Rethinking biology: What role does physical structure play in the development of cells?

Key points: Direction selectivity has been widely studied as an example of a complex neural computation. Directional GABA release from starburst amacrine cells (SBACs) is critical for generating directional signals in direction-selective ganglion cells. The mechanisms producing the directional release remain unclear. For SBACs, ordered distribution of sustained and transient bipolar cell inputs along the dendrites is proposed to generate directional GABA release. This study tests whether this hypothesis applies to ON-type SBACs. EPSCs activated at proximal and distal dendritic locations have the same time course. Therefore, the ordered arrangement of inputs from bipolar cells with different kinetic properties cannot be responsible for generating directional GABA release from ON-type SBACs. Abstract: Direction selectivity in the retina relies critically on directionally asymmetric GABA release from the dendritic tips of starburst amacrine cells (SBACs). GABA release from each radially directed dendrite is larger for motion outward from the soma toward the dendritic tips than for motion inwards toward the soma. The biophysical mechanisms generating these directional signals remain controversial. A model based on electron-microscopic reconstructions of the mouse retina proposed that an ordered arrangement of kinetically distinct bipolar cell inputs to ON- and OFF-type SBACs could produce directional GABA release. We tested this prediction by measuring the time course of EPSCs in ON-type SBACs in the mouse retina, activated by proximal and distal light stimulation. Contrary to the prediction, the kinetics of the excitatory inputs were independent of dendritic location. Computer simulations based on 3D reconstructions of SBAC dendrites demonstrated that the response kinetics of distal inputs were not significantly altered by dendritic filtering. These direct physiological measurements, do not support the hypothesis that directional signals in SBACs arise from the ordered arrangement of kinetically distinct bipolar cell inputs. Stincic, Todd & Smith, Robert & Taylor, William. (2016). Time course of EPSCs in ON-type starburst amacrine cells is independent of dendritic location. The Journal of Physiology. 594. . 10.1113/JP272384. Dionisio

Lewis, Sian. (2017). Sensory processing: The eyes have it. Nature Reviews Neuroscience. 18. . 10.1038/nrn.2017.31. Dionisio

Dragonflies are superb aerial predators, plucking tiny insect prey from the sky. This ability depends on a visual system that has fascinated scientists for decades, and now one of its visual-target-detecting neurons has been shown to anticipate the image path of prey. Frye, Mark. (2017). Insect Vision: A Neuron that Anticipates an Object’s Path. Current Biology. 27. R1076-R1078. 10.1016/j.cub.2017.08.049. Dionisio

A recent study shows that retinal direction selectivity influences a subset of cells in primary visual cortex which respond to the optic flow associated with forward motion, while other cortical direction selective cells perform this computation independently. Morrie, Ryan & B. Feller, Marla. (2017). Motion Vision: Cortical Preferences Influenced by Retinal Direction Selectivity. Current Biology. 27. R710-R713. 10.1016/j.cub.2017.05.083. Dionisio

Detecting visual features in the environment, such as motion direction, is crucial for survival. The circuit mechanisms that give rise to direction selectivity in a major visual center, the superior colliculus (SC), are entirely unknown. We optogenetically isolate the retinal inputs that individual direction-selective SC neurons receive and find that they are already selective as a result of precisely converging inputs from similarly tuned retinal ganglion cells. The direction-selective retinal input is linearly amplified by intracollicular circuits without changing its preferred direction or level of selectivity. Finally, using two-photon calcium imaging, we show that SC direction selectivity is dramatically reduced in transgenic mice that have decreased retinal selectivity. Together, our studies demonstrate a retinal origin of direction selectivity in the SC and reveal a central visual deficit as a consequence of altered feature selectivity in the retina. Shi, Xuefeng & Barchini, Jad & Acaron Ledesma, Hector & Koren, David & Jin, Yanjiao & Liu, Xiaorong & Wei, Wei & Cang, Jianhua. (2017). Retinal Origin of Direction Selectivity in the Superior Colliculus. Nature Neuroscience. 20. . 10.1038/nn.4498. Dionisio

The circuit mechanisms that give rise to direction selectivity in the retina have been studied extensively but how direction selectivity is established in retinorecipient areas of the brain is less well understood. Using functional imaging in larval zebrafish we examine how the direction of motion is encoded by populations of neurons at three layers of the optic tectum; retinal ganglion cell axons (RGCs), a layer of superficial inhibitory interneurons (SINs), and periventricular neurons (PVNs), which constitute the majority of neurons in the tectum. We show that the representation of motion direction is transformed at each layer. At the level of RGCs and SINs the direction of motion is encoded by three direction-selective (DS) subtypes tuned to upward, downward, and caudal-to-rostral motion. However, the tuning of SINs is significantly narrower and this leads to a conspicuous gap in the representation of motion in the rostral-to-caudal direction at the level of SINs. Consistent with previous findings we demonstrate that, at the level of PVNs the direction of motion is encoded by four DS cell types which include an additional DS PVN cell type tuned to rostral-to-caudal motion. Strikingly, the tuning profile of this emergent cell type overlaps with the gap in the representation of rostral-to-caudal motion at the level of SINs. Using our functional imaging data we constructed a simple computational model that demonstrates how the emergent population of PVNs is generated by the interactions of cells at each layer of the tectal network. The model predicts that PVNs tuned to rostral-to-caudal motion can be generated via convergence of DS RGCs tuned to upward and downward motion and feedforward tuned inhibition via SINs which suppresses responses to non-preferred directions. Thus, by reshaping directional tuning that is inherited from the retina inhibitory inputs from SINs can generate a novel subtype of DS PVN and in so doing enhance the encoding of directional stimuli. Abbas, Fatima & A. Triplett, Marcus & J. Goodhill, Geoffrey & Meyer, Martin. (2017). A Three-Layer Network Model of Direction Selective Circuits in the Optic Tectum. Frontiers in Neural Circuits. 11. 88. 10.3389/fncir.2017.00088. Dionisio

Images projected onto the retina of an animal eye are rarely still. Instead, they usually contain motion signals originating either from moving objects or from retinal slip caused by self-motion. Accordingly, motion signals tell the animal in which direction a predator, prey, or the animal itself is moving. At the neural level, visual motion detection has been proposed to extract directional information by a delay-and-compare mechanism, representing a classic example of neural computation. Neurons responding selectively to motion in one but not in the other direction have been identified in many systems, most prominently in the mammalian retina and the fly optic lobe. Technological advances have now allowed researchers to characterize these neurons' upstream circuits in exquisite detail. Focusing on these upstream circuits, we review and compare recent progress in understanding the mechanisms that generate direction selectivity in the early visual system of mammals and flies. Mauss, Alex & Vlasits, Anna & Borst, Alexander & Feller, Marla. (2017). Visual Circuits for Direction Selectivity. Annual review of neuroscience. 40. . 10.1146/annurev-neuro-072116-031335. Expected final online publication date for the Annual Review of Neuroscience Volume 40 is July 8, 2017. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates. Dionisio

Although much is known about the regenerative capacity of retinal ganglion cells, very significant barriers remain in our ability to restore visual function following traumatic injury or disease-induced degeneration. Here we summarize our current understanding of the factors regulating axon guidance and target engagement in regenerating axons, and review the state of the field of neural regeneration, focusing on the visual system and highlighting studies using other model systems that can inform analysis of visual system regeneration. This overview is motivated by a Society for Neuroscience Satellite meeting, “Reconnecting Neurons in the Visual System,” held in October 2015 sponsored by the National Eye Institute as part of their “Audacious Goals Initiative” and co-organized by Carol Mason (Columbia University) and Michael Crair (Yale University). The collective wisdom of the conference participants pointed to important gaps in our knowledge and barriers to progress in promoting the restoration of visual system function. This article is thus a summary of our existing understanding of visual system regeneration and provides a blueprint for future progress in the field. C. Crair, Michael & A. Mason, Carol. (2016). Reconnecting Eye to Brain. Journal of Neuroscience. 36. 10707-10722. 10.1523/JNEUROSCI.1711-16.2016. Dionisio

The roles of glia and polyamines (PA) in brain function and dysfunction are highlighted in this review. We emphasize that PA accumulation preferentially in glia, but not in neurons, is clearly evolutionarily determined; it is found throughout the brain, retina, peripheral nervous system, and in glial-neuronal co-cultures of multiple species, including man. This phenomenon raises key questions: (i) What are the mechanisms that underlie such uneven distribution, accumulation and release from glia? (ii) What are the consequences of PA fluxes within the brain on neuronal function? (iii) What are the roles of PAs in brain disorders and diseases? This review includes suggestions on the roles of PAs, such as putrescine (PT), spermidine (SPD), spermine (SPM) and their derivatives as novel glio-transmitters in brain since PA affect many neuronal and glial receptors, channels and transporters. Polyamines hitherto have been neglected, although it is evident that these molecules are key elements for normal brain function and their metabolic disorders, apparently, cause the development of many pathological syndromes and diseases. The study of endogenous PA allows one to put forward the basic principles of scientific research on glio-neuronal interactions and clinical therapies, which are based on the exclusivity of glial cells in terms of accumulation of PA and PA-dependent functions. Skatchkov, Serguei & Antonov, Sergei & Eaton, Misty. (2016). Glia and glial polyamines. Role in brain function in health and disease. Biochemistry (Moscow) Supplement Series A: Membrane and Cell Biology. 10. 73-98. 10.1134/S1990747816010116. Dionisio

The article deals with problems of color perception under LED lighting. We revealed that inadequate perception of a signal color by a driver led to greater risks of transport accidents. We reviewed both Jung-Helmholtz three-color hypothesis and a modern one based on fiber-optical approach to functioning of "Mueller cells and cones" system. We made an attempt to explain a number of effects related to visibility curves and time delays when defining color of light signals. Our research on assessing influence exerted by LED lighting on functional state and working capacity of railway workers during which we applied occupational selection techniques revealed negative changes. We proved there was a decrease in functional resistance to color sense between red and green signals as well as longer response time for complicated sight-motor reaction and significant decrease in readiness to emergency actions (resistance to monotony) in examined individuals. The article also contains data on time peculiarities which are characteristic for defining signals color in relation to red signal (650 nm). We showed that when red color LEDs with wave length much shorter than 650 nm were used in signaling devices it caused risks of inadequate color detection, longer reaction to inhibiting signals, and greater possibility of transport accidents and negative events in everyday life. These peculiarities should be taken into account when designing traffic lights and other signaling devices which provide transport safety. We also proved that signaling traffic lights for transport systems should be designed allowing for physiology of color perception by a human visual analyzer; application of LEDs with wave length shorter than 650 nm should be absolutely excluded Kaptsov, V.A. & Deinego, V.N.. (2017). Health risks occurring when color is percepted under led lighting. Health Risk Analysis. 16-25. 10.21668/health.risk/2017.2.02.eng. Dionisio

We studied intermediate filaments (IFs) in the retina of the Pied flycatcher (Ficedula hypoleuca) in the foveolar zone. Single IFs span Muller cells (MC) lengthwise; cylindrical bundles of IFs (IFBs) appear inside the cone inner segment (CIS) at the outer limiting membrane (OLM) level. IFBs adjoin the cone cytoplasmatic membrane, following lengthwise regularly spaced, forming a skeleton of the CIS, located above the OLM. IFBs follow along the cone outer segment (COS), with single IFs separating from the IFB, touching and entering in-between the light-sensitive disks of the cone membrane. We propose a mechanism of exciton transfer from the inner retinal surface to the visual pigments in the photoreceptor cells. This includes excitation transfer in donor-acceptor systems, from the IF donors to the rhodopsin acceptors, with theoretic efficiency over 80%. This explains high image contrast in fovea and foveola in daylight, while the classical mechanism that describes M\"uller cells as optical lightguides operates in night vision, with loss of resolution traded for sensitivity. Our theory receives strong confirmation in morphology and function of the cones and pigment cells. In daylight the lateral surface of the photosensor disks is blocked from the (scattered or oblique) light by the pigment cells. Thus the light energy can only get to the cone via intermediate filaments that absorb photons in the Muller cell endfeet and conduct excitons to the cone. Thus, the disks are consumed at their lateral surfaces, moving to the apex of the cone, with new disks produced below. An alternative hypothesis of direct light passing through the cone with its organelles and hitting the lowest disk contradicts morphological evidence, as thus all of the other disks would have no useful function in daylight vision. Zueva, Lidia & Golubeva, Tatiana & Korneeva, Elena & Inyushin, Mikhail & Khmelinskii, Igor & Makarov, Vladimir. (2017). Mechanism of light energy transport in the avian retina. . Dionisio

Presently we continue our studies of the quantum mechanism of light energy transmission in the form of excitons by axisymmetric nanostructures with electrically conductive walls. Using our theoretical model, we analyzed the light energy transmission by biopolymers forming optical channels within retinal Müller cells. There are specialized intermediate filaments (IF) 10–18 nm in diameter, built of electrically conductive polypeptides. Presently, we analyzed the spectral selectivity of these nanostructures. We found that their transmission spectrum depends on their diameter and wall thickness. We also considered the classical approach, comparing the results with those predicted by the quantum mechanism. We performed experimental measurements on model quantum waveguides, made of rectangular nanometer-thick chromium (Cr) tracks. The optical spectrum of such waveguides varied with their thickness. We compared the experimental absorption/transmission spectra with those predicted by our model, with good agreement between the two. We report that the observed spectra may be explained by the same mechanisms as operating in metal nanolayers. Both the models and the experiment show that Cr nanotracks have high light transmission efficiency in a narrow spectral range, with the spectral maximum dependent on the layer thickness. Therefore, a set of intermediate filaments with different geometries may provide light transmission over the entire visible spectrum with a very high (~ 90%) efficiency. Thus, we believe that high contrast and visual resolution in daylight are provided by the quantum mechanism of energy transfer in the form of excitons, whereas the ultimate retinal sensitivity of the night vision is provided by the classical mechanism of photons transmitted by the Müller cell light-guides. Khmelinskii, Igor & Golubeva, Tatiana & Korneeva, Elena & Inyushin, Mikhail & Zueva, Lidia & Makarov, Vladimir. (2017). Spectral selectivity model for light transmission by the intermediate filaments in Müller cells. Journal of Photochemistry and Photobiology B: Biology. 173. . 10.1016/j.jphotobiol.2017.06.001. Dionisio

Visually guided behaviour at its sensitivity limit relies on single-photon responses originating in a small number of rod photoreceptors. For decades, researchers have debated the neural mechanisms and noise sources that underlie this striking sensitivity. To address this question, we need to understand the constraints arising from the retinal output signals provided by distinct retinal ganglion cell types. It has recently been shown in the primate retina that On and Off parasol ganglion cells, the cell types likely to underlie light detection at the absolute visual threshold, differ fundamentally not only in response polarity, but also in the way they handle single-photon responses originating in rods. The On pathway provides the brain with a thresholded, low-noise readout and the Off pathway with a noisy, linear readout. We outline the mechanistic basis of these different coding strategies and analyse their implications for detecting the weakest light signals. We show that high-fidelity, nonlinear signal processing in the On pathway comes with costs: more single-photon responses are lost and their propagation is delayed compared with the Off pathway. On the other hand, the responses of On ganglion cells allow better intensity discrimination compared with the Off ganglion cell responses near visual threshold. This article is part of the themed issue ?Vision in dim light?. Takeshita, Daisuke & Smeds, Lina & Ala-Laurila, Petri. (2017). Processing of single-photon responses in the mammalian On and Off retinal pathways at the sensitivity limit of vision. Philosophical Transactions of the Royal Society B: Biological Sciences. 372. 20160073. 10.1098/rstb.2016.0073. Dionisio

Cellular luminescence is the emission of photons by living cells due to various biophysical and biochemical processes, mostly associated with cellular metabolism. In this review paper we summarize today's understanding of four luminescence-dependent phenomena in the eye, i.e., phosphenes, retinal discrete dark noise, negative afterimages and the development of retinogeniculate projections in the brain. We review the phenomena above in the context of knowledge gained from experimental and theoretical works. Finally we discuss this knowledge in terms of its physiological significance. Salari, Vahid & Scholkmann, Felix & Vimal, Ram Lakhan Pandey & Csaszar-Nagy, Noemi & Aslani, Mehdi & Bokkon, Istvan. (2017). Phosphenes, retinal discrete dark noise, negative afterimages and retinogeniculate projection: A review of a new explanatory framework based on endogenous ocular luminescence. Progress in Retinal and Eye Research. 60. . 10.1016/j.preteyeres.2017.07.001. Dionisio

Analysis of everyday human gaze behaviour has significant potential for ubiquitous computing, as evidenced by a large body of work in gaze-based human-computer interaction, attentive user interfaces, and eye-based user modelling. However, current mobile eye trackers are still obtrusive, which not only makes them uncomfortable to wear and socially unacceptable in daily life, but also prevents them from being widely adopted in the social and behavioural sciences. To address these challenges we present InvisibleEye, a novel approach for mobile eye tracking that uses millimetre-size RGB cameras that can be fully embedded into normal glasses frames. To compensate for the cameras’ low image resolution of only a few pixels, our approach uses multiple cameras to capture different views of the eye, as well as learning-based gaze estimation to directly regress from eye images to gaze directions. We prototypically implement our system and characterise its performance on three large-scale, increasingly realistic, and thus challenging datasets: 1) eye images synthesised using a recent computer graphics eye region model, 2) real eye images recorded of 17 participants under controlled lighting, and 3) eye images recorded of four participants over the course of four recording sessions in a mobile setting. We show that InvisibleEye achieves a top person-specific gaze estimation accuracy of 1.79° using four cameras with a resolution of only 5 × 5 pixels. Our evaluations not only demonstrate the feasibility of this novel approach but, more importantly, underline its significant potential for finally realising the vision of invisible mobile eye tracking and pervasive attentive user interfaces. Tonsen, Marc & Steil, Julian & Sugano, Yusuke & Bulling, Andreas. (2017). InvisibleEye: Mobile Eye Tracking Using Multiple Low-Resolution Cameras and Learning-Based Gaze Estimation. Proceedings of the ACM on Interactive, Mobile, Wearable and Ubiquitous Technologies. 1. 1-21. 10.1145/3130971. Dionisio

Eye and gaze movements play an essential role in identifying individuals' emotional states, cognitive activities, interests, and attention among other behavioral traits. Besides, they are natural, fast, and implicitly reflect the targets of interest, which makes them a highly valuable input modality in human-computer interfaces. Therefore, tracking gaze movements, in other words, eye tracking is of great interest to a large number of disciplines, including human behaviour research, neuroscience, medicine, and human-computer interaction. Tracking gaze movements accurately is a challenging task, especially under unconstrained conditions. Over the last two decades, significant advances have been made in improving the gaze estimation accuracy. However, these improvements have been achieved mostly under controlled settings. Meanwhile, several concerns have arisen, such as the complexity, inflexibility and cost of the setups, increased user effort, and high sensitivity to varying real-world conditions. Despite various attempts and promising enhancements, existing eye tracking systems are still inadequate to overcome most of these concerns, which prevent them from being widely used. In this thesis, we revisit these concerns and introduce a novel multi-camera eye tracking framework. The proposed framework achieves a high estimation accuracy while requiring a minimal user effort and a non-intrusive flexible setup. In addition, it provides improved robustness to large head movements, illumination changes, use of eye wear, and eye type variations across users. We develop a novel real-time gaze estimation framework based on adaptive fusion of multiple single-camera systems, in which the gaze estimation relies on projective geometry. Besides, to ease the user calibration procedure, we investigate several methods to model the subject-specific estimation bias, and consequently, propose a novel approach based on weighted regularized least squares regression. The proposed method provides a better calibration modeling than state-of-the-art methods, particularly when using low-resolution and limited calibration data. Being able to operate with low-resolution data also enables to utilize a large field-of-view setup, so that large head movements are allowed. To address aforementioned robustness concerns, we propose to leverage multiple eye appearances simultaneously acquired from various views. In comparison with conventional single view approach, the main benefit of our approach is to more reliably detect gaze features under challenging conditions, especially when they are obstructed due to large head pose or movements, or eye glasses effects. We further propose an adaptive fusion mechanism to effectively combine the gaze outputs obtained from multi-view appearances. To this effect, our mechanism firstly determines the estimation reliability of each gaze output and then performs a reliability-based weighted fusion to compute the overall point of regard. In addition, to address illumination and eye type robustness, the setup is built upon active illumination and robust feature detection methods are developed. The proposed framework and methods are validated through extensive simulations and user experiments featuring 20 subjects. The results demonstrate that our framework provides not only a significant improvement in gaze estimation accuracy but also a notable robustness to real-world conditions, making it suitable for a large spectrum of applications. Arar, Nuri Murat. (2017). Robust Eye Tracking Based on Adaptive Fusion of Multiple Cameras. . 10.5075/epfl-thesis-7933. Dionisio

The formation of skeletal muscle during embryogenesis involves the commitment of mesodermal progenitors to the myogenic lineage and their fusion to form fibers followed by the expression of muscle structural genes [...] Our demonstrations reveal two additional functions for CF2 not yet reported. First, CF2, is involved in the Mef2 transcriptional regulation. KSecond, CF2 acts at two closely related levels: contributing to the control of fiber size and to the number of nuclei that every fiber will have during embryo muscle differentiation.

CF2 transcription factor is involved in the regulation of Mef2 RNA levels, nuclei number and muscle fiber size Juan J. Arredondo,#* Jorge Vivar,# Sara Laine-Menéndez, Leticia Martínez-Morentin, and Margarita Cervera PLoS One. 2017; 12(6): e0179194. doi: 10.1371/journal.pone.0179194 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5472297/pdf/pone.0179194.pdf

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

Building and maintaining muscles is a crucial aspect for the fitness of most metazoan organisms. The proper differentiation and maintenance of myofibers is fundamental to a functional musculature. [...] Mib2 plays an additional important role in the development of adult thorax muscles, particularly in maintaining the larval templates for the dorsal longitudinal indirect flight muscles during metamorphosis. [...] a connection between Mib2 and Notch signaling during flight muscle development remains an interesting possibility that needs to be addressed in future experiments. The identity of the critical Mib2 targets during DLM formation remains to be identified. In this regard, our novel viable hypomorphic alleles could serve as excellent tools for future genetic or proteomic approaches.

Identification of the essential protein domains for Mib2 function during the development of the Drosophila larval musculature and adult flight muscles. Domsch K1, Acs A1, Obermeier C1, Nguyen HT1, Reim I1. PLoS One. 2017 Mar 10;12(3):e0173733. doi: 10.1371/journal.pone.0173733. eCollection 2017. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5345843/pdf/pone.0173733.pdf

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

[...] a critical role for macrophage-derived ECM may be more ubiquitous than previously recognized. It is unclear why embryonic BM components like Col IV require local delivery by hemocytes, while in larvae they are thought to diffuse from the fat body [...] [...] it is unclear whether hemocytes associated with the ovary plaster Col IV in a manner similar to embryonic hemocytes or shed soluble Col IV similarly to the larval fat body [...] [...] there are differences between the mechanisms of de novo BM formation in the embryo versus homeostatic mechanisms involved in BM growth [...] [...] specific hemocyte-dependent mechanism of delivery during de novo BM formation.

