsp70 machine itself makes it such a versatile tool. Recent years have brought about significant progress in understanding the underlying mechanisms of interdomain communication in Hsp70s. Despite these advances many questions are still not solved.

Insights into the molecular mechanism of allostery in Hsp70s. Mayer MP1, Kityk R1. Front Mol Biosci. ;2:58. doi: 10.3389/fmolb.2015.00058.

Dionisio

The discovery that the 70 kD “uncoating ATPase,” which removes clathrin coats from vesicles after endocytosis, is the constitutively expressed Hsc70 chaperone was a surprise. How Hsp110 activity is itself regulated to make Hsc70-free clathrin available for endocytosis is unclear [...] The question of how Hsc70:clathrin association is controlled so as to coordinate clathrin availability with endocytic activity may therefore reduce, at least in part, to the question of how Hsp110 activity is regulated. Currently, answers to this question must remain largely speculative [...] How might phosphorylation regulate Hsp110 NEF activity? Again, any answer must be speculative [...] There is no information on how this loop might regulate Hsp110 activity [...] All of these highly speculative mechanisms await testing by future experimentation.

The role of molecular chaperones in clathrin mediated vesicular trafficking Rui Sousa and Eileen M. Lafe Front Mol Biosci. 2: 26. doi: 10.3389/fmolb.2015.00026

Dionisio

Hsp70s use ATP hydrolysis to disrupt protein-protein associations and to move macromolecules. One example is the Hsc70- mediated disassembly of the clathrin coats that form on vesicles during endocytosis.

Clathrin-coat disassembly illuminates the mechanisms of Hsp70 force generation. Sousa R1, Liao HS2, Cuéllar J3, Jin S1, Valpuesta JM3, Jin AJ2, Lafer EM1. Nat Struct Mol Biol. doi: 10.1038/nsmb.3272.

Dionisio

It is tempting to speculate that a PLT-mediated mechanistic module might be utilized as a common strategy to regenerate desired organs in plant species where de novo shoot regeneration is naturally blocked at intermediate developmental phases.

PLETHORA Genes Control Regeneration by a Two-Step Mechanism. Kareem A1, Durgaprasad K1, Sugimoto K2, Du Y3, Pulianmackal AJ1, Trivedi ZB1, Abhayadev PV1, Pinon V3, Meyerowitz EM2, Scheres B3, Prasad K4. Curr Biol. ;25(8):1017-30. doi: 10.1016/j.cub.2015.02.022.

Dionisio

It is important to note that shoot primordium initiation and complete shoot formation are separable processes. It will be revealing to probe the PLT-regulated modules in Arabidopsis accessions that display natural variation in regeneration responses. Regulatory modules controlling intermediate steps of organ regeneration remain to be elucidated across the plant kingdom.

PLETHORA Genes Control Regeneration by a Two-Step Mechanism. Kareem A1, Durgaprasad K1, Sugimoto K2, Du Y3, Pulianmackal AJ1, Trivedi ZB1, Abhayadev PV1, Pinon V3, Meyerowitz EM2, Scheres B3, Prasad K4. Curr Biol. ;25(8):1017-30. doi: 10.1016/j.cub.2015.02.022.

Dionisio

[...] several questions pertaining to role of CUC genes during regeneration remain unanswered. [...] how do CUC genes promote shoot regeneration? When is CUC activity required, and how are CUC genes regulated during regeneration? How does CUC2 complete the shoot formation program from shoot progenitor cells?

PLETHORA Genes Control Regeneration by a Two-Step Mechanism. Kareem A1, Durgaprasad K1, Sugimoto K2, Du Y3, Pulianmackal AJ1, Trivedi ZB1, Abhayadev PV1, Pinon V3, Meyerowitz EM2, Scheres B3, Prasad K4. Curr Biol. ;25(8):1017-30. doi: 10.1016/j.cub.2015.02.022.

Dionisio

[...] the mechanisms by which the external hormone application establishes pluripotency and ensures the completion of organ formation remain largely unknown. Our studies discover previously unrecognized critical roles of PLT genes in establishing pluripotency and their absolute necessity for shoot regeneration.

PLETHORA Genes Control Regeneration by a Two-Step Mechanism. Kareem A1, Durgaprasad K1, Sugimoto K2, Du Y3, Pulianmackal AJ1, Trivedi ZB1, Abhayadev PV1, Pinon V3, Meyerowitz EM2, Scheres B3, Prasad K4. Curr Biol. ;25(8):1017-30. doi: 10.1016/j.cub.2015.02.022.

Dionisio

Regeneration, a remarkable example of developmental plasticity displayed by both plants and animals, involves successive developmental events driven in response to environmental cues. Despite decades of study on the ability of the plant tissues to regenerate complete fertile shoot system after inductive cues, the mechanisms by which cells acquire pluripotency and subsequently regenerate complete organs remain unknown.

PLETHORA Genes Control Regeneration by a Two-Step Mechanism. Kareem A1, Durgaprasad K1, Sugimoto K2, Du Y3, Pulianmackal AJ1, Trivedi ZB1, Abhayadev PV1, Pinon V3, Meyerowitz EM2, Scheres B3, Prasad K4. Curr Biol. ;25(8):1017-30. doi: 10.1016/j.cub.2015.02.022.

Dionisio

Plant roots can regenerate after excision of their tip, including the stem cell niche. [...] multiple cell types can reconstitute stem cells, demonstrating the latent potential of untreated plant cells. The transcriptome of regenerating cells prior to stem cell activation resembles that of an embryonic root progenitor. [...] the signaling domains of the hormones auxin and cytokinin mirror their embryonic dynamics [...] [...] plant root regeneration follows, on a larger scale, the developmental stages of embryonic patterning and is guided by spatial information provided by complementary hormone domains.

Root Regeneration Triggers an Embryo-like Sequence Guided by Hormonal Interactions. Efroni I1, Mello A1, Nawy T1, Ip PL1, Rahni R1, DelRose N1, Powers A2, Satija R3, Birnbaum KD4. Cell. 165(7):1721-33. doi: 10.1016/j.cell.2016.04.046.

"...guided by spatial information provided by complementary hormone domains." Did anybody say "information"? :) Dionisio

Coherent organ growth requires a fine balance between cell division and cell differentiation. Intriguingly, plants continuously develop organs post-embryonically thanks to the activity of meristems that allow growth and environmental plasticity. The number of transit-amplifying cells, which undergo a finite number of cell divisions in the proximal meristem (the division zone), can influence the rate of the overall root growth. Therefore, a tight control of the cell number within the meristem tunes the driving force of the root growth. How, mechanistically, SCR controls ARR1 expression in different ways from different root tissues will require much further work.

A SCARECROW-based regulatory circuit controls Arabidopsis thaliana meristem size from the root endodermis. Moubayidin L1,2, Salvi E3, Giustini L3, Terpstra I4,5, Heidstra R4,6, Costantino P3, Sabatini S3. Planta. ;243(5):1159-68. doi: 10.1007/s00425-016-2471-0.

Dionisio

[...] future experiments that aim to understand the details of the SHR-SCR GRN should focus on a time scale of hours to measure its dynamics. These results only scratch the surface of what is likely to be a complex network regulating the spatial localization of SHR as a mobile transcription factor and developmental regulator. [...] the application of in vivo molecule tracking techniques is virtually limitless, which opens exciting new opportunities in all fields of biology.

Tracking transcription factor mobility and interaction in Arabidopsis roots with fluorescence correlation spectroscopy. Clark NM1,2, Hinde E3, Winter CM4, Fisher AP1, Crosti G4, Blilou I5, Gratton E3, Benfey PN4, Sozzani R1. Elife. ;5. pii: e14770. doi: 10.7554/eLife.14770.

Dionisio

In plants, the intercellular movement of transcription factors and the spatio-temporal control of protein complex formation regulate many processes including cell fate specification. Taken together, these results provide insights into the molecular mechanisms by which SCR regulates SHR movement. They also raise new questions, such as how SCR maintains SHR in multimeric forms, and how formation of higher oligomeric complexes helps restrict SHR movement.

Tracking transcription factor mobility and interaction in Arabidopsis roots with fluorescence correlation spectroscopy. Clark NM1,2, Hinde E3, Winter CM4, Fisher AP1, Crosti G4, Blilou I5, Gratton E3, Benfey PN4, Sozzani R1. Elife. ;5. pii: e14770. doi: 10.7554/eLife.14770.

Dionisio

To understand complex regulatory processes in multicellular organisms, it is critical to be able to quantitatively analyze protein movement and protein-protein interactions in time and space. Stem cells are a specific type of cell found in both plants and animals. These cells can divide to produce daughter cells that can take on the role of any of the different tissues and organs within the plant or animal. During development, multicellular organisms must coordinate patterning, maintenance, and growth of different cell types. This dynamic coordination is achieved through complex spatio-temporal signaling mechanisms [...]

Tracking transcription factor mobility and interaction in Arabidopsis roots with fluorescence correlation spectroscopy. Clark NM1,2, Hinde E3, Winter CM4, Fisher AP1, Crosti G4, Blilou I5, Gratton E3, Benfey PN4, Sozzani R1. Elife. ;5. pii: e14770. doi: 10.7554/eLife.14770.

Dionisio

The development of multicellular organisms relies on the coordinated control of cell divisions leading to proper patterning and growth1–3. The molecular mechanisms underlying pattern formation, particularly the regulation of formative cell divisions, remain poorly understood. Our results indicate that proper pattern formation is achieved through transcriptional regulation of specific cell-cycle genes in a cell-type- and developmental-stage-specific context. Taken together, we provide evidence for a direct link between developmental regulators, specific components of the cell-cycle machinery and organ patterning. [...] tight spatiotemporal regulation of specific cell-cycle genes is required for proper root pattern formation.

Spatiotemporal regulation of cell-cycle genes by SHORTROOT links patterning and growth R. Sozzani,1,* H. Cui,1,*† M. A. Moreno-Risueno,1 W. Busch,1 J. M. Van Norman,1 T. Vernoux,1,† S. M. Brady,1 W. Dewitte,2 J. A. H. Murray,2 and P. N. Benfey Nature. 466(7302): 128–132. doi: 10.1038/nature09143

Dionisio

Any comments on 1772? Why is it that this discussion thread, which is loaded with so many references to recent biology-related research papers, doesn't seem to attract the attention of all the folks who get so actively engaged in heated biology-related arguments within more philosophical discussion threads? :) Dionisio

1773-1775 are related Dionisio

Comments and General Discussion on “The Anatomical Problem Posed by Brain Complexity and Size: A Potential Solution” Javier DeFelipe,1,2,3,* Rodney J. Douglas,4 Sean L. Hill,5 Ed S. Lein,6 Kevan A. C. Martin,4 Kathleen S. Rockland,7,8,* Idan Segev,9,10,11,* Gordon M. Shepherd,12 and Gábor Tamás Front Neuroanat. 10: 60. doi: 10.3389/fnana.2016.00060 PMCID: PMC4901047 http://journal.frontiersin.org/article/10.3389/fnana.2016.00060/full

Dionisio

It seems clear that only by combining studies at all three levels (macro-, meso-, and nano-scopic) can we fully understand the structural arrangement of the brain as a whole. However, despite the fact that neuroscience has advanced spectacularly in recent decades from genetic, molecular, morphological and physiological perspectives, the question remains as to why we are still so pessimistic about adopting this kind of combined approach. The simple reason for this is that there are enormous gaps between each of these disciplines—gaps which remain practically unexplored.

The anatomical problem posed by brain complexity and size: a potential solution. DeFelipe J Front Neuroanat. 9:104. doi: 10.3389/fnana.2015.00104.

Dionisio

The central nervous system works as a whole (Figure ?(Figure1),1), and it is well established that the principles of structural design (spatial distribution, number and types of neurons, and synapses per volume, etc.) differ considerably in the different parts of the nervous system, as well as between species and strains.

The anatomical problem posed by brain complexity and size: a potential solution. DeFelipe J1. Front Neuroanat. 9:104. doi: 10.3389/fnana.2015.00104.

Emphasis mine. Did anybody say 'design'? :) Dionisio

1. tRNA regulation: 1.1 Are the tRNA genes expressed straightforwardly as per the central dogma, i.e. without any post-transcriptional or post-translational modifications? 1.2 Are their expressions triggered by some kind of signaling pathways associated with specific spatiotemporal conditions? 2. aminoacyl tRNA synthetase (aaRS) regulation: 2.1 Are the aaRS genes expressed straightforwardly as per the central dogma, i.e. without any post-transcriptional or post-translational modifications? 2.2 Are their expressions triggered by some kind of signaling pathways associated with specific spatiotemporal conditions? 3. Is there any known spatiotemporal/quantitative relation between the above processes (1) and (2)?

The fitness landscape of a tRNA gene Chuan Li, Wenfeng Qian, Calum J. Maclean, and Jianzhi Zhang Science. 352(6287): 837–840. doi: 10.1126/science.aae0568

Dionisio

All cells discriminate environmental signals and generate appropriate intracellular responses.

Thematic Minireview Series: Complexities of Cellular Signaling Revealed by Simple Model Organisms. Dohlman HG1. J Biol Chem.;291(15):7786-7. doi: 10.1074/jbc.R116.722934.

Dionisio

Morphogens such as Hedgehog, Wingless, Decapentaplegic, and Fibroblast growth factor distribute in concentration gradients across fields of cells in the tissues of developing animals. Their distributions are generated by transport along actin-based cytonemes [...] and direct exchange between producing and receiving cells at morphogenetic synapses where release and uptake of secreted proteins is regulated [...]. The generation of the Bcd concentration gradients in the pre-cellular embryo would appear to have little in common with the gradients that form by cytoneme-mediated dispersion across fields of cells, but we pose the question whether they do. Neither appears to be dependent on passive diffusion and both appear to involve dispersion along cytoskeletal cables. The critical attribute that these mechanisms share is that they provide ways to regulate movement in space and time.

Bicoid gradient formation and function in the Drosophila pre-syncytial blastoderm Zehra Ali-Murthy and Thomas B Kornberg eLife. 2016; 5: e13222. doi: 10.7554/eLife.13222

Dionisio

As an embryo develops, a single cell transforms into a collection of different types of cells. One protein that is crucial for this process in fruit fly embryos is Bicoid. The discovery of the concentration gradient of Bicoid (Bcd) protein in the early Drosophila embryo established the existence and functional importance of a morphogen gradient for the first time [...]

Bicoid gradient formation and function in the Drosophila pre-syncytial blastoderm Zehra Ali-Murthy and Thomas B Kornberg eLife. 2016; 5: e13222. doi: 10.7554/eLife.13222

Dionisio

Bicoid (Bcd) protein distributes in a concentration gradient that organizes the anterior/posterior axis of the Drosophila embryo. It has been understood that bcd RNA is sequestered at the anterior pole during oogenesis, is not translated until fertilization, and produces a protein gradient that functions in the syncytial blastoderm after 9–10 nuclear divisions.

Bicoid gradient formation and function in the Drosophila pre-syncytial blastoderm Zehra Ali-Murthy and Thomas B Kornberg eLife. 2016; 5: e13222. doi: 10.7554/eLife.13222

Dionisio

[...] higher order representations of task rules are underpinned by neural representations which represent effector modality. Such a distributed form of representation is best termed multi modal rather than supra-modal and may not always be apparent when standard univariate statistical analysis techniques are applied to fMRI data.

Multi-modal representation of effector modality in frontal cortex during rule switching Timothy L. Hodgson1*, Benjamin A. Parris2, Abdelmalek Benattayallah3 and Ian R. Summers3 Front. Hum. Neurosci., http://dx.doi.org/10.3389/fnhum.2015.00486

Dionisio

Understanding the activity and regulation of the Hippo pathway may offer new insights into other areas of developmental biology that evolve from understanding of this cell-fate specification in the early embryonic cell. [...] the Hippo pathway is not a stand-alone signaling pathway; recent experiments demonstrate that other signaling pathways, (e.g., Notch) work in concert with the Hippo pathway to regulate cell fate determination in preimplantation embryos. Cross-talk between these pathways likely contributes to ensure proper lineage differentiation in early mammalian embryo. Further studies to determine other regulatory inputs to lineage specification in the early mammalian embryo should be forthcoming soon.

Emerging Role of the Hippo Signaling Pathway in Positional-Sensing and Lineage-Specification in Mammalian Preimplantation Embryos Chanchao Lorthongpanich and Surapol Issaragrisil doi: 10.1095/?biolreprod.114.127803 Biology of Reproduction biolreprod.114.127803

Dionisio

A major priority for future research should be to design integrative studies to further elucidate the mechanisms by which AREs, GREs, RNA-BPs and also small regulatory RNAs coordinate signaling pathways involved in health and disease.

Feedback Regulation of Kinase Signaling Pathways by AREs and GREs Irina Vlasova-St. Louis and Paul R. Bohjanen Cells. 5(1): 4. doi: 10.3390/cells5010004

Dionisio

In response to environmental signals, kinases phosphorylate numerous proteins, including RNA-binding proteins such as the AU-rich element (ARE) binding proteins, and the GU-rich element (GRE) binding proteins. Posttranslational modifications of these proteins lead to a significant changes in the abundance of target mRNAs, and affect gene expression during cellular activation, proliferation, and stress responses. [...] kinase signaling pathways are involved in feedback regulation, whereby kinases regulate RNA-binding proteins that subsequently regulate mRNA stability of ARE- or GRE-containing transcripts that encode components of KSP.

Feedback Regulation of Kinase Signaling Pathways by AREs and GREs Irina Vlasova-St. Louis and Paul R. Bohjanen Cells. 5(1): 4. doi: 10.3390/cells5010004

Dionisio

A clear understanding of the biological functions of non-coding transcripts will provide novel insights into our understanding of the molecular biology. What protein networks assist the long non-coding RNAs and what is their specificity? How Many Proteins have RNA-Binding Ability? How do transcriptomic and metabolomic pathways interact with each other in the cell? What are the targets of the newly discovered RNA-binding proteins? Indeed, we do not have yet a complete understanding of how protein–RNA binding specificity is achieved and how the regulatory function of individual proteins is influenced by synergy and competition with other molecules.

The Grand Challenge of Characterizing Ribonucleoprotein Networks Gian Gaetano Tartaglia Front Mol Biosci. 3: 24. doi: 10.3389/fmolb.2016.00024

Dionisio

What are the protein components binding to coding and non-coding RNAs while they move in the cell? How variable are protein–RNA assemblies in composition? How large, dynamic and structurally heterogeneous is the spectrum or ribonucleoprotein assemblies? What is the Composition of Protein-RNA Granules Inside the Cell? What is the full range and relevance of RNA structures forming granules? Are non-coding RNA participating in RNP assemblies? What is the Function of the Long Non-Coding Part of the Transcriptome?

The Grand Challenge of Characterizing Ribonucleoprotein Networks Gian Gaetano Tartaglia Front Mol Biosci. 3: 24. doi: 10.3389/fmolb.2016.00024

Dionisio

What is the function of the non-coding part of the eukaryotic transcriptome? A clear understanding of the biological functions of coding and non-coding transcripts would provide novel insights in molecular biology. What are the protein components binding to an RNA while it is being produced? Our lack of understanding of how ribonucleoprotein complexes assemble is a major rate-limiting factor to future progress in the field. We need to generate an in-depth characterization of protein–RNA complexes that form in cells during development and in response to external stimuli.

The Grand Challenge of Characterizing Ribonucleoprotein Networks Gian Gaetano Tartaglia Front Mol Biosci. 3: 24. doi: 10.3389/fmolb.2016.00024

Dionisio

Protein–RNA interactions are at the heart of cell regulation. From transcription, processing, storage, and translation, all the stages in the life cycle of an RNA depend on interactions with proteins. Although technologies are making remarkable progress in unraveling the landscape of protein–RNA interactions, many key issues are unclear. We still have to identify how many proteins have RNA-binding ability, what are their targets and functional pathways. Moreover, while we know the number of protein-coding genes in the human genome, functional non-coding RNAs are still poorly defined.

The Grand Challenge of Characterizing Ribonucleoprotein Networks Gian Gaetano Tartaglia Front Mol Biosci. 3: 24. doi: 10.3389/fmolb.2016.00024

Dionisio

Long-non-coding RNAs (lncRNAs), RNA molecules longer than 200 nucleotides, have been involved in several biological processes and in a growing number of diseases, controlling gene transcription, pre-mRNA processing, the transport of mature mRNAs to specific cellular compartments, the regulation of mRNA stability, protein translation and turnover. The fundamental role of lncRNAs in central nervous system (CNS) is becoming increasingly evident. LncRNAs are abundantly expressed in mammalian CNS in a specific spatio-temporal manner allowing a quick response to environmental/molecular changes.

The long non-coding RNAs in neurodegenerative diseases: novel mechanisms of pathogenesis. Riva P1, Ratti A, Venturin M. Curr Alzheimer Res. 2016

Dionisio

Long noncoding RNAs (lncRNAs) are typically defined as transcripts longer than 200 nucleotides. lncRNAs can regulate gene expression at epigenetic, transcriptional, and posttranscriptional levels. Long noncoding RNAs (lncRNAs) comprise a subgroup of noncoding RNAs (ncRNAs) longer than 200 nucleotides (nt), accounting for the largest proportion of the mammalian noncoding transcriptome. lncRNAs impact AD pathogenesis because of their diverse biochemical and functional effects such as chromatin modulation, posttranscriptional and post-translational regulation, and protein complex organization. lncRNAs are not considered to be the “dark matter”, rather they have essential roles in controlling transcription and translation, as well as during genetic imprinting, genome rearrangement, chromatin modification regulation of the cell cycle, transcription, splicing, messenger RNA (mRNA) decay, and translation [...] investigation into this field is in the early stage. As the lncRNA field continues to develop, we still need to elucidate how lncRNAs operate at the molecular and cellular levels. An enhanced understanding of lncRNA biology could open more avenues to early AD diagnosis and treatment.

Long noncoding RNAs and Alzheimer’s disease Qiong Luo1,2 and Yinghui Chen1,2 Clin Interv Aging. 2016; 11: 867–872. doi: 10.2147/CIA.S107037

Emphasis mine. Dionisio

Increasing evidence indicates that epigenetic mechanisms may contribute to the pathogenesis of Alzheimer's disease [...] Although DNA methylation was previously thought to be a static process after cellular differentiation, now it is known to be highly dynamic not only in early developmental phase, but also in adult human brain in response to neural activity [...] [...] due to technological limitations it is still not possible to distinguish cell type specific methylation changes. [...] determining whether epigenomic changes are cause or consequence of the disease is a difficult challenge. Unless epigenomic studies are performed in a noninvasive manner or using small tissue biopsies, it will remain especially arduous to establish causality for neurodegenerative disorders.

Differential DNA Methylation of MicroRNA Genes in Temporal Cortex from Alzheimer's Disease Individuals Darine Villela, 1 Rodrigo F. Ramalho, 2 Aderbal R. T. Silva, 2 Helena Brentani, 3 Claudia K. Suemoto, 4 , 5 Carlos Augusto Pasqualucci, 5 , 6 Lea T. Grinberg, 5 , 7 Ana C. V. Krepischi, 1 and Carla Rosenberg Neural Plast. 2016: 2584940. doi: 10.1155/2016/2584940

Dionisio

Initiation of hair follicle (HF) is the first and most important stage of HF morphogenesis. However the precise molecular mechanism of initiation of hair follicle remains elusive. [...] the molecular mechanism of the interaction of oar-miR-3955-5p and XLOC005698 lncRNA also need further study. These results laid a foundation to screen the regulatory elements or functional genes that specifically regulate the initiation of secondary HF, [...]

Integrated Analysis of the Roles of Long Noncoding RNA and Coding RNA Expression in Sheep (Ovis aries) Skin during Initiation of Secondary Hair Follicle Yaojing Yue,# Tingting Guo,# Chao Yuan,# Jianbin Liu, Jian Guo, Ruilin Feng, Chune Niu, Xiaoping Sun, and Bohui Yang PLoS One. 11(6): e0156890. doi: 10.1371/journal.pone.0156890

Dionisio

[...] these findings have raised several further questions in the development of ectodermal organs. For example, how is the spindle orientation regulated? What are the movements and forces that cells undergo to create the shape of the bud (or peg or duct, in the case of other ectodermal organs)? To what extent are these mechanisms actually conserved across the homologous ectodermal organs? Does Shh directly trigger cell motility or does it act via, for example, Wnt signalling (or vice versa), as proposed for hair placodes (Ahtiainen et al., 2014)? The general morphogenetic mechanism by which ectodermal organs are initiated lies in the answers to these questions.

Epithelial stratification and placode invagination are separable functions in early morphogenesis of the molar tooth Jingjing Li, Lemonia Chatzeli, Eleni Panousopoulou, Abigail S. Tucker, and Jeremy B. A. Green Development. 143(4): 670–681. doi: 10.1242/dev.130187

Dionisio

[...] tooth placode suprabasal cells use dynamic rearrangements to form a contractile structure, which is capable of driving invagination concomitantly with stratification. The contractile structure driving invagination in the ectodermal placodes is topologically somewhat analogous to the contractile actin cables that drive invagination by apical constriction in epithelial monolayers, but on a vastly different scale: intercalation among cells rather than actin and myosin filaments. [...] the similarity, right down to the distribution of force-deformed nuclei, between tooth bud, hair follicle, and mammary gland primordia indicates that these ectodermal organs share the same mechanisms of physical morphogenesis. It seems highly likely that similarly detailed inspection in other organs that form by invagination of stratified placodes may reveal a similar morphogenetic signature at the cellular level.

Invagination of Ectodermal Placodes Is Driven by Cell Intercalation-Mediated Contraction of the Suprabasal Tissue Canopy Eleni Panousopoulou and Jeremy B. A. Green* PLoS Biol. 14(3): e1002405. doi: 10.1371/journal.pbio.1002405

Dionisio

Inference of spatiotemporal effects on cellular state transitions from time-lapse microscopy Michael K. Strasser, Justin Feigelman, Fabian J. Theis, and Carsten Marr BMC Syst Biol. 9: 61. doi: 10.1186/s12918-015-0208-5

Dionisio

Extraembryonic fate choice is determined by the output of a simple mutual repression circuit. It remains, however, possible that positive autoregulation of the Epi and PrE programs and a positive input of FGF/MAPK signaling on GATA expression fine-tune the response of cells during this stage of the decision process. [...] lineage commitment occurs non-synchronously in the cells of the ICM, and that the first cells to commit are fated towards the epiblast [...] FGF/MAPK signaling might thus acts as a feedback mechanism to balance proportions of two distinct cell fates in populations [...] It will be interesting to see whether this new principle applies to differentiation decisions beyond those in the preimplantation embryo.

FGF/MAPK signaling sets the switching threshold of a bistable circuit controlling cell fate decisions in embryonic stem cells Christian Schröter,* Pau Rué, Jonathan Peter Mackenzie, and Alfonso Martinez Arias* Development. 142(24): 4205–4216. doi: 10.1242/dev.127530

Dionisio

To ensure the faithful development of multicellular organisms, cell fate decisions in populations of undifferentiated cells have to be tightly balanced. It is now well established that transcriptional networks and extracellular signals together control these decisions, but how their interactions determine the proportions of cells differentiating along particular lineages is often not known.