A Moving Source of Matrix Components Is Essential for De Novo Basement Membrane Formation. Matsubayashi Y1, Louani A2, Dragu A2, Sánchez-Sánchez BJ2, Serna-Morales E2, Yolland L2, Gyoergy A3, Vizcay G4, Fleck RA4, Heddleston JM5, Chew TL5, Siekhaus DE3, Stramer BM6. Curr Biol. 2017 Nov 20;27(22):3526-3534.e4. doi: 10.1016/j.cub.2017.10.001. Epub 2017 Nov 9.

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

a critical role for macrophage-derived ECM may be more ubiquitous than previously recognized. A Moving Source of Matrix Components Is Essential for De Novo Basement Membrane Formation. Matsubayashi Y1, Louani A2, Dragu A2, Sánchez-Sánchez BJ2, Serna-Morales E2, Yolland L2, Gyoergy A3, Vizcay G4, Fleck RA4, Heddleston JM5, Chew TL5, Siekhaus DE3, Stramer BM6. Curr Biol. 2017 Nov 20;27(22):3526-3534.e4. doi: 10.1016/j.cub.2017.10.001. Epub 2017 Nov 9. Dionisio

Hox genes encode a family of transcription factors responsible for the establishment of the animal body plan. Their organisation in genomic clusters is conserved during evolution and is instrumental in defining the domain of activity of each gene in the embryo: the place and time of Hox gene expression is dictated by the position of each gene within the cluster. A unique set of Hox genes is active at each axial level along the embryonic anterior to posterior axis. These diverse complements of Hox proteins determine morphological identities by controlling the transcription of specific target genes. Changes in Hox genes number, expression and function likely participated in morphological diversification during animal evolution. Lufkin, Thomas. (2005). Hox Genes: Embryonic Development. . 10.1038/npg.els.0005046. https://www.researchgate.net/profile/Thomas_Lufkin/publication/230302351_Hox_Genes_Embryonic_Development/links/0912f50d28284341e8000000/Hox-Genes-Embryonic-Development.pdf 13 yo paper Dionisio

The occurrence of spliceosomal introns in eukaryotic genomes is highly diverse and ranges from few introns in an organism to multiple introns per gene. Introns vary with respect to their lengths, strengths of splicing signals, and position in resident genes. Higher intronic density and diversity in genetically complex organisms relies on increased efficiency and accuracy of spliceosomes for pre-mRNA splicing. Since intron diversity is critical for functions in RNA stability, regulation of gene expression and alternative splicing, RNA-binding proteins, spliceosomal regulatory factors and post-translational modifications of splicing factors ought to make the splicing process intron-specific. We recently reported function and regulation of a ubiquitin fold harboring splicing regulator, Sde2, which following activation by ubiquitin-specific proteases facilitates excision of selected introns from a subset of multi-intronic genes in Schizosaccharomyces pombe (Thakran et al. EMBO J, https://doi.org/10.15252/embj.201796751, 2017). By reviewing our findings with understandings of intron functions and regulated splicing processes, we propose possible functions and mechanism of intron-specific pre-mRNA splicing and suggest that this process is crucial to highlight importance of introns in eukaryotic genomes. Intron specificity in pre-mRNA splicing. Mishra, Shravan Kumar & Thakran, Poonam. (2018). Current Genetics. . 10.1007/s00294-017-0802-8. Dionisio

Transcription is a source of genetic instability that can notably result from the formation of genotoxic DNA:RNA hybrids, or R-loops, between the nascent mRNA and its template. Here we report an unexpected function for introns in counteracting R-loop accumulation in eukaryotic genomes. Deletion of endogenous introns increases R-loop formation, while insertion of an intron into an intronless gene suppresses R-loop accumulation and its deleterious impact on transcription and recombination in yeast. Recruitment of the spliceosome onto the mRNA, but not splicing per se, is shown to be critical to attenuate R-loop formation and transcription-associated genetic instability. Genome-wide analyses in a number of distant species differing in their intron content, including human, further revealed that intron-containing genes and the intron-richest genomes are best protected against R-loop accumulation and subsequent genetic instability. Our results thereby provide a possible rationale for the conservation of introns throughout the eukaryotic lineage. Introns Protect Eukaryotic Genomes from Transcription-Associated Genetic Instability. Bonnet, Amandine & Grosso, Ana & El Kaoutari, Abdessamad & Coleno, Emeline & Presle, Adrien & C. Sridhara, Sreerama & Janbon, Guilhem & Géli, Vincent & de Almeida, Sérgio & Palancade, Benoît. (2017). Molecular Cell. in press. . 10.1016/j.molcel.2017.07.002. Dionisio

Reproductive aging is characterized by a marked decline in oocyte quality that contributes to infertility, miscarriages, and birth defects. This decline is multifactorial, and the underlying mechanisms are under active investigation. Here, we performed RNA-Seq on individual growing follicles from reproductively young and old mice to identify age-dependent functions in oocytes. This unbiased approach revealed genes involved in cellular processes known to change with age, including mitochondrial function and meiotic chromosome segregation, but also uncovered previously unappreciated categories of genes related to proteostasis and organelles required for protein metabolism. We further validated our RNA-Seq data by comparing nucleolar structure and function in oocytes from reproductively young and old mice, as this organelle is central for protein production. We examined key nucleolar markers, including upstream binding transcription factor (UBTF), an RNA polymerase I cofactor, and fibrillarin, an rRNA methyltransferase. In oocytes from mice of advanced reproductive age, UBTF was primarily expressed in giant fibrillar centers (GFCs), structures associated with high levels of rDNA transcription, and fibrillarin expression was increased ~2-fold. At the ultrastructural level, oocyte nucleoli from reproductively old mice had correspondingly more prominent fibrillar centers and dense fibrillar centers relative to young controls and more ribosomes were found in the cytoplasm. Taken together, our findings are significant because the growing oocyte is one of the most translationally active cells in the body and must accumulate high-quality maternally derived proteins to support subsequent embryo development. Thus, perturbations in protein metabolism are likely to have a profound impact on gamete health. E. Duncan, Francesca & Jasti, Susmita & Paulson, Ariel & M. Kelsh, John & Fegley, Barbara & L. Gerton, Jennifer. (2017). Age-associated dysregulation of protein metabolism in the mammalian oocyte. Aging Cell. 16. . 10.1111/acel.12676. https://www.researchgate.net/publication/320308458_Age-associated_dysregulation_of_protein_metabolism_in_the_mammalian_oocyte/fulltext/59dd081e45851561891382a4/320308458_Age-associated_dysregulation_of_protein_metabolism_in_the_mammalian_oocyte.pdf Dionisio

Aging is a ubiquitous complex process characterized by tissue degeneration and loss of cellular fitness. Genome instability (GIN) has long been implicated as a main causal factor in aging. The most severe form of genomic instability is whole chromosome instability (W-CIN), a state where dysfunction in chromosome segregation leads to whole chromosomes gains and losses. Aneuploidy is commonly linked to pathological states. It is a hallmark of spontaneous abortions and birth defects and it is observed virtually in every human tumor. There is mounting evidence that W-CIN increases with age, with the underlying hypothesis that some of the age-related loss of fitness phenotypes may be the result of W-CIN. Methodologically, the detection of stochastic W-CIN during the aging process poses unique challenges: aneuploid cells are scattered among diploid cells and, contrary to the cancer genome where aneuploidy is present in the background of massive ploidy changes, the number of aneuploid chromosome per cells is usually low (few per cell). Aging-associated aneuploidy is also largely stochastic or with limited clonal expansion. Therefore analysis at the single-cell level and the examination of a large number of cells is necessary. Here we describe a modification of the standard fluorescent in situ hybridization (FISH) protocol adapted for the detection of low-frequency mosaic aneuploidy in interphase cells isolated from the adult brain or within frozen tissue sections. This approach represents a straightforward method for the single-cell analysis of W-CIN in mammalian cells. It is based on the combination of four probes mapping to two different chromosomes and analysis of interphase cells, highly reducing false positives and enabling studying W-CIN also in post-mitotic tissues. A. Andriani, Grasiella & Montagna, Cristina. (2017). FISH Analysis of Aging-Associated Aneuploidy in Neurons and Nonneuronal Brain Cells. Neuromethods. 271-298. 10.1007/978-1-4939-7280-7_14. https://www.researchgate.net/profile/Cristina_Montagna4/publication/319639553_FISH_Analysis_of_Aging-Associated_Aneuploidy_in_Neurons_and_Nonneuronal_Brain_Cells/links/5a0b18aaaca2721a23f9a443/FISH-Analysis-of-Aging-Associated-Aneuploidy-in-Neurons-and-Nonneuronal-Brain-Cells.pdf Dionisio

A long standing axiom in the field of teratology states that the teratogenic period, when most birth defects are produced, occurs during the third to eighth weeks of development post-fertilization. Any insults prior to this time are thought to result in a slowing of embryonic growth from which the conceptus recovers or death of the embryo followed by spontaneous abortion. However, new insights into embryonic development during the first two weeks, including formation of the anterior-posterior, dorsal-ventral, and left-right axes, suggests that signaling pathways regulating these processes are prime targets for genetic and toxic insults. Establishment of the left-right (laterality) axis is particularly sensitive to disruption at very early stages of development and these perturbations result in a wide variety of congenital malformations, especially heart defects. Thus, the time for teratogenic insults resulting in birth defects should be reset to include the first two weeks of development. W. Sadler, Thomas. (2017). Establishing the Embryonic Axes: Prime Time for Teratogenic Insults. Journal of Cardiovascular Development and Disease. 4. 15. 10.3390/jcdd4030015. http://www.mdpi.com/2308-3425/4/3/15/pdf Dionisio

A societal preference of delaying maternal age at first childbirth has increased reliance on assisted reproductive technologies/therapies (ART) to conceive a child. Oocytes that have undergone physiologic aging (?35 years for humans) are now commonly used for ART, yet evidence is building that suboptimal reproductive environments associated with aging negatively affect oocyte competence and embryo development – although the mechanisms underlying these relationship are not yet well understood. Epigenetic programming of the oocyte occurs during its growth within a follicle, so the ovarian stimulation protocols that administer exogenous hormones, as part of the first step for all ART procedures, may prevent the gamete from establishing an appropriate epigenetic state. Therefore, understanding how oocyte age versus physiologic age independently and synergistically affect the epigenetic programming of these gametes, and how this may affect their developmental competence, are crucial to improved ART outcomes. Here, we review studies that measured the developmental outcomes affected by superovulation and aging, focusing on how the epigenome (i.e., global and imprinted DNA methylation, histone modifications, and epigenetic modifiers) of gametes and embryos acquired from females undergoing physiologic aging and exogenous ovarian stimulation are affected. This article is protected by copyright. All rights reserved Lynn Marshall, Kira & Melissa Rivera, Rocío. (2017). The effects of superovulation and reproductive aging on the epigenome of the oocyte and embryo: Superovulation and aging affect the epigenome. Molecular Reproduction and Development. . 10.1002/mrd.22951. Had we remained in Eden, none of this would have been an issue. Dionisio

Fibrillarin is one of the most important nucleolar proteins that have been shown as essential for life. Fibrillarin localizes primarily at the periphery between fibrillar center and dense fibrillar component as well as in Cajal bodies. In most plants there are at least two different genes for fibrillarin. In Arabidopsis thaliana both genes show high level of expression in transcriptionally active cells. Here, we focus on two important differences between A. thaliana fibrillarins. First and most relevant is the enzymatic activity by AtFib2. The AtFib2 shows a novel ribonuclease activity that is not seen with AtFib1. Second is a difference in the ability to interact with phosphoinositides and phosphatidic acid between both proteins. We also show that the novel ribonuclease activity as well as the phospholipid binding region of fibrillarin is confine to the GAR domain. The ribonuclease activity of fibrillarin reveals in this study represents a new role for this protein in rRNA processing. Rodriguez-Corona, Ulises & Pereira-Santana, Alejandro & Sobol, Margarita & Rodriguez-Zapata, Luis & Hozák, Pavel & Castaño, Enrique. (2017). Novel Ribonuclease Activity Differs between Fibrillarins from Arabidopsis thaliana. Frontiers in Plant Science. 8. . 10.3389/fpls.2017.01878. https://www.researchgate.net/profile/Alejandro_Pereira-Santana/publication/320734165_Novel_Ribonuclease_Activity_Differs_between_Fibrillarins_from_Arabidopsis_thaliana/links/59f89152aca272607e2f570d/Novel-Ribonuclease-Activity-Differs-between-Fibrillarins-from-Arabidopsis-thaliana.pdf Dionisio

RNA-binding ubiquitin ligases (RBULs) have the potential to link RNA-mediated mechanisms to protein ubiquitylation. Despite this, the cellular functions, substrates and interaction partners of most RBULs remain poorly characterized. Affinity purification (AP) combined with quantitative mass spectrometry (MS)-based proteomics is a powerful approach for analyzing protein functions. Mapping the physiological interaction partners of RNA-binding proteins has been hampered by their intrinsic properties, in particular the existence of low-complexity regions, which are prone to engage in non-physiological interactions. Here, we used an adapted AP approach to identify the interaction partners of human RBULs harboring different RNA-binding domains. To increase the likelihood of recovering physiological interactions, we combined control and bait-expressing cells prior to lysis. In this setup, only stable interactions that were originally present in the cell will be identified. We exploit gene function similarity between the bait proteins and their interactors to benchmark our approach in its ability to recover physiological interactions. We reveal that RBULs engage in stable interactions with RNA-binding proteins involved in different steps of RNA metabolism as well as with components of the ubiquitin conjugation machinery and ubiquitin-binding proteins. Our results thus demonstrate their capacity to link posttranscriptional regulation with the ubiquitin system. Hildebrandt, Andrea & Alanis-Lobato, Gregorio & Voigt, Andrea & Zarnack, Kathi & Andrade, Miguel & Beli, Petra & König, Julian. (2017). Interaction profiling of RNA-binding ubiquitin ligases reveals a link between posttranscriptional regulation and the ubiquitin system. Scientific Reports. 7. . 10.1038/s41598-017-16695-6. https://www.researchgate.net/publication/321369667_Interaction_profiling_of_RNA-binding_ubiquitin_ligases_reveals_a_link_between_posttranscriptional_regulation_and_the_ubiquitin_system/fulltext/5a20b6530f7e9b4d1927feb9/321369667_Interaction_profiling_of_RNA-binding_ubiquitin_ligases_reveals_a_link_between_posttranscriptional_regulation_and_the_ubiquitin_system.pdf Dionisio

Background The Midas cichlid species complex (Amphilophus spp.) is widely known among evolutionary biologists as a model system for sympatric speciation and adaptive phenotypic divergence within extremely short periods of time (a few hundred generations). The repeated parallel evolution of adaptive phenotypes in this radiation, combined with their near genetic identity, makes them an excellent model for studying phenotypic diversification. While many ecological and evolutionary studies have been performed on Midas cichlids, the molecular basis of specific phenotypes, particularly adaptations, and their underlying coding and cis-regulatory changes have not yet been studied thoroughly. Results For the first time in any New World cichlid, we use Tol2 transposon-mediated transgenesis in the Midas cichlid (Amphilophus citrinellus). By adapting existing microinjection protocols, we established an effective protocol for transgenesis in Midas cichlids. Embryos were injected with a Tol2 plasmid construct that drives enhanced green fluorescent protein (eGFP) expression under the control of the ubiquitin promoter. The transgene was successfully integrated into the germline, driving strong ubiquitous expression of eGFP in the first transgenic Midas cichlid line. Additionally, we show transient expression of two further transgenic constructs, ubiquitin::tdTomato and mitfa::eGFP. Transgenesis in Midas cichlids will facilitate further investigation of the genetic basis of species-specific traits, many of which are adaptations. Conclusion Transgenesis is a versatile tool not only for studying regulatory elements such as promoters and enhancers, but also for testing gene function through overexpression of allelic gene variants. As such, it is an important first step in establishing the Midas cichlid as a powerful model for studying adaptive coding and non-coding changes in an ecological and evolutionary context. Kratochwil, Claudius & Sefton, Maggie & Liang, Yipeng & Meyer, Axel. (2017). Tol2 transposon-mediated transgenesis in the Midas cichlid (Amphilophus citrinellus) - Towards understanding gene function and regulatory evolution in an ecological model system for rapid phenotypic diversification. BMC Developmental Biology. 17. 15. 10.1186/s12861-017-0157-x. https://www.researchgate.net/profile/Claudius_Kratochwil/publication/321261482_Tol2_transposon-mediated_transgenesis_in_the_Midas_cichlid_Amphilophus_citrinellus_-_Towards_understanding_gene_function_and_regulatory_evolution_in_an_ecological_model_system_for_rapid_phenotypic_div/links/5a1979bda6fdcc50ade812db/Tol2-transposon-mediated-transgenesis-in-the-Midas-cichlid-Amphilophus-citrinellus-Towards-understanding-gene-function-and-regulatory-evolution-in-an-ecological-model-system-for-rapid-phenotypic-div.pdf Dionisio

Background In recent years, next generation high throughput sequencing technologies have proven to be useful tools for investigations concerning the genomics or transcriptomics also of non-model species. Consequently, ornithologists have adopted these technologies and the respective bioinformatics tools to survey the genomes and transcriptomes of a few avian non-model species. The Common Blackbird is one of the most common bird species living in European cities, which has successfully colonized urban areas and for which no reference genome or transcriptome is publicly available. However, to target questions like genome wide gene expression analysis, a reference genome or transcriptome is needed. Methods Therefore, in this study two Common Blackbirds were sacrificed, their mRNA was isolated and analyzed by RNA-Seq to de novo assemble a transcriptome and characterize it. Illumina reads (125 bp paired-end) and a Velvet/Oases pipeline led to 162,158 transcripts. For the annotation (using Blast+), an unfiltered protein database was used. SNPs were identified using SAMtools and BCFtools. Furthermore, mRNA from three single tissues (brain, heart and liver) of the same two Common Blackbirds were sequenced by Illumina (75 bp single-end reads). The draft transcriptome and the three single tissues were compared by their BLAST hits with the package VennDiagram in R. Results Following the annotation against protein databases, we found evidence for 15,580 genes in the transcriptome (all well characterized hits after annotation). On 18% of the assembled transcripts, 144,742 SNPs were identified which are, consequently, 0.09% of all nucleotides in the assembled transcriptome. In the transcriptome and in the single tissues (brain, heart and liver), 10,182 shared genes were found. Discussion Using a next-generation technology and bioinformatics tools, we made a first step towards the genomic investigation of the Common Blackbird. The de novo assembled transcriptome is usable for downstream analyses such as differential gene expression analysis and SNP identification. This study shows the importance of the approach to sequence single tissues to understand functions of tissues, proteins and the phenotype. Koglin, Sven & Trense, Daronja & Wink, Michael & Sauer?Gürth, Hedwig & Tietze, Thomas. (2017). Characterization of a de novo assembled transcriptome of the Common Blackbird (Turdus merula). PeerJ. 5. . 10.7717/peerj.4045. https://www.researchgate.net/profile/Sven_Koglin/publication/321778940_Characterization_of_a_de_novo_assembled_transcriptome_of_the_Common_Blackbird_Turdus_merula/links/5a315e44a6fdcc9b2d34c843/Characterization-of-a-de-novo-assembled-transcriptome-of-the-Common-Blackbird-Turdus-merula.pdf Dionisio

Migration is a widespread phenomenon across the animal kingdom as a response to seasonality in environmental conditions. Partially migratory populations are populations that consist of both migratory and residential individuals. Such populations are very common, yet their stability has long been debated. The inheritance of migratory activity is currently best described by the threshold model of quantitative genetics. The inclusion of such a genetic threshold model for migratory behavior leads to a stable zone in time and space of partially migratory populations under a wide range of demographic parameter values, when assuming stable environmental conditions and unlimited genetic diversity. Migratory species are expected to be particularly sensitive to global warming, as arrival at the breeding grounds might be increasingly mistimed as a result of the uncoupling of long-used cues and actual environmental conditions, with decreasing reproduction as a consequence. Here, we investigate the consequences for migratory behavior and the stability of partially migratory populations under five climate change scenarios and the assumption of a genetic threshold value for migratory behavior in an individual-based model. The results show a spatially and temporally stable zone of partially migratory populations after different lengths of time in all scenarios. In the scenarios in which the species expands its range from a particular set of starting populations, the genetic diversity and location at initialization determine the species’ colonization speed across the zone of partial migration and therefore across the entire landscape. Abruptly changing environmental conditions after model initialization never caused a qualitative change in phenotype distributions, or complete extinction. This suggests that climate change-induced shifts in species’ ranges as well as changes in survival probabilities and reproductive success can be met with flexibility in migratory behavior at the species level, which will reduce the risk of extinction. Cobben, Marleen & van Noordwijk, Arie. (2017). Consequences of the genetic threshold model for observing partial migration under climate change scenarios. Ecology and Evolution. 7. . 10.1002/ece3.3357. https://www.researchgate.net/publication/319612606_Consequences_of_the_genetic_threshold_model_for_observing_partial_migration_under_climate_change_scenarios/fulltext/59b4d9e0458515a5b4926f1f/319612606_Consequences_of_the_genetic_threshold_model_for_observing_partial_migration_under_climate_change_scenarios.pdf Dionisio

Project Ecological genomics of adaptation to environmental change Luciano B BeheregarayLuciano B Beheregaray · Chris BrauerChris Brauer · Michael P HammerMichael P Hammer · Show all 8 collaborators Goal: Rapid environmental and climatic change represents a clear and urgent challenge for conservation and evolutionary biologists – this is particularly so in aquatic ecosystems, which are experiencing some of the fastest rates of change. We are implementing a research program in ecological genomics to understand population adaptations and responses to environmental change in ecologically important aquatic organisms. Our program integrates comparative ecological genomics (in the wild and in the lab), phenotypic data and spatially-explicit modelling approaches to assess adaptation and vulnerability of aquatic biodiversity to environmental and climatic change. For details about this and other similar research programs please visit: http://www.molecularecology.flinders.edu.au/molecular-ecology-lab/research-programs/ Dionisio

Epigenetics has attracted considerable attention with respect to its potential value in many areas of agricultural production, particularly under conditions where the environment can be manipulated or natural variation exists. Here we introduce key concepts and definitions of epigenetic mechanisms, including DNA methylation, histone modifications and non-coding RNA, review the current understanding of epigenetics in both fish and shellfish, and propose key areas of aquaculture where epigenetics could be applied. The first key area is environmental manipulation, where the intention is to induce an ‘epigenetic memory’ either within or between generations to produce a desired phenotype. The second key area is epigenetic selection, which, alone or combined with genetic selection, may increase the reliability of producing animals with desired phenotypes. Based on aspects of life history and husbandry practices in aquaculture species, the application of epigenetic knowledge could significantly affect the productivity and sustainability of aquaculture practices. Conversely, clarifying the role of epigenetic mechanisms in aquaculture species may upend traditional assumptions about selection practices. Ultimately, there are still many unanswered questions regarding how epigenetic mechanisms might be leveraged in aquaculture. Gavery, Mackenzie & Roberts, Steven. (2017). Epigenetic considerations in aquaculture. PeerJ. 5. e4147. 10.7717/peerj.4147. https://peerj.com/articles/4147.pdf Dionisio

Wild stocks of Pacific salmonids have experienced sharp declines in abundance over the past century. Consequently, billions of fish are released each year for enhancing abundance and sustaining fisheries. However, the beneficial role of this widely used management practice is highly debated since fitness decrease of hatchery-origin fish in the wild has been documented. Artificial selection in hatcheries has often been invoked as the most likely explanation for reduced fitness, and most studies to date have focused on finding signatures of hatchery-induced selection at the DNA level. We tested an alternative hypothesis, that captive rearing induces epigenetic reprogramming, by comparing genome-wide patterns of methylation and variation at the DNA level in hatchery-reared coho salmon (Oncorhynchus kisutch) with those of their wild counterparts in two geographically distant rivers. We found a highly significant proportion of epigenetic variation explained by the rearing environment that was as high as the one explained by the river of origin. The differentially methylated regions show enrichment for biological functions that may affect the capacity of hatchery-born smolts to migrate successfully in the ocean. Shared epigenetic variation between hatchery-reared salmon provides evidence for parallel epigenetic modifications induced by hatchery rearing in the absence of genetic differentiation between hatchery and natural-origin fish for each river. This study highlights epigenetic modifications induced by captive rearing as a potential explanatory mechanism for reduced fitness in hatchery-reared salmon. le luyer, Jeremy & Laporte, Martin & Beacham, Terry & Kaukinen, Karia & E Withler, Ruth & Leong, Jong & Rondeau, Eric & Koop, Ben & Bernatchez, Louis. (2017). Parallel epigenetic modifications induced by hatchery rearing in a Pacific salmon. Proceedings of the National Academy of Sciences. 114. . 10.1073/pnas.1711229114. https://www.researchgate.net/profile/Jeremy_Le_Luyer/publication/321197011_Parallel_epigenetic_modifications_induced_by_hatchery_rearing_in_a_Pacific_salmon/links/5a146931a6fdccd697bbe364/Parallel-epigenetic-modifications-induced-by-hatchery-rearing-in-a-Pacific-salmon.pdf Dionisio

We examined spatio-temporal genetic variation at 53 single nucleotide polymorphisms in anadromous Arctic char populations from Western Greenland, a region experiencing pronounced climate change. The study was based on contemporary and historical samples, the latter represented by DNA extracted from otoliths and scales from the 1950s–1960s. We investigated whether genetic population structure was temporarily stable or unstable, the latter due to relatively small spawning and nursery areas combined with a harsh Arctic environment. Furthermore, in order to evaluate the potential for adaptive responses and local adaptation we estimated effective population size (Ne) and migration rate (m). Temporal stability of genetic population structure was suggested, based on a hierarchical analysis of genetic differentiation showing much higher differentiation among samples from different populations (FCT = 0.091) than among temporal samples from the same populations (FSC = 0.01). This was further supported by a neighbor-joining tree and assignment of individuals that showed high contingency between historical and contemporary samples. Estimates of Ne were high (> 500) in three out of four populations, with a lower estimate in one population potentially reflecting fishing pressure or suboptimal environmental conditions. Estimates of m were in most cases low, ? 0.01. Ne and m estimates suggest a potential for adaptive responses and local adaptation. However, long generation time may also cause adaptive responses by microevolution to be unable to track climate change, especially considering the low migration rates that reduce potential evolutionary rescue by gene flow from populations better adapted to the altered environments. Christensen, Camilla & Jacobsen, Magnus & Nygaard, Rasmus & Hansen, Michael. (2018). Spatiotemporal genetic structure of anadromous Arctic char (Salvelinus alpinus) populations in a region experiencing pronounced climate change. Conservation Genetics. 1-14. 10.1007/s10592-018-1047-x. Dionisio

Migration is a ubiquitous life history trait with profound evolutionary and ecological consequences. Recent developments in telemetry and genomics, when combined, can bring significant insights on the migratory ecology of non-model organisms in the wild. Here, we used this integrative approach to document dispersal, gene flow and potential for local adaptation in anadromous Arctic Char from six rivers in the Canadian Arctic. Acoustic telemetry data from 124 tracked individuals indicated asymmetric dispersal, with a large proportion of fish (72%) tagged in three different rivers migrating up the same short river in the fall. Population genomics data from 6,136 SNP markers revealed weak, albeit significant, population differentiation (average pairwise FST = 0.011) and asymmetric dispersal was also revealed by population assignments. Approximate Bayesian Computation simulations suggested the presence of asymmetric gene flow, although in the opposite direction to that observed from the telemetry data, suggesting that dispersal does not necessarily lead to gene flow. These observations suggested that Arctic Char home to their natal river to spawn, but may overwinter in rivers with the shortest migratory route to minimize the costs of migration in non-breeding years. Genome scans and genetic-environment associations identified 90 outlier markers putatively under selection, 23 of which were in or near a gene. Of these, at least four were involved in muscle and cardiac function, consistent with the hypothesis that migratory harshness could drive local adaptation. Our study illustrates the power of integrating genomics and telemetry to study migrations in non-model organisms in logistically challenging environments such as the Arctic. Moore, Jean-Sébastien & Harris, Les & le luyer, Jeremy & Sutherland, Ben & Rougemont, Quentin & Tallman, Ross & Fisk, Aaron & Bernatchez, Louis. (2017). Genomics and telemetry suggest a role for migration harshness in determining overwintering habitat choice, but not gene flow, in anadromous Arctic Char. Molecular Ecology. 26. . 10.1111/mec.14393. https://www.researchgate.net/profile/Jean-Sebastien_Moore/publication/320738125_Genomics_and_telemetry_suggest_a_role_for_migration_harshness_in_determining_overwintering_habitat_choice_but_not_gene_flow_in_anadromous_Arctic_Char/links/59fc6afc0f7e9b9968bd7c47/Genomics-and-telemetry-suggest-a-role-for-migration-harshness-in-determining-overwintering-habitat-choice-but-not-gene-flow-in-anadromous-Arctic-Char.pdf Dionisio

The colonization of urban environments by animals is often accompanied by earlier breeding and associated changes in seasonal schedules. Accelerated timing of seasonal reproduction in derived urban populations is a potential cause of evolutionary divergence from ancestral populations if differences in physiological processes that regulate reproductive timing become fixed over time. We compared reproductive development in free-living and captive male dark-eyed juncos deriving from a population that recently colonized a city (~35 years) and ceased migrating to that of conspecifics that live in sympatry with the urban population during winter and spring but migrate elsewhere to breed. We predicted that the earlier breeding sedentary urban birds would exhibit accelerated reproductive development in the spring along the hypothalamic-pituitary-gonadal (HPG) axis as compared to migrants. We found that free-living sedentary urban and migrant juncos differed at the level of the pituitary when measured as baseline luteinizing hormone (LH) levels, but not in increased LH when challenged with Gonadotropin-Releasing Hormone (GnRH). Among captives held in a common garden, and at the level of the gonad, we found that sedentary urban birds produced more testosterone in response to GnRH than migrants living in the same common environment, suggesting greater gonadal sensitivity in the derived urban population. Greater gonadal sensitivity could arise from greater upstream activation by LH or FSH or from reduced suppression of gonadal development by the adrenal axis. We compared abundance of gonadal transcripts for LH receptor (LHR), follicle stimulating hormone receptor (FSHR), glucocorticoid receptor (GR), and mineralocorticoid receptor (MR) in the common-garden, predicting either more abundant transcripts for LHR and FSHR or fewer transcripts for GR and MR in the earlier breeding sedentary urban breeders, as compared to the migrants. We found no difference in the expression of these genes. Together these data suggest that advanced timing of reproduction in a recently derived urban population is facilitated by earlier increase in upstream baseline activity of the HPG and earlier release from gonadal suppression by yet-to-be-discovered mechanisms. Evolutionarily, our results suggest that potential for gene flow between seasonally sympatric populations may be limited due to urban-induced advances in the timing of reproduction and resulting allochrony with ancestral forms. Fudickar, Adam & J. Greives, Timothy & Abolins-Abols, Mikus & Atwell, Jonathan & Meddle, Simone & Friis, Guillermo & Stricker, Craig & Ketterson, Ellen. (2017). Mechanisms Associated with an Advance in the Timing of Seasonal Reproduction in an Urban Songbird. Frontiers in Ecology and Evolution. 5. 85. 10.3389/fevo.2017.00085. https://www.researchgate.net/profile/Simone_Meddle/publication/318871742_Mechanisms_Associated_with_an_Advance_in_the_Timing_of_Seasonal_Reproduction_in_an_Urban_Songbird/links/5983202da6fdcca7b66e2e2c/Mechanisms-Associated-with-an-Advance-in-the-Timing-of-Seasonal-Reproduction-in-an-Urban-Songbird.PDF Dionisio

Seasonal migration is a widespread phenomenon, which is found in many different lineages of animals. This spectacular behaviour allows animals to avoid seasonally adverse environmental conditions to exploit more favourable habitats. Migration has been intensively studied in birds, which display astonishing variation in migration strategies, thus providing a powerful system for studying the ecological and evolutionary processes that shape migratory behaviour. Despite intensive research, the genetic basis of migration remains largely unknown. Here we used state-of-the-art radio-tracking technology to characterize the migratory behaviour of a partially migratory population of European blackbirds (Turdus merula) in southern Germany. We compared gene expression of resident and migrant individuals using high-throughput transcriptomics in blood samples. Analyses of sequence variation revealed a non-significant genetic structure between blackbirds differing by their migratory phenotype. We detected only four differentially expressed genes between migrants and residents, which might be associated with hyperphagia, moulting, and enhanced DNA replication and transcription. The most pronounced changes in gene expression occurred between migratory birds depending on when, in relation to their date of departure, blood was collected. Overall, the differentially expressed genes detected in this analysis may play crucial roles in determining the decision to migrate, or in controlling the physiological processes required for the onset of migration. These results provide new insights into, and testable hypotheses for, the molecular mechanisms controlling the migratory phenotype and its underlying physiological mechanisms in blackbirds and other migratory bird species. This article is protected by copyright. All rights reserved. Franchini, Paolo & Irisarri, Iker & Fudickar, Adam & Schmidt, Andreas & Meyer, Axel & Wikelski, Martin & Partecke, Jesko. (2017). Animal tracking meets migration genomics: Transcriptomic analysis of a partially migratory bird species. Molecular Ecology. . 10.1111/mec.14108. https://www.researchgate.net/profile/Adam_Fudickar/publication/315434379_Animal_tracking_meets_migration_genomics_Transcriptomic_analysis_of_a_partially_migratory_bird_species/links/59df800fa6fdccfcfda38457/Animal-tracking-meets-migration-genomics-Transcriptomic-analysis-of-a-partially-migratory-bird-species.pdf Dionisio

Myrosin cells accumulate myrosinases in their vacuoles to catalyze the production of toxic compounds when tissues are damaged by herbivores. Myrosin cells are positioned adjacent to the abaxial side of the vasculature but their origin is unclear. To determine whether the myrosin cells are differentiated from vascular precursor cells, we generated a transgenic Arabidopsis line that expressed a myrosin cell reporter together with one of three vascular precursor cell reporters. The myrosin-positive cells were discontinuously distributed while the vascular precursor-positive cells were continuously distributed. The fluorescent signals of the myosin and vascular reporters did not overlap. Furthermore, the shape of myrosin-positive cells was different from the shape of vascular precursor-positive cells. These results indicate that myosin cells develop independently of the vasculature. Shirakawa, Makoto & Ueda, Haruko & Shimada, Tomoo & Hara-Nishimura, Ikuko. (2016). Myrosin cells are differentiated directly from ground meristem cells and are developmentally independent of the vasculature in Arabidopsis leaves. Plant Signaling & Behavior. 11. 00-00. 10.1080/15592324.2016.1150403. https://www.researchgate.net/profile/Makoto_Shirakawa/publication/297891491_Myrosin_cells_are_differentiated_directly_from_ground_meristem_cells_and_are_developmentally_independent_of_the_vasculature_in_Arabidopsis_leaves/links/59dcd8e30f7e9bdd752dd0b8/Myrosin-cells-are-differentiated-directly-from-ground-meristem-cells-and-are-developmentally-independent-of-the-vasculature-in-Arabidopsis-leaves.pdf Dionisio

The co-ordinated positioning of veins, mesophyll cells and stomata across a leaf is crucial for efficient gas exchange and transpiration, and therefore for overall function. In monocot leaves, stomatal cell files are positioned at the flanks of underlying longitudinal leaf veins, rather than directly above or below. This pattern suggests either that stomatal formation is inhibited in epidermal cells directly in contact with the vein, or that specification is induced in cells files beyond the vein. The SHORTROOT pathway specifies distinct cell-types around the vasculature in sub-epidermal layers of both root and shoots, with cell-type identity determined by distance from the vein. To test whether the pathway has the potential to similarly pattern epidermal cell-types, we expanded the expression domain of the rice OsSHR2 gene, which we show is restricted to developing leaf veins, to include bundle sheath cells encircling the vein. In transgenic lines, which were generated using the orthologous ZmSHR1 gene to avoid potential silencing of OsSHR2, stomatal cell files were observed both in the normal position and in more distant positions from the vein. Contrary to theoretical predictions, and to phenotypes observed in eudicot leaves, the increase in stomatal density did not enhance photosynthetic capacity or increase mesophyll cell density. Collectively these results suggest that the SHORTROOT pathway may co-ordinate the positioning of veins and stomata in monocot leaves, and that distinct mechanisms may operate in monocot and eudicot leaves to co-ordinate stomatal patterning with the development of underlying mesophyll cells. Schuler, Mara & V. Sedelnikova, Olga & Walker, Berkley & Westhoff, Peter & A. Langdale, Jane. (2017). SHORTROOT-Mediated Increase in Stomatal Density Has No Impact on Photosynthetic Efficiency. Plant Physiology. 176. pp.01005.2017. 10.1104/pp.17.01005. https://www.researchgate.net/profile/Berkley_Walker/publication/320995365_SHORTROOT-Mediated_Increase_in_Stomatal_Density_Has_No_Impact_on_Photosynthetic_Efficiency/links/5a13333c0f7e9b1e572e88f5/SHORTROOT-Mediated-Increase-in-Stomatal-Density-Has-No-Impact-on-Photosynthetic-Efficiency.pdf Dionisio

Stomata are simultaneously tasked with permitting the uptake of carbon dioxide for photosynthesis while limiting water loss from the plant. This process is mainly regulated by guard cell control of the stomatal aperture, but recent advancements have highlighted the importance of several genes that control stomatal development. Using targeted genetic manipulations of the stomatal lineage and a combination of gas exchange and microscopy techniques, we show that changes in stomatal development of the epidermal layer lead to coupled changes in the underlying mesophyll tissues. This coordinated response tends to match leaf photosynthetic potential (Vcmax) with gas?exchange capacity (gsmax), and hence the uptake of carbon dioxide for water lost. We found that different genetic regulators systematically altered tissue coordination in separate ways: the transcription factor SPEECHLESS (SPCH) primarily affected leaf size and thickness, whereas peptides in the EPIDERMAL PATTERNING FACTOR (EPF) family altered cell density in the mesophyll. It was also determined that interlayer coordination required the cell?surface receptor TOO MANY MOUTHS (TMM). These results demonstrate that stomata?specific regulators can alter mesophyll properties, which provides insight into how molecular pathways can organize leaf tissues to coordinate gas exchange and suggests new strategies for improving plant water?use efficiency. J. Dow, Graham & Berry, Joseph & C. Bergmann, Dominique. (2017). Disruption of stomatal lineage signaling or transcriptional regulators has differential effects on mesophyll development, but maintains coordination of gas exchange. New Phytologist. 216. . 10.1111/nph.14746. https://www.researchgate.net/publication/319204070_Disruption_of_stomatal_lineage_signaling_or_transcriptional_regulators_has_differential_effects_on_mesophyll_development_but_maintains_coordination_of_gas_exchange/fulltext/599b0125aca272dff128d5f8/319204070_Disruption_of_stomatal_lineage_signaling_or_transcriptional_regulators_has_differential_effects_on_mesophyll_development_but_maintains_coordination_of_gas_exchange.pdf Dionisio

The development and patterning of stomata in the plant epidermis has emerged as an ideal system for studying fundamental plant developmental processes. Over the past twenty years most studies of stomata have used the model dicotyledonous plant Arabidopsis thaliana. However, cultivated monocotyledonous grass (or Gramineae) varieties provide the majority of human nutrition, and future research into grass stomata could be of critical importance for improving food security. Recent studies using Brachypodium distachyon, Hordeum vulgare (barley) and Oryza sativa (rice) have led to the identification of the core transcriptional regulators essential for stomatal initiation and progression in grasses, and begun to unravel the role of secretory signaling peptides in controlling stomatal developmental. This review revisits how stomatal developmental unfolds in grasses, and identifies key ontogenetic steps for which knowledge of the underpinning molecular mechanisms remains outstanding. Hepworth, Christopher & Caine, Robert & Harrison, Emily & Sloan, Jennifer & Gray, Julie. (2017). Stomatal development: focusing on the grasses. Current opinion in plant biology. 41. 1-7. 10.1016/j.pbi.2017.07.009. Dionisio

Stem cell regeneration is crucial for both cell turnover and tissue healing in multicellular organisms. In Arabidopsis roots, a reduced group of cells known as the quiescent center (QC) acts as a cell reservoir for surrounding stem cells during both normal growth and in response to external damage. Although cells of the QC have a very low mitotic activity, plant hormones such as brassinosteroids (BR) can promote QC divisions. Here, we used a tissue-specific strategy to investigate the spatial signaling requirements of BR-mediated QC divisions. We generated stem cell niche-specific receptor knockout lines by placing an artificial microRNA against BRI1 (BRASSINOSTEROID RESPONSE INSENSITIVE 1) under the control of the QC-specific promoter WOX5. Additionally, QC-specific knock-in lines for BRI1 and its downstream transcription factor BES1 (BRI1-EMS-SUPPRESOR1) were also created using the WOX5 promoter. By analyzing the roots of these lines, we uncover that BES1-mediated signaling cell-autonomously promotes QC divisions, that BRI1 is essential for sensing nearby inputs and triggering QC divisions, and that DNA damage promotes BR-dependent paracrine signaling in the stem cell niche as a prerequisite to stem cell replenishment. Lozano-Elena, Fidel & Planas Riverola, Ainoa & Vilarrasa-Blasi, Josep & Schwab, Rebecca & Caño-Delgado, Ana. (2017). Paracrine brassinosteroid signaling at the stem cell niche controls cellular regeneration. Journal of Cell Science. jcs.204065. 10.1242/jcs.204065. http://jcs.biologists.org/content/early/2017/12/13/jcs.204065.full.pdf Dionisio

Development of stomata, valves on the plant epidermis for optimal gas exchange and water control, is fine-tuned by multiple signaling peptides with unique, overlapping, or antagonistic activities. EPIDERMAL PATTERNING FACTOR1 (EPF1) is a founding member of the secreted peptide ligands enforcing stomatal patterning. Yet, its exact role remains unclear. Here, we report that EPF1 and its primary receptor ERECTA-LIKE1 (ERL1) target MUTE, a transcription factor specifying the proliferation-to-differentiation switch within the stomatal cell lineages. In turn, MUTE directly induces ERL1. The absolute co-expression of ERL1 and MUTE, with the co-presence of EPF1, triggers autocrine inhibition of stomatal fate. During normal stomatal development, this autocrine inhibition prevents extra symmetric divisions of stomatal precursors likely owing to excessive MUTE activity. Our study reveals the unexpected role of self-inhibition as a mechanism for ensuring proper stomatal development and suggests an intricate signal buffering mechanism underlying plant tissue patterning. Qi, Xingyun & Han, Soon-Ki & H Dang, Jonathan & M Garrick, Jaqueline & Ito, Masaki & K. Hofstetter, Alex & Torii, Keiko. (2017). Autocrine regulation of stomatal differentiation potential by EPF1 and ERECTA-LIKE1 ligand-receptor signaling. eLife Sciences. 6. e24102. 10.7554/eLife.24102. https://www.researchgate.net/profile/Keiko_Torii/publication/322116826_Autocrine_regulation_of_stomatal_differentiation_potential_by_EPF1_and_ERECTA-LIKE1_ligand-receptor_signaling/links/5a45df75a6fdcce1971a91f2/Autocrine-regulation-of-stomatal-differentiation-potential-by-EPF1-and-ERECTA-LIKE1-ligand-receptor-signaling.pdf Dionisio

The development and patterning of stomata in the plant epidermis has emerged as an ideal system for studying fundamental plant developmental processes. Over the past twenty years most studies of stomata have used the model dicotyledonous plant Arabidopsis thaliana. However, cultivated monocotyledonous grass (or Gramineae) varieties provide the majority of human nutrition, and future research into grass stomata could be of critical importance for improving food security. Recent studies using Brachypodium distachyon, Hordeum vulgare (barley) and Oryza sativa (rice) have led to the identification of the core transcriptional regulators essential for stomatal initiation and progression in grasses, and begun to unravel the role of secretory signaling peptides in controlling stomatal developmental. This review revisits how stomatal developmental unfolds in grasses, and identifies key ontogenetic steps for which knowledge of the underpinning molecular mechanisms remains outstanding. Hepworth, Christopher & Caine, Robert & Harrison, Emily & Sloan, Jennifer & Gray, Julie. (2017). Stomatal development: focusing on the grasses. Current opinion in plant biology. 41. 1-7. 10.1016/j.pbi.2017.07.009. Dionisio

@305 addendum

In plants, extracellular signals are primarily sensed by plasma membrane-localized receptor-like kinases (RLKs). ERECTA is a leucine-rich repeat RLK that together with its paralogs ERECTA-like 1 (ERL1) and ERL2 regulates multiple aspects of plant development. ERECTA forms complexes with a range of co-receptors and senses secreted cysteine-rich small proteins from the EPF/EPFL family. Currently the mechanism of the cytoplasmic domain activation and transmission of the signal by ERECTA is unclear. To gain a better understanding we performed a structure–function analysis by introducing altered ERECTA genes into erecta and erecta erl1 erl2 mutants. These experiments indicated that ERECTA’s ability to phosphorylate is functionally significant, and that while the cytoplasmic juxtamembrane domain is important for ERECTA function, the C-terminal tail is not. An analysis of multiple putative phosphorylation sites identified four amino acids in the activation segment of the kinase domain as functionally important. Homology of those residues to functionally significant amino acids in multiple other plant RLKs emphasizes similarities in RLK function. Specifically, our data predicts Thr812 as a primary site of phosphor-activation and potential inhibitory phosphorylation of Tyr815 and Tyr820. In addition, our experiments suggest that there are differences in the molecular mechanism of ERECTA function during regulation of stomata development and in elongation of above-ground organs.

Z Kosentka, Pawel & Zhang, Liang & A Simon, Yonas & Satpathy, Binita & Maradiaga, Richard & Mitoubsi, Omar & Shpak, Elena. (2017). Identification of critical functional residues of receptor-like kinase ERECTA. Journal of experimental botany. 68. . 10.1093/jxb/erx022.