FGF/MAPK signaling sets the switching threshold of a bistable circuit controlling cell fate decisions in embryonic stem cells Christian Schröter,* Pau Rué, Jonathan Peter Mackenzie, and Alfonso Martinez Arias* Development. 142(24): 4205–4216. doi: 10.1242/dev.127530

Dionisio

Intracellular transcriptional regulators and extracellular signaling pathways together regulate the allocation of cell fates during development, but how their molecular activities are integrated to establish the correct proportions of cells with particular fates is not known.

FGF/MAPK signaling sets the switching threshold of a bistable circuit controlling cell fate decisions in embryonic stem cells Christian Schröter,* Pau Rué, Jonathan Peter Mackenzie, and Alfonso Martinez Arias* Development. 142(24): 4205–4216. doi: 10.1242/dev.127530

Dionisio

The major question is now whether it is possible to predict plant performance based on microbiome composition and diversity. [...] the time is ripe to move on to the next challenge and link microbiome composition with function.

Networking in the Plant Microbiome Marcel G. A. van der Heijden and Martin Hartmann PLoS Biol. 14(2): e1002378. doi: 10.1371/journal.pbio.1002378

Dionisio

Our observations of an enriched DNA-methylation signature only in TBX3-null and not in the TBX3-low cells indicate additional epigenetic mechanisms that may be implicated and warrant further investigation [...] [...] the intimate connection between TBX3 and DPPA3 remains and needs to be explored in detail in future studies.

A Dynamic Role of TBX3 in the Pluripotency Circuitry Ronan Russell,1,7 Marcus Ilg,1,7 Qiong Lin,2,7 Guangming Wu,3,7 André Lechel,1 Wendy Bergmann,1 Tim Eiseler,1 Leonhard Linta,4 Pavan Kumar P.,5 Moritz Klingenstein,4 Kenjiro Adachi,3 Meike Hohwieler,1 Olena Sakk,6 Stefanie Raab,4 Anne Moon,5 Martin Zenke,2 Thomas Seufferlein,1 Hans R. Schöler,3 Anett Illing,1,8 Stefan Liebau,4,8 and Alexander Kleger Stem Cell Reports. 5(6): 1155–1170. doi: 10.1016/j.stemcr.2015.11.003

Dionisio

Although we know several of the key players that are involved in the establishment of pluripotent and extra-embryonic fates, there is still little information about how these mechanisms are coordinated in vivo. The challenge for the future will be to determine the precise molecular mechanisms that direct the differences in epigenetic programming in individual cells as the embryo progresses through its normal development.

The BAF chromatin remodelling complex is an epigenetic regulator of lineage specification in the early mouse embryo Maryna Panamarova,1,2 Andy Cox,1,2 Krzysztof B. Wicher,1,2 Richard Butler,1 Natalia Bulgakova,1,2,3 Shin Jeon,4 Barry Rosen,5 Rho H. Seong,4 William Skarnes,5 Gerald Crabtree,6 and Magdalena Zernicka-Goetz Development. 143(8): 1271–1283. doi: 10.1242/dev.131961

Dionisio

Cul5-containing ubiquitin ligases regulate a variety of signaling pathways by targeting particular substrates for proteasomal degradation or competing for protein–protein interactions. However, many Cul5-containing ubiquitin ligases remain to be studied, and a complete list of substrates or binding proteins of Cul5 is not available. Considering that some viruses hijack Cul5 to degrade antiviral proteins, it might be better to study the function of Cul5 during virus infection. Certain viruses target Elongin C-interacting Cul5 (and in some cases Cul2) for hijacking, although the cause remains undetermined. Studies focusing on Elongin C might shed light on the physiological functions of Cul5.

The role of cullin 5-containing ubiquitin ligases Fumihiko Okumura,corresponding author Akiko Joo-Okumura, Kunio Nakatsukasa, and Takumi Kamura Cell Div. 11: 1. doi: 10.1186/s13008-016-0016-3

Dionisio

[...] have uncovered essential roles for dynamic regulation of cytoskeleton and cell adhesion in neuronal migration. [...] the spatio-temporal regulation of these cellular events remains unclear. [...] the dynamic behavior of each endosome in migrating neurons in cortical slices remains to be observed. Continual technological advances in in vivo cell biology and related research fields will shed light on unsolved questions to help us better understand the whole picture of cerebral cortical development.

Cellullar insights into cerebral cortical development: focusing on the locomotion mode of neuronal migration Takeshi Kawauchi Front Cell Neurosci. 9: 394. doi: 10.3389/fncel.2015.00394

Dionisio

The brain is divided into many compartments, such as nuclei, layered structures, and cortical areas, allowing highly organized role allocations. The systematically allocated neuronal populations are generated from spatially restricted regions, the ventricular, and subventricular zones. Therefore, a long-distance migration from the ventricular side to the final destination is essential for constructing a functional brain.

Cellullar insights into cerebral cortical development: focusing on the locomotion mode of neuronal migration Takeshi Kawauchi Front Cell Neurosci. 9: 394. doi: 10.3389/fncel.2015.00394

Dionisio

The stage is now set for further experiments investigating the details of ASTN-2 functioning in neuronal and other cells, including its role in PCP determination, and also for the determination of structures for full-length ASTN-2, for ASTN-1 and the BRINPs which, like ASTN-2, have modified MACPF/CDC domains seemingly lacking a basis on which to form pores such as other MACPF/CDC proteins form.

Structure of astrotactin-2: a conserved vertebrate-specific and perforin-like membrane protein involved in neuronal development Tao Ni, Karl Harlos, Robert Gilbert DOI: 10.1098/rsob.160053 Open Biology The Royal Society Publishing

Dionisio

This kinase is an important energy sensor that is present throughout our lifespan. Several stimuli and transduction pathways tightly modulate its expression. Its role must be precisely described in order to develop therapeutic strategies and prevent CNS diseases.

Mammalian Target of Rapamycin: Its Role in Early Neural Development and in Adult and Aged Brain Function Carla Garza-Lombó and María E. Gonsebatt Front Cell Neurosci. 2016; 10: 157. doi: 10.3389/fncel.2016.00157

Dionisio

There is need of more in vivo studies that show the timing, region and cell specificity of mTOR activation/inhibition. It is also important to identified the signaling pathways and effectors that specifically participate in each these process. We also need to understand which mechanisms spatiotemporally modulate or balance mTOR expression and how their disruption is associated with neurodegenerative diseases. Addressing these gaps would help to generate therapeutic strategies.

Mammalian Target of Rapamycin: Its Role in Early Neural Development and in Adult and Aged Brain Function Carla Garza-Lombó and María E. Gonsebatt Front Cell Neurosci. 2016; 10: 157. doi: 10.3389/fncel.2016.00157

Dionisio

The kinase mammalian target of rapamycin (mTOR) integrates signals triggered by energy, stress, oxygen levels, and growth factors. It regulates ribosome biogenesis, mRNA translation, nutrient metabolism, and autophagy. mTOR participates in various functions of the brain, such as synaptic plasticity, adult neurogenesis, memory, and learning. mTOR is present during early neural development and participates in axon and dendrite development, neuron differentiation, and gliogenesis, among other processes.

Mammalian Target of Rapamycin: Its Role in Early Neural Development and in Adult and Aged Brain Function Carla Garza-Lombó and María E. Gonsebatt Front Cell Neurosci. 2016; 10: 157. doi: 10.3389/fncel.2016.00157

Dionisio

Although synaptic plasticity in neural circuits is orchestrated by an ocean of genes, molecules, and proteins, the underlying mechanisms remain poorly understood. The abundant evidence uncovers powerful regulatory role and mechanism of miRNA in various aspects of synaptic plasticity ranges from dendritic spine morphology and synaptic formation to plasticity-related protein synthesis [...] [...] miRNA is a crucial regulator in synaptic plasticity. A deep insight into the mechanism through which the miRNA works for synaptic plasticity is significantly necessary before miRNA is applied to novel therapeutic intervention for neurological disorders. Thus, establishment of the entire framework of plasticity-related miRNAs will be a challenge in the near future.

Role of MicroRNA in Governing Synaptic Plasticity Yuqin Ye, 1 , 2 Hongyu Xu, 1 Xinhong Su, 1 and Xiaosheng He Neural Plast. 4959523. doi: 10.1155/2016/4959523

Dionisio

It is strongly believed that there are some signals at the epigenetic level that regulate the fate of the stem cells [...] Though all of the cells in our body contain the same genetic makeup, these genes are not necessarily active at all times, rather they are expressed at times when needed, in a highly controlled fashion. This tightly-regulated gene expression in our body is governed by epigenetics. The mechanism of gene regulation does not depend on the DNA sequences [17], but is perpetuated as a “memory” that is carried on from one cell to another during cell division [...]

Role of Epigenetics in Stem Cell Proliferation and Differentiation: Implications for Treating Neurodegenerative Diseases Bhairavi Srinageshwar, Panchanan Maiti, Gary L. Dunbar, and Julien Rossignol Int J Mol Sci. 17(2): 199. doi: 10.3390/ijms17020199

Dionisio

These stem cells have the unique property of being totipotent, meaning they can give rise to any type of cell in the organism, including a placenta. The two major properties of stem cells are proliferation and differentiation. [...] the precise mechanism(s) whereby stem cells normally proliferate and differentiate into specific lineages, or even what determines the fate of these stem cells, is not yet understood. Gaining new insights into these endogenous processes may assist researchers with how exogenous stem cells may be more efficiently manipulated in ways that would optimize their therapeutic efficacy for treating neurodegenerative diseases.

Role of Epigenetics in Stem Cell Proliferation and Differentiation: Implications for Treating Neurodegenerative Diseases Bhairavi Srinageshwar, Panchanan Maiti, Gary L. Dunbar, and Julien Rossignol Int J Mol Sci. 17(2): 199. doi: 10.3390/ijms17020199

Dionisio

Some of these epigenetic mechanisms include DNA methylation and histone modifications, which have a direct impact on the way that genes are expressed in stem cells and how they drive these cells into a mature lineage. Understanding how the stem cells are behaving and giving rise to mature cells can be used to inform researchers on effective ways to design stem cell-based treatments. All cells in an organism are derived from pre-existing cells, beginning with the fertilized egg, which forms the blastocyst, which, in turn, gives rise to the cells of the entire organism [...]

Role of Epigenetics in Stem Cell Proliferation and Differentiation: Implications for Treating Neurodegenerative Diseases Bhairavi Srinageshwar, Panchanan Maiti, Gary L. Dunbar, and Julien Rossignol Int J Mol Sci. 17(2): 199. doi: 10.3390/ijms17020199

Dionisio

Spatial and temporal regulation of gene expression in the NSCs population is established and maintained by the coordinated interaction between transcription factors and epigenetic regulators which control stem cell fate. Epigenetic mechanisms are heritable alterations in genome function that do not involve changes in DNA sequence itself but that modulate gene expression, acting as mediators between the environment and the genome. Determining the mechanisms by which neural stem cells maintain self-renewal capacity and at the same time generate differentiated progeny is a central challenge in stem cell biology. [...] epigenetic gene regulation plays a crucial role in the control of stem cell behaviour. Epigenetic mechanisms include changes in chromatin structure that provides a way for coordinately activating or repressing genes during proliferation and differentiation. Extracellular signaling from the microenvironment or niche in which NSCs reside in vivo interacts with these diverse epigenetic mechanisms, thus regulating transcription factors and intracellular pathways.

Epigenetic regulation of stemness maintenance in the neurogenic niches. Montalbán-Loro R, Domingo-Muelas A, Bizy A, Ferrón SR World J Stem Cells. 7(4):700-10. doi: 10.4252/wjsc.v7.i4.700

Dionisio

A major scientific challenge of our times is to successfully implement advances in stem cell biology for the treatment of human diseases. Although ES cells have the capacity to give rise to all cell lineages, their therapeutic potential is limited due to teratoma formation and ethical concerns [...] Elucidating the specific effects of stress hormones and most importantly, the molecular machinery implicated in NSC biology could provide unique insights in the treatment of diseases of the nervous system without raising ethical concerns.

Neural stem cells respond to stress hormones: distinguishing beneficial from detrimental stress Yassemi Koutmani, and Katia P. Karalis Front Physiol. 6: 77. doi: 10.3389/fphys.2015.00077

Dionisio

Embryonic stem (ES) cells are characterized by their unique ability for self-renewal and their potential to differentiate into any type of functional somatic cell. Generation of functional neurons by NSCs is an elegant, dynamically regulated process, extremely active during gestation, reduced in the early postnatal period, and maintained in low rates in the adult. As anticipated by the enormous importance of neurogenesis, this process is under the strict control of a multitude of intrinsic and extrinsic factors. One of the most complex physiological processes with prominent effects in both the embryonic and the adult NSCs, is stress. Despite the widely recognized impact of stress hormones on neurogenesis, little progress has been made in the elucidation of the molecular mechanisms that underlie this outcome. Determining the molecular components of the actions of stress hormones on NSCs activity will be a hallmark in the research on stress but also in the field of regenerative medicine in general.

Neural stem cells respond to stress hormones: distinguishing beneficial from detrimental stress Yassemi Koutmani, and Katia P. Karalis Front Physiol. 6: 77. doi: 10.3389/fphys.2015.00077

Dionisio

Neural stem cells (NSCs), the progenitors of the nervous system, control distinct, position-specific functions and are critically involved in the maintenance of homeostasis in the brain. The responses of these cells to various stressful stimuli are shaped by genetic, epigenetic, and environmental factors via mechanisms that are age and developmental stage-dependent and still remain, to a great extent, elusive. All the above suggest the intriguing hypothesis that NSCs are an important part of the adaptive response to stressors via direct and indirect, specific mechanisms.

Neural stem cells respond to stress hormones: distinguishing beneficial from detrimental stress Yassemi Koutmani, and Katia P. Karalis Front Physiol. 6: 77. doi: 10.3389/fphys.2015.00077

Dionisio

It was long believed that mammalian neurogenesis, i.e., the process of generating functional neurons from neural precursors, occurred only during embryonic and perinatal stages [...] Exosomes, as messengers able to modulate the physiology of the niche, might originate from cells residing within the niche or from distant cells/tissues, thus having access to the neurogenic niche through the vasculature (blood-circulating exosomes) or by volume transmission via the CSF. The contribution of specific cell- and tissue-derived exosomes on adult neurogenesis should be further investigated with the use of proper animal models in which exosomes should be labeled with the use of molecular biology techniques, and later should be validated in health and disease with the use of a panel of biomarkers able to define specific exosome populations. We envisage that, in the near future, many of this work will be addressed by a growing community of researchers interested in the role of exosomes in disease-related processes that, among others, affect the neurogenic niche in a yet unsuspected manner.

Exosomes as Novel Regulators of Adult Neurogenic Niches Luis Federico Bátiz,1,2,3,* Maite A. Castro,1,2,4 Patricia V. Burgos,1,2,5 Zahady D. Velásquez,1,3 Rosa I. Muñoz,1,3 Carlos A. Lafourcade,6 Paulina Troncoso-Escudero,1,4 and Ursula Wyneken Front Cell Neurosci. 2015; 9: 501. doi: 10.3389/fncel.2015.00501

Dionisio

In the developing central nervous system, most neurogenesis occurs in the ventricular and subventricular proliferative zones. It is essential that an organ and its blood supply should develop together in synchrony to allow optimal conditions for the different stages of growth, differentiation and changing functional requirements. Both the CSF and the vasculature of the brain provide regulatory niches for neurogenesis in the developing and adult brain. The localization of neurogenic niches makes them sensitive to circulating soluble factors. The local and systemic control of the neurogenic niches therefore has significant impact on brain function throughout life. [...] it is essential that we increase our understanding of the control of neurogenic niches [...]

Neurogenic niches in the brain: help and hindrance of the barrier systems Helen B. Stolp1,* and Zoltán Molnár Front Neurosci. 9: 20. doi: 10.3389/fnins.2015.00020

Dionisio

[...] we have identified an important role of Alix in preserving the characteristics and functionality of an apical TJ complex responsible for epithelial cell polarity. Alix exerts these functions by securing the correct positioning and interactions of junctional proteins within a macromolecular assembly with the actomyosin cytoskeleton [...] These findings add a tier to the regulation of junctional complexes in the epithelium that extend beyond the CP and the ependymal [...] It is tempting to speculate that the diverse functions of Alix may be primarily related to the capacity of this scaffold protein to directly interact with the actin cytroskeleton, thereby creating the most favourable setting for components of multiprotein complexes to assemble in a timely, spatial and dynamic manner and to target them to specific cellular microdomains.

Alix-mediated assembly of the actomyosin–tight junction polarity complex preserves epithelial polarity and epithelial barrier Yvan Campos,1 Xiaohui Qiu,1 Elida Gomero,1 Randall Wakefield,2 Linda Horner,2 Wojciech Brutkowski,3 Young-Goo Han,4 David Solecki,4 Sharon Frase,2 Antonella Bongiovanni,5 and Alessandra d’Azzo Nat Commun. 7: 11876. doi: 10.1038/ncomms11876

Dionisio

[...] by interacting with F-actin, the Par complex and ZO-1, Alix ensures the formation and maintenance of the apically restricted actomyosin–tight junction complex. [...] in this capacity Alix plays a role in the establishment of apical–basal polarity and in the maintenance of the epithelial barrier. [...] the molecular signals that regulates the connection between different TJ complexes and the actomyosin network to support a functional epithelial barrier are still poorly understood in a mammalian system [...]

Alix-mediated assembly of the actomyosin–tight junction polarity complex preserves epithelial polarity and epithelial barrier Yvan Campos,1 Xiaohui Qiu,1 Elida Gomero,1 Randall Wakefield,2 Linda Horner,2 Wojciech Brutkowski,3 Young-Goo Han,4 David Solecki,4 Sharon Frase,2 Antonella Bongiovanni,5 and Alessandra d’Azzo Nat Commun. 7: 11876. doi: 10.1038/ncomms11876

Dionisio

Maintenance of epithelial cell polarity and epithelial barrier relies on the spatial organization of the actin cytoskeleton and proper positioning/assembly of intercellular junctions. However, how these processes are regulated is poorly understood.

Alix-mediated assembly of the actomyosin–tight junction polarity complex preserves epithelial polarity and epithelial barrier Yvan Campos,1 Xiaohui Qiu,1 Elida Gomero,1 Randall Wakefield,2 Linda Horner,2 Wojciech Brutkowski,3 Young-Goo Han,4 David Solecki,4 Sharon Frase,2 Antonella Bongiovanni,5 and Alessandra d'Azzo Nat Commun. 7: 11876. doi: 10.1038/ncomms11876

Dionisio

Understanding the amazingly complex human cerebral cortex requires a map (or parcellation) of its major subdivisions, known as cortical areas. Making an accurate areal map has been a century-old objective in neuroscience.

A multi-modal parcellation of human cerebral cortex Matthew F. Glasser, Timothy S. Coalson, Emma C. Robinson, Carl D. Hacker, John Harwell, Essa Yacoub, Kamil Ugurbil, Jesper Andersson, Christian F. Beckmann, Mark Jenkinson, Stephen M. Smith & David C. Van Essen Nature (2016) doi:10.1038/nature18933

Dionisio

Ascl1 regulates early development, well before neurogenesis, by repressing mesendoderm induction by VegT in Xenopus. The function of the N-terminal sequence of ASCL1 is less well understood. Further study is needed to better understand how the pre-neurula expression of Ascl1 functions as a transactivator and promotes neurogenesis. It remains unclear whether or how much Ascl1 protein is maternally stored. More studies are needed in future to unravel the function of the multifaceted cell fate regulator Ascl1.

A novel role for Ascl1 in the regulation of mesendoderm formation via HDAC-dependent antagonism of VegT Li Gao,1,* Xuechen Zhu,1,* Geng Chen,1 Xin Ma,2 Yan Zhang,1 Aftab A. Khand,1 Huijuan Shi,1 Fei Gu,1 Hao Lin,1 Yuemeng Chen,3 Haiyan Zhang,1 Lei He,1 and Qinghua Tao1 Development. 143(3): 492–503. doi: 10.1242/dev.126292

Dionisio

The transforming growth factor beta (TGF?) related signaling is one of the most important signaling pathways regulating early developmental events. Smad2 and Smad3 possess differential sensitivities in relaying TGF? signaling and have distinct roles in regulating early developmental events. Future work is needed to investigate how Smad3 regulates neural lineage development in concert with canonical TGF?/Smad2 pathway at the transcriptional level.

Smad2 and Smad3 have differential sensitivity in relaying TGF? signaling and inversely regulate early lineage specification Ling Liu,1,4 Xu Liu,1 Xudong Ren,1 Yue Tian,1 Zhenyu Chen,1 Xiangjie Xu,1 Yanhua Du,3 Cizhong Jiang,3 Yujiang Fang,1 Zhongliang Liu,1 Beibei Fan,1 Quanbin Zhang,1 Guohua Jin,2 Xiao Yang,5 and Xiaoqing Zhang Sci Rep. 6: 21602. doi: 10.1038/srep21602

Dionisio

We can now imagine how the genome is used during embryogenesis. The only missing piece is: what is the actual signal that tells each cell what part of the genome to sequester and to what level, and what part of the genome to leave exposed. Why is that signal confined to a particular subset of cells? Why is the signal received only at certain times during embryogenesis? We think we have found the missing signal. It is differentiation waves transmitted by the cell state splitter organelle.

The organelle of differentiation in embryos: the cell state splitter Natalie K. Gordon and Richard Gordon Theor Biol Med Model. 13: 11. doi: 10.1186/s12976-016-0037-2

Dionisio

Most organisms have cells that are all totipotent, meaning each cell has the same DNA, but uses determination to select which differon to access in each cell. The main problem is then: how does determination occur, when considered as the selection of which cell uses which differon of genes?

The organelle of differentiation in embryos: the cell state splitter Natalie K. Gordon and Richard Gordon Theor Biol Med Model. 13: 11. doi: 10.1186/s12976-016-0037-2

Dionisio

Differentiation waves are reasonably robust, in that they can accommodate variations in cell numbers, cell size, embryo size, and a wide range of temperature and other environmental fluctuations [...] [...] the cybernetic embryo has become a testable hypothesis. By thinking of the embryo in terms of differentiation waves that have goals in the cybernetic sense, we have a theory of how the embryo builds itself that is experimentally testable. The model only requires we accept the cell state splitter as the organelle of differentiation.

The organelle of differentiation in embryos: the cell state splitter Natalie K. Gordon and Richard Gordon Theor Biol Med Model. 13: 11. doi: 10.1186/s12976-016-0037-2

cybernetic embryo? waves that have goals? say what? :) Dionisio

This is real fun: watching reductionist bottom-up research of a marvelous top-down design! Dionisio

#1718 addendum https://www.youtube.com/embed/HXjn6srhAlY Dionisio

That all of these interactions between genetically identical cells should somehow work themselves out in the creation of many distinct microenvironments, all in the right place at the right time, is about as plausible as having a musically untrained crowd of chattering people suddenly switch their cacophony to four part harmony and perform Mozart’s complete Ave Verum Corpus [...]

The organelle of differentiation in embryos: the cell state splitter Natalie K. Gordon and Richard Gordon Theor Biol Med Model. 13: 11. doi: 10.1186/s12976-016-0037-2

Very interesting illustration. Dionisio

Regulatory gene network models, like gradient models, lack any specific mechanism for defining the timing and the location of specific expression.

The organelle of differentiation in embryos: the cell state splitter Natalie K. Gordon and Richard Gordon Theor Biol Med Model. 13: 11. doi: 10.1186/s12976-016-0037-2

Duh! It was obvious from the very beginning that the required spatiotemporal complex specified information is missing. Why did it take them so long to figure out that? Oh, well! what else is new? Dionisio

Multicellular organisms are made of 4D spatiotemporal arrays of different cell types. There is a widespread assumption that the environment somehow determines which cells in an embryo become which kinds. Morphogens are the basis for the concept of positional information which presumes that a cell can know its position by “reading” the concentration of the molecules of the gradients and then deciding what it is supposed to do, by “looking up” its coordinates in some sort of stored table in its DNA. Morphogens are still widely taught, along with gene regulatory networks, as a full explanation of embryogenesis. There are numerous problems with the morphogen gradient model: [...] Many doubts about the functioning or existence of these so-called “morphogen” gradients have been raised, with alternatives and elaborations, and transport mechanisms other than diffusion being proposed.

The organelle of differentiation in embryos: the cell state splitter Natalie K. Gordon and Richard Gordon Theor Biol Med Model. 13: 11. doi: 10.1186/s12976-016-0037-2

Emphasis mine. The unending story continues... Dionisio

The cell state splitter is a membraneless organelle at the apical end of each epithelial cell in a developing embryo. Embryogenesis may be represented then as a bifurcating differentiation tree, each edge representing one cell type. In combination with the differentiation waves they propagate[how?], cell state splitters explain[how?] the spatiotemporal course of differentiation in the developing embryo.

The organelle of differentiation in embryos: the cell state splitter Natalie K. Gordon and Richard Gordon Theor Biol Med Model. 13: 11. doi: 10.1186/s12976-016-0037-2

do they really explain it or just add up more complexity to the explanation? :) Dionisio

Noggin4 is a Noggin family secreted protein whose molecular and physiological functions remain unknown. [...] it is important to elucidate the functions of the third sub-family of Noggins, Noggin4, which comprises members with substantially less homology with other Noggins (approximately 35%) and thus may exhibit different molecular and physiological activity. Noggin4 operates as a long-range inhibitor of a principal ligand of the canonical Wnt signalling pathway, Wnt8. It would be interesting to verify whether Noggin4, like Frzb, is also unable to antagonise Wnt3a activity. [...] it would be interesting to address a potential role for Noggin4 in blocking signalosome formation and/or function.

Noggin4 is a long-range inhibitor of Wnt8 signalling that regulates head development in Xenopus laevis Fedor M. Eroshkin,1,* Alexey M. Nesterenko,b,1,2,* Alexander V. Borodulin,1 Natalia Yu. Martynova,1 Galina V. Ermakova,1 Fatima K. Gyoeva,3 Eugeny E. Orlov,1 Alexey A. Belogurov,1 Konstantin A. Lukyanov,1 Andrey V. Bayramov,c,1 and Andrey G. Zaraisky Sci Rep. 2016; 6: 23049. doi: 10.1038/srep23049

Dionisio

[...] there must be other molecules and mechanisms in the embryo that refine and shape the Nodal morphogen gradient. [...] the Nodal gradient is dependent upon diffusion, binding, and degradation of the morphogen. It will be interesting to determine how Oep/Cripto co-receptors and Lefty shape the active signaling gradient. It is not known if the ECM or HSPGs play a role in modulating the Nodal morphogen gradient [...] [...] the differential stability of Nodal ligands play key roles in shaping the Nodal gradient and activity range. [...] diffusion, extracellular interactions i.e., Nodal-receptor binding, Nodal-Lefty inhibitor binding, and selective ligand destruction collectively shape and refine the Nodal morphogen gradient.

Extracellular interactions and ligand degradation shape the nodal morphogen gradient Yin Wang,1,2,† Xi Wang,3,† Thorsten Wohland,2,3,* and Karuna Sampath eLife. 5: e13879. doi: 10.7554/eLife.13879

Dionisio

The correct distribution and activity of secreted signaling proteins called morphogens is required for many developmental processes. Nodal morphogens play critical roles in embryonic axis formation in many organisms. Models proposed to generate the Nodal gradient include diffusivity, ligand processing, and a temporal activation window. But how the Nodal morphogen gradient forms in vivo remains unclear.

Extracellular interactions and ligand degradation shape the nodal morphogen gradient Yin Wang,1,2,† Xi Wang,3,† Thorsten Wohland,2,3,* and Karuna Sampath eLife. 5: e13879. doi: 10.7554/eLife.13879

Dionisio

[...] HSC development in the embryo involves stage-dependent interactions between dorsal, ventral and lateral domains of the AGM region, mediated at least partly by the interplay of SCF, Shh, BMP4 and Noggin. Further detailed analysis will be required to better understand the complexity of the AGM signalling landscape in which HSC development takes place. [...] is currently unclear whether any factors become expressed in a polarized manner within the reaggregates and as such, whether polarization is also a pre-requisite for HSC maturation. How exactly HSC maturation dynamics depend on overlapping concentrations of factors requires further analysis.

Inductive interactions mediated by interplay of asymmetric signalling underlie development of adult haematopoietic stem cells Céline Souilhol,1 Christèle Gonneau,1 Javier G. Lendinez,1 Antoniana Batsivari,1 Stanislav Rybtsov,1 Heather Wilson,1 Lucia Morgado-Palacin,1 David Hills,1 Samir Taoudi,2,3,4 Jennifer Antonchuk,5 Suling Zhao,1 and Alexander Medvinskya,1 Nat Commun. 2016; 7: 10784. doi: 10.1038/ncomms10784

Dionisio

gpuccio

“In the end, all we can say is that the kidney knows how to regulate sodium, and we don’t!”

Yes, that seems like a very accurate statement that shows the honesty and humility of its author. Perhaps today they know much more about kidney functioning than the did back then, but new questions have appeared. Regarding my medical condition anecdote, at this point the sodium has come up within the desirable range in the last few lab results. :) But during the intensive investigation I think one doctor noted that the pituitary gland appeared sending 'unexpected' signals for the kidney to release more sodium than it should have. I'm glad to know you still look at some papers referenced here. Dionisio

Dionisio: Sorry for your sodium problems. Nephrology is one of those fields in medicine which are as interesting from a physiologic point of view as they are clinically frustrating. I remember that, many years ago, I was reading a nephrology textbook and, at the end of the chapter about sodium regulation, there was a statement which was more or less: "In the end, all we can say is that the kidney knows how to regulate sodium, and we don't!" I don't think that things have changed much. :) gpuccio

gpuccio, It's good to read your comments again! Thank you. I know of a young medical doctor -a friend of one of my children's- who after graduating from medical school and later completing the pediatric residence training, went on to complete a fellowship in pediatric nephrology. However, apparently none of them have time to read this blog. :) Last year, when I was diagnosed with hyponatremia, the doctors who treated me explored the potential endocrinology signaling association between pituitary gland, thyroid gland and electrolytes regulation in the kidneys. Maybe I did not get it exactly right, but I remember they went into something like that. I ended up being seen by various different specialists (internal medicine, nephrology, endocrinology, cardiovascular, neurology, urology). Lots of tests. MRIs did not reveal any possible tumors. Basically the exact cause wasn't identified. Lately the sodium level got back to normal, but maybe mainly through diet adjustments. :) The whole learning experience was very humbling to me (and perhaps to some of those doctors too?). Dionisio

[...] it is now time to thoroughly investigate the individual transport of morphogens and the intercellular communication between involved cells by actual cell biological techniques.

Special Morphological Features at the Interface of the Renal Stem/Progenitor Cell Niche Force to Reinvestigate Transport of Morphogens During Nephron Induction Will W. Minuth* and Lucia Denk Biores Open Access. 5(1): 49–60. doi: 10.1089/biores.2015.0039

it is now time to thoroughly investigate ? Why now? why not before? Wasn't "thorough investigation" the scientific approach to answer difficult questions and resolve complex problems? When did that approach change? Why? Note this is related to preceding posts @1700-1705 too. Dionisio

Dionisio: Thank you for this interesting link. Nephrology was indeed my first passion in medicine. The morphological and functional complexity of the kidney is absolutely amazing, and should be enough to convert any sincere neo darwinist to the cause of Intelligent (Very Intelligent) Design! gpuccio

Previously it was assumed that mesenchymal and epithelial cells in the renal stem/progenitor cell niche have an intimate contact and that the reciprocal transport of morphogens during induction of a nephron is based exclusively on diffusion. However, recent morphological findings illustrate that mesenchymal and epithelial cell bodies are separated by a striking interface consisting of textural extracellular matrix. Further on, projections of mesenchymal cells cross the interface to establish an intercellular communication with epithelial cells via tunneling nanotubes. Regarding the heterogeneously composed group of involved morphogens in combination with the special microenvironment in the interface and the presence of tunneling nanotubes, an exchange of morphogens alone by diffusion seems highly unlikely. Instead, due to flexibility of mesenchymal cell projections including tunneling nanotubes, it is probable that most of morphogens are transported this path at the right time, punctual site, and dosed amount. Whether microvesicles are involved in the transport of morphogens within the renal stem/progenitor cell niche has to be explored.

Special Morphological Features at the Interface of the Renal Stem/Progenitor Cell Niche Force to Reinvestigate Transport of Morphogens During Nephron Induction Will W. Minuth* and Lucia Denk Biores Open Access. 5(1): 49–60. doi: 10.1089/biores.2015.0039

Oh no! wrong assumption again? [note this commentary is not about this paper but about all previous papers that have missed the point] Why did they rush to draw a conclusion without having all the questions answered? Perhaps some questions had not been even asked yet? Why? What kind of scientific approach is that? Where did humility go? Wasn't it obvious that diffusion alone couldn't explain the spatiotemporal specificity of the morphogen distribution? Dionisio

Formation of a nephron depends on reciprocal signaling of different morphogens between epithelial and mesenchymal cells within the renal stem/progenitor cell niche. Previously, it has been surmised that a close proximity exists between both involved cell types and that morphogens are transported between them by diffusion. However, actual morphological data illustrate that mesenchymal and epithelial stem/progenitor cell bodies are separated by a striking interface.

Special Morphological Features at the Interface of the Renal Stem/Progenitor Cell Niche Force to Reinvestigate Transport of Morphogens During Nephron Induction Will W. Minuth* and Lucia Denk Biores Open Access. 5(1): 49–60. doi: 10.1089/biores.2015.0039

striking? Not exactly how it was assumed? Diffusion was assumed as the spatiotemporal morphogen distribution mechanism without having enough evidence to confirm it? Diffusion alone didn't answer all the associated questions? Dionisio

The selectivity of FGFs for different binding structures in glycosaminoglycans provides a means to probe the distribution of these binding sites in Rama 27 cell pericellular matrix and to determine the effect this has on the diffusion of the FGFs. A number of different mechanisms are likely to regulate the distribution of these binding sites [...] The high multiplicity of interactions, both between proteins and polysaccharide and between the polysaccharide-binding proteins themselves [...] is likely to produce a dynamic network of interlinked molecules. This would then be responsible for the long-range (supramolecular) structure of the pericellular matrix, which determines its spatial binding capabilities for individual proteins. [...] although extracellular matrix in cartilage is specialized, in other tissues, an analogous situation may exist, where pericellular, extracellular and basement membrane matrices may exhibit different types of supramolecular structure and consequently have different functions.

Selectivity in glycosaminoglycan binding dictates the distribution and diffusion of fibroblast growth factors in the pericellular matrix Changye Sun,1 Marco Marcello,2 Yong Li,1 David Mason,2 Raphaël Lévy,1 and David G. Fernig1 Open Biol. 6(3): 150277. doi: 10.1098/rsob.150277

Dionisio

The range of biological outcomes generated by many signalling proteins in development and homeostasis is increased by their interactions with glycosaminoglycans, particularly heparan sulfate (HS). This interaction controls the localization and movement of these signalling proteins, but whether such control depends on the specificity of the interactions is not known. [...] the specificity of the interactions of proteins with glycosaminoglycans controls their binding and diffusion. Moreover, cells regulate the spatial distribution of different protein-binding sites in glycosaminoglycans independently of each other, implying that the extracellular matrix has long-range structure.

Selectivity in glycosaminoglycan binding dictates the distribution and diffusion of fibroblast growth factors in the pericellular matrix Changye Sun,1 Marco Marcello,2 Yong Li,1 David Mason,2 Raphaël Lévy,1 and David G. Fernig1 Open Biol. 6(3): 150277. doi: 10.1098/rsob.150277

What determines the specificity of the interactions of proteins? How is that specificity determined? Dionisio

Morphogen gradients induce sharply defined domains of gene expression in a concentration-dependent manner, yet how cells interpret these signals in the face of spatial and temporal noise remains unclear. [...] RA forms a noisy gradient during critical stages of hindbrain patterning [...] [...] cells use distinct intracellular binding proteins to attenuate noise in RA levels. Animal cells need to be able to communicate with each other so that they can work together in tissues and organs. To do so, cells release signaling molecules that can move around within a tissue and be detected by receptors on other cells. Cells responding to signals need to be able to distinguish these signals from random fluctuations (i.e., noise) [...] Morphogens are long-range signals thought to induce different cell behaviors in a concentration-dependent manner, but how such graded signals can be established in the face of noise and how they specify sharp boundaries of target gene expression remain unclear. These mechanisms are likely to be similar in other signaling systems and critical for embryonic development and adult physiology [...]

Noise modulation in retinoic acid signaling sharpens segmental boundaries of gene expression in the embryonic zebrafish hindbrain Julian Sosnik,1,2,3 Likun Zheng,2,4 Christopher V Rackauckas,2,4 Michelle Digman,1,2,5 Enrico Gratton,1,2,5 Qing Nie,1,2,4 and Thomas F Schilling eLife. 5: e14034. doi: 10.7554/eLife.14034

Dionisio

Morphogens were originally defined as secreted signaling molecules that diffuse from local sources to form concentration gradients, which specify multiple cell fates. More recently morphogen gradients have been shown to incorporate a range of mechanisms including short-range signal activation, transcriptional/translational feedback, and temporal windows of target gene induction. Many critical cell–cell signals implicated in both embryonic development and disease, such as Wnt, fibroblast growth factor (Fgf), hedgehog (Hh), transforming growth factor beta (TGFb), and retinoic acid (RA), are thought to act as morphogens, but key information on signal propagation and ligand distribution has been lacking for most. The zebrafish provides unique advantages for genetics and imaging to address gradients during early embryonic stages when morphogens help establish major body axes. This has been particularly informative for RA, where RA response elements (RAREs) driving fluorescent reporters as well as Fluorescence Resonance Energy Transfer (FRET) reporters of receptor binding have provided evidence for gradients, as well as regulatory mechanisms that attenuate noise and enhance gradient robustness in vivo. Here we summarize available tools in zebrafish and discuss their utility for studying dynamic regulation of RA morphogen gradients, through combined experimental and computational approaches.

Chapter 7 – Visualizing retinoic acid morphogen gradients T.F. Schilling, J. Sosnik, Q. Nie Methods in Cell Biology Volume 133, Pages 139–163 The Zebrafish — Cellular and Developmental Biology, Part A Cellular Biology doi:10.1016/bs.mcb.2016.03.003

[emphasis mine] This pattern seems to repeat in biology:

Original assumption: [...] were originally defined as [...] After more research produces new light-shedding discoveries, correction of the wrong -or at least incomplete- original assumption: More recently [...] have been shown to incorporate a range of mechanisms

However, sometimes the original assumptions get confirmed by new research. What could possibly cause that difference? What determines that the original hypothesis gets either confirmed or corrected by newer research? In the morphogen gradient case it should have been obvious from the beginning that diffusion alone wouldn't be sufficient. At least they could have asked: What could determine the spatiotemporal activation of the morphogen sources? How could it be that scientists would miss such a logical conclusion? Dionisio

Bacteria differ in number and location of their flagella that appear in regular patterns at the cell surface (flagellation pattern). Despite the plethora of bacterial species, only a handful of these patterns exist. The correct flagellation pattern is a prerequisite for motility, but also relates to biofilm formation and the pathogenicity of disease-causing flagellated bacteria. However, the mechanisms that maintain location and number of flagella are far from being understood. Here, we review our knowledge on mechanisms that enable bacteria to maintain their appropriate flagellation pattern. While some peritrichous flagellation patterns might occur by rather simple stochastic processes, other bacterial species appear to rely on landmark systems to define the designated flagellar position. Such landmarks are the Tip system of Caulobacter crescentus or the signal recognition particle (SRP)-GTPase FlhF and the MinD/ParA-type ATPase FlhG (synonyms: FleN, YlxH and MinD2). The latter two proteins constitute a regulatory circuit essential for diverse flagellation patterns in many Gram-positive and negative species. The interactome of FlhF/G (e.g. C-ring proteins FliM, FliN, FliY or the transcriptional regulator FleQ/FlrA) seems evolutionary adapted to meet the specific needs for a respective pattern. This variability highlights the importance of the correct flagellation pattern for motile species.

How bacteria maintain location and number of flagella? Jan S. Schuhmacher, Kai M. Thormann, Gert Bange DOI: http://dx.doi.org/10.1093/femsre/fuv034 812-822 FEMS Microbiology Reviews

Emphasis mine. Dionisio

Many motile bacteria swim by rotating their motility organ, the flagellum. Rotation of the flagellum is driven by a motor at its base, and torque is generated by the rotor–stator interaction coupled with the specific ion flow through the channel in the stator. Because the stator works as an energy-conversion complex in the motor, understanding the functional mechanism of the stator is critically important. But its characterization has been hampered due to the difficulty in isolating the functional stator complex from the membrane. Recently, successful new approaches for studying the stator have been reported that reveal its novel properties. Two of those, visualization of the in vivo behavior of stator units using fluorescently tagged proteins and structure-guided functional analyses of the soluble region in the stator, are summarized in this short review. Highlights The bacterial flagellum is driven by a rotary motor embedded in the cell envelope. Torque is generated by the rotor–stator interaction coupled with ion flux through the stator. Installed stator units are exchangeable and can respond to environmental changes. Upon assembly into the motor, the stator is activated by a conformational change in its B subunit.

Dynamism and regulation of the stator, the energy conversion complex of the bacterial flagellar motor Seiji Kojima doi:10.1016/j.mib.2015.07.015 Current Opinion in Microbiology Volume 28, Pages 66–71 Growth and development: eukaryotes and prokaryotes

Dionisio

Motor proteins are molecules which convert chemical energy to mechanical work and are responsible for motility across all levels: for transport within a cell, for the motion of an individual cell in its surroundings, and for movement in multicellular aggregates, such as muscles. The bacterial flagellar motor is one of the canonical examples of a molecular complex made from several motor proteins, which self-assembles on demand and provides the locomotive force for bacteria. This locomotion provides a key aspect of bacteria’s prevalence. Here, we outline the biophysics behind the assembly, the energetics, the switching and the rotation of this remarkable nanoscale electric motor that is Nature’s first wheel.

How Biophysics May Help Us Understand the Flagellar Motor of Bacteria Which Cause Infections Matthew A. B. Baker pp 231-243 Advances in Experimental Medicine and Biology Volume 915 2016 Biophysics of Infection Editors: Mark C. Leake ISBN: 978-3-319-32187-5

Dionisio

Although the external components, the hook and the filament, are known to rotate, having been tethered to glass or marked by latex beads, the rotation of the internal components has remained only a reasonable assumption. Here, by using polarized light to bleach and probe an internal YFP-FliN fusion, we show that the innermost components of the cytoplasmic ring rotate at a rate similar to that of the hook.

Internal and external components of the bacterial flagellar motor rotate as a unit Basarab G. Hosu, Vedavalli S. J. Nathan, and Howard C. Berg PNAS 113 (17) 4783-4787 doi: 10.1073/pnas.1511691113

Dionisio

The emergence of cryo-ET and subtomogram averaging provide new avenues for studying intact flagellar motors in cells with unprecedented detail. It is expected that significant advances in cryo-ET, in combination with subtomogram averaging and molecular tools, will provide novel structural insights into many important processes of bacterial flagella: the stator–rotor interaction, protein secretion and assembly, and switching and rotation.

Molecular Architecture of the Bacterial Flagellar Motor in Cells Xiaowei Zhao,† Steven J. Norris,†‡ and Jun Liu* Biochemistry. 53(27): 4323–4333. doi: 10.1021/bi500059y http://pubs.acs.org/doi/full/10.1021/bi500059y

Dionisio

The bacterial flagellum is one of the most thoroughly studied prokaryotic motility organelles. Our understanding of this molecular machine has advanced dramatically over the past several decades. More atomic structures of flagellar components are emerging. However, the structure and function of the intact flagellar motor are far from fully understood at the molecular level.

Molecular Architecture of the Bacterial Flagellar Motor in Cells Xiaowei Zhao,† Steven J. Norris,†‡ and Jun Liu* Biochemistry. 53(27): 4323–4333. doi: 10.1021/bi500059y http://pubs.acs.org/doi/full/10.1021/bi500059y

Dionisio

The flagellum is one of the most sophisticated self-assembling molecular machines in bacteria. [...] our understanding of flagellar assembly and rotational mechanisms remains incomplete, in part because of the limited structural information available regarding the intact rotor–stator complex and secretion apparatus.

Molecular Architecture of the Bacterial Flagellar Motor in Cells Xiaowei Zhao,† Steven J. Norris,†‡ and Jun Liu* Biochemistry. 53(27): 4323–4333. doi: 10.1021/bi500059y http://pubs.acs.org/doi/full/10.1021/bi500059y

Dionisio

reducibly complex?

Although it is known that diverse bacterial flagellar motors produce different torques, the mechanism underlying torque variation is unknown. The disk complex therefore forms a separate and previously unappreciated additional biogenesis step in ?-proteobacteria that occurs after the conserved assembly of the flagellar type III secretion system, rotor, switch, rod, hook, and filament. We now are pursuing a follow-up study to understand the phylogeny and probe the origins of these disk complexes. MotB also must interact with PflB, because these two proteins colocalize in subtomogram averages, and deletion of pflB results in the failure of MotB to incorporate into the motor, further supporting our conclusion that the disk complex functions to scaffold stator complexes. Although this model is clearly a simplification of the process, and biophysical studies reveal that additional stator complexes provide incrementally smaller torque contributions (14), we believe the salient features of our model's predictions are compelling. Alternatively, additional stator complexes may act as more sensitive mechanosensors. The observation that these variables scale together, but without strict correlation, provides a mechanistic insight: No strict stoichiometric or symmetric correspondence is necessary for motor function. This lack of strict correlation also suggests a clear reducibly complex [?] pathway for the evolution of higher-torque motors, because the increases in C-ring and stator-ring radii can be staggered progressively and asynchronously [...] through the addition of spacers while a functional motor is maintained. Together these results indicate that different bacteria have modified their motors to produce torques suited to their environments. Such modification of the mechanical output of a molecular machine is not without precedent, because similar observations have been made in the unrelated F-ATPase rotor ring (53). In addition to describing the evolution [i.e. adaptation] of higher torque, this study illustrates a mechanism for adapting mechanical output that might be capitalized on in future synthetic repurposing of molecular machinery.

Diverse high-torque bacterial flagellar motors assemble wider stator rings using a conserved protein scaffold Morgan Beebya,1, Deborah A. Ribardob, Caitlin A. Brennanc,2, Edward G. Rubyc,3, Grant J. Jensend,e, and David R. Hendrixsonb,1 PNAS vol. 113 no. 13 E1917–E1926, doi: 10.1073/pnas.1518952113 http://www.pnas.org/content/113/13/E1917.abstract

[Emphasis mine] reducibly complex? What kind of reduction they refer to? Is this about removing fundamental parts of the machine or just modifying some parts for adaptation purpose? Aren't they talking about increasing C-ring and stator-ring radii by adding spacers in order to increase the torque of an existing system? Also see these clear terms: have modified modification this study illustrates a mechanism for adapting Isn't this a clear example of built-in adaptation mechanisms? In this paper the term 'evolved' seems to refer to 'adapted' an existing machine to different environments through modifications of the parameters associated with some parts. Did I miss something in the text? Dionisio

Translation of the detected small intergenic ORFs may have biological function even if the translation product has no function. Ribosome binding or translation of short ORFs may have key gene regulatory roles in both prokaryotes and eukaryotes.42–45 Yet, many of the intergenic translation initiation sites were not obviously related to nearby coding genes, though ribosome binding to such RNAs may affect its function by changing its structure or stability

Comprehensive identification of translation start sites by tetracycline-inhibited ribosome profiling Kenji Nakahigashi,1,* Yuki Takai,1 Michiko Kimura,2 Nozomi Abe,1 Toru Nakayashiki,3,† Yuh Shiwa,4,‡ Hirofumi Yoshikawa,4,5 Barry L. Wanner,6 Yasushi Ishihama,2 and Hirotada Mori DNA Res. 23(3): 193–201. doi: 10.1093/dnares/dsw008

Dionisio

Our data extend recent studies showing unexpected transcriptome complexity in several bacteria and suggest that antisense RNA regulation is widespread. A large proportion (36%) of operons are complex with internal promoters or terminators that generate multiple transcription units. [...] we observed differential expression of polycistronic genes, despite being in the same operons, indicating that E. coli operon architecture allows fine-tuning of gene expression. [...] deeper layers of transcriptional regulation in bacteria are likely to be revealed in the future. [...] AS transcripts are highly conserved in E. coli and appear to be noncoding RNA, suggesting that they are involved in regulation of gene expression, as has been proposed for excludons in bacteria (34) and lncRNAs in eukaryotes The transcriptome intricacy we observed in E. coli appears to be a general property of the domain bacteria, as the transcriptomes of several other bacteria appear to be similarly intricate.

Unprecedented high-resolution view of bacterial operon architecture revealed by RNA sequencing. Conway T1, Creecy JP2, Maddox SM2, Grissom JE2, Conkle TL2, Shadid TM2, Teramoto J3, San Miguel P4, Shimada T, Ishihama A5, Mori H6, Wanner BL7 MBio. 2014 Jul 8;5(4):e01442-14. doi: 10.1128/mBio.01442-14.

Dionisio

Transcriptional regulatory mechanisms can be broadly categorized into two classes. On one hand, response mechanisms can convert environmental cues into specific transcriptional responses. On the other hand, gene expression is continuously adjusted to adapt to varying environmental conditions [...] The specificity, if any, of each of these mechanisms with respect to the set of co-regulated genes, nevertheless remains to be understood. [...] a large part of the specific basal coordination of transcription might rely exclusively on the interplay among RNAP, DNA, and mRNA.

Insights into the Mechanisms of Basal Coordination of Transcription Using a Genome-Reduced Bacterium Ivan Junier, E. Besray Unal, Eva Yus, Verónica Lloréns-Rico, Luis Serrano DOI: http://dx.doi.org/10.1016/j.cels.2016.04.015 Cell Systems Volume 2, Issue 6, p391–401

Dionisio

Coordination of transcription in bacteria occurs at supra-operonic scales, but the extent, specificity, and mechanisms of such regulation are poorly understood. [...] the degree of co-expression between co-directional adjacent operons, and more generally between genes, is tightly related to their capacity to be transcribed en bloc into the same mRNA. [...] the basal coordination of transcription is mediated by the physical entities and mechanical properties of the transcription process itself, and that operon-like behaviors may strongly vary from condition to condition.

Insights into the Mechanisms of Basal Coordination of Transcription Using a Genome-Reduced Bacterium Ivan Junier, E. Besray Unal, Eva Yus, Verónica Lloréns-Rico, Luis Serrano DOI: http://dx.doi.org/10.1016/j.cels.2016.04.015 Cell Systems Volume 2, Issue 6, p391–401

Dionisio

[...] the precise role of PTIP in early kidney development remains to be defined. This information is critically needed to fully understand the epigenetic basis of nephric lineage specification. Interestingly, overexpression of Notch or inactivation of Fgf signaling in the cap mesenchyme also triggers premature differentiation of nephron progenitors [Barak et al., 2012; Boyle et al., 2011], suggesting that Six2 stem cells are “primed” for differentiation, and raises the question of whether chromatin-based mechanisms balance the cell fate decisions between renewal and differentiation in this multipotent population. In the future, it will be important to decipher the epigenetic codes of modular enhancers in progenitor and nephrogenic genes utilizing native freshly isolated mouse and human Six2 cells.

Epigenetic States of Nephron Progenitors and Epithelial Differentiation Mazhar Adli, Mahmut Parlak, Yuwen Li, and Samir El-Dahr J Cell Biochem. 116(6): 893–902. doi: 10.1002/jcb.25048

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. The big picture looks more interesting with every new discovery. That’s why we look forward, with increasing anticipation, to reading newer research papers that shed more light on the elaborate cellular and molecular choreographies operating within the biological systems. Dionisio

Certain chromatin marks such as Lysine 36 tri-methylation of Histone H3 (H3K36me3) that is observed in the gene body of actively transcribed genes is an important epigenomic feature. However, the epigenetic function of this mark is yet to be understood.

Epigenetic States of Nephron Progenitors and Epithelial Differentiation Mazhar Adli, Mahmut Parlak, Yuwen Li, and Samir El-Dahr J Cell Biochem. 116(6): 893–902. doi: 10.1002/jcb.25048

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. The big picture looks more interesting with every new discovery. That’s why we look forward, with increasing anticipation, to reading newer research papers that shed more light on the elaborate cellular and molecular choreographies operating within the biological systems. Dionisio

Notably, throughout developmental and cellular differentiation process, chromatin structure is dynamically regulated to allow expression of lineage specific genes from the same genome. Thus, the information that regulates lineage or cell type specific gene expression program is not genetic information. Broadly speaking, nearly 200 different cell types in our body carry the same genetic information and yet they are functionally and phenotypically different. The information that provides memory for lineage specific gene expression program is epi-genetic (above-genetic) information.

Epigenetic States of Nephron Progenitors and Epithelial Differentiation Mazhar Adli, Mahmut Parlak, Yuwen Li, and Samir El-Dahr J Cell Biochem. 116(6): 893–902. doi: 10.1002/jcb.25048

Did anybody say information ? :) As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. The big picture looks more interesting with every new discovery. That’s why we look forward, with increasing anticipation, to reading newer research papers that shed more light on the elaborate cellular and molecular choreographies operating within the biological systems. Dionisio

Chromatin is a key regulator of all DNA-templated cellular processes. From Gene transcription to DNA replication and repair, numerous vital activities are tightly controlled by chromatin structure, which tightly packs nearly 2-meter long DNA molecule into nucleus of every human cell. The basic building blocks of chromatin are nucleosomes; that are composed of DNA molecule wrapped around histone protein dimers (H2A, H2B, H3 and H4). Nucleosomes organization is neither random nor uniform across the genome. Genomic information is partitioned into tightly packaged “closed” compartments called heterochromatin and actively regulated “open” chromatin regions called euchromatin [Zhou et al., 2011].