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

Stomata are dispersed pores found in the epidermis of land plants that facilitate gas exchange for photosynthesis while minimizing water loss. Stomata are formed from progenitor cells, which execute a series of differentiation events and stereotypical cell divisions. The sequential activation of master regulatory basic-helix-loop-helix (bHLH) transcription factors controls the initiation, proliferation and differentiation of stomatal cells. Cell-cell communication mediated by secreted peptides, receptor kinases, and downstream mitogen- activated kinase cascades enforces proper stomatal patterning, and an intrinsic polarity mechanism ensures asymmetric cell divisions. As we review here, recent studies have provided insights into the intrinsic and extrinsic factors that control stomatal development. These findings have also highlighted striking similarities between plants and animals with regards to their mechanisms of specialized cell differentiation.

Han, S.-K & Torii, Keiko. (2016). Lineage-specific stem cells, signals and asymmetries during stomatal development. Development. 143. 1259-1270. 10.1242/dev.127712. https://www.researchgate.net/profile/Keiko_Torii/publication/301536187_Lineage-specific_stem_cells_signals_and_asymmetries_during_stomatal_development/links/571e93d308aefa648899a376/Lineage-specific-stem-cells-signals-and-asymmetries-during-stomatal-development.pdf

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

@305 addendum https://www.researchgate.net/profile/Elena_Shpak/publication/313819497_Identification_of_critical_functional_residues_of_receptor-like_kinase_ERECTA/links/58ad973645851503be91cb07/Identification-of-critical-functional-residues-of-receptor-like-kinase-ERECTA.pdf Dionisio

These results suggest that there are distinct signaling requirements for ERECTA in different developmental processes and imply that ERECTA might transmit the signal to downstream targets in different ways. The receptor-like kinases BAK1 and SCRAMBLED have also been shown to control multiple pathways using distinct signaling mechanisms with different requirements for their kinase domain function [...]

Identification of critical functional residues of receptor-like kinase ERECTA Pawel Z. Kosentka, Liang Zhang, Yonas A. Simon, Binita Satpathy, Richard Maradiaga, Omar Mitoubsi and Elena D. Shpak Journal of Experimental Botany doi:10.1093/jxb/erx022

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

It has been argued here that the discontent is better understood as stemming from a few inescapable properties of living things, which lead to disappointment with evolutionary biology, and a nagging feeling that reform must be overdue. Evolutionary biology, like history, but unlike other natural sciences, raises issues of purpose and agency, alongside those of complexity and generality [...] It is remarkable, for example, that much of the funding for challenging current practice in evolutionary biology comes from The John Templeton Foundation (Pennisi 2016), which is committed to using science to reveal underlying purpose, and rejecting what Nagel (2012) calls “the Materialist Neo-Darwinian Conception of Nature”. [...] claims that evolutionary biology is misguided or importantly incomplete are not harmless, but actively hinder progress in the field. [...] a field that urgently needs reform is a field “in crisis” (Mazur 2010), and when it fails to reform, this lends credibility to claims that scientists are, at best, hidebound and foolish, and at worst, guilty of ideologically-motivated deception (Mazur 2010; Teresi 2011).

What’s wrong with evolutionary biology? John J. Welch Biology & Philosophy March 2017, Volume 32, Issue 2, pp 263–279

Dionisio

[...] one research programme: the study of adaptive function. [...] traits of all kinds might be adaptations [...] Such research uses ideas related to optimization, including tools from engineering and economics, and often represents evolution in terms of (imaginary) agents with (imaginary) agendas. Hypothesizing about adaptive rationales is easy to do badly, and difficult to do well.

What’s wrong with evolutionary biology? John J. Welch Biology & Philosophy March 2017, Volume 32, Issue 2, pp 263–279

Dionisio

[...] the theory of natural selection causes additional problems. One problem is its deceptive simplicity [...] [...] it is an idea that we all think we understand, but which continues to divide experts [...] [...] natural selection causes problems, not only because it is mindless and amoral, but because it can seem downright immoral. [...] Darwinist explanations inherently invoke selfishness and greed as the most important driving forces [...] [...] Darwin’s own emphasis on “struggle” probably rests on a mistake [...]

What’s wrong with evolutionary biology? John J. Welch Biology & Philosophy March 2017, Volume 32, Issue 2, pp 263–279

Dionisio

The characteristics of life also guarantee that the explanatory frameworks of evolutionary biology will be disappointing to some. Disappointment is caused partly by the sheer complexity of life’s dynamical processes. This means that our predictive power will always be weak in certain ways, and that our descriptions of evolution will always be enormous simplifications.

What’s wrong with evolutionary biology? John J. Welch Biology & Philosophy March 2017, Volume 32, Issue 2, pp 263–279 https://link.springer.com/content/pdf/10.1007%2Fs10539-016-9557-8.pdf

Dionisio

Some problems for evolutionary biology are caused by the basic characteristics of life. Some banal practical problems are caused by the sheer scope of evolutionary biology. [...] new data appear at a very rapid rate, particularly, in recent years, from molecular biology.

What’s wrong with evolutionary biology? John J. Welch Biology & Philosophy March 2017, Volume 32, Issue 2, pp 263–279 https://link.springer.com/content/pdf/10.1007%2Fs10539-016-9557-8.pdf

Dionisio

Evo-devo despacito? :)

Usually, evolutionary economists equate evolutionary theory with modern Darwinism. However, the rise of evolutionary developmental biology (Evo-Devo) puts into question the monopoly of Darwinism in evolutionary biology. The major divergences between the two paradigms in evolutionary biology are drawn in the analysis of three trade-offs: population vs. typological thinking, creative role of natural selection vs. internal (inherent) change, and microevolution vs. macroevolution. It is argued here that the Evo-Devo breakthrough helps us to understand better the limits to Darwinism in the social realm and outline the contours of an alternative paradigm in evolutionary economics that favors structural macroevolution and what Schumpeter called “change from within”.

The challenge of Evo-Devo: implications for evolutionary economists George Liagouras https://doi.org/10.1007/s00191-017-0525-5 Journal of Evolutionary Economics September 2017, Volume 27, Issue 4, pp 795–823

Dionisio

The epidermis of aerial plant organs is thought to be limiting for growth, because it acts as a continuous load-bearing layer, resisting tension. Leaf epidermis contains jigsaw puzzle piece-shaped pavement cells whose shape has been proposed to be a result of subcellular variations in expansion rate that induce local buckling events. Paradoxically, such local compressive buckling should not occur given the tensile stresses across the epidermis. Using computational modeling, we show that the simplest scenario to explain pavement cell shapes within an epidermis under tension must involve mechanical wall heterogeneities across and along the anticlinal pavement cell walls between adjacent cells. Combining genetics, atomic force microscopy, and immunolabeling, we demonstrate that contiguous cell walls indeed exhibit hybrid mechanochemical properties. Such biochemical wall heterogeneities precede wall bending. Altogether, this provides a possible mechanism for the generation of complex plant cell shapes.

Mechanochemical Polarization of Contiguous Cell Walls Shapes Plant Pavement Cells Mateusz Majda, Peter Grones, Ida-Maria Sintorn, Thomas Vain, Pascale Milani, Pawel Krupinski, Beata Zagórska-Marek, Corrado Viotti, Henrik Jönsson, Ewa J. Mellerowicz, Olivier Hamant, Stéphanie Robert DOI: http://dx.doi.org/10.1016/j.devcel.2017.10.017 Volume 43, Issue 3, p290–304.e4, Developmental Cell

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

Coordinated development of multicellular organisms depends on the ability of cells to assess their relative positions within the growing organism. This is achieved through intercellular communication, commonly based on the production and perception of mobile signaling molecules. [...] the mobile signals used by plants to instruct cell-fate decisions, such as hormones and peptide ligands, are distinct from those of animals [...]

Boundary Formation through a Direct Threshold-Based Readout of Mobile Small RNA Gradients Damianos S.Skopelitis, Anna H.Benkovics, Aman Y.Husbands, Marja C.P.Timmermans Developmental Cell 43, 1–9 Volume 43, Issue 3, Pages 265-273.e6 https://doi.org/10.1016/j.devcel.2017.10.003 https://www.researchgate.net/profile/Aman_Husbands/publication/320639868_Boundary_Formation_through_a_Direct_Threshold-Based_Readout_of_Mobile_Small_RNA_Gradients/links/5a1ec9c4a6fdccc6b7f8b6bc/Boundary-Formation-through-a-Direct-Threshold-Based-Readout-of-Mobile-Small-RNA-Gradients.pdf

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

Small RNAs have emerged as a new class of mobile signals. Here, we investigate their mechanism of action and show that mobile small RNAs generate sharply defined domains of target gene expression through an intrinsic and direct threshold-based readout of their mobility gradients. This readout is highly sensitive to small RNA levels at the source, allowing plasticity in the positioning of a target gene expression boundary. Besides patterning their immediate targets, the readouts of opposing small RNA gradients enable specification of robust, uniformly positioned developmental boundaries. These patterning properties of small RNAs are reminiscent of those of animal morphogens. However, their mode of action and the intrinsic nature of their gradients distinguish mobile small RNAs from classical morphogens and present a unique direct mechanism through which to relay positional information. Mobile small RNAs and their targets thus emerge as highly portable, evolutionarily tractable regulatory modules through which to create pattern.

Boundary Formation through a Direct Threshold-Based Readout of Mobile Small RNA Gradients Damianos S.Skopelitis, Anna H.Benkovics, Aman Y.Husbands, Marja C.P.Timmermans Developmental Cell 43, 1–9 Volume 43, Issue 3, Pages 265-273.e6 https://doi.org/10.1016/j.devcel.2017.10.003

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

Exploring biogenic amine receptors and downstream regulatory pathways involved in insect behavior and derived social functions will advance our understanding of how the eusocial insect brain evolved perceptual and cognitive capacities in association with sociality. Broader sampling is required to gain phylogenetic insight into the evolution of aminergic control systems. Determining patterns of conservation and/or diversification of aminergic regulatory mechanisms of social behavior will benefit from studies of insect genera that include solitary and eusocial species. Despite the widespread activity of biogenic amines, functional patterns appear. 5-HT may control energy expenditure through feeding behavior and circadian rhythms, DA regulates fertility, thus modulating task performance in eusocial species, and OA modulates appetitive learning associated with feeding and nestmate recognition. Advances in epigenetics (Libbrecht et al., 2016), neurogenetics (Friedman and Gordon, 2016), and the integration of sociobiology and neurochemistry (Kamhi and Traniello, 2013) will aid in future research.

Origins of Aminergic Regulation of Behavior in Complex Insect Social Systems J. Frances Kamhi,1,* Sara Arganda,2,3 Corrie S. Moreau,4 and James F. A. Traniello Front Syst Neurosci. 2017; 11: 74. doi: 10.3389/fnsys.2017.00074

Parole, parole, parole… Where’s the beef? The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

Neuromodulators are conserved across insect taxa, but how biogenic amines and their receptors in ancestral solitary forms have been co-opted to control behaviors in derived socially complex species is largely unknown. Synthesizing current findings that reveal potential ancestral roles of monoamines in insects, we identify physiological processes and conserved behaviors under aminergic control, consider how biogenic amines may have evolved to modulate complex social behavior, and present focal research areas that warrant further study.

Origins of Aminergic Regulation of Behavior in Complex Insect Social Systems J. Frances Kamhi,1,* Sara Arganda,2,3 Corrie S. Moreau,4 and James F. A. Traniello Front Syst Neurosci. 2017; 11: 74. doi: 10.3389/fnsys.2017.00074

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

[...] our candidate sets of genes for sterility form functional modules within the living bee brain's TRN. Moreover, these same gene sets colocate to a single, albeit large, region of the TRN's topology. This spatially organized and convergent pattern contrasts with a null expectation for functionally unrelated genes to be haphazardly distributed throughout the network. Our meta-genomic analysis therefore provides first evidence for a truly “social transcriptome” that may regulate the conditional expression of honeybee worker sterility.

Structure and function of gene regulatory networks associated with worker sterility in honeybees Julia A. Sobotka, Mark Daley, Sriram Chandrasekaran, Benjamin D. Rubin, Graham J. Thompson DOI: 10.1002/ece3.1997 Ecology and Evolution http://onlinelibrary.wiley.com/doi/10.1002/ece3.1997/epdf

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

Cascades of transcriptional regulation are the common source of the forward drive in all developmental systems. Increases in complexity and specificity of gene expression at successive stages are based on the collaboration of varied combinations of transcription factors already expressed in the cells to turn on new genes, and the logical relationships between the transcription factors acting and becoming newly expressed from stage to stage are best visualized as gene regulatory networks. However, gene regulatory networks used in different developmental contexts underlie processes that actually operate through different sets of rules, which affect the kinetics, synchronicity, and logical properties of individual network nodes. Contrasting early embryonic development in flies and sea urchins with adult mammalian hematopoietic development from stem cells, major differences are seen in transcription factor dosage dependence, the silencing or damping impacts of repression, and the impact of cellular regulatory history on the parts of the genome that are accessible to transcription factor action in a given cell type. These different features not only affect the kinds of models that can illuminate developmental mechanisms in the respective biological systems, but also reflect the evolutionary needs of these biological systems to optimize different aspects of development.

Rothenberg, E.V. HPLS (2017) 39: 37. https://doi.org/10.1007/s40656-017-0164-z

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

This paper presents “optimal identification,” a framework for using experimental data to identify the optimality conditions associated with the feedback control law implemented in the measurements. The technique compares closed loop trajectory measurements against a reduced order model of the open loop dynamics, and uses linear matrix inequalities to solve an inverse optimal control problem as a convex optimization that estimates the controller optimality conditions. In this study, the optimal identification technique is applied to two examples, that of a millimeter-scale micro-quadrotor with an engineered controller on board, and the example of a population of freely flying Drosophila hydei maneuvering about forward flight. The micro-quadrotor results show that the performance indices used to design an optimal flight control law for a micro-quadrotor may be recovered from the closed loop simulated flight trajectories, and the Drosophila results indicate that the combined effect of the insect longitudinal flight control sensing and feedback acts principally to regulate pitch rate.

Faruque, I.A., Muijres, F.T., Macfarlane, K.M. et al. Biol Cybern (2018). https://doi.org/10.1007/s00422-017-0742-x

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

The rich experiences of an intentional, goal-oriented life emerge, in an unpredictable fashion, from the basic laws of physics. Here I argue that this unpredictability is no mirage: there are true gaps between life and non-life, mind and mindlessness, and even between functional societies and groups of Hobbesian individuals. These gaps, I suggest, emerge from the mathematics of self-reference, and the logical barriers to prediction that self-referring systems present. Still, a mathematical truth does not imply a physical one: the universe need not have made self-reference possible. It did, and the question then is how. In the second half of this essay, I show how a basic move in physics, known as renormalization, transforms the "forgetful" second-order equations of fundamental physics into a rich, self-referential world that makes possible the major transitions we care so much about. While the universe runs in assembly code, the coarse-grained version runs in LISP, and it is from that the world of aim and intention grows.

Origin Gaps and the Eternal Sunshine of the Second-Order Pendulum Simon DeDeo https://scirate.com/arxiv/1712.03113

Parole, parole, parole... Where's the beef? The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

It is an exciting time for research into life's origins. Both the origins of life and the search for life on other worlds will benefit from re-conceptualizing the nature of life, leading to new approaches and new progress on long-standing questions. [...] it will be up to an emerging community of scholars to develop these approaches into new frameworks, merging theory and experiment, to solve the problem of the origins of life and start the next chapter on one of the great open questions in science.

Re-conceptualizing the origins of life Sara I. Walker, N. Packard, G. D. Cody DOI: 10.1098/rsta.2016.0337 http://rsta.royalsocietypublishing.org/content/375/2109/20160337.full.pdf

Parole, parole, parole... Where's the beef? The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

The origin of life is widely regarded as one of the most important open problems in science. It is also notorious for being one of the most difficult. [...] researchers have been able to generate nearly all components of living cells under different plausible scenarios for prebiotic environments. But, these ‘bottom-up’ approaches have not yet generated anything nearly as complex as a living cell. At most we are lucky to generate short polypeptides or polynucleotides or simple vesicles—a far cry from the complexity of anything living.

Re-conceptualizing the origins of life Sara I. Walker, N. Packard, G. D. Cody DOI: 10.1098/rsta.2016.0337 http://rsta.royalsocietypublishing.org/content/375/2109/20160337.full.pdf

Parole, parole, parole... Where's the beef? The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

Over the last several hundred years of scientific progress, we have arrived at a deep understanding of the non-living world. We have not yet achieved an analogous, deep understanding of the living world. The origins of life is our best chance at discovering scientific laws governing life, because it marks the point of departure from the predictable physical and chemical world to the novel, history-dependent living world. This theme issue aims to explore ways to build a deeper understanding of the nature of biology, by modelling the origins of life on a sufficiently abstract level, starting from prebiotic conditions on Earth and possibly on other planets and bridging quantitative frameworks approaching universal aspects of life. The aim of the editors is to stimulate new directions for solving the origins of life. The present introduction represents the point of view of the editors on some of the most promising future directions.

Re-conceptualizing the origins of life Sara I. Walker, N. Packard, G. D. Cody DOI: 10.1098/rsta.2016.0337 http://rsta.royalsocietypublishing.org/content/375/2109/20160337.full.pdf

Parole, parole, parole... Where's the beef? The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

Downward causation is the controversial idea that ‘higher’ levels of organization can causally influence behaviour at ‘lower’ levels of organization.

Coarse-graining as a downward causation mechanism Jessica C. Flack Phil. Trans. R. Soc. A375: 20160338. http://dx.doi.org/10.1098/rsta.2016.0338 http://rsta.royalsocietypublishing.org/content/375/2109/20160338.full.pdf

Parole, parole, parole... Where's the beef? The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

[...] downward causation describes how information might cascade from higher-level components through lower levels. “The kind of computation performed and resultant output, and hence the detailed switching of transistors at the micro level, depends on the kind of programme loaded into the computer (word processor, music, or graphics for example) – a high level concept.” - (Ellis, 2008) [...] we can analyse our “system” of interest in three major levels (Marr, 1982): 1. Computational: what does the system do and why? 2. Algorithmic: how does the system is doing it? 3. Implementation: what is the structure of the system [...] mapping the structure of a system e.g., brain may not be the best option we have to understand its function. Computational neuroscience tries to work primarily not in the structural level but the algorithmic level.

Causality in Neuroscience, an Essay Kayson Fakhar DOI: 10.13140/RG.2.2.10215.55205 Biological Psychology Lab, Department of Psychology, European Medical School, Carl von Ossietzky University, Oldenburg, Germany, In Progress, https://www.researchgate.net/profile/Kayson_Fakhar2/publication/319987272_Causality_in_Neuroscience_an_Essay/links/59c51c68aca272c71bb8d58c/Causality-in-Neuroscience-an-Essay.pdf

Parole, parole, parole... Where's the beef? The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

Origin of behaviours is one of the most puzzling issues in religions, philosophy and science. Complex systems cannot or hardly can be described and investigated as a unified single scale phenomenon. [...] the brain is a complex system, which can be investigated thoroughly in many levels of organization [...] components of each level have their own properties. These components interact [with] each other via various mechanisms and thus influencing other levels’ output. [...] there are differences between “levels of organisation” and the “levels of investigation”. The same categorisation is relevant for scientists, as a biochemist, one might be only interested in the interaction between molecules and measures the behaviour of a cell culture as a part of the brain. A problem of communication may arise here between scientists who are working on the same subject e.g., the brain.

Causality in Neuroscience, an Essay Kayson Fakhar DOI: 10.13140/RG.2.2.10215.55205 Biological Psychology Lab, Department of Psychology, European Medical School, Carl von Ossietzky University, Oldenburg, Germany, In Progress, https://www.researchgate.net/profile/Kayson_Fakhar2/publication/319987272_Causality_in_Neuroscience_an_Essay/links/59c51c68aca272c71bb8d58c/Causality-in-Neuroscience-an-Essay.pdf

Parole, parole, parole... Where's the beef? The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

A reliable understanding of the nature or causation is the core feature of science. [...] top-down causation changes the nature of the lower elements. There is not just a situation of invariant lower level elements obeying physical laws; rather we have the nature of lower level elements being changed by context. Often the way this occurs ensures that the way the lower level elements obey physical laws fulfils higher level purposes. This is then an aspect of adaptive selection.

ON THE NATURE OF CAUSATION IN COMPLEX SYSTEMS George F R Ellis http://www.newdualism.org/papers/G.Ellis/RSSA2008.pdf

Where's the beef? The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

UD is publicly presented as an ID website, hence ID topics should be discussed. And these days I think the main ID topic is biology research, where real complex functionally specified informational complexity is increasingly being revealed by dedicated scientists using more sophisticated technologies that allow the wet lab researchers to peek deeper within the biological systems “in vivo”, dumping an avalanche of data on the cloud servers for many dry lab researchers to process it using better computer systems and algorithms. Multilayered controls within marvelously designed biological systems are leaving researchers speechless. Multidisciplinary research teams are working hard in many scientific institutions trying to understand all that functional complexity. As outstanding questions get answered, new ones are raised. It’s beyond fantastic. But we ain’t seen nothing yet. The most fascinating discoveries are still ahead. The noise we’re hearing is just the cacophony produced by the orchestra musicians tuning their individual instruments separately. That’s why we read so many times expressions like “surprisingly” and “unexpectedly” in the research papers. That’s the result of their narrow-minded reductionist bottom-up research approach. But that’s most of the information available to us today, so we have to use it in our studies. We haven’t heard the orchestra playing the most wonderful symphony yet. The curtains are not quite open. The beautiful biological ballet choreography hasn’t been displayed with all its splendor. All that is still ahead. We should encourage more young students who like science to consider pursuing biology-related research careers. Then they’ll enjoy seeing true wonders beyond anything they ever imagined. 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 Giovanni Pezzulo, Michael Levin J. R. Soc. Interface 2016 13 20160555; DOI: 10.1098/rsif.2016.0555 http://rsif.royalsocietypublishing.org/content/13/124/20160555

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

[...] the consequence of altered Hippo signaling in specific tissues on whole-body physiology, and the effect of such changes upon disease progression remains unexplored. Future studies aimed at understanding the integrative nature of the Hippo pathway on human physiology will be required to reveal the extent that this pathway influences biological function and the implications of targeting this pathway for clinical benefit.

Watt KI, Harvey KF and Gregorevic P (2017) Regulation of Tissue Growth by the Mammalian Hippo Signaling Pathway. Front. Physiol. 8:942. doi: 10.3389/fphys.2017.00942

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

Genetic elements compete for transmission through meiosis, when haploid gametes are created from a diploid parent. Selfish elements can enhance their transmission through a process known as meiotic drive. In female meiosis, selfish elements drive by preferentially attaching to the egg side of the spindle. This implies some asymmetry between the two sides of the spindle, but the molecular mechanisms underlying spindle asymmetry are unknown. Here we found that CDC42 signaling from the cell cortex regulated microtubule tyrosination to induce spindle asymmetry and that non-Mendelian segregation depended on this asymmetry. Cortical CDC42 depends on polarization directed by chromosomes, which are positioned near the cortex to allow the asymmetric cell division. Thus, selfish meiotic drivers exploit the asymmetry inherent in female meiosis to bias their transmission.