Epigenetic States of Nephron Progenitors and Epithelial Differentiation Mazhar Adli, Mahmut Parlak, Yuwen Li, and Samir El-Dahr J Cell Biochem. 116(6): 893–902. doi: 10.1002/jcb.25048

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. The big picture looks more interesting with every new discovery. That’s why we look forward, with increasing anticipation, to reading newer research papers that shed more light on the elaborate cellular and molecular choreographies operating within the biological systems. Dionisio

[...] it is essential to characterize the epigenomic modifiers and their modifications under normal physiological conditions. The transcription factor Pax2 was identified as a major epigenetic player in the early specification of the kidney. Notably, the progenitors of all nephrons that reside in the cap mesenchyme display a unique bivalent histone signature (expressing repressive epigenetic marks alongside activation marks) on lineage-specific genes. These cells are deemed poised for differentiation and commitment to the nephrogenic lineage. In response to the appropriate inducing signal, these genes lose their repressive histone marks, which allow for their expression in nascent nephron precursors.

Epigenetics mechanisms in renal development. Hilliard SA1, El-Dahr SS Pediatr Nephrol. (7):1055-60. doi: 10.1007/s00467-015-3228-x.

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. The big picture looks more interesting with every new discovery. That’s why we look forward, with increasing anticipation, to reading newer research papers that shed more light on the elaborate cellular and molecular choreographies operating within the biological systems. Dionisio

[...] high-throughput molecular profiling and genome engineering technology will generate an unprecedented volume of data for many cellular lineages in the coming years.

An integrated systems biology approach identifies positive cofactor 4 as a factor that increases reprogramming efficiency Junghyun Jo,1,† Sohyun Hwang,2,† Hyung Joon Kim,3,† Soomin Hong,1 Jeoung Eun Lee,3 Sung-Geum Lee,3 Ahmi Baek,3 Heonjong Han,2 Jin Il Lee,4 Insuk Lee,2,* and Dong Ryul Lee Nucleic Acids Res. 44(3): 1203–1215. doi: 10.1093/nar/gkv1468

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. The big picture looks more interesting with every new discovery. That’s why we look forward, with increasing anticipation, to reading newer research papers that shed more light on the elaborate cellular and molecular choreographies operating within the biological systems. Dionisio

Pluripotency represents a cell state comprising a fine-tuned pattern of transcription factor activity required for embryonic stem cell (ESC) self-renewal. TBX3 is the earliest expressed member of the T-box transcription factor family and is involved in maintenance and induction of pluripotency. It would be of interest in the future to perform live-time imaging studies to track the fate of various TBX3 states to their progeny in pre- and postimplantation embryonic stages. Intriguingly, recent studies implicated that the pluripotency circuitry can be perturbed in both directions [...] Further studies need to clarify the precise role of TBX3 for germ cell development, particularly in light of the intimate connection between DPPA3/STELLA and TBX3. [...] the intimate connection between TBX3 and DPPA3 remains and needs to be explored in detail in future studies. [...] additional epigenetic mechanisms that may be implicated and warrant further investigation.

A Dynamic Role of TBX3 in the Pluripotency Circuitry Ronan Russell,1,7 Marcus Ilg,1,7 Qiong Lin,2,7 Guangming Wu,3,7 André Lechel,1 Wendy Bergmann,1 Tim Eiseler,1 Leonhard Linta,4 Pavan Kumar P.,5 Moritz Klingenstein,4 Kenjiro Adachi,3 Meike Hohwieler,1 Olena Sakk,6 Stefanie Raab,4 Anne Moon,5 Martin Zenke,2 Thomas Seufferlein,1 Hans R. Schöler,3 Anett Illing,1,8 Stefan Liebau,4,8 and Alexander Kleger1, Stem Cell Reports. 5(6): 1155–1170. doi: 10.1016/j.stemcr.2015.11.003

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. The big picture looks more interesting with every new discovery. That’s why we look forward, with increasing anticipation, to reading newer research papers that shed more light on the elaborate cellular and molecular choreographies operating within the biological systems. Dionisio

Dynamic control of gene expression is essential for the development of a totipotent zygote into an embryo with defined cell lineages. The accessibility of genes responsible for cell specification to transcriptional machinery is dependent on chromatin remodelling complexes such as the SWI\SNF (BAF) complex. However, the role of the BAF complex in early mouse development has remained unclear. [...] novel role of BAF-dependent chromatin remodelling in mouse development via regulation of lineage specification. The surprising time-dependent effect of downregulation of the core BAF complex subunits could suggest a dynamic requirement for the BAF complex in the regulation of pluripotency. How might this difference in BAF155 mobilisation between the lineages be controlled? The question of how repression of Nanog in TE is achieved mechanistically by the BAF155-BRG1-containing complex remains open. Although we know several of the key players that are involved in the establishment of pluripotent and extra-embryonic fates, there is still little information about how these mechanisms are coordinated in vivo. The challenge for the future will be to determine the precise molecular mechanisms that direct the differences in epigenetic programming in individual cells as the embryo progresses through its normal development.

The BAF chromatin remodelling complex is an epigenetic regulator of lineage specification in the early mouse embryo. Panamarova M1, Cox A1, Wicher KB1, Butler R2, Bulgakova N3, Jeon S4, Rosen B5, Seong RH4, Skarnes W5, Crabtree G6, Zernicka-Goetz M7. Development. 143(8):1271-83. doi: 10.1242/dev.131961

[emphasis mine] surprising ? why? As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. The big picture looks more interesting with every new discovery. That’s why we look forward, with increasing anticipation, to reading newer research papers that shed more light on the elaborate cellular and molecular choreographies operating within the biological systems. Dionisio

Our understanding of how morphogens activate graded signaling in tissues has been dominated by the pre-molecular era assumption that secreted ligands diffuse from a source to form concentration gradients, and this assumption has naturally progressed into the formulation of models that include diffusion as a major determinant in patterning by morphogens. Although in some contexts, such as the establishment of left-right asymmetry, Nodal can act at long range [...] the work presented here shows that the formation of the Nodal signaling domain at the blastula margin is explained by [1] short-range signaling activation, [2] signaling dynamics, and [3] transcriptional/translational regulation.

A Temporal Window for Signal Activation Dictates the Dimensions of a Nodal Signaling Domain Antonius L. van Boxtel, John E. Chesebro, Claire Heliot, Marie-Christine Ramel, Richard K. Stone, Caroline S. Hill DOI: http://dx.doi.org/10.1016/j.devcel.2015.09.014 Developmental Cell Volume 35, Issue 2, p175–185

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. The big picture looks more interesting with every new discovery. That’s why we look forward, with increasing anticipation, to reading newer research papers that shed more light on the elaborate cellular and molecular choreographies operating within the biological systems. Dionisio

The crucial determinant of the temporal window is the delayed translation of the Lft1/2 proteins, which is mediated by miR-430. How the repressive action of miR-430 is lifted at 50% epiboly to allow Lft1/2 translation is not yet known and requires further investigation. [...] the size of the domain is dictated by the delay in Lefty translation. [...] concentration and duration of signaling can be translated into positional information. [...] the importance of timing of signaling activation also rationalizes the normal development of ndr1 mutants [...]

A Temporal Window for Signal Activation Dictates the Dimensions of a Nodal Signaling Domain Antonius L. van Boxtel, John E. Chesebro, Claire Heliot, Marie-Christine Ramel, Richard K. Stone, Caroline S. Hill DOI: http://dx.doi.org/10.1016/j.devcel.2015.09.014 Developmental Cell Volume 35, Issue 2, p175–185

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. The big picture looks more interesting with every new discovery. That’s why we look forward, with increasing anticipation, to reading newer research papers that shed more light on the elaborate cellular and molecular choreographies operating within the biological systems. Dionisio

[...] the importance of diffusion of endogenous Ndr1/2 remains unclear [...] [...] to what extent miR-430s contribute to the formation of the Nodal signaling domain is unknown. Our data do not support the reaction-diffusion model, but instead, we propose that Nodal activates signaling in a temporal window that is defined by a miR-430-mediated delay of Lft1/2 translation. In this way, temporal information is converted into spatial information in the developing embryo.

A Temporal Window for Signal Activation Dictates the Dimensions of a Nodal Signaling Domain Antonius L. van Boxtel, John E. Chesebro, Claire Heliot, Marie-Christine Ramel, Richard K. Stone, Caroline S. Hill DOI: http://dx.doi.org/10.1016/j.devcel.2015.09.014 Developmental Cell Volume 35, Issue 2, p175–185

temporal information is converted into spatial information ? Did anybody say "information"? Did thy mean "complex specified information" i.e. the purpose-driven nonmaterial stuff some folks dislike so much? :) Dionisio

#1675 correction Sorry, forgot to add: [emphasis mine] Also, missed a character '>' and the rest of the trailing text got displayed in bold characters. My fault. It should've appeared this way instead:

dominated by the assumption? How reliable is that kind of domination? :) other mechanisms ? Oops!!! Oh, no! Wrong assumption? again? Why did they assume that? Oh, well. What else is new? Same ol' same ol' :) It ain't gonna change. Humility doesn't come in the birth package. It's not an attribute of the natural human condition. It must be acquire by mysterious means. :(

BTW, the paper referenced @1674 and @1675 seems very juicy. Maybe we can squeeze more juice out of it. Polecam! :) Dionisio

In the development and patterning of embryonic and adult tissues, secreted signaling molecules of the Wnt, Fgf, Hedgehog, and transforming growth factor ? (TGF-?) families can act as morphogens to activate different transcriptional programs along a signaling gradient [...] Ideas of how morphogens impart spatial information have been dominated by the assumption that these molecules form concentration gradients by diffusion, inducing dose-dependent responses in the receiving field of cells. However, it is becoming increasingly clear that for some ligands, for example, Hedgehog, Wnt, and Fgf, other mechanisms, such as short-range signaling activation, transcriptional feedback, and cellular rearrangements, underlie morphogen function [...]

A Temporal Window for Signal Activation Dictates the Dimensions of a Nodal Signaling Domain Antonius L. van Boxtel, John E. Chesebro, Claire Heliot, Marie-Christine Ramel, Richard K. Stone, Caroline S. Hill DOI: http://dx.doi.org/10.1016/j.devcel.2015.09.014 Developmental Cell Volume 35, Issue 2, p175–185

dominated by the assumption ? How reliable is that kind of domination? :) other mechanisms</strong ? Oops!!! Oh, no! Wrong assumption? again? Why did they assume that? Oh, well. What else is new? Same ol' same ol' :) It ain't gonna change. Humility doesn't come in the birth package. It's not an attribute of the natural human condition. It must be acquire by mysterious means. :( Dionisio

Morphogen signaling is critical for the growth and patterning of tissues in embryos and adults, but how morphogen signaling gradients are generated in tissues remains controversial. [...] endogenous Nodal is unlikely to diffuse over a long range. [...] short-range Nodal signaling activation in a temporal window is sufficient to determine the dimensions of the Nodal signaling domain. The size of this temporal window is set by the differentially timed production of Nodal and Lefty, which arises mainly from repression of Lefty translation by the microRNA miR-430. Thus, temporal information is transformed into spatial information to define the dimensions of the Nodal signaling domain and, consequently, to specify mesendoderm.

A Temporal Window for Signal Activation Dictates the Dimensions of a Nodal Signaling Domain Antonius L. van Boxtel, John E. Chesebro, Claire Heliot, Marie-Christine Ramel, Richard K. Stone, Caroline S. Hill DOI: http://dx.doi.org/10.1016/j.devcel.2015.09.014 Developmental Cell Volume 35, Issue 2, p175–185

temporal information is transformed into spatial information to define the dimensions of the Nodal signaling domain and, consequently, to specify mesendoderm. say what? that's a mouthful statement. Did anybody say 'information'? 'to define'? 'to specify'? do they mean that information was transformed for a special purpose? Dionisio

The correct distribution and activity of secreted signaling proteins called morphogens is required for many developmental processes. Nodal morphogens play critical roles in embryonic axis formation in many organisms. Models proposed to generate the Nodal gradient include diffusivity, ligand processing, and a temporal activation window. But how the Nodal morphogen gradient forms in vivo remains unclear. [...] diffusivity, extra-cellular interactions, and selective ligand destruction collectively shape the Nodal morphogen gradient. Taken together, these findings strongly suggest there must be other molecules and mechanisms in the embryo that refine and shape the Nodal morphogen gradient. The diffusional movement of morphogens can also be altered by transient binding to other molecules such as receptors or to components of the extracellular matrix [...] [...] one possible mechanism to shape the gradient is transient binding of Nodal proteins to immobilized diffusion regulators [...] Another potential mechanism for gradient formation is rapid clearance of molecules during diffusion [...] [...] cells selectively destroy Nodal ligands by recognizing the lysosome-targeting signal, since the ligands have to be internalized. [...] simulations have not taken into consideration cell divisions or binding to other factors that could influence the gradient. [...] the Nodal gradient is dependent upon diffusion, binding, and degradation of the morphogen. [...] some aspects of the system have not been taken into account in our simulations. It will be interesting to determine how Oep/Cripto co-receptors and Lefty shape the active signaling gradient. It is not known if the ECM or HSPGs play a role in modulating the Nodal morphogen gradient [...] [...] diffusion, extracellular interactions i.e., Nodal-receptor binding, Nodal-Lefty inhibitor binding, and selective ligand destruction collectively shape and refine the Nodal morphogen gradient.

Extracellular interactions and ligand degradation shape the nodal morphogen gradient Yin Wang, Xi Wang, Thorsten Wohland, and Karuna Sympathy eLife. 2016; 5: e13879. doi: 10.7554/eLife.13879 https://elifesciences.org/content/5/e13879

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. The big picture looks more interesting with every new discovery. That’s why we look forward, with increasing anticipation, to reading newer research papers that shed more light on the elaborate cellular and molecular choreographies operating within the biological systems. Dionisio

Proteins searching and recognizing specific sites on DNA is required for initiating all major biological processes. While the details of the protein search for targets on DNA in purified in vitro systems are reasonably well understood, the situation in real cells is much less clear. The presence of other types of molecules on DNA should prevent reaching the targets, but experiments show that, surprisingly, the molecular crowding on DNA influences the search dynamics much less than expected. [...] the dimensionality of the search trajectories specifies whether the crowding will affect the target finding.

Crowding on DNA in Protein Search for Targets Alexey A. Shvets and Anatoly B. Kolomeisky J. Phys. Chem. Lett., 2016, 7, pp 2502–2506 DOI: 10.1021/acs.jpclett.6b00905 Role of Static and Dynamic Obstacles in the Protein Search for Targets on DNA Alexey Shvets, Maria Kochugaeva, and Anatoly B. Kolomeisky J. Phys. Chem. B, Article ASAP DOI: 10.1021/acs.jpcb.5b09814 Protein search for multiple targets on DNA Martin Lange, Maria Kochugaeva and Anatoly B. Kolomeisky J. Chem. Phys. 143, 105102 DOI: http://dx.doi.org/10.1063/1.4930113 ? Dynamics of the Protein Search for Targets on DNA in the Presence of Traps Martin Lange, Maria Kochugaeva, and Anatoly B. Kolomeisky J. Phys. Chem. B, 119 (38), pp 12410–12416 DOI: 10.1021/acs.jpcb.5b07303

[emphasis mine] Dionisio

Mammalian reproduction is uniquely characterized by the formation of the placenta, a transient extraembryonic organ that mediates dynamic interaction between embryonic and maternal tissues and ensures successful development of the embryo proper. This intimate relationship between the embryo and mother is crucially dependent upon trophoblast cells as they mediate uterine implantation, initiate the process of placentation, and modulate vascular, endocrine and immunological properties to support successful pregnancy. [...] their relevance in postimplantation trophoblast development needs to be addressed. [...] the precise functions of these factors or their target genes at distinct stages of trophoblast development are yet to be identified. [...] how these signaling pathways alter transcriptional mechanisms to establish cell type-specific gene expression programs are poorly understood. [...] it is still not known whether these proteins are required for trophoblast development in humans [...] [...] how does a specific environmental factor modulate transcriptional mechanisms in trophoblast cells remains poorly understood. Future studies in these contexts utilizing recent technologies such as single-cell transcriptome analyses, genome-wide identification of transcription factor targets, as well as gene editing tools will help to address these fundamental mechanistic questions [...]

Transcriptional Regulators of the Trophoblast Lineage in Mammals with Hemochorial Placentation Jason G Knott and Soumen Paul doi: 10.1530/REP-14-0072 REP-14-0072v1 148/6/R121

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. The big picture looks more interesting with every new discovery. That’s why we look forward, with increasing anticipation, to reading newer research papers that shed more light on the elaborate cellular and molecular choreographies operating within the biological systems. Dionisio

There is growing evidence that transcription and nuclear organization are tightly linked. Yet, whether transcription of thousands of long noncoding RNAs (lncRNAs) could play a role in this packaging process remains elusive. Although some lncRNAs have been found to have clear roles in nuclear architecture (e.g., FIRRE, NEAT1, XIST, and others), the vast majority remain poorly understood. In this Perspective, we highlight how the act of transcription can affect nuclear architecture. We synthesize several recent findings into a proposed model where the transcription of lncRNAs can serve as guide-posts for shaping genome organization. This model is similar to the game “cat’s cradle,” where the shape of a string is successively changed by opening up new sites for finger placement. Analogously, transcription of lncRNAs could serve as “grip holds” for nuclear proteins to pull the genome into new positions. This model could explain general lncRNA properties such as low abundance and tissue specificity. Overall, we propose a general framework for how the act of lncRNA transcription could play a role in organizing the 3D genome.

“Cat’s Cradling” the 3D Genome by the Act of LncRNA Transcription Marta Melé, John L. Rinn DOI: http://dx.doi.org/10.1016/j.molcel.2016.05.011 Molecular Cell, Volume 62, Issue 5, p657–664

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. The big picture looks more interesting with every new discovery. That's why we look forward, with increasing anticipation, to reading newer research papers that shed more light on the elaborate cellular and molecular choreographies operating within the biological systems. Dionisio

Information encoded in DNA is interpreted, modified, and propagated as chromatin. The diversity of inputs encountered by eukaryotic genomes demands a matching capacity for transcriptional outcomes provided by the combinatorial and dynamic nature of epigenetic processes. Advances in genome editing, visualization technology, and genome-wide analyses have revealed unprecedented complexity of chromatin pathways, offering explanations to long-standing questions and presenting new challenges.

Greater Than the Sum of Parts: Complexity of the Dynamic Epigenome Alexey A. Soshnev, Steven Z. Josefowicz, C. David Allis DOI: http://dx.doi.org/10.1016/j.molcel.2016.05.004 Molecular Cell, Volume 62, Issue 5, p681–694

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. The big picture looks more interesting with every new discovery. That's why we look forward, with increasing anticipation, to reading newer research papers that shed more light on the elaborate cellular and molecular choreographies operating within the biological systems. Dionisio

Dual-specificity MAP kinase (MAPK) phosphatases (MKPs or DUSPs) are well-established negative regulators of MAPK signalling in mammalian cells and tissues. By virtue of their differential subcellular localisation and ability to specifically recognise, dephosphorylate and inactivate different MAPK isoforms, they are key spatiotemporal regulators of pathway activity. This reinforces the importance of signalling plasticity and pathway remodelling in the emergence of drug resistance and it is perhaps no surprise that MKPs, as major regulators of MAPK activity, are key players in this process.

The regulation of oncogenic Ras/ERK signalling by dual-specificity mitogen activated protein kinase phosphatases (MKPs) Andrew M. Kidger, Stephen M. Keyse doi:10.1016/j.semcdb.2016.01.009 Seminars in Cell & Developmental Biology Volume 50, Pages 125–132 Gap Junctions Feedback control of cell signalling

Dionisio

The proinflammatory cytokine tumor necrosis factor (TNF) orchestrates complex multicellular processes through a wide variety of changes that it induces in cell functions. Major gaps still remain in our knowledge of the cellular and molecular basis for these three modes of TNF action. Tumor necrosis factor (TNF), a cytokine generated by a variety of different cells—most effectively by mononuclear phagocytes—in response to a wide range of immune stimuli and stress conditions, is one of the major regulators of inflammation. As in Akira Kurosawa's famous film Rashomon, so too in the study of the highly pleiotropic function of TNF the notion of reality lies in the eye of the beholder. Scientists tend to focus on the feature of TNF function that is highlighted by the particular TNF activity that they study. [...] given the great heterogeneity of the ways in which inflammation contributes to defense, and the multiple means by which TNF affects cellular functions in inflammation, future studies are likely to reveal additional ways in which the nature, extent and duration of TNF function are controlled. The complexity of the subject is continuing to unfold and substantial effort will be required over the coming years to address the open questions.

The cybernetics of TNF: Old views and newer ones David Wallach doi:10.1016/j.semcdb.2015.10.014 Seminars in Cell & Developmental Biology Volume 50, Pages 105–114 Gap Junctions Feedback control of cell signalling

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. The big picture looks more interesting with every new discovery. Dionisio

Cytokinesis is the final process in the cell cycle that physically divides one cell into two. [...] cytokinesis is driven by a contractile actomyosin ring (AMR) and the simultaneous formation of a primary septum, which serves as template for cell wall deposition. AMR assembly, constriction, primary septum formation and cell wall deposition are successive processes and tightly coupled to cell cycle progression to ensure the correct distribution of genetic material and cell organelles among the two rising cells prior to cell division. The role of the AMR in cytokinesis and the molecular mechanisms that drive AMR constriction and septation are the focus of current research. [...] cells have [...] robust systems that ensure high fidelity in coordinating cell division processes. Research over the last two decades has identified essential components of the cell division machinery as well as their complex interactions throughout the cell cycle. Structural information, investigations into the molecular mechanisms and of key and regulatory components have given insight into how the AMR drives cytokinesis. However, we do not completely understand the basic mechanisms that drive and coordinate AMR constriction and septum formation. A future milestone in the field will be to establish an in vitro system that is able to simulate in vivo characteristics of the cell division machinery. This would allow one to investigate the underlying mechanisms in a fully tunable manner. In vivo evidence has demonstrated that the formation of extracellular matrix and the involved membrane associated proteins might be essential for the function of the AMR and even for its assembly. The implementation of these aspects in an in vitro system will be challenging.

Actomyosin ring driven cytokinesis in budding yeast Franz Meitinger, Saravanan Palani doi:10.1016/j.semcdb.2016.01.043 Seminars in Cell & Developmental Biology Volume 53, May 2016, Pages 19–27 Cytokinetic ring construction and constriction Fibroblast Growth factor signalling

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

Fibroblast growth factors (FGFs) have long been attributed to influence morphogenesis in embryonic development. Signaling by FGF morphogen encodes positional identity of tissues by creating a concentration gradient over the developing embryo. Various mechanisms that influence the development of such gradient have been elucidated in the recent past. These mechanisms of FGF gradient formation present either as an extracellular control over FGF ligand diffusion or as a subcellular control of FGF propagation and signaling. In this review, we describe our current understanding of FGF as a morphogen, the extracellular control of FGF gradient formation by heparan sulfate proteoglycans (HSPGs) and mechanisms of intracellular regulation of FGF signaling that influence gradient formation.

Mechanisms of FGF gradient formation during embryogenesis Revathi Balasubramanian, Xin Zhang Seminars in Cell & Developmental Biology Volume 53, May 2016, Pages 94–100 Cytokinetic ring construction and constriction Fibroblast Growth factor signalling doi:10.1016/j.semcdb.2015.10.004

Dionisio

Post-translational modifications (PTMs) occur on nearly all proteins. Many domains within proteins are modified on multiple amino acid sidechains by diverse enzymes to create a myriad of possible protein species. How these combinations of PTMs lead to distinct biological outcomes is only beginning to be understood. Most proteins are post-translationally regulated in some manner by enzymes that directly alter the chemical makeup of the protein. These enzymes can be proteases, transferases (kinases, acetyltransferases, methyltransferases, glycosyltransferases, etc.), or enzymes that remove groups (phosphatases, deacetylases, glycosidases, etc.). PTMs are known to act alone and in combination to regulate nearly all aspects of protein function. Thus, deciphering how PTMs are coordinately regulated is of fundamental importance to our understanding of biology. PTMs function in concert to regulate biological function. Emerging and longstanding evidence suggests that PTM codes can extend beyond single proteins. Protein interaction landscapes very likely emerge from the interplay between multiple layers of PTM coordination. That is to say that PTM “codes” can coordinate groups of proteins such as those found within a multi-protein complex. Yet another layer of PTM regulation that extends beyond protein complexes has been discovered for histone code “readers” – proteins whose assembly on histone tails is dynamically regulated by combinatorial PTMs. Our understanding of how concerted PTMs coordinate biological function is in its infancy. We are beginning to understand how combinations of PTMs can affect structure and function of single proteins [...]. However, the story is far from over. Emerging evidence suggests that PTM “codes” (in as much as a “code” or combination of PTMs is defined by its necessity in a functional process) extend beyond the level of a single-protein. With the seemingly boundless amounts of data emerging from MS-based PTM studies, deciphering functional PTM codes will likely benefit from systems-level analyses and network theory, which become increasingly useful with further integration of proteomic technology and combinatorial biophysical assays.

Deciphering post-translational modification codes Edited by Wilhelm Just Adam P. Lothropa, Matthew P. Torresb, , , Stephen M. Fuchs doi:10.1016/j.febslet.2013.01.047 FEBS Letters Volume 587, Issue 8, Pages 1247–1257 The many faces of proteins

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

The cell is the basic unit of life and contains many tightly regulated molecular machines, all of which contain proteins. Dynamics are essential for protein function. To maintain their proper function in cells these proteins must operate at the right place and at the right time. The dynamic nature of proteins is essential for their function, and protein function depends on environment. Thus, how the cellular environment affects these dynamics is a major concern. The ultimate goal for protein science is to study proteins in their natural cellular environment in the post-reductionist era of biochemistry.

Protein dynamics in living cells studied by in-cell NMR spectroscopy Edited by Wilhelm Just Conggang Li, , Maili Liu doi:10.1016/j.febslet.2012.12.023 FEBS Letters Volume 587, Issue 8, Pages 1008–1011 The many faces of proteins

there yet? :) Dionisio

Molecular machines made of proteins are highly dynamic and carry out sophisticated biological functions. The vital activities of cells depend on the activities of molecular machines made of proteins with various functions. HS-AFM allows us to carry out more detailed inquiries or answer questions that have been difficult or impossible to address by other methods. Thus, HS-AFM provides the opportunity to make unexpected new findings. [...] it is expected that the expanded exploration by dynamic HS-AFM imaging will be carried out for a wide range of biomolecular systems in the near future. Thus, a comprehensive and deeper understanding of how biological molecular machines operate is expected to be attained and accelerated. This capacity will provide new opportunities for the in situ dynamic imaging of molecular machines on higher-order structures such as live mitochodoria, nuclei, and neuronal spines.

Molecular machines directly observed by high-speed atomic force microscopy Toshio Ando FEBS Letters Volume 587, Issue 8, , Pages 997–1007 The many faces of proteins doi:10.1016/j.febslet.2012.12.024

Dionisio

Domain swapping in proteins is an important mechanism of functional and structural innovation. However, despite its ubiquity and importance, the physical mechanisms that lead to domain swapping are poorly understood. Domain swapping depends nonmonotonically on the protein concentration, with domain-swapped dimers occurring at intermediate concentrations and nonspecific interactions between partially unfolded proteins occurring at high concentrations.

A Simple Model of Protein Domain Swapping in Crowded Cellular Environments Jaie C. Woodard1, 2, Sachith Dunatunga3, Eugene I. Shakhnovich doi:10.1016/j.bpj.2016.04.033 Biophysical Journal Volume 110, Issue 11, 7 June 2016, Pages 2367–2376

"Domain swapping depends nonmonotonically on the protein concentration,..." What does the protein concentration depend on? Dionisio

Traditionally, biochemical studies are performed in dilute homogenous solutions, which are very different from the dense mixture of molecules found in cells. Thus, the physiological relevance of these studies is in question. Obtaining quantitative biochemical information on reactions inside living cells is currently a main challenge of the field, as the complexity of the intracellular milieu was what motivated crowding research to begin with. Virtually all aspects of cellular and multi-cellular activities involve the formation of protein complexes. While intuitively, crowding might be conceived as a force that compacts any molecular system, the different branches of the field – theories, computer simulations and wet in vitro experiments – have converged to show that the truth is in the details Crowding research is now facing the challenge of traversing from in vitro to in vivo measurements. This effort will tell whether reaction constants measured in the test tube under dilute conditions are reproduced inside living cells.

Formation of protein complexes in crowded environments – From in vitro to in vivo Yael Phillip,Gideon Schreiber Volume 587, Issue 8, Pages 1046–1052 The many faces of proteins doi:10.1016/j.febslet.2013.01.007 http://www.sciencedirect.com/science/article/pii/S0014579313000264

There yet? :) Dionisio

The zona pellucida (ZP) surrounding the oocyte is an extracellular fibrillar matrix that plays critical roles during fertilization including species-specific gamete recognition and protection from polyspermy. [...] sequence similarity between ZP domains is low across species and thus the mechanism for the conservation of ZP/egg coat structure and its function is not known. [...] amyloidogenesis may be a conserved mechanism for ZP structure and function across billions of years of evolution. [...] amyloid formation may be a conserved mechanism for assembly and function of egg coat/ZP/mating proteins. Knowledge that many proteins unrelated to fertilization also contain ZP domains and are known to form fibrils and extracellular matrices would suggest that they too form amyloids for functional purposes. Many proteins that possess ZP domains are involved in cell-cell interactions and cell shape suggesting that amyloidogenesis may be a conserved mechanism for these basic cell biological processes

Amyloid Properties of the Mouse Egg Zona Pellucida Egge N, Muthusubramanian A, Cornwall GA (2015) . PLoS ONE 10(6): e0129907. doi:10.1371/journal.pone.0129907

Dionisio

If we were to design a proteome, what types and what proportion of amino acids would we use in order to optimize properties such as the diversity of sequences and structures, their robustness to mutations, or their ability to fold efficiently? [...] different amino acid compositions induce vastly different sequences-structure maps.

The Amino Acid Alphabet and the Architecture of the Protein Sequence-Structure Map. I. Binary Alphabets Evandro Ferrada http://dx.doi.org/10.1371/journal.pcbi.1003946

Dionisio

#1656 addendum

[...] it will be of great interest quantitatively to investigate the phase diagram of chromosome structures at different stages of the cell cycle and further to evaluate the significance of the suggested ideal chromosome model as a starting point for dynamical analysis. Equally interesting will be the study of the structure–dynamics–function relationships that are crucial to understanding protein biology, but now in the much more complex context of gene regulation, and seek possible structural imprints of epigenetic memory in chromosome conformation

Dionisio

Chromosome conformation capture experiments provide a rich set of data concerning the spatial organization of the genome. We use these data along with a maximum entropy approach to derive a least-biased effective energy landscape for the chromosome. Simulations of the ensemble of chromosome conformations based on the resulting information theoretic landscape not only accurately reproduce experimental contact probabilities, but also provide a picture of chromosome dynamics and topology. The topology of the simulated chromosomes is probed by computing the distribution of their knot invariants. The simulated chromosome structures are largely free of knots. Topologically associating domains are shown to be crucial for establishing these knotless structures. The simulated chromosome conformations exhibit a tendency to form fibril-like structures like those observed via light microscopy. The topologically associating domains of the interphase chromosome exhibit multistability with varying liquid crystalline ordering that may allow discrete unfolding events and the landscape is locally funneled toward "ideal" chromosome structures that represent hierarchical fibrils of fibrils.

Topology, structures, and energy landscapes of human chromosomes Zhang B, Wolynes PG Proc Natl Acad Sci U S A. 112(19):6062-7. doi: 10.1073/pnas.1506257112. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4434716/

Dionisio

Spatial Organization of Epigenomes

The role of genome architecture in transcription regulation has become the focus of an increasing number of studies over the past decade. Chromatin organization can have a significant impact on gene expression by promoting or restricting the physical proximity between regulatory DNA elements. Given that any change in chromatin state has the potential to alter DNA folding and the proximity between control elements, the spatial organization of chromatin is inherently linked to its molecular composition. In this review, we explore how modulators of chromatin state and organization might keep gene expression in check. We discuss recent findings and present some of the less well-studied aspects of spatial genome organization such as chromatin dynamics and regulation by non-coding RNAs. http://www.ncbi.nlm.nih.gov/pubmed/26986719 http://link.springer.com/article/10.1007%2Fs40610-016-0028-4

Put your 3D glasses on: plant chromatin is on show

The three-dimensional organization of the eukaryotic nucleus and its chromosomal conformation have emerged as important features in the complex network of mechanisms behind gene activity and genome connectivity dynamics, which can be evidenced in the regionalized chromosomal spatial distribution and the clustering of diverse genomic regions with similar expression patterns. The development of chromatin conformation capture (3C) techniques has permitted the elucidation of commonalities between the eukaryotic phyla, as well as important differences among them. The growing number of studies in the field performed in plants has shed light on the structural and regulatory features of these organisms. For instance, it has been proposed that plant chromatin can be arranged into different conformations such as Rabl, Rosette-like, and Bouquet, and that both short- and long-range chromatin interactions occur in Arabidopsis. In this review, we compile the current knowledge about chromosome architecture characteristics in plants, as well as the molecular events and elements (including long non-coding RNAs, histone and DNA modifications, chromatin remodeling complexes, and transcription factors) shaping the genome three-dimensional conformation. Furthermore, we discuss the developmental outputs of genome topology-mediated gene expression regulation. It is becoming increasingly clear that new tools and techniques with higher resolution need to be developed and implemented in Arabidopsis and other model plants in order to better understand chromosome architecture dynamics, from an integrative perspective with other fields of plant biology such as development, stress biology, and finally agriculture. http://www.ncbi.nlm.nih.gov/pubmed/27129951

Three-dimensional regulation of transcription

Cells can adapt to environment and development by reconstructing their transcriptional networks to regulate diverse cellular processes without altering the underlying DNA sequences. These alterations, namely epigenetic changes, occur during cell division, differentiation and cell death. Numerous evidences demonstrate that epigenetic changes are governed by various types of determinants, including DNA methylation patterns, histone posttranslational modification signatures, histone variants, chromatin remodeling, and recently discovered chromosome conformation characteristics and non-coding RNAs (ncRNAs). Here, we highlight recent efforts on how the two latter epigenetic factors participate in the sophisticated transcriptional process and describe emerging techniques which permit us to uncover and gain insights into the fascinating genomic regulation. http://www.ncbi.nlm.nih.gov/pubmed/25670626 http://link.springer.com/article/10.1007%2Fs13238-015-0135-7

Chromatin organization in pluripotent cells: emerging approaches to study and disrupt function

Translating the vast amounts of genomic and epigenomic information accumulated on the linear genome into three-dimensional models of nuclear organization is a current major challenge. In response to this challenge, recent technological innovations based on chromosome conformation capture methods in combination with increasingly powerful functional approaches have revealed exciting insights into key aspects of genome regulation. These findings have led to an emerging model where the genome is folded and compartmentalized into highly conserved topological domains that are further divided into functional subdomains containing physical loops that bring cis-regulatory elements to close proximity. Targeted functional experiments, largely based on designable DNA-binding proteins, have begun to define the major architectural proteins required to establish and maintain appropriate genome regulation. Here, we focus on the accessible and well-characterized system of pluripotent cells to review the functional role of chromatin organization in regulating pluripotency, differentiation and reprogramming. http://www.ncbi.nlm.nih.gov/pubmed/26206085 http://bfg.oxfordjournals.org/content/early/2015/07/22/bfgp.elv029.long

Dionisio

Surprisingly, SKN-1 is activated by signals from this fat, which appears to derive from unconsumed yolk that was produced for reproduction. During reproduction, cells in the gut produce yolk—which is rich in fats—that will be provided to germ cells to nourish the developing embryo. Worms lacking germline stem cells are not able to reproduce, but they continue to make yolk. Steinbaugh et al. found that the build up of the yolk activates SKN-1, which in turn inhibits the further accumulation of fats.

Lipid-mediated regulation of SKN-1/Nrf in response to germ cell absence Michael J Steinbaugh, Sri Devi Narasimhan,Stacey Robida-Stubbs,Lorenza E Moronetti Mazzeo,Jonathan M Dreyfuss,John M Hourihan,Prashant Raghavan,Theresa N Operaña,Reza Esmaillie,T Keith Blackwell •DOI: http://dx.doi.org/10.7554/eLife.07836 eLife 2015;4:e07836

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

Lipids play a pivotal role in embryogenesis as structural components of cellular membranes, as a source of energy, and as signaling molecules. On the basis of a collection of temperature-sensitive embryonic lethal mutants, a systematic database search, and a subsequent microscopic analysis of >300 interference RNA (RNAi)-treated/mutant worms, we identified a couple of evolutionary conserved genes associated with lipid storage in Caenorhabditis elegans embryos. The genes include cpl-1 (cathepsin L-like cysteine protease), ccz-1 (guanine nucleotide exchange factor subunit), and asm-3 (acid sphingomyelinase), which is closely related to the human Niemann-Pick disease-causing gene SMPD1. The respective mutant embryos accumulate enlarged droplets of neutral lipids (cpl-1) and yolk-containing lipid droplets (ccz-1) or have larger genuine lipid droplets (asm-3). The asm-3 mutant embryos additionally showed an enhanced resistance against C band ultraviolet (UV-C) light. Herein we propose that cpl-1, ccz-1, and asm-3 are genes required for the processing of lipid-containing droplets in C. elegans embryos. Owing to the high levels of conservation, the identified genes are also useful in studies of embryonic lipid storage in other organisms.

Genetics of Lipid-Storage Management in Caenorhabditis elegans Embryos. Schmökel V1, Memar N2, Wiekenberg A2, Trotzmüller M3, Schnabel R2, Döring F4. Genetics. 202(3):1071-83. doi: 10.1534/genetics.115.179127.

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

TBC-2 is required for yolk protein storage during embryonic development and provide strong correlative data indicating that yolk constitutes an important energy source for larval survival during L1 diapause. [...] too much RAB-7 activity drives fusion between yolk granules and lysosomes in tbc-2(tm2241) mutants, but further analysis will be required to determine the molecular mechanisms involved. While yolk serves as a food source for the embryo in egg laying species, the full requirements for yolk in C. elegans is not known. Since mutations in the yolk receptor, rme-2, are partially lethal, it would suggest that yolk is important for embryonic development, but it is also possible that RME-2 has additional requirements during embryogenesis [...] tbc-2, rme-1, and rme-6, while not essential under standard laboratory conditions, are likely important for survival in the wild.

Chotard L, Skorobogata O, Sylvain M-A, Shrivastava S, Rocheleau CE (2010) TBC-2 Is Required for Embryonic Yolk Protein Storage and Larval Survival during L1 Diapause in Caenorhabditis elegans. PLoS ONE 5(12): e15662. doi:10.1371/journal.pone.0015662 http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0015662

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

The trace element iron is crucial for living organisms, since it plays essential roles in numerous cellular functions. Systemic iron overload and the elevated level of ferritin, a ubiquitous intracellular protein that stores and releases iron to maintain the iron homeostasis in cells, has long been epidemiologically associated with obesity and obesity-related diseases. However, the underlying mechanisms of this association remain unclear. Here, using Caenorhabditis elegans, we show that iron overload induces the expression of sgk-1, encoding the serum and glucocorticoid-inducible kinase, to promote the level of ferritin and fat accumulation. Mutation of cyp-23A1, encoding a homolog of human cytochrome P450 CYP7B1 that is related to neonatal hemochromatosis, further enhances the elevated expression of ftn-1, sgk-1, and fat accumulation. sgk-1 positively regulates the expression of acs-20 and vit-2, genes encoding homologs of the mammalian FATP1/4 fatty acid transport proteins and yolk lipoproteins, respectively, to facilitate lipid uptake and translocation for storage under iron overload. This study reveals a completely novel pathway in which sgk-1 plays a central role to synergistically regulate iron and lipid homeostasis, offering not only experimental evidence supporting a previously unverified link between iron and obesity, but also novel insights into the pathogenesis of iron and obesity-related human metabolic diseases.

Iron Overload Coordinately Promotes Ferritin Expression and Fat Accumulation in Caenorhabditis elegans. Wang H1, Jiang X1, Wu J1, Zhang L1, Huang J2, Zhang Y3, Zou X4, Liang B5 Genetics. ;203(1):241-53. doi: 10.1534/genetics.116.186742

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

[...] we could identify novel genetic regulators of yolk protein production in C. elegans, hereby improving our knowledge on invertebrate control of yolk production, a process assumed to only serve reproduction. [...] our findings still suggest an additional investment in yolk, opening up new research possibilities as to the why and how of this energy-costly process.

New genetic regulators question relevance of abundant yolk protein production in C. elegans Liesbeth Van Rompay,1Charline Borghgraef,1Isabel Beets,1Jelle Caers,1 and Liesbet Temmerman Sci Rep. 5: 16381. doi: 10.1038/srep16381

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

Thousands of sense-antisense mRNA-lncRNA gene pairs occur in the mammalian genome. While there is usually little doubt about the function of the coding transcript, the function of the lncRNA partner is mostly untested. [...] many antisense lncRNAs have no specific trans function, possibly only regulating the linked coding genes in cis. Anterior-posterior patterning determines cell fates and tissue specification during gastrulation. [...] it remains unclear why EVX1?/? mice display minimal defects, despite a clear function for EVX1 in regulating A-P patterning in EBs. LncRNAs are an important new class of genetic material with a variety of biochemical activities. Some have proven key regulatory roles in development and differentiation. This does not rule out a possible cis function for Evx1as in the regulation of Evx1. Further coding-lncRNA pairs need be carefully dissected using precise genetic tools to develop general principles which accurately describe their biological functions. We suggest that it is likely that some lncRNAs may function in trans to exert broad effects on gene expression, some function in cis to regulate their coding partner, and some may simply be non-functional bi-products of intense transcriptional activity at the partner coding gene’s promoter or enhancer.

The Evx1/Evx1as gene locus regulates anterior-posterior patterning during gastrulation Charles C. Bell,1 Paulo P. Amaral,2,* Anton Kalsbeek,2,3 Graham W. Magor,1 Kevin R. Gillinder,1 Pierre Tangermann,2 Lorena di Lisio,1 Seth W. Cheetham,1,4,* Franziska Gruhl,1,4,† Jessica Frith,2,5 Michael R. Tallack,1,2 Ke-Lin Ru,2,5 Joanna Crawford,2 John S. Mattick,3,6 Marcel E. Dinger,3,4,6 and Andrew C. Perkinsa,1,2,7 Scientific Reports 6, Article number: 26657 (2016) doi:10.1038/srep26657 http://www.nature.com/articles/srep26657#discussion

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

lincRNA research is at a very interesting juncture—thousands of lincRNA genes have been identified, and the diverse functional and mechanistic underpinnings of a few well-studied examples suggest that many of these (hundreds, if not more) might participate in important and diverse aspects of biology. Recent observations regarding lincRNA genomics and evolution, such as their frequently cytoplasmic accumulation or their frequently syntenic loci despite undetectable sequence conservation, only add to the mysteries of lincRNA function and mechanism. With all this intrigue, biologists with diverse interests and backgrounds are exploring how lincRNAs might participate in the biological processes that they study. The insights on the horizon will help separate this rag-tag set of transcripts into coherent, well-defined subclasses, thereby enabling the information gained from the study of one lincRNA to be more reliably leveraged for the understanding of many others, and ultimately providing a firm grasp on how many of the thousands of lincRNA genes found in the cell are functional.

lincRNAs: Genomics, Evolution, and Mechanisms Igor Ulitsky and David P. Bartel DOI: http://dx.doi.org/10.1016/j.cell.2013.06.020

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

It remains difficult to determine which exon combinations co-occur in long multiply spliced transcripts and to discriminate between independent lincRNAs and fragments of alternative mRNA isoforms or pseudogenes. Repetitive elements are also reported to play important mechanistic roles in lincRNAs, by facilitating base pairing with other RNAs containing repeats from the same family [...] or through other, less understood mechanisms The extent to which lincRNAs found in gene deserts near developmental TFs are functional or fundamentally different from other lincRNAs is unclear. Secondary structure is important for most noncoding RNA classes, including some long noncoding RNA [...] but the prevalence of secondary structure-mediated roles in lincRNA biology remains unknown.

lincRNAs: Genomics, Evolution, and Mechanisms Igor Ulitsky and David P. Bartel http://www.cell.com/cell/fulltext/S0092-8674(13)00759-9

Dionisio

Recent advances in transcriptome sequencing have made it possible to distinguish ubiquitously expressed long non-coding RNAs (UE lncRNAs) from tissue-specific lncRNAs (TS lncRNAs), thereby providing clues to their cellular functions.

Identifying and functionally characterizing tissue-specific and ubiquitously expressed human lncRNAs Chunjie Jiang1,*, Yongsheng Li1,*, Zheng Zhao1,*, Jianping Lu1, Hong Chen1, Na Ding1, Guangjuan Wang1, Juan Xu1, Xia Li1 DOI: 10.18632/oncotarget.6859

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

While long non-coding RNAs play key roles in disease and development, few structural studies have been performed to date for this emerging class of RNAs. Previous structural studies are reviewed, and a pipeline is presented to determine secondary structures of long non-coding RNAs. Similar to riboswitches, experimentally determined secondary structures of long non-coding RNAs for one species, may be used to improve sequence/structure alignments for other species. As riboswitches have been classified according to their secondary structure, a similar scheme could be used to classify long non-coding RNAs

Towards structural classification of long non-coding RNAs. Sanbonmatsu KY1. Biochim Biophys Acta. 2016 Jan;1859(1):41-5. doi: 10.1016/j.bbagrm.2015.09.011

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

The field of structural biology has the unique advantage of being able to provide a comprehensive picture of biological mechanisms at the molecular and atomic level. Long noncoding RNAs (lncRNAs) represent the new frontier in the molecular biology of complex organisms yet remain the least characterised of all the classes of RNA. Thousands of new lncRNAs are being reported each year yet very little structural data exists for this rapidly expanding field. The length of lncRNAs ranges from 200 nt to over 100 kb in length and they generally exhibit low cellular abundance. Therefore, obtaining sufficient quantities of lncRNA to use for structural analysis is challenging. However, as technologies develop structures of lncRNAs are starting to emerge providing important information regarding their mechanism of action.

The ins and outs of lncRNA structure: How, why and what comes next? Blythe AJ1, Fox AH2, Bond CS3. Biochim Biophys Acta. 2016 Jan;1859(1):46-58. doi: 10.1016/j.bbagrm.2015.08.009.

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

Current experimental methods to identify the functions of a large number of the candidates of long non-coding RNAs (lncRNAs) are limited in their throughput. Therefore, it is essential to know which tools are effective for understanding lncRNAs so that reasonable speed and accuracy can be achieved.

Bioinformatics tools for lncRNA research. Iwakiri J1, Hamada M2, Asai K3. Biochim Biophys Acta. 2016 Jan;1859(1):23-30. doi: 10.1016/j.bbagrm.2015.07.014.

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

The pervasive transcription of genomes into long noncoding RNAs has been amply demonstrated in recent years and garnered much attention. Similarly, emerging 'epitranscriptomics' research has shown that chemically modified nucleosides, thought to be largely the domain of tRNAs and other infrastructural RNAs, are far more widespread and can exert unexpected influence on RNA utilization. Both areas are characterized by the often-ephemeral nature of the subject matter in that few individual examples have been fully assessed for their molecular or cellular function, and effects might often be subtle and cumulative.

The emerging epitranscriptomics of long noncoding RNAs. Shafik A1, Schumann U2, Evers M3, Sibbritt T4, Preiss T5. Biochim Biophys Acta. 2016 Jan;1859(1):59-70. doi: 10.1016/j.bbagrm.2015.10.019

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

Long noncoding RNAs (lncRNAs) are increasingly recognized as functional regulatory components in eukaryotic gene regulation. Distinct classes of lncRNAs have been identified in eukaryotes and they play roles in various regulatory networks. Growing numbers of regulatory lncRNAs are being recognized and shown to function in virtually every aspect of biology in eukaryotes. Challenges will be to distinguish regulatory lncRNAs from transcriptional noise. It is likely, however, that molecular understanding of the role of lncRNAs will shed light on this ‘dark matter’ in the genome as an important layer in gene regulatory network in many eukaryotes.

Long noncoding RNA: unveiling hidden layer of gene regulatory networks Eun-Deok Kim and Sibum Sung doi:10.1016/j.tplants.2011.10.008

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

High-throughput sequencing has revealed that the majority of RNAs have no capacity to encode protein. Among these non-coding transcripts, recent work has focused on the roles of long noncoding RNAs (lncRNAs) of >200 nucleotides. Although many of their attributes, such as patterns of expression, remain largely unknown, lncRNAs have key functions in transcriptional, post-transcriptional, and epigenetic gene regulation; Also, new work indicates their functions in scaffolding ribonuclear protein complexes. In plants, genome-wide identification of lncRNAs has been conducted in several species, including Zea mays, and recent research showed that lncRNAs regulate flowering time in the photoperiod pathway, and function in nodulation.

Exploring the Secrets of Long Noncoding RNAs Mingyang Quan 1,2?, Jinhui Chen 1,2? and Deqiang Zhang 1,2,* ? Int. J. Mol. Sci. 2015, 16(3), 5467-5496; doi:10.3390/ijms16035467

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

Although thousands of long non-coding RNAs (lncRNAs) have been discovered in eukaryotes, very few molecular mechanisms have been characterized due to an insufficient understanding of lncRNA structure. Therefore, investigations of lncRNA structure and subsequent elucidation of the regulatory mechanisms are urgently needed. However, since lncRNA are high molecular weight molecules, which makes their crystallization difficult, obtaining information about their structure is extremely challenging, and the structures of only several lncRNAs have been determined so far.

Understanding the Functions of Long Non-Coding RNAs through Their Higher-Order Structures Rui Li, Hongliang Zhu and Yunbo Luo? Int. J. Mol. Sci. 2016, 17(5), 702; doi:10.3390/ijms17050702

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

Sequential generation of neurons and glial cells during development is critical for the wiring and function of the cerebral cortex. This process requires accurate coordination of neural progenitor cell (NPC) fate decisions, by NPC-autonomous mechanisms as well as by negative feedback from neurons. During cortical development, neuroepithelial/apical neural progenitor cells (AP) undergo divisions that are initially symmetrical and increase the size of the progenitor pool. At the onset of neurogenesis, some divisions become asymmetric and generate AP and either neurons or intermediate/basal progenitors (BP) which have limited self-renewal capacity and are committed to an excitatory glutamatergic neuron phenotype. Regulatory mechanisms are hence likely to operate in parallel and it will be challenging to understand how they are integrated in vivo during development [...]

Feedback regulation of apical progenitor fate by immature neurons through Wnt7–Celsr3–Fzd3 signalling Wei Wang,1,* Yves Jossin,1 Guoliang Chai,1 Wen-Hui Lien,2 Fadel Tissir,a,1,† and Andre M. Goffinet Nat Commun. 2016; 7: 10936. doi: 10.1038/ncomms10936 http://www.nature.com/ncomms/2016/160304/ncomms10936/full/ncomms10936.html

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

Morphogenesis and physiology of tissues and organs requires planar cell polarity (PCP) systems that orient and coordinate cells and their behaviors, but the relationship between PCP systems has been controversial. Animals have many asymmetric organs. Wings, for example, are aerodynamically shaped and have a clear front, back, top and bottom, and even additions to these organs, such as feathers on the wing, often need to be oriented in a specific manner. Future studies should aim to work out the number of systems that polarize cells and how they are connected in different tissues.

Coordination of planar cell polarity pathways through Spiny-legs Ambegaonkar AA1,2,3, Irvine KD1,2,3. Elife. ;4. pii: e09946. doi: 10.7554/eLife.09946. eLife 2015;4:e09946 http://elifesciences.org/content/4/e09946v2

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

Planar cell polarity signaling directs the polarization of cells within the plane of many epithelia. The direction of polarity in the D-wing is therefore likely determined by a novel mechanism independent of microtubule polarity. In the P-abd, Prickle and Spiny-legs interpret at least two directional cues through a microtubule-polarity-independent mechanism. Planar cell polarity (PCP) is the alignment of cells within the plane of an epithelium orthogonal to the apicobasal axis. [...] a more definitive understanding of how Pk and Sple are altering tissue polarity in the D-wing will require a better understanding of the mechanism of any distal or margin derived directional signal. The mechanisms through which Pk and Sple not only control microtubule polarity but also interpret signals from this unknown cryptic source are not clear. Whether analogous binding occurs between Pk and Ft is unknown. [...] the mechanisms governing the direction of bristle growth are relatively unstudied as compared to those governing the direction of hair growth. The D-wing and P-abd thus provide two additional signaling paradigms that can, going forward, be used for discovery of additional cell biological and signaling mechanisms important for PCP.

Prickle isoforms control the direction of tissue polarity by microtubule independent and dependent mechanisms Katherine A. Sharp1,2 and Jeffrey D. Axelrod1 Biol Open. 5(3): 229–236. doi: 10.1242/bio.016162 http://bio.biologists.org/content/5/3/229

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

A fundamental question is how complex structures are maintained after their initial specification. Stem cells reside in a specialized microenvironment, called niche, which provides essential signals controlling stem cell behavior. In all adult tissues harboring stem cells, the niche has a critical function as an organizer, which recruits the stem cells and provides the microenvironment that supports stem cell identity. The niche is a vital component of all stem cell systems. From its initial specification throughout adult life, the niche preserves stem cell identity thereby building a dynamic system ensuring sustained tissue homeostasis, cell renewal and balanced response of the organism to challenges such as injury or disease. This underlines the complexity and robustness of the integrin protein network, and reflects the complex epistatic effects among genetically interacting players. [...] getting more insights into the mechanisms of epistatic relations among the integrin-interacting network components is beyond the focus of this study. All these factors coordinate their action towards a functional male stem cell niche, which is required for the testis to functionally mature, to become part of the male genitalia and to be able to produce healthy gametes.