Spindle asymmetry drives non-Mendelian chromosome segregation Takashi Akera1, Lukáš Chmátal1, Emily Trimm1, Karren Yang1, Chanat Aonbangkhen2, David M. Chenoweth2, Carsten Janke3,4, Richard M. Schultz1, Michael A. Lampson Science 03 Nov 2017: Vol. 358, Issue 6363, pp. 668-672 DOI: 10.1126/science.aan0092

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

The vast majority of eukaryotes have two copies of each chromosome and reproduce sexually. Meiosis is a vital process that produces gametes (eggs and sperm) by reducing the number of chromosome copies to one; fertilization between egg and sperm restores the chromosome copy number to two. During female meiosis, one set of chromosomes is expelled into a tiny cell called a polar body, whereas the other is segregated into the egg. It is a fundamental tenet of genetics that there is a random, 50% chance for any particular chromosome to be segregated into the egg versus the polar body. However, cases in which one copy of a chromosome is inherited with greater than 50% frequency have been reported in many species (1), but the molecular mechanism of this preferential inheritance has remained obscure. Recent work has indicated that centromeres, the chromosomal regions that form attachments to microtubules that mediate chromosome segregation during meiosis, compete with each other for inheritance during female meiosis (2). Thus, the essential DNA sequences that mediate accurate chromosome segregation are actually “selfish” (or parasitic) genetic elements that have invaded our genome. On page 668 of this issue, Akera et al. (3) provide the most detailed molecular mechanism to date that explains how a parasitic DNA sequence has used the asymmetry of oocyte meiosis to ensure its own inheritance and therefore its spread through populations. http://www.sciencemag.org/about/science-licenses-journal-article-reuse

Competing chromosomes explain junk DNA Francis J. McNally Science 03 Nov 2017: Vol. 358, Issue 6363, pp. 594-595 DOI: 10.1126/science.aaq0200

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

Guided by biological curiosity, exploratory bioinformatics analysis of the single-cell RNA-seq and related data yields many actionable insights. One of the surprising observations is that genes with similar expression patterns in early embryogenesis share specific transposons in their promoters. During ZGA, while LTRs are linked to transient, forceful and early induction of several hundred genes, SINE elements are associated with the upregulation of thousands of essential genes. The machinery that transcribes retro-transposons may also be used to establish the expression landscape of early embryos.

Exploratory bioinformatics investigation reveals importance of “junk” DNA in early embryo development Steven Xijin Ge BMC Genomics 2017 18:200 https://doi.org/10.1186/s12864-017-3566-0

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

Data from the literature suggest that lncRNA, often via interaction with proteins, functions in specific genomic loci or use their own transcription loci for regulatory activity. In this review, we summarize recent findings supporting the importance of DNA loci in lncRNA function and the underlying molecular mechanisms via cis or trans regulation, and discuss their implications in cancer. In addition, we use the 8q24 genomic locus, a region containing interactive SNPs, DNA regulatory elements and lncRNAs, as an example to illustrate how single-nucleotide polymorphism (SNP) located within lncRNAs may be functionally associated with the individual’s susceptibility to cancer.

Junk DNA and the long non-coding RNA twist in cancer genetics H Ling, K Vincent, M Pichler, R Fodde, I Berindan-Neagoe, F J Slack & G A Calin Oncogene 34, 5003–5011 doi:10.1038/onc.2014.456

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

The central dogma of molecular biology states that the flow of genetic information moves from DNA to RNA to protein. However, in the last decade this dogma has been challenged by new findings on non-coding RNAs (ncRNAs) such as microRNAs (miRNAs). More recently, long non-coding RNAs (lncRNAs) have attracted much attention due to their large number and biological significance. Many lncRNAs have been identified as mapping to regulatory elements including gene promoters and enhancers, ultraconserved regions and intergenic regions of protein-coding genes. Yet, the biological function and molecular mechanisms of lncRNA in human diseases in general and cancer in particular remain largely unknown.

Junk DNA and the long non-coding RNA twist in cancer genetics H Ling, K Vincent, M Pichler, R Fodde, I Berindan-Neagoe, F J Slack & G A Calin Oncogene 34, 5003–5011 doi:10.1038/onc.2014.456

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

Many regions of the genome replicate asynchronously and are expressed monoallelically. It is thought that asynchronous replication may be involved in choosing one allele over the other, but little is known about how these patterns are established during development. We show that, unlike somatic cells, which replicate in a clonal manner, embryonic and adult stem cells are programmed to undergo switching, such that daughter cells with an early-replicating paternal allele are derived from mother cells that have a late-replicating paternal allele. Furthermore, using ground-state embryonic stem (ES) cells, we demonstrate that in the initial transition to asynchronous replication, it is always the paternal allele that is chosen to replicate early, suggesting that primary allelic choice is directed by preset gametic DNA markers. Taken together, these studies help define a basic general strategy for establishing allelic discrimination and generating allelic diversity throughout the organism.

Programming asynchronous replication in stem cells Hagit Masika, Marganit Farago, Merav Hecht, Reba Condiotti, Kirill Makedonski, Yosef Buganim, Tal Burstyn-Cohen, Yehudit Bergman & Howard Cedar Nature Structural & Molecular Biology 24, 1132–1138 (2017) doi:10.1038/nsmb.3503

embryonic and adult stem cells are programmed to undergo switching are programmed? how? The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

Assembly of the small ribosomal subunit from an RNA strand and 33 proteins is an intricate and dynamic process. Two cryo-EM studies now provide insight into a complicated complex of at least 51 trans-factors that act on the preribosomal small subunit to sequentially fold it into a 3D molecular machine.

Ribosome origami Joanna Rorbach, Shintaro Aibara & Alexey Amunts Cryoelectron microscopy, Ribosome, RNA folding Nature Structural & Molecular Biology 24, 879–881 (2017) doi:10.1038/nsmb.3497

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

. Dionisio

Deadenylation of mRNAs is generally associated with translational inhibition and mRNA decay. A study now reports that, unexpectedly, highly expressed genes tend to have shorter poly(A) tails and suggests that poly(A) tails can be 'pruned', generating a 30-nucleotide-biased phased distribution, likely due to protection by poly(A)-binding proteins.

Poly(A) tails: longer is not always better Luciana A Castellano & Ariel A Bazzini Nature Structural & Molecular Biology 24, 1010–1011 (2017) doi:10.1038/nsmb.3509

unexpectedly? The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

The helicase intrinsic to DNA polymerase ? (Pol?), the versatile mediator of microhomology-based repair of DNA double-strand breaks and stalled replication forks, is now revealed to be a member of an elite group of proteins known as annealing helicases. This small family of enzymes remodels DNA intermediates in multiple repair processes that are crucial to preserving genome stability and warding off cancer and aging.

Pol? helicase: drive or reverse Judith L Campbell & Hongzhi Li Nature Structural & Molecular Biology 24, 1007–1008 (2017) doi:10.1038/nsmb.3510

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

During protein synthesis, mRNA and tRNAs must be moved rapidly through the ribosome while maintaining the translational reading frame. This process is coupled to large- and small-scale conformational rearrangements in the ribosome, mainly in its rRNA. The free energy from peptide-bond formation and GTP hydrolysis is probably used to impose directionality on those movements. We propose that the free energy is coupled to two pawls, namely tRNA and EF-G, which enable two ratchet mechanisms to act separately and sequentially on the two ribosomal subunits.

The ribosome moves: RNA mechanics and translocation Harry F Noller, Laura Lancaster, Jie Zhou & Srividya Mohan Nature Structural & Molecular Biology 24, 1021–1027 (2017) doi:10.1038/nsmb.3505

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

So we conclude chemotaxis of myxomycetes represents a clear comparative example of how certain fundamental capabilities for the origin of cognition may arise in the minimum living systems, and how this is possible only through the action of regulatory mechanisms. It is only in the presence of regulation that specific disturbances acquire a meaning for the system. This becomes, thus, a biosemiotic foundation of the basics of cognitive minimum principles by which emerging regulatory system factors acquire those minimum principles offered in cognitive biology [...] [...] slime mould provides an insightful example of a biosemiotic entity able to perform cognitive tasks and to explain the first steps from mechanistic automation to decision, as well as of coordination and cooperation, and also an ideal testbed for consciousness as a minimal conscious biological organism. [...] the slime mould perceives its world in parallel, process the information perceived concurrently, makes decisions in a decentralised manner and represents the decision, or results of the computation, in spatially distributed configuration of its protoplasmic tubes; the tubes configuration per se might act a program, [...]

Slime mould: the fundamental mechanisms of biological cognition Jordi Vallverd´ua, Oscar Castroa, Richard Maynec, Max Talanovb, Michael Levinf, Frantisek Balu?skae, Yukio Gunjid, Audrey Dussutourg, Hector Zenilh, Andrew Adamatzkyc https://www.researchgate.net/publication/321488794 December 2017 DOI: 10.13140/RG.2.2.14221.84969

Where's the beef? The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

One of the long-standing mysteries of evolutionary genomics is the source of the wide phylogenetic diversity in genome nucleotide composition (G?+?C versus A?+?T), which must be a consequence of interspecific differences in mutation bias, the efficiency of selection for different nucleotides or a combination of the two. [...] although genomic G?+?C composition is strongly driven by mutation bias, it is also substantially modified by direct selection and/or as a by-product of biased gene conversion. Moreover, G?+?C composition at fourfold redundant sites is consistently elevated above the neutral expectation—more so than for any other class of sites.

Evolutionary determinants of genome-wide nucleotide composition Hongan Long, Way Sung, Sibel Kucukyildirim, Emily Williams, Samuel F. Miller, Wanfeng Guo, Caitlyn Patterson, Colin Gregory, Chloe Strauss, Casey Stone, Cécile Berne, David Kysela, William R. Shoemaker, Mario E. Muscarella, Haiwei Luo, Jay T. Lennon, Yves V. Brun & Michael Lynch Nature Ecology & Evolution (2018) doi:10.1038/s41559-017-0425-y

The known -not the unknown- clearly points to complex functionally specified informational complexity 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.

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.pdf

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

Further investigations will be necessary to gain a better molecular understanding of the various mechanisms and the contributions that they make in each tissue. [...] positional information is not a static measure but a process that arises from the dynamics of interactions within the network. [...] 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 [...]

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.pdf

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

Over 2-yo paper, referenced in another thread, but interesting enough to repeat it:

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 2015 142: 3996-4009; doi: 10.1242/dev.129452 http://dev.biologists.org/content/142/23/3996.full.pdf

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

Focal adhesions (FAs) are multifaceted organelles that link the extracellular matrix (ECM) to the cell's contractile actin cytoskeleton to determine adhesion strength and mechanosensing and to regulate cell polarity, survival, and mitosis [...] Taken together, our data are supportive of a working model whereby hiPSC colonies exist as an integrated assembly of weakly adhering inner “center” cells, with low ?1-integrin activity, surrounded by a border of “edge” cells with large “cornerstone” FAs with high SRC and integrin activity linked by strong contractile VSFs. Together, these structures generate the fence required to maintain compact pluripotent colony morphology.

A Strong Contractile Actin Fence and Large Adhesions Direct Human Pluripotent Colony Morphology and Adhesion Elisa Närvä,1 Aki Stubb,1 Camilo Guzmán,1 Matias Blomqvist,1 Diego Balboa,2 Martina Lerche,1 Markku Saari,1 Timo Otonkoski,2,3 and Johanna Ivaska Stem Cell Reports. 2017 Jul 11; 9(1): 67–76. doi: 10.1016/j.stemcr.2017.05.021

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

Cell-type-specific functions and identity are tightly regulated by interactions between the cell cytoskeleton and the extracellular matrix (ECM). Human pluripotent stem cells (hPSCs) have ultimate differentiation capacity and exceptionally low-strength ECM contact, yet the organization and function of adhesion sites and associated actin cytoskeleton remain poorly defined.

A Strong Contractile Actin Fence and Large Adhesions Direct Human Pluripotent Colony Morphology and Adhesion Elisa Närvä,1 Aki Stubb,1 Camilo Guzmán,1 Matias Blomqvist,1 Diego Balboa,2 Martina Lerche,1 Markku Saari,1 Timo Otonkoski,2,3 and Johanna Ivaska Stem Cell Reports. 2017 Jul 11; 9(1): 67–76. doi: 10.1016/j.stemcr.2017.05.021

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

The growth of a metazoan body relies on a series of highly coordinated cell-fate decisions by stem cells which can undergo self-renewal, reversibly enter a quiescent state, or terminally commit to a cell specification program. To guide their decisions, stem cells make frequent use of ubiquitylation, a post-translational modification that can affect the activity, interaction landscape, or stability of stem cell proteins. In this review we discuss novel findings that have provided insight into ubiquitin-dependent mechanisms of stem cell control and revealed how an essential and highly conserved protein modification can shape metazoan development.

Ubiquitin-Dependent Regulation of Stem Cell Biology. Werner A1, Manford AG1, Rape M2. Trends Cell Biol. 2017 Aug;27(8):568-579. doi: 10.1016/j.tcb.2017.04.002. Epub 2017 May 18.

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

Circular RNAs (circ-RNAs), a novel class of noncoding RNAs, are a popular topic in animal research because they have potential as post-transcriptional regulators and diagnostic markers. Research in plants is only now emerging, but indicates that circ-RNAs could also be a crucial class of noncoding regulators.

Are Circular RNAs New Kids on the Block? Sang-Moo Lee Hyun Gi Kong Choong-Min Ryu https://doi.org/10.1016/j.tplants.2017.03.007 Trends in Plant Science Volume 22, Issue 5, May 2017, Pages 357-360

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

The discovery of lncRNAs laid the groundwork for future functional studies of lncRNAs in trifoliate orange. Therefore, to understand the biological role of lncRNAs and their regulatory mechanisms in woody plants, future research should include functional analyses of these genes using overexpression or RNA interference gene silencing strategies in trifoliate orange to elucidate their specific roles.

Genome-wide screening and characterization of long non-coding RNAs involved in flowering development of trifoliate orange (Poncirus trifoliata L. Raf.). Wang CY1, Liu SR1, Zhang XY1, Ma YJ1, Hu CG1, Zhang JZ1 Sci Rep. 2017 Feb 24;7:43226. doi: 10.1038/srep43226.

Work in progress... stay tuned. The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

[...] the function of most lncRNAs remains unknown [...] [...] lncRNAs may play regulatory roles by interacting with RNA, DNA, and protein-coding genes [...] [...] lncRNAs can act either in cis or in trans to regulate protein-coding gene expression in animals and plants [...]

Genome-wide screening and characterization of long non-coding RNAs involved in flowering development of trifoliate orange (Poncirus trifoliata L. Raf.). Wang CY1, Liu SR1, Zhang XY1, Ma YJ1, Hu CG1, Zhang JZ1 Sci Rep. 2017 Feb 24;7:43226. doi: 10.1038/srep43226.

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

[...] little is known about the functions and regulatory mechanisms of lncRNAs [...] One intriguing mechanism is lncRNA-miRNA cross-talk [...] [...] some lncRNAs may be involved in trifoliate orange flowering [...] [...] lncRNAs may be regulated by multiple pathways besides the miRNA pathway [...] These results may reflect underlying differences in the regulatory mechanism of lncRNAs among different species.

Genome-wide screening and characterization of long non-coding RNAs involved in flowering development of trifoliate orange (Poncirus trifoliata L. Raf.). Wang CY1, Liu SR1, Zhang XY1, Ma YJ1, Hu CG1, Zhang JZ1 Sci Rep. 2017 Feb 24;7:43226. doi: 10.1038/srep43226.

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

Several flowering regulatory pathways have been identified to date, such as the vernalization, photoperiod, circadian clock, age, and gibberellin pathways [...] These findings suggest complicated regulation mechanisms in flower formation and flowering in perennial woody plants compared with model plants.

Genome-wide screening and characterization of long non-coding RNAs involved in flowering development of trifoliate orange (Poncirus trifoliata L. Raf.). Wang CY1, Liu SR1, Zhang XY1, Ma YJ1, Hu CG1, Zhang JZ1 Sci Rep. 2017 Feb 24;7:43226. doi: 10.1038/srep43226.

complicated regulation mechanisms? Hmm... The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

LncRNAs can also regulate intron splicing of the sense transcripts by masking splicing sites through its complementary sequences. For example, alternative splicing competitor lncRNA (ASCO-lncRNA) can hijack nuclear speckle RNA-binding protein (NSR) to alter splicing patterns of transcripts in response to auxin in Arabidopsis [...]

Genome-wide screening and characterization of long non-coding RNAs involved in flowering development of trifoliate orange (Poncirus trifoliata L. Raf.). Wang CY1, Liu SR1, Zhang XY1, Ma YJ1, Hu CG1, Zhang JZ1 Sci Rep. 2017 Feb 24;7:43226. doi: 10.1038/srep43226.

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

[...] lncRNAs may regulate protein-coding gene expression at the post-transcriptional and transcriptional levels. [...] lncRNAs are involved in diverse biological processes in mammals such as regulation of mating type, pluripotency of embryonic stem cells, apoptosis, organogenesis, and various diseases [...] [...] some lncRNAs have also been characterized functionally in plant developmental processes and stress-responsive pathways [...]

Genome-wide screening and characterization of long non-coding RNAs involved in flowering development of trifoliate orange (Poncirus trifoliata L. Raf.). Wang CY1, Liu SR1, Zhang XY1, Ma YJ1, Hu CG1, Zhang JZ1 Sci Rep. 2017 Feb 24;7:43226. doi: 10.1038/srep43226.

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

Recently, our understanding of the biological functions of lncRNAs has experienced a large step forward in mammals; however, studies investigating the functions of lncRNAs in plants are still in their infancy, especially those regarding their functions during reproduction

Genome-wide screening and characterization of long non-coding RNAs involved in flowering development of trifoliate orange (Poncirus trifoliata L. Raf.). Wang CY1, Liu SR1, Zhang XY1, Ma YJ1, Hu CG1, Zhang JZ1 Sci Rep. 2017 Feb 24;7:43226. doi: 10.1038/srep43226.

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

The importance of lncRNAs has been immensely underestimated in early studies because of their low expression, low sequence conservation compared with mRNAs, and their designation as transcriptional noise5. Accumulating evidence indicates that lncRNAs play critical roles in various biological processes in animals and plants

Genome-wide screening and characterization of long non-coding RNAs involved in flowering development of trifoliate orange (Poncirus trifoliata L. Raf.). Wang CY1, Liu SR1, Zhang XY1, Ma YJ1, Hu CG1, Zhang JZ1 Sci Rep. 2017 Feb 24;7:43226. doi: 10.1038/srep43226.

wrong assumptions, again? Oops! The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

Transcriptome sequencing in various organisms has revealed that extensive transcription derived from approximately 90% of the genome generates a large proportion of non-coding RNAs (ncRNAs)1. The ncRNAs are classified into two types: housekeeping ncRNAs, which consist of rRNAs, tRNAs, small nucleolar RNAs, and small nuclear RNAs, and regulatory ncRNAs, which include microRNAs (miRNAs), small interfering RNAs (siRNAs), and long non-coding RNAs (lncRNA)2,3.

Genome-wide screening and characterization of long non-coding RNAs involved in flowering development of trifoliate orange (Poncirus trifoliata L. Raf.). Wang CY1, Liu SR1, Zhang XY1, Ma YJ1, Hu CG1, Zhang JZ1 Sci Rep. 2017 Feb 24;7:43226. doi: 10.1038/srep43226.

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

Long non-coding RNAs (lncRNAs) have been demonstrated to play critical regulatory roles in post-transcriptional and transcriptional regulation in Arabidopsis. However, lncRNAs and their functional roles remain poorly characterized in woody plants, including citrus.

Genome-wide screening and characterization of long non-coding RNAs involved in flowering development of trifoliate orange (Poncirus trifoliata L. Raf.). Wang CY1, Liu SR1, Zhang XY1, Ma YJ1, Hu CG1, Zhang JZ1 Sci Rep. 2017 Feb 24;7:43226. doi: 10.1038/srep43226.

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

Quantitative Cell Biology (QCB)is yielding an astounding amount of new cell biological information. This, in turn, is profoundly transforming the world within which cell biology is practiced. It is also posing new challenges. Perhaps the most serious challenge is that, as technology generates data at unprecedented volumes and speeds, researchers are increasingly becoming “data rich but discovery poor.” The biological information collected is proving more complicated to assess than initially assumed, and researchers are finding they are gathering more information than they can analyze in a meaningful way. Overcoming this problem is not easy.

Interdisciplinary innovations are key to effective use of quantitative biological information Jennifer Lippincott-Schwartz Mol Biol Cell. 2015 Nov 5; 26(22): 3893. doi: 10.1091/mbc.E15-09-0644 PMCID: PMC4710218 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4710218/pdf/3893.pdf http://www.molbiolcell.org/content/26/22/3893.full.pdf+html

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

Extension of research data repository system to support direct compute access to biomedical datasets: enhancing Dataverse to support large datasets https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5546227/pdf/nihms817636.pdf Data publication with the structural biology data grid supports live analysis https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4786681/pdf/ncomms10882.pdf The science is in the data https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5668855/pdf/m-04-00714.pdf Data archiving and availability in an era of open science https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5331459/pdf/m-04-00001.pdf Dionisio

The frontier of data discoverability: Why we need to share our data https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5664969/pdf/apps.1700111.pdf Computational Biology in the 21st Century: Scaling with Compressive Algorithms https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5615407/pdf/nihms894489.pdf Big Data access and infrastructure for modern biology: case studies in data repository utility http://onlinelibrary.wiley.com/doi/10.1111/nyas.13281/epdf Distributed data networks: a blueprint for Big Data sharing and healthcare analytics http://onlinelibrary.wiley.com/doi/10.1111/nyas.13287/epdf Dionisio

Biology's Big Problem: There's Too Much Data to Handle https://www.wired.com/2013/10/big-data-biology/ Big biological impacts from big data http://www.sciencemag.org/features/2014/06/big-biological-impacts-big-data Implications of Big Data for cell biology https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4501356/pdf/2575.pdf Biology: The big challenges of big data http://www.nature.com/articles/498255a Computational biologists: moving to the driver's seat https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5701351/pdf/13059_2017_Article_1357.pdf Dionisio

In two chapters of his book On Growth and Form, D'Arcy Thompson used numerous biological and physical observations to show how principles from mathematics and physics – such as pressure differences, surface tension and viscosity – could explain cell shapes and packing within tissues. In this Review, we depict influences that enabled the genesis of his ideas, report examples of his visionary observations and trace his impact over the past 100 years. Recently, his ideas have been revisited as a new field of research emerged, linking cell-level physics with epithelial tissue structure and development. We critically discuss the potential and the limitations of both Thompson's and the modern approaches.