Stage-specific control of niche positioning and integrity in the Drosophila testis Lisa Schardta, b ,Janina-Jacqueline Andera, Ingrid Lohmanna, , , Fani Papagiannouli doi:10.1016/j.mod.2015.07.009 Mechanisms of Development Volume 138, Part 3, Pages 336–348 http://www.sciencedirect.com/science/article/pii/S0925477315300113

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

The asymmetric distribution of various proteins and RNAs is essential for all stages of animal development, and establishment and maintenance of this cellular polarity are regulated by a group of conserved polarity determinants. Neurons are probably the most polarized/compartmentalized cell type in the human body. Their polarity establishment starts with the specification of dendrites and axons. Further compartmentalization occurs during the formation of dendritic spines, which receive most of the excitatory synaptic inputs in the brain. The establishment of cell polarity is essential at all stages of animal development, as segregation of different cellular domains is key to the physiological functions of all cell types. While great progress has been made in understanding the function of this important group of proteins in spine development, many questions remain. Future research will pave the way to understanding of how these conserved polarity proteins help shape the synaptic connections and how they contribute to cognitive functions of the brain.

Polarity Determinants in Dendritic Spine Development and Plasticity Huaye Zhang Neural Plasticity Volume 2016 (2016), Article ID 3145019, 10 pages http://dx.doi.org/10.1155/2016/3145019 http://www.hindawi.com/journals/np/2016/3145019/

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

Further studies would be important to understand what the role of cilia during renal tubular development is or whether their function during tubular morphogenesis is, instead, dispensable. [...] while the central role of PCP in the developing renal tubule has been unequivocally proven, its role in cystogenesis is less clear.

Role of the Polycystins in Cell Migration, Polarity, and Tissue Morphogenesis. Nigro EA1, Castelli M2, Boletta A3. Cells. ;4(4):687-705. doi: 10.3390/cells4040687 http://www.mdpi.com/2073-4409/4/4/687

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

The planar cell polarity (PCP) pathway is a cell-contact mediated mechanism for transmitting polarity information between neighboring cells. Whether neuroepithelial planar polarity directs posterior migration or simply enables it, and through what effectors PCP signaling regulates filopodial dynamics in vivo are important questions to be answered in future work.

PCP Signaling between Migrating Neurons and their Planar-Polarized Neuroepithelial Environment Controls Filopodial Dynamics and Directional Migration Davey CF1, Mathewson AW1, Moens CB1. http://dx.doi.org/10.1371/journal.pgen.1005934 http://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1005934

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

Several important questions need to be addressed [...] [...] the relevance of the observed gene up-regulations to the adaptation of Hydra to the loss of neurogenesis needs to be confirmed by functional studies. [...] maintenance of their developmental programmes*. [...] local injury-induced epithelial plasticity might also participate in head regeneration. [...] the cellular functions [...] need to be explored. Epithelial cells play multiple functions [...] and several of them might be affected by [...] genetic changes, such as cell-to-cell communication, epithelial conduction through gap junctions, cell adhesion, cell cycle regulation or differentiation. [...] genes are maintained repressed by signals from the surrounding i-cells and/or the interstitial progenitors [...] [...] continuous crosstalk between the interstitial and the epithelial cell lineages [...] [...] elimination of the interstitial cells enhance regeneration in a regeneration-deficient mutant strain. Further studies will test this mechanism and potentially identify novel components of the signalling between interstitial and epithelial cell lineages. [...] deciphering the interstitial–epithelial crosstalk [...] might highlight some aspects [...]

Loss of neurogenesis in Hydra leads to compensatory regulation of neurogenic and neurotransmission genes in epithelial cells Y. Wenger, W. Buzgariu, B. Galliot DOI: 10.1098/rstb.2015.0040 http://rstb.royalsocietypublishing.org/content/371/1685/20150040

(*) developmental programmes? As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

Hydra continuously differentiates a sophisticated nervous system made of mechanosensory cells (nematocytes) and sensory–motor and ganglionic neurons from interstitial stem cells. However, this dynamic adult neurogenesis is dispensable for morphogenesis. Indeed animals depleted of their interstitial stem cells and interstitial progenitors lose their active behaviours but maintain their developmental fitness, and regenerate and bud when force-fed. [...] epitheliomuscular cells seemingly enhance their sensing ability when neurogenesis is compromised. This unsuspected* plasticity might reflect the extended multifunctionality of epithelial-like cells [...] [...] the central body column [where i-cells are located] of the adult Hydra polyp is neurogenic, whereas the extremities contain a dense and highly differentiated nervous system [...] [...] epithelial cells adapt to the loss of i-cells by enhancing some sensing/acting functions so that the animal can remain fit, survive and develop when necessary. [...] epitheliomuscular cells in Hydra are highly plastic, undergoing sustained modification of their transcriptional programme** after the elimination of interstitial cells.

Loss of neurogenesis in Hydra leads to compensatory regulation of neurogenic and neurotransmission genes in epithelial cells Y. Wenger, W. Buzgariu, B. Galliot DOI: 10.1098/rstb.2015.0040 http://rstb.royalsocietypublishing.org/content/371/1685/20150040

(*) unsuspected? (**) transcriptional programme? As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

The fundamental forces that shaped human brain network topology at evolutionary time scales remain poorly understood [...] [...] different types of networks are likely to be generated by different mechanisms, and their topology may give clues as to the mechanisms that created them. Network topology may contain information on the design* principles of biological networks [...] Exploiting complex network theory's full potential will suppose a few conceptual quantum leaps. The statistical mechanics assumptions representing the backbone of complex network theory and their conceptual and methodological implications will have to be interiorized. At the same time, some of its intrinsic limits will need to be acknowledged and overcome. Neuroscience will have to both resort to hitherto unexploited existing network tools, particularly accounting for dynamical aspects of brain activity, and stimulate fresh theoretical effort, so as to produce network constructs better catering for its specific needs, instead of importing wholesale and readymade concepts originally meant to describe systems in many ways qualitatively different from the brain.

Functional brain networks: great expectations, hard times and the big leap forward David Papo, Massimiliano Zanin, José Angel Pineda-Pardo, Stefano Boccaletti, Javier M. Buldú DOI: 10.1098/rstb.2013.0525 http://rstb.royalsocietypublishing.org/content/369/1653/20130525

[emphasis mine] (*) design? :) As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

Looking forward with increasing anticipation to reading future research papers shedding more light on the elaborate cellular and molecular choreographies orchestrated within the biological systems. Will be back. Ciao! Paká! Hasta luego! :) Dionisio

Systems approaches have been taken to understand the global dynamics in cellular processes, which have allowed for novel identification of developmental regulators. [...] it is unclear how the loci-specific changes occur to give rise to different cell types [...] [...] it remains unknown how these mechanisms work in combination to mediate the spatial organization for establishing cardiac-specific gene expression.

How the proteome packages the genome for cardiovascular development Elaheh Karbassi and Thomas M. Vondriska DOI: 10.1002/pmic.201400131 http://onlinelibrary.wiley.com/doi/10.1002/pmic.201400131/abstract

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

[...] lncRNAs have the potential to solve a major riddle of chromatin biology: how are chromatin remodeling enzymes and structural proteins targeted to the correct genes in a development- and stimulus-responsive manner? lncRNAs are an exciting interface between the transcriptome, genome and proteome for regulating developmental (and adult) phenotypes in part because so much remains unknown about how they function. What are the proteins that guide lncRNAs to the proper histone modifications? Are the lncRNA-protein complexes heterogeneous in a single cell? Are all histone modifications of a given type bound by a given lncRNA in a terminally differentiated cell (e.g. is every nucleosome with H3K27me3 bound by Braveheart and/or Fendrr)? Are the protein binding partners for individual lncRNAs dynamic at a single locus and do the complexes change genomic residence during development?

How the proteome packages the genome for cardiovascular development Elaheh Karbassi and Thomas M. Vondriska DOI: 10.1002/pmic.201400131 http://onlinelibrary.wiley.com/doi/10.1002/pmic.201400131/abstract

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

A major unanswered question in the field of chromatin structural proteins relates to the basic logic of their function. [...] the extent and functional consequences of PTM on non-nucleosomal proteins is not well understood. Are these proteins non-specific “bricks and mortar” for genome packaging or do they form distinct species of complexes, perhaps with regulation through PTM, and have individual target loci? Answers to these questions will require creative combination of proteomics to map protein complexes with epigenomics to determine which members of said complexes confer specificity.

How the proteome packages the genome for cardiovascular development Elaheh Karbassi and Thomas M. Vondriska DOI: 10.1002/pmic.201400131 http://onlinelibrary.wiley.com/doi/10.1002/pmic.201400131/abstract

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

Future studies integrating the current enhancer datasets with three-dimensional chromatin architecture measurements [17] will be important to understand how organization of the genome is coordinated in vivo to orchestrate cell fate [...] [...] whether these enhancers are shared or distinct from those associated with cardiac hypertrophy [52] is another question that, when answered, will advance our understanding of the scales at which cellular programming in disease mimics that in development. A model for how DNA methylation contributes to higher-order chromatin structure (between the scale of nucleosome and chromosome) is currently lacking [...] [...] case-control studies are lacking to understand the basal differences in DNA methylation between cells in the cardiovascular lineage. [...] whether and how chromatin architecture can influence nuclear plasticity and cell function has not been explored in the heart.

How the proteome packages the genome for cardiovascular development Elaheh Karbassi and Thomas M. Vondriska DOI: 10.1002/pmic.201400131 http://onlinelibrary.wiley.com/doi/10.1002/pmic.201400131/abstract

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

[...] interactions between different histone methylating complexes are highly coordinated. [...] link between the functions of chromatin structure and tissue-specific transcription factors. [...] the specific role it [H2A.Z] plays in regulation of cardiomyocyte differentiation and heart development has not been established. Future studies using ChIP-seq for endogenous histone-modifying enzymes will be required to elucidate how these proteins coordinate with cardiac transcription factors in vivo and at different developmental stages.

How the proteome packages the genome for cardiovascular development Elaheh Karbassi and Thomas M. Vondriska DOI: 10.1002/pmic.201400131 http://onlinelibrary.wiley.com/doi/10.1002/pmic.201400131/abstract

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

Cardiac development involves signaling by stage-specific transcription factors that define branching into cellular lineages. [...] how these signaling pathways regulate chromatin architecture to fine tune global gene expression patterns and the chromatin level factors that determine specialization of cardiomyocytes into atrial, ventricular, and conduction cells remain unknown. [...] emergent areas in which proteomics and systems biology can advance our understanding of the epigenetics of development. [...] the individual functions in chromatin maintenance and regulation of packaging are less established, and how these modifications interact in a coordinate fashion to mediate chromatin architecture during developmental transitions, is yet to be determined.

How the proteome packages the genome for cardiovascular development Elaheh Karbassi and Thomas M. Vondriska DOI: 10.1002/pmic.201400131 http://onlinelibrary.wiley.com/doi/10.1002/pmic.201400131/abstract

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

The human transcriptome comprises >80 000 protein-coding transcripts and the estimated number of proteins synthesized from these transcripts is in the range of 250 000 to 1 million. These transcripts and proteins are encoded by less than 20 000 genes, suggesting extensive regulation at the transcriptional, post-transcriptional, and translational level. Here we review how RNA sequencing (RNA-seq) technologies have increased our understanding of the mechanisms that give rise to alternative transcripts and their alternative translation. We highlight four different regulatory processes: alternative transcription initiation, alternative splicing, alternative polyadenylation, and alternative translation initiation. We discuss their transcriptome-wide distribution, their impact on protein expression, their biological relevance, and the possible molecular mechanisms leading to their alternative regulation. We conclude with a discussion of the coordination and the interdependence of these four regulatory layers.

Alternative mRNA transcription, processing, and translation: insights from RNA sequencing Eleonora de Klerk, Peter A.C. ‘t Hoen doi:10.1016/j.tig.2015.01.001 http://www.sciencedirect.com/science/article/pii/S0168952515000025

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

[...] it remains unclear how transcription factors regulate transcription in the heart and which genes are associated with cardiovascular diseases in humans. [...] the reason why mutations in the genes regulating H3K4 methylation, but not other histone modifications, are significantly enriched in CHDs is still unclear [...] [...] it may be important to elucidate how the dysregulation of H3K4 methylation changes global gene expression pattern during heart development. [...] it is still unclear whether genome-wide chromatin modifications, including histone modifications and DNA methylation, are changed in cardiovascular diseases and how dysregulation of chromatin regulation leads to these diseases is not fully elucidated. Moreover, it should be elucidated why specific heart regions, including the septum, are easily affected by transcriptional dysregulation. Because each heart region activates different enhancers during heart development,94 it is necessary to elucidate how gene expression is regulated in these regions by next-generation sequencing for understanding the mechanisms of the onset of CHDs.

Elucidating the mechanisms of transcription regulation during heart development by next-generation sequencing Keisuke Nimura1 and Yasufumi Kaneda1 Journal of Human Genetics (2016) 61, 5–12; doi:10.1038/jhg.2015.84 http://www.nature.com/jhg/journal/v61/n1/full/jhg201584a.html

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

Pluripotent stem cells (PSCs) represent a unique kind of stem cell, as they are able to indefinitely self-renew and hold the potential to differentiate into any derivative of the three germ layers. The molecular mechanisms underlying pluripotency represent a major field of research. An orchestra* of transcription factors, chromatin regulators, signaling transducers, miRNAs and lncRNAs play coordinately in pluripotent cells. Each of them cannot be considered a solo player. Complex networks and feedback loops exist, which comprise members of each class of regulatory factors. The paucity of functional studies is in striking contrast with the number of annotated lncRNAs (thousands) that are specifically enriched in ESCs and/or described as interactors of crucial pluripotency regulators, such as Polycomb and Trithorax complexes. We expect, in the near future, a substantial increase of functional studies describing new examples of lncRNAs acting in network with other master regulators in the definition of the pluripotent state.

Long Noncoding RNA Regulation of Pluripotency Alessandro Rosa1 and Monica Ballerina Stem Cells International Volume 2016, Article ID 1797692, 9 pages http://dx.doi.org/10.1155/2016/1797692 http://www.hindawi.com/journals/sci/2016/1797692/

(*) orchestra? As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

Embryonic stem cells (ESCs) hold great promises for treating and studying numerous devastating diseases. The molecular basis of their potential is not completely understood. Large noncoding RNAs (lncRNAs) are an important class of gene regulators that play essential roles in a variety of physiologic and pathologic processes. Dozens of lncRNAs are now identified to control ESC self-renewal and differentiation.

Large Noncoding RNAs Are Promising Regulators in Embryonic Stem Cells Ya-Pu Li, Yangming Wang doi:10.1016/j.jgg.2015.02.002 http://www.sciencedirect.com/science/article/pii/S1673852715000338

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

Surprisingly* these embryos survive throughout gastrulation exhibiting no defects in the ICM and epiblast. Thus, we presume that Esrrb can be compensated by other factors in this complex transcriptional network maintaining pluripotency. Further investigations are necessary to clarify molecular mechanisms to date, but regarding its attested role in trophoblast specification we classified Esrrb to be an extraembryonic-class gene. Although both the pluripotency circuitry and early lineage commitment mechanisms have been studied in great detail, there is still a broad gap of knowledge regarding the distinct regulatory complexes governing these events. TFs interact in network in a spatial and temporal manner to exit pluripotency and establish different lineages in the early embryo.

Clair E. Weidgang, Thomas Seufferlein, Alexander Kleger, and Martin Mueller, “Pluripotency Factors on Their Lineage Move,” Stem Cells International, vol. 2016, Article ID 6838253, 16 pages, 2016. doi:10.1155/2016/6838253 http://www.hindawi.com/journals/sci/2016/6838253/

(*) Surprisingly? As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

The regulatory events that define the timing and site of gastrulation initiation still remain rather unclear. Molecularly, this gatekeeper function is exerted by alternate partnering and changes in cobound factors to orchestra[te] cell fate choice by alternating target gene binding. Tbx3 is embedded in the core pluripotency networks to sustain stemness but also strongly directs early embryonic development by either transcriptional activation of differentiating gene programmes or modification of chromatin structures. As Sall4 associates with the NuRD complex, both genes could act together in sustaining pluripotency. But due to lacking evidence this hypothesis remains an assumption.

Clair E. Weidgang, Thomas Seufferlein, Alexander Kleger, and Martin Mueller, “Pluripotency Factors on Their Lineage Move,” Stem Cells International, vol. 2016, Article ID 6838253, 16 pages, 2016. doi:10.1155/2016/6838253 http://www.hindawi.com/journals/sci/2016/6838253/

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

Pluripotent stem cells are characterized by continuous self-renewal while maintaining the potential to differentiate into cells of all three germ layers. A precise interplay of signaling axes regulates ground state conditions and acts in concert with a combination of key transcription factors. The complexity of the regulatory networks, which maintain pluripotency, has previously been described. Complex interactions between signalling axes precisely regulate various states of pluripotency, such as the ground and the primed state, and act in concert with a combination of key transcription factors (TFs). However, detailed underlying insights into how these transcription factors orchestrate cell fate decisions remain largely elusive.

Clair E. Weidgang, Thomas Seufferlein, Alexander Kleger, and Martin Mueller, “Pluripotency Factors on Their Lineage Move,” Stem Cells International, vol. 2016, Article ID 6838253, 16 pages, 2016. doi:10.1155/2016/6838253 http://www.hindawi.com/journals/sci/2016/6838253/

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

Stress is normal during early embryogenesis and transient, elevated stress is commonplace. Stress in the milieu of the peri-implantation embryo is a summation of maternal hormones, and other elements of the maternal milieu, that signal preparedness for development and implantation. The interaction of stress enzymes and TFs in the early embryo and its stem cells are a continuing central focus of research.

Molecular biology of the stress response in the early embryo and its stem cells. Puscheck EE1, Awonuga AO, Yang Y, Jiang Z, Rappolee DA. Cell Signaling During Mammalian Early Embryo Development Volume 843 of the series Advances in Experimental Medicine and Biology pp 77-128 http://link.springer.com/chapter/10.1007/978-1-4939-2480-6_4?no-access=true

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

[...] despite the complex stochastic kinetics of transcription, and the multiple ways that these kinetics can be modulated [...], some simple unifying features emerge. The mechanistic basis for this prevalent phenomenology is yet to be elucidated [...] [...] multiple additional factors may contribute to mRNA heterogeneity. Additional work, both experimental and theoretical, is required to delineate the relative contribution of all these factors to the eventual mRNA statistics that we measure.

Single-cell analysis of transcription kinetics across the cell cycle Skinner SO1,2,3, Xu H1,2,4, Nagarkar-Jaiswal S5, Freire PR6, Zwaka TP5,7, Golding I1,2,3,4. Elife. 29;5. pii: e12175. doi: 10.7554/eLife.12175. http://elifesciences.org/content/5/e12175v2

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

How are cells able to maintain constant levels of mRNA when the number of genes in a cell doubles ahead of cell division? How do replicating cells compensate for this so that mRNA levels remain constant? Imagine trying to maintain a constant speed while driving a car. The cell cycle poses additional challenges for cells. For one, cell division immediately halves mRNA production, and so mRNA levels must increase in preparation for this event. This is achieved through a mechanism that monitors the volume of the cell and increases burst size accordingly [...]

Bursting through the cell cycle Ben-Moshe S1, Itzkovitz S1. Elife. 7;5. pii: e14953. doi: 10.7554/eLife.14953. DOI: http://dx.doi.org/10.7554/eLife.14953 http://elifesciences.org/content/5/e14953v1

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

The E2F transcription factor is a key cell cycle regulator. [...] the cell cycle regulator is repurposed in post-mitotic cells. Surprisingly*, E2F requirement was restricted to late myogenesis when muscles undergo extensive growth. How the expression of late myogenic genes is maintained in adult muscles is not completely understood. Other factors that may operate at this point to maintain muscle gene expression have not yet been identified [...] An unexpected** finding of our work is that the lethality of E2F-deficient animals is largely due to the requirement of E2F in adult skeletal muscles. Intriguingly***, mammalian E2F factors were shown to regulate differentiation of various cell types by promoting tissue-specific transcriptional programmes. [...] the role of E2F in the regulation of tissue-specific transcriptional programmes is highly conserved, and the relevance of our findings extends beyond the fly model.

E2F function in muscle growth is necessary and sufficient for viability in Drosophila Maria Paula Zappia1, & Maxim V. Frolov1, doi:10.1038/ncomms10509 Nature Communications Volume:7, Article number:10509 http://www.nature.com/ncomms/2016/160129/ncomms10509/full/ncomms10509.html

(*) Surprisingly? (**) unexpected? (***) Intriguingly? As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

Cell cycle proteins are important regulators of diverse cell fate decisions, and in this capacity have pivotal roles in neurogenesis and brain development. The mechanisms by which cell cycle regulation is integrated with cell fate control in the brain and other tissues are poorly understood, and an outstanding question is whether the cell cycle machinery regulates fate decisions directly or instead as a secondary consequence of proliferative control. The classical cell cycle regulatory pRb/E2f pathway has emerged as an important effector of fate decisions in a number of cell types, including in the brain. The cell cycle machinery is a pivotal regulator of brain development and function by influencing key cell fate decisions, typically via E2f transcription factor activity. E2f transcription factors are poised as widespread regulators of cell fate-associated genes in NPCs, establishing a pervasive direct role for the cell cycle machinery in fate determination, and E2f3 is associated with specialized, tissue-specific differentiation programs. This finding underscores the importance of identifying factor-specific targets in an unbiased manner to fully appreciate the genetic mechanisms driving biological phenomena. [...] in cells that are actively making stem cell fate decisions, pRb/E2f factors can direct these decisions independently from cell cycle regulation [...] through direct regulation of networks of cell fate-associated genes. We unexpectedly* identified Ctcf as a potential regulatory co-factor for E2f3 at differentiation genes in NPCs. More functional analyses are required to determine if this association is unique to NPCs or is more widespread, and to clarify how Ctcf–E2f interactions impact transcription. We were also surprised** to observe that E2f3 binds target sites in a highly tissue-specific manner in NPCs compared with MBs. It will be important for future studies to examine E2f3a&b binding patterns in other tissue and cell types to reveal the extent by which E2f3 may function as a determinant of tissue-specific differentiation programs***.

Tissue-specific targeting of cell fate regulatory genes by E2f factors. Julian LM1, Liu Y2, Pakenham CA1, Dugal-Tessier D1, Ruzhynsky V1, Bae S3, Tsai SY3, Leone G3, Slack RS1, Blais A2. Cell Death Differ.;23(4):565-75. doi: 10.1038/cdd.2015.36. http://www.nature.com/cdd/journal/v23/n4/full/cdd201536a.html

(*) unexpectedly? (**) surprised? (***) differentiation programs? As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

Paired box (Pax) genes encode for transcription factors that are considered key players in organogenesis and embryonic development. The importance of alternative splicing as a mechanism for divergent evolution* is established. [...] a mechanism through which alternative splicing contributes to the increase of complexity at the level of protein function. [...] the exact junction sequence between exon 2 and intron 2 is not known [...] [...] an important re-arrangement of coding and non-coding sequences in the region of paired domain took place during evolution*. Introns are required for alternative splicing and alternative splicing increases the size of the proteome, thus increasing the level of complexity in higher eukaryotes. Moreover, introns have been found to harbor many conserved non-coding elements, necessary for gene regulation. [...] at this stage, it is not easy to conclude as to the regulation of these isoforms. Nonetheless there is an indication of a temporal regulation [...], which requires further investigation.

Pax2/5/8 and Pax6 alternative splicing events in basal chordates and vertebrates: a focus on paired box domain Peter Fabian, Iryna Kozmikova, Zbynek Kozmik and Chrysoula N. Pantzartzi* Front. Genet., http://dx.doi.org/10.3389/fgene.2015.00228 http://journal.frontiersin.org/article/10.3389/fgene.2015.00228/full

(*) [how? what determined the sequence of cut&paste steps? what triggered it? what stopped it?] As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

While advances over the past few years have greatly expanded our view of the functional importance of transcriptional regulation by E2Fs and PPs, the mechanistic understanding of their role in stem cell fate regulation is in its infancy. We need a better understanding of which stem cell populations rely on E2F/PP activity when making key cell fate decisions, as well as which epigenetic co-factors contribute to gene class and cell type-specific gene expression. [...] it will be important [...] to understand the full extent of E2F/PP function in stem cell fate control. [...] will shed important mechanistic insight on the epigenetic role of E2Fs/PPs in cell fate decision making. An important question for future investigations, which is currently largely unaddressed, is how E2Fs and PPs may regulate cell fate genes in post-mitotic cells. Gaining a clearer understanding of the mechanisms underlying epigenetic cell fate regulation by E2Fs/PPs by addressing these key questions will have important implications in the contexts of tumorigenesis and disease, development, tissue homeostasis, and regeneration.

Transcriptional control of stem cell fate by E2Fs and pocket proteins Lisa M. Julian1,* and Alexandre Blais2,3,* Front Genet. 6: 161. doi: 10.3389/fgene.2015.00161 http://journal.frontiersin.org/article/10.3389/fgene.2015.00161/full

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

The CRISPR–Cas9 system holds the potential to revolutionize developmental biology by making it possible to probe with exquisite control the interplay between genome activity and developmental events such as cell proliferation, differentiation, and morphogenesis.

A CRISPR view of development Melissa M. Harrison1, Brian V. Jenkins2, Kate M. O’Connor-Giles3,4 and Jill Wildonger2 10.1101/gad.248252.114 Genes & Dev. 28: 1859-1872 http://genesdev.cshlp.org/content/28/17/1859.full

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

Coordination of differentiation and cell cycle progression represents an essential process for embryonic development and adult tissue homeostasis. These mechanisms ultimately determine the quantities of specific cell types that are generated. Despite their importance, the precise molecular interplays between cell cycle machinery and master regulators of cell fate choice remain to be fully uncovered. [...] cell cycle regulators can orchestrate cell fate decisions by organising transcriptional networks in human stem cells. [...] E2F factors could orchestrate stem cell and progenitor differentiation in a diversity of tissues, underlining that cell cycle control of cell fate choice could be a common mechanism between a diversity of progenitors. [...] the basic mechanisms uncovered by these studies could also be relevant for adult stem cells and represent an important step toward understanding the balance between differentiation and self-renewal during organ development and repair

Initiation of stem cell differentiation involves cell cycle-dependent regulation of developmental genes by Cyclin D Siim Pauklin,1 Pedro Madrigal,1,2 Alessandro Bertero,1 and Ludovic Vallier1, Genes Dev.; 30(4): 421–433. doi: 10.1101/gad.271452.115 http://genesdev.cshlp.org/content/30/4/421.full

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

Gastrulation is a critical milestone of early embryogenesis in mammals when the primary germ layers are formed and the multipotent embryonic cells are allocated to the progenitors of tissue lineages within the germ layers. Morphogenesis of the germ layers during gastrulation entails a complex mechanism that regulates the proliferation, movement, and patterning of cell populations, and the choreography of switches in genetic and signaling activity that may drive lineage specification and tissue modeling in the embryo. [...] the molecular controls in time and space that underpin the exit of cells from the multipotent state, the specification of lineage-restricted progenitors and the regionalization of cell fates pertaining to the establishment of the body plan are not fully known. A holistic knowledge of the activity of the genome specifically at gastrulation is essential for gleaning a better understanding of the molecular mechanism for lineage specification and embryonic patterning.

Spatial Transcriptome for the Molecular Annotation of Lineage Fates and Cell Identity in Mid-gastrula Mouse Embryo Guangdun Peng, Shengbao Sue, Jun Chen, Weiyang Chen, Chang Liu, Fang Yu, Ran Wang, Shirui Chen, Na Sun, Guizhong Cui, Lu Song, Patrick P.L. Tam, Jing-Dong J. Han, Naihe Jingo DOI: http://dx.doi.org/10.1016/j.devcel.2016.02.020 Developmental Cell Volume 36, Issue 6, p681–697 http://www.cell.com/developmental-cell/fulltext/S1534-5807(16)30075-2

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

Modifications of the ground-state developmental programme are orchestrated by different combinations of MADS-domain transcription factors encoded by floral organ identity genes. [...] much less is known about cell type-specific target genes. [...] the interaction between organ identity genes and general regulators of organ development may produce the overall structure of floral organs on which organ-specific cell types and structures are added or suppressed by interaction with more specialized gene expression programmes. One important next step will be to test how floral organ identity genes modify organ morphology through changes in the temporal or spatial expression patterns of general regulators of shoot development. In the years to come, these approaches may finally give a full understanding of exactly how shoot organs can be ‘metamorphosed’ [...]

Control of patterning, growth, and differentiation by floral organ identity genes Robert Sablowski J. Exp. Bot. (2015) doi: 10.1093/jxb/eru514 http://jxb.oxfordjournals.org/content/early/2015/01/20/jxb.eru514.full

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

Floral morphogenesis is the result of the interaction of an elaborate network of factors [...] Amongst the vast variety in flower shapes and colours in nature, most are composed of the same basic four organs arranged in concentric rings or whorls: sepals, petals, stamens and carpels. Of those, only the two internal organs produce gametes – male gametes in pollen produced in stamens, and female gametes within carpels. Once fertilization occurs, carpel tissues develop into the fruit containing the seeds. Future studies will no doubt go on to further test the relationships among these genes in multiple mutant combinations to reveal the effects of this additional redundancy [...]

Duplicate MADS genes with split roles Valérie Hecht J. Exp. Bot. (2016) 67 (6): 1609-1611. doi: 10.1093/jxb/erw086 http://jxb.oxfordjournals.org/content/67/6/1609.full

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

The genetic code letters, codons, are in all life forms translated to protein building blocks, amino acids, on ribosomes with the help of tRNAs. [...] the quality of the ensembles of proteins in cells is determined by “error hot spots” in code translation, where amino acid substitutions are frequent. It is conceivable that G:C/C:G base pairs in the first codon position confer stacking free energies that favor U:G mismatched rather than matched base pairs in the second codon position. The question of why middle-position U:G mismatches have much smaller d values when associated with tRNA Glu UUC tRNAUUCGlu and tRNA His GUG tRNAGUGHis than with tRNA Tyr GUA tRNAGUATyr , tRNA Asp GUC tRNAGUCAsp and, in particular, tRNA Lys UUU tRNAUUULys (Table S1), will, however, remain unanswered. This may suggest a general decoding pattern such that the base pair in the first codon position greatly affects the level of discrimination against third codon position mismatches. This hypothesis, which may be a determinant of codon use patterns, will need further testing against larger datasets of translational d values. [...] precious little is known about the stacking interactions in codon–anticodon helices on the ribosome. Understanding the physical chemistry of the tRNA-dependent d-value variations will provide keys to the evolutionary constraints that have led to the present-day design of the tRNAs that translate the genetic code. It is likely that this variation pattern will be extended as our knowledge of cognate codon reading increases. Knowledge of the complete cognate codon reading pattern will be particularly important [...] We are optimistic that the present dataset and its future extensions will serve as an inspiration and testing ground for theoretical approaches to explain the accuracy of codon reading and its idiosyncratic variation with tRNA type and codon context. We do hope that the linear trade-off lines for efficiency and accuracy of genetic code translation will further our understanding of its determinants in the living cell.

Accuracy of initial codon selection by aminoacyl-tRNAs on the mRNA-programmed bacterial ribosome Jingji Zhang, Ka-Weng Ieong, Magnus Johansson, and Måns Ehrenberg PNAS, vol. 112 no. 31, 9602–9607, doi: 10.1073/pnas.1506823112 http://www.pnas.org/content/112/31/9602.full

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

The circadian clock, an internal timekeeping system, is implicated in the regulation of metabolism and physiology [...] [...] molecular mechanisms and key regulators are mostly unknown.

Transcriptional Control of Antioxidant Defense by the Circadian Clock Sonal A. Patel, Nikkhil S. Velingkaar, and Roman V. Kondratov Antioxid Redox Signal. ; 20(18): 2997–3006. doi: 10.1089/ars.2013.5671 http://online.liebertpub.com/doi/abs/10.1089/ars.2013.5671

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

Posttranscriptional modifications at the wobble position of transfer RNAs play a substantial role in deciphering the degenerate genetic code on the ribosome. Modifications of RNA are carried out by complex cellular pathways, which involve countless protein enzymes and catalytic RNA–protein complexes, which primarily target tRNAs and, to a lesser extent, ribosomal RNA and mRNAs. [...] proper understanding of most often subtle fine-tuning effects of tRNA modifications on the codon–anticodon pairing geometries would require advanced experimental system consisting of full-length ligands and complete ribosome. From the observation we can derive both a wider spatial tolerance of the wobble base-pair environment than expected before and, on the other hand, a certain degree of strictness imposed on the base pair, forcing it into the conformation unusual for a relaxed duplex. [...] discrimination between tRNAs is primarily founded on spatial fit rather than on the number of hydrogen bonds between the ‘closed’ decoding centre and the codon–anticodon duplex.

Novel base-pairing interactions at the tRNA wobble position crucial for accurate reading of the genetic code Alexey Rozov, Natalia Demeshkina,Iskander Khusainov, Eric Westhof, Marat Yusupov & Gulnara Yusupova Nature Communications Volume:7,Article number:10457 DOI:doi:10.1038/ncomms10457 http://www.nature.com/ncomms/2016/160121/ncomms10457/full/ncomms10457.html

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

Cellular health and growth requires protein synthesis to be both efficient to ensure sufficient production, and accurate to avoid producing defective or unstable proteins. Less is known about the effect of modification on near-cognate decoding and some of that has been controversial. [...] the distinct changes in accuracy reflect an essential difference between the pairs of tRNAs. To understand how modification interferes with near-cognate decoding by these tRNAs structural studies of modified and unmodified tRNAs will be required. A clear understanding of the effect of Q on tRNA Tyr QUA tRNA QUATyr will require solution of the structure of the tRNA bound to A site cognate and near-cognate codons. [...] the effect of anticodon loop modifications depends on their structural context.

Effects of tRNA modification on translational accuracy depend on intrinsic codon–anticodon strength Nandini Manickam, Kartikeya Joshi, Monika J. Bhatt, and Philip J. Firebaugh Nucl. Acids Res. 44 (4): 1871-1881. doi: 10.1093/nar/gkv1506 http://nar.oxfordjournals.org/content/44/4/1871.full

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

Nucleotide modifications in the anticodons of transfer RNAs (tRNA) play a central role in translation efficiency, fidelity, and regulation of translation, but, for most of these modifications, the details of their function remain unknown. [...] it remains unclear whether inosine is widely used in eukaryotes to restrict or expand the pairing capacity of A34 containing codons. The reason why stretches of TAPS amino acids are enriched in ADAT-dependent codons remains to be determined.

Distribution of ADAT-Dependent Codons in the Human Transcriptome Àlbert Rafels-Ybern,1 Camille Stephan-Otto Attolini,1 and Lluís Ribas de Pouplana Int. J. Mol. Sci., 16(8), 17303-17314; doi:10.3390/ijms160817303 http://www.mdpi.com/1422-0067/16/8/17303/htm

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

The C–U interactions are puzzling because of the close distance between the O2 atoms: 2.9–3.0 Å. C and U, in their classical forms, have carbonyl O atoms in position 2 and their close proximity would give rise to substantial repulsive interactions between them unless a hydrogen atom is present in between. [...] there is a controversy as to whether CUG-BP1 is hyperphosphorylated in the presence of CCUG repeats, so it remains to be determined if PKC is activated by CCUG.

Watson-Crick-like pairs in CCUG repeats: evidence for tautomeric shifts or protonation Wojciech Rypniewski, Katarzyna Banaszak, Tadeusz Kuli?ski and Agnieszka Kiliszek doi: 10.1261/rna.052399.115 RNA 2016. 22: 22-31 http://rnajournal.cshlp.org/content/22/1/22

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

The circadian clock is a cellular timekeeping mechanism that helps organisms from bacteria to humans to organize their behaviour and physiology around the solar cycle. Circadian rhythms are ubiquitous biological rhythms with a period of about 24 h that are generated by single-cell molecular clocks. These cellular timing systems orchestrate a multitude of metabolic processes as uncovered by several global surveys of rhythmic transcripts , proteins and metabolites. [...] circadian redox oscillations may originate from a cell-autonomous biochemical oscillator. [...] it is likely that the distinction between circadian and redox pathways will become more and more difficult to define. A recurring theme in chronobiology is the interplay between circadian and metabolic cycles. [...] rhythmic respiration controlled by the clock is likely to feed back onto transcriptional rhythms through redox mechanisms. Understanding further how redox and circadian cycles are coupled together will be of great importance for understanding the basic mechanisms of timekeeping and their integration into cellular physiology. [...] it is plausible that the architecture of the circadian system is based on several layers, including overt circadian rhythms, transcriptional oscillations and redox oscillations [...]

Interplay between cellular redox oscillations and circadian clocks G. Rey and A. B. Reddy* DOI: 10.1111/dom.12519 Diabetes, Obesity and Metabolism Supplement: The Islet and Metabolism Keep Time. Proceedings of the 16th Servier-IGIS Symposium, St Jean Cap Ferrat, France, 9–12 April 2015 Volume 17, Issue Supplement S1, pages 55–64 http://onlinelibrary.wiley.com/doi/10.1111/dom.12519/full

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

Peroxiredoxins (Prxs) are a very large and highly conserved family of peroxidases that reduce peroxides, with a conserved cysteine residue, designated the “peroxidatic” Cys (CP) serving as the site of oxidation by peroxides [...] As in all biology, acronyms are overwhelming in Prx literature. Prx acts on muiltiple steps of MAPK signaling pathways in various organisms. The oscillation in 2-Cys Prx–SO2H abundance appears to be a cellular clock output driven by an underlying rhythm in oxidative metabolism. [...] the in vivo relevance of chaperone function is yet to be established.

Overview on Peroxiredoxin Sue Goo Rhee* Mol. Cells 2016; 39(1): 1~5 http://dx.doi.org/10.14348/molcells.2016.2368 http://www.molcells.org/journal/view.html?doi=10.14348/molcells.2016.2368

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

Redox signalling comprises the biology of molecular signal transduction mediated by reactive oxygen (or nitrogen) species. Intracellular redox state determines the direction of redox reactions that occur in the cell, and is determined by the balance of pro-oxidants compared with antioxidants. [...] there is good evidence for cellular redox state being circadian regulated. [...] it is premature to conclude there is an important role for redox signalling in the mammalian cellular clock. [...] need to understand the molecular underpinnings of PRX-SO2/3 oscillations – what is the timing mechanism that drives them? Inducible expression/repression models would be of great utility here. [...] there exists great potential for cross fertilisation between research into redox signalling and circadian rhythms. [...] it is of prime importance to establish explicitly whether crosstalk occurs bidirectionally and its mechanism(s), [...] [...] investigating whether the cell interprets a redox signal differently, depending upon the (biological) time of day.

Reciprocal Control of the Circadian Clock and Cellular Redox State - a Critical Appraisal Marrit Putker*, and John Stuart O’Neill* Mol. Cells 2016; 39(1): 6~19 http://dx.doi.org/10.14348/molcells.2016.2323 http://www.molcells.org/journal/view.html?doi=10.14348/molcells.2016.2323

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

The mammalian suprachiasmatic nucleus (SCN) drives daily rhythmic behavior and physiology, yet a detailed understanding of its coordinated transcriptional programmes is lacking. The daily cycles of life in mammals are driven by a small region of the brain called the suprachiasmatic nucleus (or SCN). The SCN receives signals from sunlight and other environmental factors to help coordinate most aspects of daily biological activity and behaviour. To work correctly, it is essential that the SCN switches certain genes on and off at exactly the right time. However, many questions remain over the identity of these genes and how their levels of activity change during a 24-hour period. More work is required to determine how the timing or relative level of gene expression mediates these light-induced behavioural changes. [...] oscillations in the SCN transcriptome play an important role in gating the differential responses to light, a fundamental circadian process. The complex relationship between photic and non-photic cues and their relative roles in phase adjustment must also be considered [...] The novel and canonical Cry1 isoforms are expressed in antiphase, as confirmed by qPCR from LCM SCN samples [...], indicating an unanticipated mode of temporal regulation in the SCN for this core clock gene. [...] this first temporal analysis of the SCN using RNA-sequencing reveals the presence of a twin-peaking transcriptional module with a suspected function in circadian control, and identifies thousands of novel transcripts, including a novel Cry1 isoform, which may play important roles in SCN function.

Temporal transcriptomics suggest that twin-peaking genes reset the clock William G Pembroke, Arran Babbs, Kay E Davies,* Chris P Ponting,* and Peter L Oliver* DOI: http://dx.doi.org/10.7554/eLife.10518.001 eLife. 2015; 4: e10518. doi: 10.7554/eLife.10518 http://elifesciences.org/content/4/e10518v2

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

[...] the comparison between mpfa and opfa indicated that the translation of PFA in B. amyloliquefaciens was complicated and required further study.

A new strategy to express the extracellular ?-amylase from Pyrococcus furiosus in Bacillus amyloliquefaciens Ping Wang1 n1, Peili Wang1 n1, Jian Tian1, Xiaoxia Yu1, Meihui Chang1, Xiaoyu Chu1 & Ningfeng Wu Scientific Reports 6, Article number: 22229 (2016) doi:10.1038/srep22229 http://www.nature.com/articles/srep22229

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

Bacterial genomes encode the biosynthetic potential to produce hundreds of thousands of complex molecules with diverse applications, from medicine to agriculture and materials. The pathways leading to the production of these molecules often comprise dozens of genes spanning large areas of the genome and are controlled by complex regulatory networks with some of the most interesting molecules being produced by non-model organisms.

Synthetic biology to access and expand nature's chemical diversity Michael J. Smanski,1, 2, Hui Zhou,2, Jan Claesen,3, Ben Shen,4, Michael A. Fischbach3, & Christopher A. Voigt Nature Reviews Microbiology Volume:14, Pages:135–149 (2016)DOI:doi:10.1038/nrmicro.2015.24 http://www.nature.com/nrmicro/journal/v14/n3/full/nrmicro.2015.24.html

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

Knowledge of protein 3D structures has significantly accelerated scientific discovery in many research areas, including protein biological function, drug screening and design, and human health and disease. It remains a significant challenge for structural genomics consortiums to crystalize and solve the 3D structures of proteins that possess important biological functions, but are difficult to crystalize. To promote further investigation, the Crysalis design mode integrates several bioinformatics tools to annotate predicted secondary structure elements, residue solvent accessibility, disordered regions, transmembrane regions, functional domains, and conserved sites. [...] may accelerate experimental studies and help to determine the crystal structures of biologically important proteins.

Crysalis: an integrated server for computational analysis and design of protein crystallization Huilin Wang1, Liubin Feng1, Ziding Zhang2, Geoffrey I. Webb3, Donghai Lin1 & Jiangning Song Scientific Reports 6, Article number: 21383 (2016) doi:10.1038/srep21383 http://www.nature.com/articles/srep21383

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

[...] the major contribution of Wnt signalling is in induction of the later endodermal marker Sox17 and consolidation of the endoderm gene regulatory network. [...] it may be of interest to explore how the molecular pathways uncovered in this study operate in human cancers. [...] does dysregulation of TCF7L1/FOXA2 lead to loss of differentiated features, [...] ?

Convergence of cMyc and ?-catenin on Tcf7l1 enables endoderm specification Gillian Morrison1,†,*, Roberta Scognamiglio2,3, Andreas Trumpp2,3 and Austin Smith DOI: 10.15252/embj.201592116 The EMBO Journal Volume 35, Issue 3, pages 356–368 http://onlinelibrary.wiley.com/doi/10.15252/embj.201592116/full

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

It would be of interest in the future to perform live-time imaging studies to track the fate of various TBX3 states to their progeny in pre- and postimplantation embryonic stages. Further studies need to clarify the precise role of TBX3 for germ cell development, particularly in light of the intimate connection between DPPA3/STELLA and TBX3 [...] [...] the intimate connection between TBX3 and DPPA3 remains and needs to be explored in detail in future studies. Our observations of an enriched DNA-methylation signature only in TBX3-null and not in the TBX3-low cells indicate additional epigenetic mechanisms that may be implicated and warrant further investigation [...]

A Dynamic Role of TBX3 in the Pluripotency Circuitry Ronan Russell,1,7 Marcus Ilg,1,7 Qiong Lin,2,7 Guangming Wu,3,7 André Lechel,1 Wendy Bergmann,1 Tim Eiseler,1 Leonhard Linta,4 Pavan Kumar P.,5 Moritz Klingenstein,4 Kenjiro Adachi,3 Meike Hohwieler,1 Olena Sakk,6 Stefanie Raab,4 Anne Moon,5 Martin Zenke,2 Thomas Seufferlein,1 Hans R. Schöler,3 Anett Illing,1,8 Stefan Liebau,4,8 and Alexander Kleger1 DOI: http://dx.doi.org/10.1016/j.stemcr.2015.11.003 http://www.cell.com/stem-cell-reports/fulltext/S2213-6711(15)00339-2

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

Chronic stress induces signalling from the sympathetic nervous system (SNS) and drives cancer progression, although the pathways of tumour cell dissemination are unclear. [...] limiting the effects of SNS signalling to prevent tumour cell dissemination through lymphatic routes may provide a strategy to improve cancer outcomes. It will be important to define stromal sources of VEGFC. [...] it will be important to define the direct effect of stress on lymphatic vasculature function [...] Further studies using strategies such as cell-specific knockout will be required to assess the effect of ?-adrenergic signalling on these various cell populations and determine their respective contributions to remodelling of lymphatic vasculature. [...] the capacity of anaesthetic sympathectomy to limit tumour cell dissemination or perioperative inflammation is still unclear [...]

Chronic stress in mice remodels lymph vasculature to promote tumour cell dissemination Caroline P. Le,1, Cameron J. Nowell,1, Corina Kim-Fuchs,1, 2, Edoardo Botteri,3, Jonathan G. Hiller,4, Hilmy Ismail,4, Matthew A. Pimentel,1, Ming G. Chai,1, Tara Karnezis,5, 6, Nicole Rotmensz,3, Giuseppe Renne,7, Sara Gandini,3, Colin W. Pouton,8, Davide Ferrari,9, Andreas Möller,10, Steven A. Stacker5, 6, & Erica K. Sloan Nature CommunicationsVolume:7,Article number:10634DOI:doi:10.1038/ncomms10634 http://www.nature.com/ncomms/2016/160301/ncomms10634/full/ncomms10634.html

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

A major endeavor in synthetic biology is to program functions of cells and cell populations in a predictable manner [...] When engineering a circuit, the host cell is typically considered a static “chassis”, or a reactor for the biochemical reactions associated with the circuit function. Depending on environmental conditions, including stress, nutrient, and temperature, many bacteria can form spatial structures consisting of cell aggregates, [...] that allow them to achieve functions beyond the capability of individual cells or homogenous cell populations. [...] this property represents a novel design strategy to engineer sophisticated functions in engineered cell populations. Drawing inspiration from natural systems, we sought to develop a platform technology [...] [...] an essential property of multicellular bacterial structures in nature [...] —a combination of spatial arrangement and dynamic environment sensing.

Coupling spatial segregation with synthetic circuits to control bacterial survival Shuqiang Huang, Anna Jisu Lee, Ryan Tsoi, Feilun Wu, Ying Zhang, Kam W Leong, Lingchong You DOI 10.15252/msb.20156567 Molecular Systems Biology (2016) 12: 859 http://msb.embopress.org/content/12/2/859

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

"...enormous scientific, engineering and institutional challenges remain."

Advances in sequencing technology have triggered a tsunami of genomic data, and these are joined by waves of information from other '-omics' studies, clinical trials and patient records. Analysis of this big data is launching the era of precision medicine — but enormous scientific, engineering and institutional challenges remain. Big data in biomedicine http://www.nature.com/nature/outlook/big-data/?WT.mc_id=BAN_NA_1511_BIGDATA

Complex complexity. Work in progress... stay tuned. Dionisio

ER molecular chaperones and folding enzymes are multidomain proteins that are designed to support nascent proteins entering ER lumen to achieve their native conformation, mediate post-translational modification, prevent misfolded protein aggregation, and facilitate exit from the ER. Here, we illustrate the multifunctional nature of many ER associated molecular chaperones and folding enzymes and unique functional overlap of these proteins all designed to support the many functions of the ER membrane. The ER is at the heart of many, if not all cellular processes. As mentioned, the ER is the site of protein folding, post-translational modifications, and QC of secretory and transmembrane proteins, maintaining Ca2+ for signaling, and is involved in ER stress and protein degradation. To help the ER perform these vast and diverse functions, resident ER chaperones work in both in concert to achieve both their general and specialized functions.

The many functions of the endoplasmic reticulum chaperones and folding enzymes Laura Halperin†, Joanna Jung† and Marek Michalak* DOI: 10.1002/iub.1272 IUBMB Life Volume 66, Issue 5, pages 318–326 http://onlinelibrary.wiley.com/doi/10.1002/iub.1272/full

Did anybody say 'designed'? [Emphasis mine] Dionisio

Oscillatory responses are ubiquitous in regulatory networks of living organisms, a fact that has led to extensive efforts to study and replicate the circuits involved. However, to date, design principles that underlie the robustness of natural oscillators are not completely known. In biomolecular regulatory networks, oscillatory systems control many vital functions, including circadian rhythms [...], glycolysis [...], DNA damage response [...], among others [...] [...] the requirements for robust oscillations in biomolecular networks are yet to be identi?ed. [...] biomolecular regulatory networks often operate under uncertain conditions and considerable levels of biomolecular noise [...] Robustness, the ability of a system to maintain functionality under perturbations, is therefore of paramount importance in any biomolecular regulatory network. [...] there is not yet a thorough and comprehensive set of guidelines for engineering robust oscillators.

Design principles for robust oscillatory behavior Sebastian M. Castillo-Hair, Elizabeth R. Villota, Alberto M. Coronado doi:10.?1007/?s11693-015-9178-6 Systems and Synthetic Biology Volume 9, Issue 3, pp 125-133 http://link.springer.com/article/10.1007/s11693-015-9178-6?no-access=true http://link.springer.com/content/esm/art:10.1007/s11693-015-9178-6/file/MediaObjects/11693_2015_9178_MOESM1_ESM.pdf http://link.springer.com/content/pdf/10.1007%2Fs11693-015-9178-6.pdf http://www.ncbi.nlm.nih.gov/pubmed/26279706

Did anybody say 'design'? :) Dionisio

The cellular–molecular mechanism for regulating circadian rhythms is located primarily in the suprachiasmatic nuclei (SCN) of the hypothalamus in mammals. The major ‘clock’ genes include the period genes, Per1 and Per2, the cryptochrome genes, Cry1 and Cry2, the clock (circadian locomotor output cycles kaput) gene, and the Bmal1 (aryl hydrocarbon receptor nuclear translocator-like) gene. The suprachiasmatic nuclei (SCN) of the hypothalamus regulates most circadian rhythms. Melatonin provides a feedback signal to the suprachiasmatic nuclei. Feedback loops control clock genes. A major unanswered question is how melatonin stimulates transcription of the SCN molecular clock genes. Clearly, additional clarification related to the effects of melatonin on feedback of PER/CRY and REV-ERB? on Bmal1 transcription is needed. [...] the circadian interaction of melatonin and the proteasome in the SCN and PT has yet to be fully characterized. Peripheral tissues also contain the classical molecular timing molecules. How does melatonin influence clock genes: translation or transcription? [...] rhythms in the SCN ‘clock’ regulate to some degree rhythms in peripheral tissues. These considerations raise a number of questions concerning the role of melatonin in proteasome-regulated transcription of clock genes.

Melatonin feedback on clock genes: a theory involving the proteasome Jerry Vriend1,* and Russel J. Reiter2 DOI: 10.1111/jpi.12189 Journal of Pineal Research Volume 58, Issue 1, pages 1–11, http://onlinelibrary.wiley.com/doi/10.1111/jpi.12189/full

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

The beneficial effects of melatonin (N-acetyl-5-methoxytryptamine) on human health are well known and are frequently associated with the attenuation of oxidative damage [1-9]. The protective effects of melatonin against the deleterious effects caused by oxidative stress (OS) are well documented [10-18]. One of the most appealing properties of melatonin, which distinguishes it from most antioxidants, is that its metabolites also have the ability to scavenge reactive oxygen species (ROS) and reactive nitrogen species (RNS). The continuous protection exerted by melatonin and its metabolites, referred as the free radical scavenging cascade [19-21], makes melatonin highly effective, even at low concentrations, in protecting organisms from OS [...] [...] melatonin and its metabolite AMK constitute an efficient team of scavengers capable of deactivating a wide variety of ROS, under different conditions.

On the free radical scavenging activities of melatonin's metabolites, AFMK and AMK Annia Galano1,*, Dun Xian Tan2 and Russel J. Reiter2 DOI: 10.1111/jpi.12010 Journal of Pineal Research Volume 54, Issue 3, pages 245–257, http://onlinelibrary.wiley.com/doi/10.1111/jpi.12010/full

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

Melatonin (N-acetyl-5-methoxytryptamine) is a ubiquitous molecule with pleiotropic actions in different organisms. It performs many important functions in human, animals, and plants; these range from regulating circadian rhythms in animals to controlling senescence in plants. [...] a possible role of melatonin in fruit development cannot be precluded; however, this still needs to be verified. [...] the biosynthesis of melatonin in plant species can be altered by the introduction of genes from vertebrates [...] The mechanisms of action of melatonin is not clearly understood in plants [...] In plants, this aspect is a missing link in understanding the biological functions of melatonin and it requires the attention of plant scientists. Melatonin enhances the phytoremediative capacity of plants, but further studies are required. Whether melatonin improves the phytoremediative capacity of the hyperaccumulator plant species would be important to document, and if so mechanism involved would require definition. [...] it is not known whether all plant organs synthesize this indoleamine. Its mechanism of transport throughout the plant also must be explored. Further detailed investigations [...] needs clarification.