‘The Forms of Tissues, or Cell-aggregates’: D'Arcy Thompson's influence and its limits François Graner, Daniel Riveline Development 2017 144: 4226-4237; doi: 10.1242/dev.151233

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

D'Arcy Thompson was a true pioneer, applying mathematical concepts and analyses to the question of morphogenesis over 100?years ago. The centenary of his famous book, On Growth and Form, is therefore a great occasion on which to review the types of computer modeling now being pursued to understand the development of organs and organisms. Here, I present some of the latest modeling projects in the field, covering a wide range of developmental biology concepts, from molecular patterning to tissue morphogenesis. Rather than classifying them according to scientific question, or scale of problem, I focus instead on the different ways that modeling contributes to the scientific process and discuss the likely future of modeling in developmental biology.

Computer modeling in developmental biology: growing today, essential tomorrow James Sharpe Development 2017 144: 4214-4225; doi: 10.1242/dev.151274

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

Underlying the process of development is an intricate gene regulatory program that involves modules of genes invoked at different times and in different spaces throughout an organism. [...] an important question is how variation across these organs is encoded in gene regulatory programs. [...] from the same set of genes we get different types of teeth. Teeth are serial organs that develop from a combination of epithelial and mesenchymal tissues. [...] it is of acute interest to understand the molecular mechanisms that distinguish the different types of molar. [...] differences are mainly due to heterochrony and the proportions of different tissue types that comprise the organ. [...] it will be interesting to explore the extent of the differences in mesenchymal tissue across different types of teeth using single-cell RNA-seq. It may also be interesting to study the interactions that occur between specific cells from different tissues. For example, examining the interactions that occur between mesenchymal and epithelial cells may help us to understand the signals that regulate tooth development and reveal the reprogramming that is required to distinguish serial organs.

It's about time: studying gene regulatory programs across serial organs Maayan Baron, Itai Yanai Baron, M. & Yanai, I. Genome Biol (2017) 18: 30. https://doi.org/10.1186/s13059-017-1166-6 https://link.springer.com/content/pdf/10.1186%2Fs13059-017-1166-6.pdf

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

The signature can be a matter of a proportion of cell types per se (like we see in the case of epithelial versus mesenchyme, cusp tissue, or chondrocyte proportion), or a matter of a proportion of cells, engaged in different parts of the cell cycle, regardless of cell type. The detection and elucidation of transcriptomic heterochronies will be a very helpful tool to gain insights into the developmental basis of species differences. More generally, we believe transcriptomic signatures in complex organs will help deciphering biological variation in a variety of contexts, from developmental biology to evolutionary biology or medical science [...]

Transcriptomic signatures shaped by cell proportions shed light on comparative developmental biology. Pantalacci S1, Guéguen L2, Petit C3, Lambert A3, Peterkovà R4, Sémon M5 Genome Biol. 2017 Feb 15;18(1):29. doi: 10.1186/s13059-017-1157-7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5312534/pdf/13059_2017_Article_1157.pdf

Evo-Devo: Dev(d) = Dev(a) + Delta(a,d) The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

Transcriptomes reveal a core developmental program modified by cell proportions, heterochronies, and inverted hourglass variation [...] serial organs develop using similar gene networks [...] [...] the two molars express more or less the same genes [...] [...] more than half of those genes have very similar temporal dynamics [...] [...] the two molars use similar gene networks, with similar temporal deployment. This identifies a molar core developmental program. [...] the two molar germs exhibit extensive differences during morphogenesis. [...] differences in developmental processes can be much sharper in early stages than commonly thought and can peak before partially resuming. [...] early variation in a core molar program is responsible for ultimate phenotypic differences. [...] transcriptomes allow determining the stage of an organ, even at a fine scale. [...] cell proportions shape clear signatures in the transcriptome of a whole organ [...]

Transcriptomic signatures shaped by cell proportions shed light on comparative developmental biology. Pantalacci S1, Guéguen L2, Petit C3, Lambert A3, Peterkovà R4, Sémon M5 Genome Biol. 2017 Feb 15;18(1):29. doi: 10.1186/s13059-017-1157-7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5312534/pdf/13059_2017_Article_1157.pdf

Dev(d) = Dev(a) + Delta(a,d) The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

In multicellular organisms, organ development is a dynamic process manifested by changes in gene expression together with changes in tissue organization. Both interact to finally shape the adult phenotype. Gene expression in a complex tissue reflects not only transcriptional regulation but also abundance of different cell types. This knowledge provides valuable insights into the cellular processes underpinning differences in organ development.

Transcriptomic signatures shaped by cell proportions shed light on comparative developmental biology. Pantalacci S1, Guéguen L2, Petit C3, Lambert A3, Peterkovà R4, Sémon M5 Genome Biol. 2017 Feb 15;18(1):29. doi: 10.1186/s13059-017-1157-7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5312534/pdf/13059_2017_Article_1157.pdf

Dev(d) = Dev(a) + Delta(a,d) The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

[...] a Turing network implemented by Bmp, Sox9, and Wnt drives digit specification. [...] this network, when modulated by morphogen gradients, recapitulates the expression patterns of Sox9 in the wild type and in perturbation experiments. Our systems biology approach reveals how a combination of growth, morphogen gradients, and a self-organizing Turing network can achieve robust and reproducible pattern formation.

Digit patterning is controlled by a Bmp-Sox9-Wnt Turing network modulated by morphogen gradients J.Raspopovic,1*L.Marcon,1*L.Russo,1J.Sharpe DOI:10.1126/science.1252960 Science

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

[...] different kinds of patterns exist that can’t be recapitulated by Turing’s original model, an example is the fur patterns of Dalmatian dogs. The spots on Dalmatian dogs appear after their birth with increasing size and contrast, indicating that other mechanisms are also involved in their formation. [...] noisy initial conditions coupled with well-defined feedback loops of the interacting factors determine, which patterns are generated [...] piebald patterns are produced when TFs trigger the production of activators, while at the same time block the production of inhibitor.

Extending the mathematical palette for developmental pattern formation: Piebaldism Michaël Dougoud1, Christian Mazza1, Beat Schwaller2, Laszlo Pecze2 1

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

The distribution of the white and colored zones does not follow the classical Turing patterns. [...] piebald patterns are of transient nature, develop from random initial conditions and rely on a system's bistability. [...] the presence of a cell-autonomous factor not only expands the range of reaction diffusion parameters in which a pattern may arise, but also extends the pattern-forming abilities of the reaction-diffusion equations.

Extending the mathematical palette for developmental pattern formation: Piebaldism Michaël Dougoud1, Christian Mazza1, Beat Schwaller2, Laszlo Pecze2 1

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

How cells coordinate with one another to form regular patterns of alternate differentiated states is a foundational question in developmental biology [...] there are several mechanisms that are known to enable multicellular self-organization of regular patterns [...]

Model reduction permits Turing instability analysis of arbitrary reaction-diffusion models Stephen Smith and Neil Dalchau DOI: 10.1101/213298

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

[...] TGF?1 controls the expression of Dmp1 and Dspp genes through Klf10 signaling [...] whether TGF?1 regulates the expression of Dspp and Dmp1 as well as dental cell differentiation via Klf5 needs to be further investigated in the future.

Klf5 Mediates Odontoblastic Differentiation through Regulating Dentin-Specific Extracellular Matrix Gene Expression during Mouse Tooth Development Zhuo Chen,1,2,* Qi Zhang,3,* Han Wang,4 Wentong Li,2 Feng Wang,2 Chunyan Wan,2,5 Shuli Deng,1 Hui Chen,1 Yixin Yin,2 Xiaoyan Li,2 Zhijian Xie,a,1 and Shuo Chen Sci Rep. 2017; 7: 46746. doi: 10.1038/srep46746

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

Klf5, a member of the Krüppel-like transcription factor family, has essential roles during embryonic development, cell proliferation, differentiation, migration and apoptosis. Our results identify Klf5 as an activator of Dmp1 and Dspp gene transcriptions by different mechanisms and demonstrate that Klf5 plays a pivotal role in odontoblast differentiation. [...] Klf5 is involved in controlling matrix deposition and mineralization of dentin. [...] the precise mechanisms of Klf5 in odontoblast differentiation are still unclear. [...] Klf5 is a functional mediator of TGF? and transactivates SM22? promoter activity in the regulation of SMC differentiation through binding to a TGF?-control element (TCE) [...] Klf5 is not only essential for cell proliferation, but also indispensable for TGF?-induced anti-proliferation, establishing Klf5 as an essential cofactor for TGF? signaling [...] the expression of Klf5, Klf10, Dspp and Dmp1 is up-regulated by TGF?1 in dental epithelial and mesenchymal cells [...]

Klf5 Mediates Odontoblastic Differentiation through Regulating Dentin-Specific Extracellular Matrix Gene Expression during Mouse Tooth Development Zhuo Chen,1,2,* Qi Zhang,3,* Han Wang,4 Wentong Li,2 Feng Wang,2 Chunyan Wan,2,5 Shuli Deng,1 Hui Chen,1 Yixin Yin,2 Xiaoyan Li,2 Zhijian Xie,a,1 and Shuo Chen Sci Rep. 2017; 7: 46746. doi: 10.1038/srep46746

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

Dynamics and control became important areas of study reflecting the laboratory ability to recognize the metabolic and regulatory activators and the products of cell activity. Work concentrates on how elements interact, communicate, and function in relation to one another across subsystems and ordinary boundaries [...] Multi-level boundaries of cell and tissue are crossed as information is linked among subunits. The current interest in regulatory channels, communication methods, and cascading molecular networks adds to the more traditional organ centered and largely mechanistic knowledge. On the horizon are dynamic theory design and engineering control models [...] Noble realized that there were larger design features inherent within heart tissue that fostered cardiac rhythm and that function was ordered, not only the result of a bottom up assembly of components. The design influenced the process; there was a regulatory environment accompanied by boundary conditions for action potential and heartbeat [...]

Systems Medicine—Complexity Within, Simplicity Without Richard Berlin, Russell Gruen,2 and James Best J Healthc Inform Res. 2017; 1(1): 119–137. doi: 10.1007/s41666-017-0002-9 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5491616/pdf/41666_2017_Article_2.pdf

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

Medicine is at a major transition point in history. Systems Theory offers organizing principles, holism, and a framework for emergent properties to form the basis for Systems Medicine. Maintaining complexity within at the leading edge of science, Systems Medicine must provide simplicity without for the human.

Systems Medicine—Complexity Within, Simplicity Without Richard Berlin, Russell Gruen,2 and James Best J Healthc Inform Res. 2017; 1(1): 119–137. doi: 10.1007/s41666-017-0002-9

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

Progress in biology has made great strides in the past few decades. Technology advances the ability to measure shorter time intervals and nano-space consequently driving biology deeper to smallest components. Today the smallest components are genes, RNA, proteins, and metabolic products, (genomics, transcriptomics, proteomics, metabolomics—omics as collective) whether organized for metabolic processes or for regulatory and communication functions.

Systems Medicine—Complexity Within, Simplicity Without Richard Berlin, Russell Gruen,2 and James Best J Healthc Inform Res. 2017; 1(1): 119–137. doi: 10.1007/s41666-017-0002-9

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

The field of TNT biology and intercellular communication has advanced from an in vitro study to that of in vivo relevance to human diseases. Recent advances in understanding the function and mechanism(s) of TNTs challenge the paradigm that gap junctions, exosomes, or cytokines, and other diffusible chemical signals are exclusive modes by which cells communicate. As the nascent field continues to grow, validated assays for studying TNT function and effects in vitro will be critical for differentiating this form of cellular transport from other modes of communication.

A transwell assay that excludes exosomes for assessment of tunneling nanotube-mediated intercellular communication Venugopal Thayanithy,1,6 Patrick O’Hare,1 Phillip Wong,1 Xianda Zhao,2 Clifford J. Steer,3,4 Subbaya Subramanian,2 and Emil Lou Cell Commun Signal. 2017; 15: 46. doi: 10.1186/s12964-017-0201-2

"Recent advances in understanding the function and mechanism(s) of [...] challenge the paradigm [...]" Haven't we read that before? The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

The importance of extracellular vesicles (EVs) in cell-cell communication has long been recognized due to their ability to transfer important cellular cargoes such as DNA, mRNA, miRNAs, and proteins to target cells. Understanding the mechanisms of exosome biogenesis could shed light on important biological processes and aid in the development of novel extracellular vesicle-based therapies for early detection and treatment of various diseases. Interest in exosomes over the past decade has been exponentially growing due to increasing knowledge of the function of these vesicles. Further understanding of the role of exosomes in intercellular communication during both normal and pathological conditions has yet to be elucidated.

Exosomes and their role in the micro-/macro-environment: a comprehensive review Naureen Javeed1 and Debabrata Mukhopadhyay J Biomed Res. 2017; 31(5): 386–394. doi: 10.7555/JBR.30.20150162

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

[...] a major challenge for understanding how exosomes may support both physiological and pathophysiological processes is being able to demonstrate in vivo EV transfer between cells. [...] a direct demonstration that functional exosome-mediated RNAs transfer is the relevant mechanism in certain biological processes is still difficult to achieve. [...] major questions on whether exosomes represent a missing piece of OB–OC communication puzzle still remain. [...] no direct demonstration of functional exosome-mediated transfer, such as results from applying an inhibitor/promotor of exosome biogenesis in vivo, is available.

Exosome-Mediated Genetic Information Transfer, a Missing Piece of Osteoblast–Osteoclast Communication Puzzle Pengbin Yin,1,† Houchen Lv,1,† Yi Li,1,† Yuan Deng,1 Licheng Zhang,1,* and Peifu Tang Front Endocrinol (Lausanne). 2017; 8: 336. doi: 10.3389/fendo.2017.00336

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

[...] important questions still remain regarding intercellular communication involving the transfer of genetic information. [...] the questions such as whether transfer occurs at endogenous levels of these molecules, and the physiological importance of this movement, especially in specific tissue or biological process still remain [...]

Exosome-Mediated Genetic Information Transfer, a Missing Piece of Osteoblast–Osteoclast Communication Puzzle Pengbin Yin,1,† Houchen Lv,1,† Yi Li,1,† Yuan Deng,1 Licheng Zhang,1,* and Peifu Tang Front Endocrinol (Lausanne). 2017; 8: 336. doi: 10.3389/fendo.2017.00336

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

The skeletal system functions and maintains itself based on communication between cells of diverse origins, especially between osteoblasts (OBs) and osteoclasts (OCs), accounting for bone formation and resorption, respectively. Further research in exosome-shuttered miRNAs in OB–OC communication may add a missing piece to the bone cells communication “puzzle.”

Exosome-Mediated Genetic Information Transfer, a Missing Piece of Osteoblast–Osteoclast Communication Puzzle Pengbin Yin,1,† Houchen Lv,1,† Yi Li,1,† Yuan Deng,1 Licheng Zhang,1,* and Peifu Tang Front Endocrinol (Lausanne). 2017; 8: 336. doi: 10.3389/fendo.2017.00336

The known -not the unknown- clearly points to complex functionally specified informational 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 [17, 130]. 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. ‘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, 2016

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

The formation of morphogen gradients is among the most fundamental biological processes during development, regeneration, and disease. 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, 2016

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

[...] morphogen sources in development might be placed at the nearly optimal position that minimizes the ambiguity of positional information. [...] the placement of morphogen sources to minimize the ambiguity of positional information is a basic principle in development of multicellular organisms [...]

Morishita, Y & Iwasa, Yoh. (2008). Optimal placement of multiple morphogen sources. Physical review. E, Statistical, nonlinear, and soft matter physics. 77. 041909. 10.1103/PhysRevE.77.041909.

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

To orchestrate the function and development of multicellular organisms, cells integrate intra- and extracellular information. This information is processed via signal networks in space and time, steering dynamic changes in cellular structure and function.

Deblurring Signal Network Dynamics. Kamps D1, Dehmelt L1. ACS Chem Biol. 12(9):2231-2239. doi: 10.1021/acschembio.7b00451

Did somebody say 'orchestrate'? The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

Sensory stimulation drives complex interactions across neural circuits as information is encoded and then transmitted from one brain region to the next. In the highly interconnected thalamocortical circuit, these complex interactions elicit repeatable neural dynamics in response to temporal patterns of stimuli that provide insight into the circuit properties that generated them. [...] thalamic state, and ultimately thalamic bursting, may play a key role in shaping more complex stimulus-evoked dynamics in the thalamocortical pathway.

Thalamic state control of cortical paired-pulse dynamics. Whitmire CJ1, Millard DC1, Stanley GB2. J Neurophysiol. 117(1):163-177. doi: 10.1152/jn.00415.2016.

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

Cells receive diverse signaling cues from their environment that trigger cascades of biochemical reactions in a dynamic manner. Single-cell imaging technologies have revealed that not only molecular species but also dynamic patterns of signaling inputs determine the fates of signal-receiving cells; however it has been challenging to elucidate how such dynamic information is delivered and decoded in complex networks of inter-cellular and inter-molecular interactions. The recent development of optogenetic technology with photo-sensitive proteins has changed this situation; the combination of microscopy and optogenetics provides fruitful insights into the mechanism of dynamic information processing at the single-cell level.

Illuminating information transfer in signaling dynamics by optogenetics. Isomura A1, Kageyama R2. Curr Opin Cell Biol. 49:9-15. doi: 10.1016/j.ceb.2017.11.002.

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

Cell signaling networks coordinate specific patterns of protein expression in response to external cues, yet the logic by which signaling pathway activity determines the eventual abundance of target proteins is complex and poorly understood. [...] IEG transcription decodes Erk dynamics through a shared band-pass filtering circuit; repeated Erk pulses transcribe IEGs more efficiently than sustained Erk inputs. However, despite highly similar transcriptional responses, each IEG exhibits dramatically different protein-level accumulation, demonstrating a high degree of post-transcriptional regulation by combinations of multiple pathways. [...] the Ras/Erk pathway is decoded by both dynamic filters and logic gates to shape target gene responses in a context-specific manner.

Tracing Information Flow from Erk to Target Gene Induction Reveals Mechanisms of Dynamic and Combinatorial Control. Wilson MZ, Ravindran PT, Lim WA, Toettcher JE Mol Cell. 67(5):757-769.e5. doi: 10.1016/j.molcel.2017.07.016.

Did somebody say 'coordinate'? Did somebody say 'decoded'? Did somebody say 'logic gates'? Like this? http://technav.ieee.org/tag/7029/logic-gates The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

@213 follow-up

Activation of extracellular signal regulated kinase (ERK) is used by many signaling pathways to control tissue patterning in a broad range of multicellular organisms.

Lighting Up ERK Activity. Shilo BZ1, Barkai N2. Dev Cell. 40(2):115-116. doi: 10.1016/j.devcel.2016.12.016

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

[...] assessing the function of Hippo pathway members in specific tissues at physiological and appropriate patho-physiological levels using more elegant approaches such as genome editing with CRISPR/CAS9, where the introduction of point-mutations, protein domain deletions, and activation of genes at the endogenous locus is possible may reveal more relevant information about the role of this pathway in the progression of disease pathologies. Future work will be required to explore how significant alterations in the activity of the Hippo pathway are to these critical cellular functions in non-cancerous tissues if we are to understand the significance of the Hippo pathway in these processes. Future studies aimed at understanding the integrative nature of the Hippo pathway on human physiology will be required to reveal the extent that this pathway influences biological function and the implications of targeting this pathway for clinical benefit.

Regulation of Tissue Growth by the Mammalian Hippo Signaling Pathway Kevin I. Watt, Kieran F. Harvey and Paul Gregorevic Front. Physiol., https://doi.org/10.3389/fphys.2017.00942

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

[...] targeting the Hippo pathway may be beneficial in particular clinical settings, with inhibition of the pro-proliferative/anti-apoptotic function of YAP and TAZ during the growth of cancer cells of particular interest. A greater understanding of this will be critical for the successful development of therapeutics targeting YAP and TAZ; particularly in light of the detrimental effects of inhibiting basal levels of YAP activity in tissues such as skeletal muscle and skin [...]

Regulation of Tissue Growth by the Mammalian Hippo Signaling Pathway Kevin I. Watt, Kieran F. Harvey and Paul Gregorevic Front. Physiol., https://doi.org/10.3389/fphys.2017.00942

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

The fine control of biological processes such as cell division, terminal differentiation, cell death (apoptosis) and metabolism in response to changes in the external environment is essential for biological organisms to maintain homeostasis and function appropriately [...] These processes are mediated by intracellular signaling networks including the Transforming-Growth Factor beta (TGF-?), Notch, WNT and Insulin-PI3K-mTOR signaling pathways that act in isolation to control the expression of sub-sets of genes, and as an orchestrated network that collectively influences biological phenotypes [...] Recent evidence also implicates the relatively less-well-characterized Hippo pathway as a major signaling pathway governing the cellular response to diverse physiological stimuli [...]

Regulation of Tissue Growth by the Mammalian Hippo Signaling Pathway Kevin I. Watt, Kieran F. Harvey and Paul Gregorevic Front. Physiol., https://doi.org/10.3389/fphys.2017.00942

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

The integrative control of diverse biological processes such as proliferation, differentiation, apoptosis and metabolism is essential to maintain cellular and tissue homeostasis. Disruption of these underlie the development of many disease states including cancer and diabetes, as well as many of the complications that arise as a consequence of aging. These biological outputs are governed by many cellular signaling networks that function independently, and in concert, to convert changes in hormonal, mechanical and metabolic stimuli into alterations in gene expression.

Regulation of Tissue Growth by the Mammalian Hippo Signaling Pathway Kevin I. Watt, Kieran F. Harvey and Paul Gregorevic Front. Physiol., https://doi.org/10.3389/fphys.2017.00942

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

Animal development is characterized by signaling events that occur at precise locations and times within the embryo, but determining when and where such precision is needed for proper embryogenesis has been a long-standing challenge. [...] embryogenesis is remarkably robust to ectopic Erk signaling, except from 1 to 4 hr post-fertilization, when perturbing the spatial extent of Erk pathway activation leads to dramatic disruptions of patterning and morphogenesis. Later in development, the effects of ectopic signaling are buffered, at least in part, by combinatorial mechanisms.

The Spatiotemporal Limits of Developmental Erk Signaling. Johnson HE1, Goyal Y2, Pannucci NL1, Schüpbach T1, Shvartsman SY2, Toettcher JE3. Dev Cell. 40(2):185-192. doi: 10.1016/j.devcel.2016.12.002.

Erk stands for "extracellular signal regulated kinase". The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

[...] it is not yet clear how control of the location, level and timing of transcription is mechanistically intertwined or to what extent, if any, these features can be modulated independently. [...] the molecular details underpinning sharpness are yet to be worked out [...] [...] the mechanism by which Zelda and other pioneer factors form open chromatin and regulate transcriptional activation is incompletely understood [...] [...] the mechanistically motivated theoretical models that lend predictive understanding from quantitative data are less developed. Gaining a deeper and more comprehensive understanding of transcriptional regulation will thus depend on our efforts to couple increasingly complex quantitative data with insightful modeling frameworks.

Transcriptional precision and accuracy in development: from measurements to models and mechanisms. Bentovim L1, Harden TT1, DePace AH2. Development. 144(21):3855-3866. doi: 10.1242/dev.146563.

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

Qualitatively, it is important to turn the right genes on in the right place and at the right time, and to keep them off otherwise [...] Quantitatively, this question is much more complicated.

Transcriptional precision and accuracy in development: from measurements to models and mechanisms. Bentovim L1, Harden TT1, DePace AH2. Development. 144(21):3855-3866. doi: 10.1242/dev.146563.

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

During development, genes are transcribed at specific times, locations and levels. [...] call for a more expansive use of mathematical modeling to exploit the wealth of quantitative data and advance our understanding of animal transcription.

Transcriptional precision and accuracy in development: from measurements to models and mechanisms. Bentovim L1, Harden TT1, DePace AH2. Development. 144(21):3855-3866. doi: 10.1242/dev.146563.

Did somebody say 'specific''? The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

The human genome encodes a great number of transcriptts whose expression needs to be precisely coordinated in space and time. [...] coordination of the single step of promoter-proximal pause-release determines the whole transcriptional response of the human genome in high fidelity. The emergence of a new repertoire of enhancers and untranscribed islands of histone H4 acetylation manifests the massive reshaping of the regulatory element landscape in stressed cells, and highlights the dynamic interplay of genes, distal regulatory elements, and the chromatin architecture.

Transcriptional response to stress is pre-wired by promoter and enhancer architecture. Vihervaara A1,2, Mahat DB2, Guertin MJ3, Chu T4,5, Danko CG4, Lis JT6, Sistonen L Nat Commun. 8(1):255. doi: 10.1038/s41467-017-00151-0.

Did somebody say "precisely coordinated"? The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

The plasticity of transcriptional programs is fundamental for all biological processes from cellular growth and differentiation to coordinated functions of tissues and organisms. The execution of distinct transcriptional steps has been extensively investigated at promoters of single genes, providing the basis for our current comprehension of the ordered interactions of DNA elements, transcriptional regulators, and transcription machinery. Our understanding of transcription is, however, severely hampered by the lack of information on how genes and distal regulatory elements are globally orchestrated in response to developmental or environmental signals, such as stress.

Transcriptional response to stress is pre-wired by promoter and enhancer architecture. Vihervaara A1,2, Mahat DB2, Guertin MJ3, Chu T4,5, Danko CG4, Lis JT6, Sistonen L Nat Commun. 8(1):255. doi: 10.1038/s41467-017-00151-0.

Did somebody say "programs"? Did somebody say "coordinated functions"? Did somebody say "globally orchestrated"? The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

Programs of gene expression are executed by a battery of transcription factors that coordinate divergent transcription from a pair of tightly linked core initiation regions of promoters and enhancers. [...] the release of promoter-proximal paused RNA polymerase into elongation functions as a critical switch at which a gene's response to stress is determined. Highly transcribed and highly inducible genes display strong transcriptional directionality and selective assembly of general transcription factors on the core sense promoter. Heat-induced transcription at enhancers, instead, correlates with prior binding of cell-type, sequence-specific transcription factors. Activated Heat Shock Factor 1 (HSF1) binds to transcription-primed promoters and enhancers, and CTCF-occupied, non-transcribed chromatin. [...] activated HSF1 binds to transcription-primed promoters and enhancers, and to CTCF occupied, untranscribed chromatin.

Transcriptional response to stress is pre-wired by promoter and enhancer architecture. Vihervaara A1,2, Mahat DB2, Guertin MJ3, Chu T4,5, Danko CG4, Lis JT6, Sistonen L Nat Commun. 8(1):255. doi: 10.1038/s41467-017-00151-0.

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

[...] TBP and TFIIB bound to core promoter regions at two separate resolvable locations that coincided with sites of divergent transcription initiation. Although the transcription of tRNA genes requires an almost entirely distinct set of machinery, TBP subunit nevertheless crosslinks at the same genomic position relative to TSSs of Pol II and Pol III transcribed tRNA genes. Therefore, TBP in complex with TFIIIB may engage the core promoter in Pol II and III systems in a fundamentally similar manner.

Genomic Organization of Human Transcription Initiation Complexes B. Franklin Pugh and Bryan J. Venters PLoS One. 11(2): e0149339. doi: 10.1371/journal.pone.0149339

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

The classic paradigm for assembling the minimal core transcription machinery at mRNA promoters starts with the recruitment of the TATA binding protein (TBP). Next is the docking of TFIIB, which straddles and locks onto TBP. Together with TFIIF, TFIIB then engages Pol II in its active site to help set the start site of transcription (TSS) [...] [...] the precise genomic organization of human transcription complexes within this context remains unclear.

Genomic Organization of Human Transcription Initiation Complexes B. Franklin Pugh and Bryan J. Venters PLoS One. 11(2): e0149339. doi: 10.1371/journal.pone.0149339

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

A repertoire of transcription initiation factors engage the core promoter of mRNA genes to recruit RNA polymerase (Pol) II to initiate transcription, yet their precise spatial organization remains unclear. [...] when Pol II moves into a transcriptionally paused state, TBP/TFIIB remain at the promoter. [...] TBP and TFIIB bound to the core promoter at two separate, resolvable locations that coincided with sites of divergent transcription initiation. [...] TBP crosslinked to tRNA genes in a similar manner as at Pol II transcribed genes.

Genomic Organization of Human Transcription Initiation Complexes B. Franklin Pugh and Bryan J. Venters PLoS One. 11(2): e0149339. doi: 10.1371/journal.pone.0149339

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

[...] in the nuclear environment, there is an equilibrium between fast (“free”) and slow (“chromatin?associated/modifying”) populations of SAGA and ATAC complexes that is regulated by the chromatin landscape, and which in turn is directly or indirectly dependent on active transcription.

Coactivators and general transcription factors have two distinct dynamic populations dependent on transcription Nikolaos Vosnakis, Marc Koch, Elisabeth Scheer, Pascal Kessler, Yves Mély, Pascal Didier and László Tora EMBO J. 36(18): 2710–2725. doi: 10.15252/embj.201696035

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

SAGA and ATAC are two distinct chromatin modifying co?activator complexes with distinct enzymatic activities involved in RNA polymerase II (Pol II) transcription regulation. [...] in the nuclei of live cells the equilibrium between fast and slow population of SAGA or ATAC complexes is regulated by active transcription via changes in the abundance of H3K4me3 on chromatin.

Coactivators and general transcription factors have two distinct dynamic populations dependent on transcription Nikolaos Vosnakis, Marc Koch, Elisabeth Scheer, Pascal Kessler, Yves Mély, Pascal Didier and László Tora EMBO J. 36(18): 2710–2725. doi: 10.15252/embj.201696035

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

This complex pattern of tight TGF? regulation also enables just a few components to control diverse biological activities and creates opportunities for diseased cells to adapt and modify these elements to use for their own growth and survival. In future work, it will be vital to incorporate information about TGF? pathway crosstalk and couple observations of pathway activity to mechanistic molecular and functional assays.

Recent advances in understanding contextual TGF? signaling Arshad Ayyaz, Liliana Attisano and Jeffrey L Wrana Version 1. F1000Res. 2017; 6: 749. doi:  10.12688/f1000research.11295.1

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

Extensive efforts in TGF? research have revealed that dynamic interactions between tissues and rapidly changing molecular contexts determine the specific biological output of TGF? signaling in intact tissues. These complex processes are designed to fine-tune cellular reactions and prevent exaggerated responses that may lead to lethal consequences in animals.

Recent advances in understanding contextual TGF? signaling Arshad Ayyaz, Liliana Attisano and Jeffrey L Wrana Version 1. F1000Res. 2017; 6: 749. doi:  10.12688/f1000research.11295.1

Did somebody say 'designed'? Did somebody say 'fine tune'? The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

Although multi-layer regulation of TGF? signaling can theoretically explain the dichotomy of activities, the exact molecular contexts that lead to opposite biological output in intact tissues remain elusive. Recent studies utilizing multiple animal and human models have addressed these contradictions and uncovered complex interactions in immune and regenerative tissues that determine specific biological outcomes of TGF? activity.

Recent advances in understanding contextual TGF? signaling Arshad Ayyaz, Liliana Attisano and Jeffrey L Wrana Version 1. F1000Res. 2017; 6: 749. doi:  10.12688/f1000research.11295.1

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

Ligands of the TGF? superfamily such as TGF?(1–3), bone morphogenetic proteins (BMPs), activins, nodal, and growth differentiation factors (GDFs) control numerous aspects of animal biology including embryonic development, organogenesis, cell fate decisions, immune modulation, stress responses, and stem cell function.

Recent advances in understanding contextual TGF? signaling Arshad Ayyaz, Liliana Attisano and Jeffrey L Wrana Version 1. F1000Res. 2017; 6: 749. doi:  10.12688/f1000research.11295.1

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

TGF? pathways govern numerous aspects of human biology from early embryonic development to regeneration, hematopoiesis, neurogenesis, and immunity. Such heavy reliance on these pathways is reflected in the susceptibility to minor perturbations in pathway components that can lead to dysregulated signaling and a diverse range of human pathologies such as cancer, fibrosis, and developmental disorders. Attempts to comprehensively resolve these signaling cascades are complicated by the long-recognized paradoxical role the pathway plays in cell biology.

Recent advances in understanding contextual TGF? signaling Arshad Ayyaz, Liliana Attisano and Jeffrey L Wrana Version 1. F1000Res. 2017; 6: 749. doi:  10.12688/f1000research.11295.1

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

An overview of Herb and dietary supplement efficacy, safety and government regulations in the United States with suggested improvements. Part 1 of 5 series https://www.researchgate.net/profile/Amy_Brown15/publication/309689799_An_overview_of_Herb_and_dietary_supplement_efficacy_safety_and_government_regulations_in_the_United_States_with_suggested_improvements_Part_1_of_5_series/links/599b59aca6fdcc500349c59a/An-overview-of-Herb-and-dietary-supplement-efficacy-safety-and-government-regulations-in-the-United-States-with-suggested-improvements-Part-1-of-5-series.pdf Kidney Toxicity Related to Herbs and Dietary Supplements: Online Table of Kidney Toxicity Cases https://www.researchgate.net/profile/Amy_Brown15/publication/306530848_Kidney_Toxicity_Related_to_Herbs_and_Dietary_Supplements_Online_Table_of_Kidney_Toxicity_Cases/links/59f244370f7e9beabfcc5fd4/Kidney-Toxicity-Related-to-Herbs-and-Dietary-Supplements-Online-Table-of-Kidney-Toxicity-Cases.pdf Liver toxicity related to herbs and dietary supplements: Online table of case reports. Part 3 of 6 https://www.researchgate.net/profile/Amy_Brown15/publication/305110694_Liver_toxicity_related_to_herbs_and_dietary_supplements_Online_table_of_case_reports_Part_3_of_6/links/599b5a3ea6fdcc500349c5a9/Liver-toxicity-related-to-herbs-and-dietary-supplements-Online-table-of-case-reports-Part-3-of-6.pdf Cancer Related to Herbs and Dietary Supplements: Online Table of Case Reports. Part 5 of 5 https://www.researchgate.net/profile/Amy_Brown15/publication/320253610_Cancer_Related_to_Herbs_and_Dietary_Supplements_Online_Table_of_Case_Reports_Part_5_of_5/links/59e661524585151e545cdc39/Cancer-Related-to-Herbs-and-Dietary-Supplements-Online-Table-of-Case-Reports-Part-5-of-5.pdf

Had we remained in Eden, none of this would have been an issue. Dionisio

[...] MBT can modify the expression of miR-155, miR-181a, miR-146a, and miR-223, which are upregulated in OA. It could be due to the heat stress and the hydrostatic pressure, since some miRNAs were found to be temperature- and mechano-responsive. Further studies are needed to better explain the mechanism of action of MBT and the role of miRNAs in OA.

Can balneotherapy modify microRNA expression levels in osteoarthritis? A comparative study in patients with knee osteoarthritis C. Giannitti, A. De Palma, N. A. Pascarelli, S. Cheleschi, N. Giordano, M. Galeazzi, Antonella Fioravanti DOI https://doi.org/10.1007/s00484-017-1420-3 International Journal of Biometeorology pp 1–6

Had we remained in Eden, none of this would have been an issue. The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

@161-162 addendum

[...] YAP is involved in the regulation of 3D tissue morphology and alignment via control of actomyosin activity, and proposed a new concept of mechano-homeostatic regulation by YAP. Further investigation of the new function of YAP in more detail will facilitate the use of induced pluripotent/embryonic stem cells to generate 3D complex organs requiring correct alignment of multiple tissues, and lead to the understanding of pathologies associated with the breakdown of YAP-mediated mechano-homeostasis.

YAP is essential for 3D organogenesis withstanding gravity Authors Yoichi Asaoka, Hiroshi Nishina, Makoto Furutani-Seiki Volume 59, Issue 1, Pages 52–58 Development, Growth and Differentiation DOI: 10.1111/dgd.12338

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

CRISPR/Cas9 MIT https://www.youtube.com/embed/2pp17E4E-O8 Dionisio

CRISPR/Cas9 NIH https://www.youtube.com/embed/ihmt9MkQY34 Dionisio

CRISPR/Cas9 https://www.youtube.com/embed/SuAxDVBt7kQ Dionisio

CRISPR/Cas9 TED https://www.youtube.com/embed/1BXYSGepx7Q Dionisio

CRISPR/Cas9 TED https://www.youtube.com/embed/TdBAHexVYzc Dionisio

CRISPR/Cas9 https://www.youtube.com/embed/0dRT7slyGhs Dionisio

Pluripotency is the potential of a single cell to generate all somatic lineages of the adult organism, comprising mesoderm, endoderm and ectoderm derivatives, as well as the germ cells. [...] pluripotent cells are present in the embryo for a significant period of time during the course of development [...] What remains unclear is how these newly described states relate to one another, and whether bona fide counterparts exist in the embryo, neither of which are trivial questions to answer.

The many faces of Pluripotency: in vitro adaptations of a continuum of in vivo states Sophie Morgani,1,2 Jennifer Nichols,2 and Anna-Katerina Hadjantonakis BMC Dev Biol. 2017; 17: 7. doi: 10.1186/s12861-017-0150-4

The known -not the unknown- clearly points to complex functionally specified informational complexity. Dionisio

[...] loss of NF45 or NF90 + NF110 impaired ESC proliferation and led to deregulated differentiation down embryonic lineages. [...] NF45 and NF90/NF110 physically interact and influence the expression of each other at different levels of regulation. [...] NF45, NF90, and NF110 operate in feedback loops that enable them, through both overlapping and independent targets, to help balance the push and pull of pluripotency and differentiation cues.

NF45 and NF90/NF110 coordinately regulate ESC pluripotency and differentiation. Ye J1,2, Jin H3,4, Pankov A5, Song JS3,4,6, Blelloch R1, RNA. 2017 Aug;23(8):1270-1284. doi: 10.1261/rna.061499.117

The known -not the unknown- clearly points to complex functionally specified informational complexity. Dionisio

While years of investigation have elucidated many aspects of embryonic stem cell (ESC) regulation, the contributions of post-transcriptional and translational mechanisms to the pluripotency network remain largely unexplored. In particular, little is known in ESCs about the function of RNA binding proteins (RBPs), the protein agents of post-transcriptional regulation.

NF45 and NF90/NF110 coordinately regulate ESC pluripotency and differentiation. Ye J1,2, Jin H3,4, Pankov A5, Song JS3,4,6, Blelloch R1, RNA. 2017 Aug;23(8):1270-1284. doi: 10.1261/rna.061499.117

The known -not the unknown- clearly points to complex functionally specified informational complexity. Dionisio

[...] a deeper knowledge of the genome dark side promises to better understand the basis of disease and help the design of novel efficient therapies. RNA secondary and tertiary structures are essential for RNA stability but also for its function, since they may create docking sites for specific RBPs. Although we have started to appreciate and explore this additional layer of complexity only recently, the study of RNA structure could unravel sets of proteins that interact with a certain ncRNA mainly via structural interface. Another challenge for the years to come will be the genome wide-analysis of RNA-protein interaction at a single cell level.

Probing Long Non-coding RNA-Protein Interactions. Barra J1,2, Leucci E1. Front Mol Biosci. 4:45. doi: 10.3389/fmolb.2017.00045.

The known -not the unknown- clearly points to complex functionally specified informational complexity. Dionisio

During and after transcription, RNAs are subjected to multiple processing and regulatory steps that are coordinated by dynamic interactions with other nucleic acids and by a variety of RNA-binding proteins (RBPs) (Moore, 2005). RBPs often follow RNAs throughout their life, regulating maturation, nuclear export, stability and eventually translation (Gehring et al., 2017), therefore identifying RBP interacting with non-coding RNAs is important to understand their function.

Probing Long Non-coding RNA-Protein Interactions. Barra J1,2, Leucci E1. Front Mol Biosci. 4:45. doi: 10.3389/fmolb.2017.00045.

The known -not the unknown- clearly points to complex functionally specified informational complexity. Dionisio

The Genome’s Dark Matter by Stephen S. Hall MIT Technology Review Dionisio

Over the past decade extensive efforts have been made to refine our understanding of the most complex mystery of life: the genome. [...] the full range of the protein-coding and non-protein-coding transcriptome is still vastly underestimated (Rinn and Chang, 2012). We now know that the eukaryotic genome is pervasively transcribed, but the protein-coding genome (that includes around 20,000 genes), only accounts for 2% of all sequences (Carninci et al., 2005). The so called “dark matter” of the genome gives rise to a broad spectrum of processed and regulated transcripts that do not appear to code for functional proteins, but seem to participate in a variety of biological processes (Fatica and Bozzoni, 2014; Huarte, 2015; Lorenzen and Thum, 2016).

Probing Long Non-coding RNA-Protein Interactions. Barra J1,2, Leucci E1. Front Mol Biosci. 4:45. doi: 10.3389/fmolb.2017.00045.

"dark matter" of the genome? Hmm... The known -not the unknown- clearly points to complex functionally specified informational complexity. Dionisio

Non-coding RNA sequences outnumber the protein-coding genes in the human genome, however our knowledge of their functions is still limited. RNA-binding proteins follow the transcripts, including non-coding RNAs, throughout their life, regulating not only maturation, nuclear export, stability and eventually translation, but also RNA functions.

Probing Long Non-coding RNA-Protein Interactions. Barra J1,2, Leucci E1. Front Mol Biosci. 4:45. doi: 10.3389/fmolb.2017.00045.

The known -not the unknown- clearly points to complex functionally specified informational complexity. Dionisio

Biological implications of the degeneracy have been intensively studied and whether the natural code is a frozen accident or a highly optimised product of evolution is still controversially discussed.

Mathematical fundamentals for the noise immunity of the genetic code. Fimmel E, Strüngmann L Biosystems. 2017 Sep 14. pii: S0303-2647(17)30237-X. doi: 10.1016/j.biosystems.2017.09.007.

Maybe none of the above? Maybe a product of intelligent design? The known -not the unknown- clearly points to complex functionally specified informational complexity. Dionisio

Different amino acids are encoded by different quantities of codons and a connection between this degeneracy and the noise immunity of genetic information is a long standing hypothesis. Symmetries in the structure of degeneracy of the genetic code are essential and give evidence of substantial advantages of the natural code over other possible ones.

Mathematical fundamentals for the noise immunity of the genetic code. Fimmel E, Strüngmann L Biosystems. 2017 Sep 14. pii: S0303-2647(17)30237-X. doi: 10.1016/j.biosystems.2017.09.007.

The known -not the unknown- clearly points to complex functionally specified informational complexity. Dionisio

Genetic coding possesses noise immunity which is the fundamental feature that allows to pass on the genetic information from parents to their descendants. Hence, since the time of the discovery of the genetic code, scientists have tried to explain the noise immunity of the genetic information.

Mathematical fundamentals for the noise immunity of the genetic code. Fimmel E, Strüngmann L Biosystems. 2017 Sep 14. pii: S0303-2647(17)30237-X. doi: 10.1016/j.biosystems.2017.09.007.

The known -not the unknown- clearly points to complex functionally specified informational complexity. Dionisio

The genetic code can be seen as a key to biological self-organisation. All living organisms have the same molecular bases - an alphabet consisting of four letters (nitrogenous bases): adenine, cytosine, guanine, and thymine. Linearly ordered sequences of these bases contain the genetic information for synthesis of proteins in all forms of life. Thus, one of the most fascinating riddles of nature is to explain why the genetic code is as it is.

Mathematical fundamentals for the noise immunity of the genetic code. Fimmel E, Strüngmann L Biosystems. 2017 Sep 14. pii: S0303-2647(17)30237-X. doi: 10.1016/j.biosystems.2017.09.007.

The known -not the unknown- clearly points to complex functionally specified informational complexity. Dionisio

As far as translation is concerned, it does not make sense to consider one code without the other. The present-day operational code is intricately carved in the structure of tRNA acceptors and cognate aaRSs, whereas the anticodon code is reduced to codon–anticodon interactions. The catalytic proteins required to accelerate this binding are divided between two very ancient enzyme superfamilies, the class I and class II aaRSs, each activating 10 of the 20 canonical amino acids [8]. The present correspondence of the two codes is provided by 20 specific aaRSs divided into two strikingly dissimilar classes of 10 members each. There are only 20 aaRSs, one for each amino acid (and, respectively, for isoacceptor tRNAs); hence, the operational code is non-degenerate

A unified model of the standard genetic code Marco V. José,1 Gabriel S. Zamudio,1 and Eberto R. Morgado R Soc Open Sci. 2017 Mar; 4(3): 160908. doi: 10.1098/rsos.160908

The known -not the unknown- clearly points to complex functionally specified informational complexity. Dionisio

It is highly improbable that the genetic code became optimized with respect to PR purely by chance.

A unified model of the standard genetic code Marco V. José,1 Gabriel S. Zamudio,1 and Eberto R. Morgado R Soc Open Sci. 2017 Mar; 4(3): 160908. doi: 10.1098/rsos.160908

The known -not the unknown- clearly points to complex functionally specified informational complexity. Dionisio

The SGC is implemented via the tRNAs that bind each codon with its anticodon. These molecules define the genetic code, by linking the specific amino acids and tRNAs with the corresponding anticodons [7]. The tRNA molecule itself displays two codes, the operational code and the anticodon code. Typically, two genetic codes are considered, to wit, the ‘classic’ code represented in tRNA by an anticodon for reading codons in mRNA, and the other is the ‘second’ [12] operational RNA code [13,36] mapped mainly to the acceptor for appropriate aminoacylation at its 3? terminus. In addition, there are also two separate codes, embedded in the tRNA anticodon and acceptor-stem bases that correspond, respectively, to amino acid size and hydrophobicity [37,38].

A unified model of the standard genetic code Marco V. José,1 Gabriel S. Zamudio,1 and Eberto R. Morgado R Soc Open Sci. 2017 Mar; 4(3): 160908. doi: 10.1098/rsos.160908

The known -not the unknown- clearly points to complex functionally specified informational complexity. Dionisio

[...] there are indeed several features that are special about the SGC: firstly, it can be partitioned exactly into two classes of aaRRs in six dimensions; secondly, it displays symmetry groups when the polar requirement (PR) is used; and thirdly, the SGC can be broken down into a product of simpler groups reflecting the pattern of degeneracy observed [...]