Nawaz MA, Huang Y, Bie Z, Ahmed W, Reiter RJ, Niu M and Hameed S (2016) Melatonin: Current Status and Future Perspectives in Plant Science. Front. Plant Sci. 6:1230. doi: 10.3389/fpls.2015.01230

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

Querius @1577 I see your valid point. Thank you. Glad to know you're enjoying reading this thread too. BTW, the paper referenced @1565 was first (indirectly) referenced in a recent OP by News (Denyse). Actually, it's part of a whole set of juicy articles that were published together by the Royal Society. The credits go to Denyse. Regarding what you wrote, here's an example: Are the small TV screens -attached to the back of the economy class seats in some airliners- required for the planes to fly? Obviously, no. Hence, are those things needed for the functioning of the planes? Really, no, they are not. Then, do they perform any function at all? Well, I barely look at them during the flights, because I read PDF documents downloaded into my tablet before the flights, but my wife sometimes mentally 'shrinks' the flight duration watching movies. Since she books most of our trips, I wonder if she would dump an airline for not having those small TVs onboard? :) I'm fascinated by the increasing information that is published out there in the biology research journals. What we have here in this UD thread is a small selection. Many papers are hidden behind paywalls. I dislike the knowledge gaps, hence I highlight them to remind myself about things I should look for in other papers in the future. My current project requires, among other tasks, gathering examples of information-processing systems seen within biology. Dionisio

The cellular–molecular mechanism for regulating circadian rhythms is located primarily in the suprachiasmatic nuclei (SCN) of the hypothalamus in mammals. The major ‘clock’ genes include the period genes, Per1 and Per2, the cryptochrome genes, Cry1 and Cry2, the clock (circadian locomotor output cycles kaput) gene, and the Bmal1 (aryl hydrocarbon receptor nuclear translocator-like) gene. The suprachiasmatic nuclei (SCN) of the hypothalamus regulates most circadian rhythms. Melatonin provides a feedback signal to the suprachiasmatic nuclei. Feedback loops control clock genes. A major unanswered question is how melatonin stimulates transcription of the SCN molecular clock genes. Clearly, additional clarification related to the effects of melatonin on feedback of PER/CRY and REV-ERB? on Bmal1 transcription is needed. [...] the circadian interaction of melatonin and the proteasome in the SCN and PT has yet to be fully characterized. Peripheral tissues also contain the classical molecular timing molecules. How does melatonin influence clock genes: translation or transcription? [...] rhythms in the SCN ‘clock’ regulate to some degree rhythms in peripheral tissues. These considerations raise a number of questions concerning the role of melatonin in proteasome-regulated transcription of clock genes.

Melatonin feedback on clock genes: a theory involving the proteasome Jerry Vriend1,* and Russel J. Reiter2 DOI: 10.1111/jpi.12189 Journal of Pineal Research Volume 58, Issue 1, pages 1–11, http://onlinelibrary.wiley.com/doi/10.1111/jpi.12189/full

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

Dionisio @ 1565,

[…] the genes represent only a small part of the genome, and the rest, including what has been injudiciously termed junk DNA, probably contains a great deal of information (following our computing analogy, this may include variable and constant definitions and so on). We need to understand the theoretical basis of biological complexity.

This is a major reason why ID is so important moving forward---to assume unknown genetic components have some sort of function (though not necessarily always expressed or used in some fashion). If instead, for example, non-coding DNA is automatically assumed to be evolutionary junk, real progress will be significantly hindered, being replaced by mildly plausible speculation as incontrovertible evolutionary fact. I'm so amazed at the information you've been posting! -Q Querius

Most developmental cell signaling in metazoans is carried out by only a small number of evolutionarily conserved, highly pleiotropic signaling cascades. The JAK/STAT pathway in vertebrates regulates many developmental events controlled by a large number of ligands and receptors. Although the pathway also has many developmental functions in Drosophila, activity appears to be regulated by just one ligand family, the Unpaired proteins. Transcriptional regulation is often more complex than the classical gene model of one isolated transcription unit controlled by dedicated enhancers and silencers. Many genes are regulated in a more complicated fashion and evidence even suggests that it is common to find coordinately expressed genes clustered on eukaryotic chromosomes [...] The regulatory mechanisms employed to control and coordinate the upd region may therefore represent an attractive and relatively compact model for study of such complex genomic regions.

Pleiotropy of the Drosophila JAK pathway cytokine Unpaired 3 in development and aging Wang L1, Sexton TR1, Venard C1, Giedt M1, Guo Q1, Chen Q1, Harrison DA2. doi:10.1016/j.ydbio.2014.09.015 Developmental Biology Volume 395, Issue 2, Pages 218–231 http://www.sciencedirect.com/science/article/pii/S0012160614004722

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

Further understanding of these dynamic complexes will require complete structural information on the missing TM segments that mediate dynamic and functional connections between these domains. To understand the workings of this machine, detailed descriptions of functional sub-complexes and their allosteric changes will be required. Presumably driven by the ATPase motor, modulated by the secreted cargo, housekeeping proteases and chaperones, these conformational transitions need to be described in molecular detail and their individual functions and dynamics require in vivo studies.

Type II secretion system: a magic beanstalk or a protein escalator Nivaskumar M1, Francetic O2. doi:10.1016/j.bbamcr.2013.12.020 Biochimica et Biophysica Acta (BBA) - Molecular Cell Research Volume 1843, Issue 8, Pages 1568–1577 Protein trafficking and secretion in bacteria http://www.sciencedirect.com/science/article/pii/S0167488913004473

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

[...] complementation studies between T2SS components need to be revisited, as the role of some T2SS components in specificity might have been overlooked due to overexpression. Similar questions are relevant for the bi-functional CMF systems [...], which promote T4P assembly and protein secretion. The folded nature of T2SS substrates suggests that a structural motif on exoprotein surface determines specific interactions leading to secretion. Despite a large number of studies and structural information available for dozens of substrates, the nature of this signal has remained elusive. One of the many major challenges is to determine how exoproteins specifically enter into this pathway and whether this specificity is determined at several levels.

Type II secretion system: a magic beanstalk or a protein escalator Nivaskumar M1, Francetic O2. doi:10.1016/j.bbamcr.2013.12.020 Biochimica et Biophysica Acta (BBA) - Molecular Cell Research Volume 1843, Issue 8, Pages 1568–1577 Protein trafficking and secretion in bacteria http://www.sciencedirect.com/science/article/pii/S0167488913004473

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

The passage of pili (6 nm in diameter), or exoprotein substrates, clearly requires a much larger channel, suggesting dramatic conformational changes to promote a wider gate opening. How this happens without causing the leakage of periplasmic contents remains a major question. Precise molecular function of GspS/GspP pilotins is still unclear and it remains possible that they act as OM receptors for the secretin, stabilizing its OM intermediate during biogenesis. The C-terminal part of GspM has been implicated in an essential function unrelated to its interaction with GspL, but the molecular basis of this role remains to be identified [...] Which substrate-binding T2SS components determine specificity and how is still unclear. In vivo structure–function analysis is required to understand the functional significance of this binding.

Type II secretion system: a magic beanstalk or a protein escalator Nivaskumar M1, Francetic O2. doi:10.1016/j.bbamcr.2013.12.020 Biochimica et Biophysica Acta (BBA) - Molecular Cell Research Volume 1843, Issue 8, Pages 1568–1577 Protein trafficking and secretion in bacteria http://www.sciencedirect.com/science/article/pii/S0167488913004473

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

Type II protein secretion systems (T2SS) are molecular machines that promote specific transport of folded periplasmic proteins in Gram-negative bacteria, across a dedicated channel in the outer membrane. [...] GspE ATP binding and hydrolysis provide energy for pseudopilus assembly and protein secretion. Clearly, a lot remains to be learned about its molecular function. [...] the globular domains of the minor pseudopilins form a stable quaternary complex that interacts specifically with the exoprotein substrate of the Xcp T2SS of P. aeruginosa. Further structural, biophysical and functional studies will be required to understand the conformational switch involved in GspD multimerization and membrane insertion.

Type II secretion system: a magic beanstalk or a protein escalator Nivaskumar M1, Francetic O2. doi:10.1016/j.bbamcr.2013.12.020 Biochimica et Biophysica Acta (BBA) - Molecular Cell Research Volume 1843, Issue 8, Pages 1568–1577 Protein trafficking and secretion in bacteria http://www.sciencedirect.com/science/article/pii/S0167488913004473

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

Outer membrane vesicles (OMVs) are constantly being discharged from the surface of Gram-negative bacteria during growth. The actual localization of RNA in association with OMVs, whether or not the RNA is inside of the vesicles is as yet unclear. [...] bacterial RNA can be released from bacteria via membrane vesicles. [...] we need to consider the potential role(s) of RNA-containing bacterial membrane vesicles in bacteria-host and bacteria-bacteria interactions.

Membrane vesicle-mediated release of bacterial RNA Annika E. Sjöström,1,2Linda Sandblad,1,2Bernt Eric Uhlin,1,2 and Sun Nyunt Waia,1 Scientific Reports 5, Article number: 15329 (2015) doi:10.1038/srep15329 http://www.nature.com/articles/

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

Major gaps in our knowledge remain. We pose questions for targeted investigation of surface-specific community-level microbial features, answers to which would advance our understanding of surface-associated microbial community ecology and the biogeochemical functions of these communities at levels from molecular mechanistic details through systems biological integration.

Dang H, Lovell CR. 2016. Microbial surface colonization and biofilm development in marine environments. Microbiol Mol Biol Rev 80:91–138. doi:10.1128/MMBR.00037-15. http://mmbr.asm.org/content/80/1/91.abstract

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

Proteomic analyses and many other studies have yet to fully account for the effect of the many cellular and environmental factors which feed into the complex process of OMV formation and regulation on sample preparation. Further analysis of OMVs may be necessary in other Gram-negative species to ascertain the existence, relationship with protein enrichment, and function of multiple vesicle subpopulations. The differences in LPS structure between these strains may influence the association of ?-hemolysin with OMVs and hint at a greater, but as of yet undiscovered, role for OM lipids and lipopolysaccharide in OMV formation. [...] the mechanistic cause for differential degrees of enrichment or exclusion for various protein cargo in OMVs is unclear [...] [...] the mechanism by which certain protein cargo is enriched or excluded from vesicles remains elusive. [...] the mechanistic details of how proteins become enriched as OMV cargo remain elusive Exactly how OMV-localized material could influence the adherence of parent bacteria is unknown.

Protein selection and export via outer membrane vesicles K.E. Bonnington, M.J. Kuehn doi:10.1016/j.bbamcr.2013.12.011 Biochimica et Biophysica Acta (BBA) - Molecular Cell Research Volume 1843, Issue 8, Pages 1612–1619 Protein trafficking and secretion in bacteria http://www.sciencedirect.com/science/article/pii/S0167488913004382

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

The active involvement of OMVs in antibiotic-resistance of bacteria emphasizes the necessity of further in-depth investigations on this aspect. Search for the inhibitors of vesicle formation [...] appears to hold some promise in therapeutics since by suppressing vesicle formation; they are likely to suppress both pathogenesis and antibiotic-resistance of the pathogens.

Vesicles-mediated resistance to antibiotics in bacteria Madhab K. Chattopadhyay and Medicharla V. Jagannadham Front. Microbiol., :http://dx.doi.org/10.3389/fmicb.2015.00758 http://journal.frontiersin.org/article/10.3389/fmicb.2015.00758/full http://journal.frontiersin.org/article/10.3389/fmicb.2015.00974/full Front. Microbiol., 10 September 2015 | http://dx.doi.org/10.3389/fmicb.2015.00974 Corrigendum: Vesicles-mediated resistance to antibiotics in bacteria Madhab K. Chattopadhyay and Medicharla V. Jagannadham* •Centre for Cellular and Molecular Biology (CSIR), Hyderabad, India A corrigendum on Vesicles-mediated resistance to antibiotics in bacteria by Chattopadhyay, M. K., and Jaganandham, M. V. (2015). Front. Microbiol. 6:758. doi: 10.3389/fmicb.2015.00758 The name of the second author should be read as Medicharla V. Jagannadham. The original article was updated.

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

In vitro analysis of the folding of OMPs with diverse structural features in the presence and the absence of BAM would greatly advance our understanding of the mechanisms involved. [...] a common assembly mechanism based on achieving a critical stability in the prepore and membrane-assisted insertion represents a new paradigm for complex OMP assembly It is unknown whether HxcQ assembly is BAM-dependent. A systematic study of secretin assembly and folding pathways by a combination of in vivo and in vitro approaches would further define these differences and reveal whether [...] The characteristics that determine whether OMP assembly is BAM-dependent or not might be encoded in the three-dimensional structure of the OMP, which remains to be determined [...]

Lipids assist the membrane insertion of a BAM-independent outer membrane protein Gerard H. M. Huysmans,a,1,* Ingrid Guilvout,1,2 Mohamed Chami,3 Nicholas N. Nickerson,1,† and Anthony P. Pugsleyb Scientific Reports 5, Article number: 15068 doi:10.1038/srep15068 http://www.nature.com/articles/srep15068#discussion

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

Spatiotemporal organization of OMPs in E. coli raises many new questions about the OM [...] [...] raising the question of whether their mechanism of insertion in the OM is distinct to that of other OMPs that move to the poles as part of OMP islands. Might this provide an explanation for the involvement of the translocation and assembly module (TAM) complex, which spans the cell envelope and is involved in auto-transporter biogenesis but the role of which remains enigmatic? Further work will be needed to reconcile these issues.

Protein–protein interactions and the spatiotemporal dynamics of bacterial outer membrane proteins Colin Kleanthous,1 Patrice Rassam,1 and Christoph G Baumann doi:10.1016/j.sbi.2015.10.007 Current Opinion in Structural Biology Volume 35, Pages 109–115 Catalysis and regulation • Protein-protein interactions http://www.sciencedirect.com/science/article/pii/S0959440X15001542

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

[...] biology, chemistry and also physics tell us how the process of translating the genetic information into life could possibly work, but we are still very far from a complete understanding of this process. A key question then is to explain the particular behaviour of living beings; why life is rather more than the sum of its parts. This is not to subscribe to vitalism, but to note that life has the capacity to operate and adapt in conditions of constant change; in a dynamical environment. This capacity to create order, to decrease entropy—at the cost of greater disorder somewhere else, as biology operates within the laws of thermodynamics—is a fundamental aspect of life. What then is life? The complexity present in a tiny amount of living matter is staggering; a single human cell is a veritable factory containing many specialized elements and possessing 2?m of genetic instructions in the form of DNA. [...] the genome, the information used to construct a human or a worm, which is written in language we have yet to decode is clearly not a simple linear list of instructions, but a program, with subroutines, callbacks, loops and all the complexity that implies, so that one can talk of the further possible combinations of instructions—the additional combinatorial complexity—of our genome over the nematode's. [...] the genes represent only a small part of the genome, and the rest, including what has been injudiciously termed junk DNA, probably contains a great deal of information (following our computing analogy, this may include variable and constant definitions and so on). We need to understand the theoretical basis of biological complexity. [...] many scientists think that we do not yet have enough information available; that more data are required. [...] we need major advances in the theoretical interpretation of such data, including a more holistic approach to biology. The complexity of many biological problems makes black box computational approaches useless without theoretical guidance. [...] it is imperative that the vast accumulation of data coming out of biological research should begin to be organized into a logical structure. [...] little is known about the grammar, the syntax and even the orthography of the book of life. [...] why and how life can exist from the point of view of the coding and decoding of genetic information.

DNA as information: at the crossroads between biology, mathematics, physics and chemistry Julyan H. E. Cartwright, Simone Giannerini, Diego L. González DOI: 10.1098/rsta.2015.0071 http://rsta.royalsocietypublishing.org/content/374/2063/20150071#abstract-1

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

[...] one would hypothesize that the probability of the quinone molecules to encounter the nitrate reductase is higher. Evidences have been provided for such quinone channeling within supercomplexes while the exact mechanism of channeling is not yet understood [...] By providing the first evidence for a spatiotemporal regulation of a respiratory complex in response to environmental conditions, this work establishes a basis for a deeper analysis on how environmental signals are translated into subcellular localization of respiratory complexes to adjust the respiration output.

Dynamic subcellular localization of a respiratory complex controls bacterial respiration François Alberge,1 Leon Espinosa,1 Farida Seduk,1 Léa Sylvi,1,† René Toci,1 Anne Walburger,1 and Axel Megaton DOI: http://dx.doi.org/10.7554/eLife.05357 eLife 2015;4:e05357 http://elifesciences.org/content/4/e05357v1

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

The complexity of cellular organization and dynamics has long been recognized in eukaryotes. However, it is only in the last decade that such complexity has started to be documented for bacteria. Our study confirms the organizational complexity of bacteria, not only with respect to the adaptation of their chemotactic and motility apparatus but also with respect to the diversity of division strategies. [...] further studies will require the establishment of genetic tools for those strains in order to decipher the molecular mechanisms underlying this strategy.

Positioning the Flagellum at the Center of a Dividing Cell To Combine Bacterial Division with Magnetic Polarity Christopher T. Lefèvrea,b, Mathieu Benneta, Stefan Klumppc, Damien Faivrea doi: 10.1128/mBio.02286-14 mBio vol. 6 no. 2 e02286-14 http://mbio.asm.org/content/6/2/e02286-14

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

Engineering self?organizing multicellular systems requires control over interactions at multiple levels of organization. Engineering population?level interactions opens new avenues of investigation. This type of system in which genetics and spatially organized population interactions contribute to the overall system behavior opens up new approaches to designing systems that possess interesting dynamics, perform information processing, and self?organize. Using the parts, devices, and techniques we have developed here, we are poised to create systems that use the spatiotemporal patterning properties of intercellular signaling to organize matter at scales from the molecular to the macroscopic.

Orthogonal intercellular signaling for programmed spatial behavior Paul K Grant, Neil Dalchau, James R Brown, Fernan Federici, Timothy J Rudge, Boyan Yordanov, Om Patange, Andrew Phillips, Jim Haseloff DOI 10.15252/msb.20156590 Molecular Systems Biology 12: 849 http://msb.embopress.org/content/12/1/849#sec-13

Complex complexity. Work in progress… stay tuned. Dionisio

Protein concentration gradients provide spatial information for cellular and developmental processes. Classical morphogen gradients translate cell position into distinct cell fate to pattern a developing organism [...] They are often able to do so robustly despite fluctuations in morphogen production, though the underlying mechanisms are debated and subject of intense research [...] Gradients also occur at much smaller scales within cells, where they impart spatial cellular order, for instance in organizing the mitotic spindle or controlling cell division [...]

Pom1 gradient buffering through intermolecular auto?phosphorylation Micha Hersch, Olivier Hachet, Sascha Dalessi, Pranav Ullal, Payal Bhatia, Sven Bergmann, Sophie G Martin DOI 10.15252/msb.20145996 Molecular Systems Biology 11: 818 http://msb.embopress.org/content/11/7/818

What determines* the location of the morphogen sources? What determines* the type of morphogen to be produced at a given source? What determines* the timing for every morphogen source to start producing a given morphogen? What determines* the amplitude of the morphogen gradients? (*) what's the underlying mechanism and how does it work? Dionisio

Information theory is gaining popularity as a tool to characterize performance of biological systems. The Drosophila patterning network has been described as performing a ‘transition from analogue to digital specification’ of cell identity. […] the question of information accessibility (the unavoidable input noise of the downstream circuit) can no longer be neglected. In general, quantifying the usefulness of information-bearing signals in contexts where channel uses are limited will require reinstating considerations of rate/fidelity trade-off, […]

Only accessible information is useful: insights from gradient-mediated patterning Mikhail Tikhonov, Shawn C. Little, Thomas Gregor DOI: 10.1098/rsos.150486 http://rsos.royalsocietypublishing.org/content/2/11/150486

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

Cell polarity is fundamental to the biology of most cells and is characterized by the asymmetric distribution of factors at the cell cortex and in the cytoplasm. Although mechanisms by which the PAR proteins establish cortical asymmetries have been characterized, relatively little is known about how they control the formation of precise and stable cytoplasmic asymmetries. […] it is not known how the PAR proteins and MEX-5/6 regulate the dynamics of PIE-1, POS-1 and MEX-1 in order to control their segregation. MEX-5/6 concentration gradients are directly coupled to the formation of the PIE-1 concentration gradient via the formation of a PIE-1 diffusion gradient.

Coupling between cytoplasmic concentration gradients through local control of protein mobility in the Caenorhabditis elegans zygote Youjun Wu, Huaiying Zhang, and Erik E. Griffin1 doi: 10.1091/mbc.E15-05-0302 Mol. Biol. Cell vol. 26 no. 17 2963-2970 http://www.molbiolcell.org/content/26/17/2963

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Dionisio

[...] many questions remain unanswered in our understanding of how polarity proteins regulate spine development and plasticity, [...] [...] current and future research will undoubtedly shed more light on how this conserved group of proteins orchestrates different pathways to shape the neuronal circuitry. Further research is needed to elucidate how septin-containing spines and septin-free spines differ in their physiological functions. It will be interesting to determine how interactions between different PCP proteins contribute to spine development and plasticity. Recent studies using superresolution microscopy have revealed interesting microdomain organizations within dendritic spines. It will be interesting to see whether the organization of these microdomains depends on the balancing acts of the polarity complexes. How these crosstalks are involved in dendritic spine development and function remains to be determined. Further studies will shed light on how signals from diverse groups of polarity determinants converge on the cytoskeleton to modulate dendritic spine development and function. Future research will pave the way to understanding of how these conserved polarity proteins help shape the synaptic connections and how they contribute to cognitive functions of the brain.

Polarity Determinants in Dendritic Spine Development and Plasticity Huaye Zhang Neural Plasticity Volume 2016 (2016), Article ID 3145019, 10 pages http://dx.doi.org/10.1155/2016/3145019 http://www.hindawi.com/journals/np/2016/3145019/

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

What could be the molecular mechanisms controlling the temporal changes in the response of retinal cells to Hh signalling? [...] more work is needed to unravel the interplay between intrinsic and extrinsic mechanisms in regulating the response of eye cells to Hh signaling. In future work, it will be interesting to investigate whether eye cells carry out stage-dependent modifications in the responsiveness to Hh signalling using similar or distinct mechanisms to those acting at different levels of the neural tube.

Dorsoventral patterning of the Xenopus eye involves differential temporal changes in the response of optic stalk and retinal progenitors to Hh signalling •Xiumei Wang†1, Giuseppe Lupo†2, 3, Rongqiao He1, Giuseppina Barsacchi4, William A Harris2 and Ying Liu Neural Development 10:7 DOI: 10.1186/s13064-015-0035-9 http://neuraldevelopment.biomedcentral.com/articles/10.1186/s13064-015-0035-9

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

[...] a role for the Wnt pathway in controlling NT patterning has not been clearly demonstrated [...] [...] a role for Hh signalling in NT patterning has not been studied [...] [...] we do not know how this might occur [...]

Opposing Shh and Fgf signals initiate nasotemporal patterning of the zebrafish retina María Hernández-Bejarano, Gaia Gestri, Lana Spawls, Francisco Nieto-López, Alexander Picker, Masazumi Tada, Michael Brand, Paola Bovolenta, Stephen W. Wilson, Florencia Cavodeassi Development 2015 142: 3933-3942; doi: 10.1242/dev.125120 http://dev.biologists.org/content/142/22/3933 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4712879/

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

How morphogen gradients govern the pattern of gene expression in developing tissues is not well understood. [...] the activity of target genes is determined by the combined input of the transcriptional effectors. [...] cis-regulatory elements integrate the activity of TFs to determine the probability and/or rate of transcription [...] It is also unclear how the affinity threshold model would apply to MR-TFs that are bifunctional, acting as transcriptional repressors in the absence of morphogen and as activators otherwise [...]

A theoretical framework for the regulation of Shh morphogen-controlled gene expression Michael Cohen, Karen M. Page, Ruben Perez-Carrasco, Chris P. Barnes, James Briscoe Development 141: 3868-3878; doi: 10.1242/dev.112573 http://dev.biologists.org/content/141/20/3868

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

Despite much progress, many questions remain. Elucidating the components and operation of the transcriptional networks continues and, for many tissues, the relative importance of the spatial or temporal component of gradients needs to be determined. How opposing gradients cross-talk and are integrated into networks is poorly understood. [...] our comparison of patterning in the Drosophila blastoderm and the vertebrate neural tube suggests a unified framework for morphogen-mediated pattern formation and establishes a research agenda that will likely take us through further revisions of this fascinating problem.

Morphogen rules: design principles of gradient-mediated embryo patterning James Briscoe, Stephen Small Development 2015 142: 3996-4009; doi: 10.1242/dev.129452 http://dev.biologists.org/content/142/23/3996

Did anybody say 'design'? :) As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

[...] most of the dynamic regulatory aspects of the metabolic transcriptional system are still poorly understood. [...] cells have two types of information storage system which are capable of transmitting specific information to the following generations, i.e., the CMS and DNA systems. [...] the essential attributes upon which cellular functionality lies have their basis in the as yet insufficiently understood Cellular Metabolic Structure. [...] without mathematics—the language of nature—it would not be possible to precisely understand metabolic dynamics and the catalytic functionality that sustains them. [...] dealing with these overwhelmingly complex issues of systemic cell biology with the desired clarity and precision is an extraordinarily difficult undertaking. [...] our current comprehension of dynamic biological phenomena in its most elemental aspects is still very incomplete and insufficient. It is truly extraordinary that in such a reduced space of merely a few microns, millions of biochemical processes form a metabolic entity that is sensitive, self-organized, self-regulated, able to process and store information, and perpetuate itself in time.

Elements of the cellular metabolic structure Ildefonso M. De la Fuente Front. Mol. Biosci., http://dx.doi.org/10.3389/fmolb.2015.00016 http://journal.frontiersin.org/article/10.3389/fmolb.2015.00016/full

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

There are different types of PTMs, e.g., phosphorylation, methylation, glycosylation, acetylation, ubiquitination, SUMOylation, etc., and the number and abundance of these modifications is constantly being updated [...] While bare DNA encodes 2 bits of information per nucleotide, even in a single protein reversible chemical modifications occur at multiple sites, allowing the encoding of a potentially large amount of information. [...] the precise mechanisms making this transition possible are not yet well understood. [...] at the molecular level, metabolic memories exhibit both long-term and short-term memory, but this issue requires further research. Metabolism can be considered to be the largest known source of complexity in nature.

Elements of the cellular metabolic structure Ildefonso M. De la Fuente Front. Mol. Biosci., http://dx.doi.org/10.3389/fmolb.2015.00016 http://journal.frontiersin.org/article/10.3389/fmolb.2015.00016/full

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

[...] many aspects of cellular dissipative structures are still poorly understood and thus deserve further attention. [...] the processing and storing of some kind of biomolecular information is a fundamental requirement for cells to be able to exhibit complex systemic behavior. [...] when considering the activity of an interrelated set of different metabolic subsystems, a highly parallel, super-complex structure of molecular information processing emerges in the network.

Elements of the cellular metabolic structure Ildefonso M. De la Fuente Front. Mol. Biosci., http://dx.doi.org/10.3389/fmolb.2015.00016 http://journal.frontiersin.org/article/10.3389/fmolb.2015.00016/full

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio

How the enzymes are organized under the complex conditions prevailing inside the cell is a crucial issue for understanding the fundamental functional architecture of cellular life. The dynamics of molecular processes that intervene in micro-compartmentation and its maintenance remain unclear. The conditions required for the emergence and sustainability of these rhythms, and how they are regulated, represent a biological problem of the highest significance.

Elements of the cellular metabolic structure Ildefonso M. De la Fuente Front. Mol. Biosci., http://dx.doi.org/10.3389/fmolb.2015.00016 http://journal.frontiersin.org/article/10.3389/fmolb.2015.00016/full

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. Dionisio