A unified model of the standard genetic code Marco V. José,1 Gabriel S. Zamudio,1 and Eberto R. Morgado R Soc Open Sci. 2017 Mar; 4(3): 160908. doi: 10.1098/rsos.160908

The known -not the unknown- clearly points to complex functionally specified informational complexity. Dionisio

The SGC is written in an alphabet of four letters (C, A, U, G), grouped into words three letters long, called triplets or codons. In general, and in most textbooks, the genetic code is represented in a two-dimensional (2D) table arranged in such a way that it is possible to readily find any amino acid from the three letters, written in the 5? to 3? direction of the codon [4,19,20]. Each of the 64 codons specifies one of the 20 amino acids or else serves as a punctuation mark signalling the end of a message.

A unified model of the standard genetic code Marco V. José,1 Gabriel S. Zamudio,1 and Eberto R. Morgado R Soc Open Sci. 2017 Mar; 4(3): 160908. doi: 10.1098/rsos.160908

The known -not the unknown- clearly points to complex functionally specified informational complexity. Dionisio

The Rodin–Ohno (RO) and the Delarue models divide the table of the genetic code into two classes of aminoacyl-tRNA synthetases (aaRSs I and II) with recognition from the minor or major groove sides of the tRNA acceptor stem, respectively. These models are asymmetric but they are biologically meaningful. On the other hand, the standard genetic code (SGC) can be derived from the primeval RNY code (R stands for purines, Y for pyrimidines and N any of them). The problem of the origin and evolution of the SGC is a fundamental challenge in biology. The amino acid specific aminoacylation of tRNAs (operational code) is localized in the acceptor stem of the tRNAs and is recognized by the corresponding aminoacyl-tRNA synthetases (aaRSs) [...]

A unified model of the standard genetic code Marco V. José,1 Gabriel S. Zamudio,1 and Eberto R. Morgado R Soc Open Sci. 2017 Mar; 4(3): 160908. doi: 10.1098/rsos.160908

The known -not the unknown- clearly points to complex functionally specified informational complexity. Dionisio

The papers referenced @166-168 were published this year. The below referenced paper by the same authors was published around 8 years ago:

“Summarizing the state of the art in the study of the code evolution, we cannot escape considerable skepticism. It seems that the two-pronged fundamental question: “why is the genetic code the way it is and how did it come to be?,” that was asked over 50 years ago, at the dawn of molecular biology, might remain pertinent even in another 50 years. Our consolation is that we cannot think of a more fundamental problem in biology.”

Origin and evolution of the genetic code: The universal enigma Eugene V. Koonin, Artem S. Novozhilov DOI: 10.1002/iub.146 Volume 61, Issue 2 Pages 99–111

In those 8 years much has been discovered in biology. However, the pseudoscientific speculative hypotheses remain imprecise and incoherent. The known -not the unknown- clearly points to complex functionally specified informational complexity. Dionisio

“It is almost impossible to discuss the origin of the code without discussing the origin of the actual biochemical mechanisms of protein synthesis” – Francis Crick

“[…] none of the three major theories of the code evolution has been fully successful in providing a definitive explanation although each has highlighted important features of the code.” “The standard genetic code (SGC) is virtually universal among extant life forms.” “The structure of the SGC is nonrandom and ensures high robustness of the code to mutational and translational errors.”

Origin and Evolution of the Universal Genetic Code. Koonin EV, Novozhilov AS Annu Rev Genet. 51:45-62. doi: 10.1146/annurev-genet-120116-024713.

Did somebody say ‘nonrandom’? Dionisio

"The origin and evolution of the translation system is a forbiddingly difficult problem, and therefore, in many studies on the code evolution, it is formally treated as a separate issue and approached almost like a mathematical puzzle [...]" Frozen Accident Pushing 50: Stereochemistry, Expansion, and Chance in the Evolution of the Genetic Code Eugene V. Koonin Life (Basel). 7(2): 22. doi: 10.3390/life7020022 Dionisio

"The genetic code that defines the rules of translation from the 4-letter nucleic acid alphabet to the 20-letter alphabet of proteins is arguably the single central informational invariant of all life forms [...]" "[...] the code is universal among modern life forms because any change in codon assignment would be highly deleterious." "[...] 49 years of code studies have elucidated notable features of the standard code, such as high robustness to errors, but failed to develop a compelling explanation for codon assignments." "In particular, stereochemical affinity between amino acids and the cognate codons or anticodons does not seem to account for the origin and evolution of the code." "The 64 triplet codons are neatly organized in sets of four or two, with the third base of a codon typically being synonymous. The assignment of codons to amino acids across the code table is clearly non-random [...]" "The grouping of similar amino acids within the same column of the code table immediately indicates that the code has a degree of robustness to mutational and translational errors. In other words, the codon assignments are organized in such a way as to minimize the deleterious effect of such errors." Frozen Accident Pushing 50: Stereochemistry, Expansion, and Chance in the Evolution of the Genetic Code Eugene V. Koonin Life (Basel). 7(2): 22. doi: 10.3390/life7020022 Dionisio

"...in spite of a vast amount of research, we only dimly perceive the evolution of life and its building blocks." The Mystery of the LUCA: Franklin M. Harold In Search of Cell History: The Evolution of Life’s Building Blocks Paul Shimmer doi: 10.1096/fj.15-0601ufm The FASEB Journal vol. 29 no. 6 2205-2206 The University of Chicago Press BTW, 'dimly perceive' seems like a very optimistic way to put it. Dionisio

The fact that caffeine can be metabolized by the liver within 1?h adds another layer of complexity in the understanding molecular mechanisms of caffeine’s effects on the brain

Acute doses of caffeine shift nervous system cell expression profiles toward promotion of neuronal projection growth Nancy Y. Yu,1 Andrea Bieder,1 Amitha Raman,2 Enrichetta Mileti,1 Shintaro Katayama,1 Elisabet Einarsdottir,1,3 Bertil B. Fredholm,4 Anna Falk,5 Isabel Tapia-Páez,1,8 Carsten O. Daub,1,6 and Juha Keri Sci Rep. 2017; 7: 11458. doi: 10.1038/s41598-017-11574-6 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5597620/pdf/41598_2017_Article_11574.pdf

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

Caffeine, the principal alkaloid in coffee, tea, and energy drinks, is one of the most consumed psychoactive substances in the world1. Studies suggest that coffee consumption affects health-related variables such as cancer2, 3, exercise performance4, diabetes5, and blood pressure6. Caffeine has been shown to affect multiple aspects of the central nervous system, and to influence e.g. cognitive performance7, memory improvement8, mood improvement9, increased alertness10, 11, increase in overall metabolism in the brain1, 12, changes in dopaminergic transmission13, and motor neuron stimulation14. Regular consumption of coffee/caffeine has been linked with possible protection against cognitive decline15, 16, especially Parkinson’s disease1, 17, 18. On the other hand, caffeine also negatively affects sleep quality1, and may increase anxiety in sensitive individuals19.

Acute doses of caffeine shift nervous system cell expression profiles toward promotion of neuronal projection growth Nancy Y. Yu,1 Andrea Bieder,1 Amitha Raman,2 Enrichetta Mileti,1 Shintaro Katayama,1 Elisabet Einarsdottir,1,3 Bertil B. Fredholm,4 Anna Falk,5 Isabel Tapia-Páez,1,8 Carsten O. Daub,1,6 and Juha Keri Sci Rep. 2017; 7: 11458. doi: 10.1038/s41598-017-11574-6 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5597620/pdf/41598_2017_Article_11574.pdf

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

Despite the fact that living organisms on the earth are continually affected by the force of gravity, they build a complicated and elaborate three-dimensional (3D) organ and maintain their forms without being crushed by gravity. Although we are not usually conscious of that fact, it is one of the most fundamental aspects of morphogenesis.

YAP is essential for 3D organogenesis withstanding gravity Authors Yoichi Asaoka, Hiroshi Nishina, Makoto Furutani-Seiki Volume 59, Issue 1, Pages 52–58 Development, Growth and Differentiation DOI: 10.1111/dgd.12338

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

Cells of our body are constantly exposed to physical forces such as tissue tension. In recent years, it has been shown that such mechanical signals greatly influence a number of cellular processes, including proliferation, differentiation, and migration. Conversely, cells maintain the mechanical properties of tissues by remodeling their own extracellular environment. To date, however, it is unclear about the molecular mechanisms to maintain the mechanical environment (“mechano-homeostasis”) in which extracellular mechanical cues are integrated with cell proliferation and differentiation to ensure tissue, organ and body form. [...] a transcriptional cofactor YAP plays a crucial role in three-dimensional organ formation and its maintenance by controlling tissue tension, and functions as a key molecule governing mechano-homeostasis.

YAP is essential for 3D organogenesis withstanding gravity Authors Yoichi Asaoka, Hiroshi Nishina, Makoto Furutani-Seiki Volume 59, Issue 1, Pages 52–58 Development, Growth and Differentiation DOI: 10.1111/dgd.12338

The known -not the unknown- clearly points to complex functionally specified informational complexity Dionisio

[...] the manner in which the morphogen gradient can properly scale to the growing tissues remains to be determined. Further investigation will be required to determine how the morphogen gradients and tissue patterns are properly formed in the growing and deforming developmental field.

Scaling of pattern formations and morphogen gradients Authors Hidehiko Inomata DOI: 10.1111/dgd.12337 Develop. Growth Differ Volume 59, Issue 1 Pages 41–51

Over a couple of years ago, a distinguished biochemistry professor commenting in this online forum answered "Yes" to the dishonest* question "Do you know exactly how morphogen gradients are formed?" (*) the question included the tricky word 'exactly' which was not written in bold text to make it easily noticeable. :) The known -not the unknown- clearly points to complex functionally specified informational complexity. Dionisio

The concentration gradient of morphogens provides positional information for an embryo and plays a pivotal role in pattern formation of tissues during the developmental processes. Morphogen-dependent pattern formations show robustness despite various perturbations. Although tissues usually grow and dynamically change their size during histogenesis, proper patterns are formed without the influence of size variations. Furthermore, even when the blastula embryo of Xenopus laevis is bisected into dorsal and ventral halves, the dorsal half of the embryo leads to proportionally patterned half-sized embryos. This robustness of pattern formation despite size variations is termed as scaling. [...] morphogens form a proper gradient shape according to the embryo size.

Scaling of pattern formations and morphogen gradients Authors Hidehiko Inomata DOI: 10.1111/dgd.12337 Develop. Growth Differ Volume 59, Issue 1 Pages 41–51

The known -not the unknown- clearly points to complex functionally specified informational complexity. Dionisio

@148-151 error correction The word "differentiation" is misspelled in those 4 posts. Sorry, my mistake. Dionisio

@156: "highly-interdependent signaling networks"? Hmm... Dionisio

The positioning of gene expression boundaries and the shape and size of organs during development are regulated by a wide range of factors, including highly-interdependent signaling networks, hormones, the egg shell, mechanical interactions, and the environment (e.g. temperature, humidity). The embryo is able to scale to spatial (e.g. egg size) and temporal (e.g. temperature change) variations with high precision. Further, it should be factored in that the Drosophila embryo is remarkably robust – there is surprisingly little embryo-to-embryo variability. To better understand scaling during development requires taking a systems approach, combining multiple factors.

Gene expression boundary scaling and organ size regulation in the Drosophila embryo Christopher Amourda, Timothy E. Saunders DOI: 10.1111/dgd.12333 Volume 59, Issue 1 Pages 21–32 Development, Growth and Differentiation

Did somebody say 'surprisingly'? The known -not the unknown- clearly points to complex functionally specified informational complexity. Dionisio

Even to the naked eye, we can observe that animals from the same (or closely related) species can differ greatly in size. Household pets are an excellent example to illustrate this, with domestic dogs having wide variation in body size yet high genetic similarity (Boyko et al. 2010). Such body size variation implies that organs adjust their size (i.e. scale) during development. Unraveling the determinants underlying such size control has been a long standing question. In particular, the relative importance of autonomous – in contrast to regulated – correction has yet to be fully understood [...]

Gene expression boundary scaling and organ size regulation in the Drosophila embryo Christopher Amourda, Timothy E. Saunders DOI: 10.1111/dgd.12333 Volume 59, Issue 1 Pages 21–32 Development, Growth and Differentiation

The known -not the unknown- clearly points to complex functionally specified informational complexity. Dionisio

How the shape and size of tissues and organs is regulated during development is a major question in developmental biology. Such regulation relies upon both intrinsic cues (such as signaling networks) and extrinsic inputs (such as from neighboring tissues). Drosophila embryogenesis provides a suitable model system for studying spatial and temporal scaling and size control in vivo.

Gene expression boundary scaling and organ size regulation in the Drosophila embryo Christopher Amourda, Timothy E. Saunders DOI: 10.1111/dgd.12333 Volume 59, Issue 1 Pages 21–32 Development, Growth and Differentiation

The known -not the unknown- clearly points to complex functionally specified informational complexity. Dionisio

[...] the tube length must match the length of the body. This organismal coordination of organ size is a complex problem, because the outer body part (epidermis) and the internal respiratory system (trachea) reach their final length while folded in the confined environment inside the eggshell.

Shape and geometry control of the Drosophila tracheal tubule Authors Shigeo Hayashi, Bo Dong DOI: 10.1111/dgd.12336 Volume 59, Issue 1 Pages 4–11 Development, Growth and Differentiation

The known -not the unknown- clearly points to complex functionally specified informational complexity. Dionisio

Crb-driven elongation expands the apical membrane along the tube axis, although the mechanism that generates this directional force remains to be elucidated. Detailed structural, mechanical, and functional studies of aECM components are still required to fully understand the diverse roles of the aECM in shaping developing organs.

Shape and geometry control of the Drosophila tracheal tubule Authors Shigeo Hayashi, Bo Dong DOI: 10.1111/dgd.12336 Volume 59, Issue 1 Pages 4–11 Development, Growth and Differentiation

The known -not the unknown- clearly points to complex functionally specified informational complexity. Dionisio

Morphogens create a top-down mechanism of pattern formation; the mutual monitoring of cellular growth state and size by the cells in a field is another layer of regulation. How do cells in one part of an organ know the size and growth status of distant cells within the same organ?

Shape and geometry control of the Drosophila tracheal tubule Authors Shigeo Hayashi, Bo Dong DOI: 10.1111/dgd.12336 Volume 59, Issue 1 Pages 4–11 Development, Growth and Differentiaion

Can cells know? The known -not the unknown- clearly points to complex functionally specified informational complexity. Dionisio

Diffusible morphogens, such as bone morphogenetic proteins and hedgehog-family proteins, expressed in the pattern-organizing centers mediate the long-range coordination of cell proliferation and cell-fate specification [...]

Shape and geometry control of the Drosophila tracheal tubule Authors Shigeo Hayashi, Bo Dong DOI: 10.1111/dgd.12336 Volume 59, Issue 1 Pages 4–11 Development, Growth and Differentiaion

The known -not the unknown- clearly points to complex functionally specified informational complexity. Dionisio

How cells in the tissue specify, alter, and interpret organismal coordinate systems remains one of the biggest challenges in developmental biology.

Shape and geometry control of the Drosophila tracheal tubule Authors Shigeo Hayashi, Bo Dong DOI: 10.1111/dgd.12336 Volume 59, Issue 1 Pages 4–11 Development, Growth and Differentiaion

The known -not the unknown- clearly points to complex functionally specified informational complexity. Dionisio

For efficient respiration, tubular airways must be constructed with an optimal diameter and length for the dimensions of the body. In Drosophila, the growth of embryonic tracheal tubules proceeds in two dimensions, by axial elongation and diameter expansion. The growth forces in each dimension are controlled by distinct genetic programs and cellular mechanisms. Recent studies reveal that the apical cortex and the apical extracellular matrix filling the luminal space are essential for the generation, balancing, and equilibrium of these growth forces.

Shape and geometry control of the Drosophila tracheal tubule Authors Shigeo Hayashi, Bo Dong DOI: 10.1111/dgd.12336 Volume 59, Issue 1 Pages 4–11 Development, Growth and Differentiaion

Did somebody say 'programs'? The known -not the unknown- clearly points to complex functionally specified informational complexity. Dionisio

Extracellular cues that regulate cellular shape, motility, and navigation are generally classified as growth promoting (i.e., growth factors/chemoattractants and attractive guidance cues) or growth preventing (i.e., repellents and inhibitors). Yet, these designations are often based on complex assays and undefined signaling pathways and thus may misrepresent direct roles of specific cues.

Amplification of F-Actin Disassembly and Cellular Repulsion by Growth Factor Signaling Jimok Yoon Sang Bum Kim Giasuddin Ahmed Jerry W. Shay Jonathan R. Terman https://doi.org/10.1016/j.devcel.2017.06.007 Volume 42, Issue 2, Pages 117-129.e8 Developmental Cell

The known -not the unknown- clearly points to complex functionally specified informational complexity. Dionisio

The canonical model for netrin1 function proposed that it acted as a long-range chemotropic axon guidance cue. In the developing spinal cord, floor-plate (FP)-derived netrin1 was thought to act as a diffusible attractant to draw commissural axons to the ventral midline. However, our recent studies have shown that netrin1 is dispensable in the FP for axon guidance. We have rather found that netrin1 acts locally: netrin1 is produced by neural progenitor cells (NPCs) in the ventricular zone (VZ), and deposited on the pial surface as a haptotactic adhesive substrate that guides Dcc+ axon growth. [...] netrin1 provides “hederal” boundaries: a local growth substrate that promotes axon extension, while also preventing local innervation of netrin1-expressing domains.

Netrin1 establishes multiple boundaries for axon growth in the developing spinal cord Supraja G. Varadarajanac Samantha J.Butler Developmental Biology Volume 430, Issue 1, Pages 177-187 https://doi.org/10.1016/j.ydbio.2017.08.001

The known -not the unknown- clearly points to complex functionally specified informational complexity. Dionisio

In the spinal cord, motor axons project out the neural tube at specific exit points, then bundle together to project toward target muscles. The molecular signals that guide motor axons to and out of their exit points remain undefined. [...] the proper position of motor exit points is determined by a “push-pull” mechanism, pulled ventrally by Netrin-1/DCC attraction and pushed dorsally by Slit/Robo repulsion.

Motor axons are guided to exit points in the spinal cord by Slit and Netrin signals Minkyung Kim Tatiana M. Fontelonga Clare H. Lee Sarah J.Barnum Grant S. Mastick Developmental Biology Volume 432, Issue 1, Pages 178-191 https://doi.org/10.1016/j.ydbio.2017.09.038

The known -not the unknown- clearly points to complex functionally specified informational complexity. Dionisio

Only tens of signaling pathways and roughly one thousand transcription factors operate in metazoan species [...] [...] the debate as to whether or not Drosophila Eya participates in the RDGN as a protein tyrosine phosphatase should remain open and hope our study will motivate further investigations, including a search for physiological substrates.

Mutations that impair Eyes absent tyrosine phosphatase activity in vitro reduce robustness of retinal determination gene network output in Drosophila. Davis TL, Hoi CSL, Rebay I PLoS One. 12(11):e0187546. doi: 10.1371/journal.pone.0187546

The known -not the unknown- clearly points to complex functionally specified informational complexity. Dionisio

A limited collection of signaling networks and transcriptional effectors directs the full spectrum of cellular behaviors that comprise development. One mechanism to diversify regulatory potential is to combine multiple biochemical activities into the same protein. Exemplifying this principle of modularity, Eyes absent (Eya), originally identified as a transcriptional co-activator within the retinal determination gene network (RDGN), also harbors tyrosine and threonine phosphatase activities. [...] Eya's tyrosine phosphatase activity, although non-essential, confers robustness to RDGN output.

Mutations that impair Eyes absent tyrosine phosphatase activity in vitro reduce robustness of retinal determination gene network output in Drosophila. Davis TL, Hoi CSL, Rebay I PLoS One. 12(11):e0187546. doi: 10.1371/journal.pone.0187546

The known -not the unknown- clearly points to complex functionally specified informational complexity. Dionisio

[...] unique regulatory capabilities that continual reorganization into new hierarchies confers on master control networks. [...] deeper understanding of such dynamics should be a priority, as accurate spatiotemporal remodeling of network topology will undoubtedly be essential for successful stem cell based therapeutic efforts.

Master regulators in development: Views from the Drosophila retinal determination and mammalian pluripotency gene networks. Davis TL, Rebay I Dev Biol. 421(2):93-107. doi: 10.1016/j.ydbio.2016.12.005

The known -not the unknown- clearly points to complex functionally specified informational complexity. Dionisio

In addition to the hierarchical transcriptional activation, extensive positive transcriptional feedback, and cooperative protein-protein interactions that enable master regulators to override competing cellular programs, recent evidence suggests that network topology must also be dynamic, with extensive rewiring of the interactions and feedback loops required to navigate the correct sequence of developmental transitions to reach a final fate.

Master regulators in development: Views from the Drosophila retinal determination and mammalian pluripotency gene networks. Davis TL, Rebay I Dev Biol. 421(2):93-107. doi: 10.1016/j.ydbio.2016.12.005

huh? say what? :) The known -not the unknown- clearly points to complex functionally specified informational complexity. Dionisio

Among the mechanisms that steer cells to their correct fate during development, master regulatory networks are unique in their sufficiency to trigger a developmental program outside of its normal context. [...] key features that underlie master regulatory potency during normal and ectopic development [...] [...] retinal determination gene network (RDGN) that directs eye development in the fruit fly [...] [...] pluripotency gene network (PGN) that maintains cell fate competency in the early mammalian embryo.

Master regulators in development: Views from the Drosophila retinal determination and mammalian pluripotency gene networks. Davis TL, Rebay I Dev Biol. 421(2):93-107. doi: 10.1016/j.ydbio.2016.12.005

Did somebody say "program"? The known -not the unknown- clearly points to complex functionally specified informational complexity. Dionisio

This mechanism may also function as a positive-feedback loop that maintains and enhances the pre-existing differences between the inner and outer cells until the cell fates are determined at the blastocyst stage.

Roles and regulations of Hippo signaling during preimplantation mouse development. Sasaki H1 Dev Growth Differ. 59(1):12-20. doi: 10.1111/dgd.12335

https://www.albert.io/blog/positive-negative-feedback-loops-biology/ https://ocw.mit.edu/resources/res-tll-004-stem-concept-videos-fall-2013/videos/information-flow/feedback-loops/ The known -not the unknown- clearly points to complex functionally specified informational complexity. Dionisio

This cell position-dependent regulatory mechanism likely functions as a fail-safe system, which corrects the errors in regulation of Hippo signaling generated in the previous stage and/or during the 16- to 32-cell transition.

Roles and regulations of Hippo signaling during preimplantation mouse development. Sasaki H1 Dev Growth Differ. 59(1):12-20. doi: 10.1111/dgd.12335

Did somebody say "fail-safe system"? https://encyclopedia2.thefreedictionary.com/fail-safe+system http://failsafesys.com/ http://technav.ieee.org/tag/750/fail-safe-systems https://www.computerhope.com/jargon/f/failsafe.htm The known -not the unknown- clearly points to complex functionally specified informational complexity. Dionisio

[...] the Hippo signaling pathway is a central player in the regulation of the first cell fate specifications [...] [...] Hippo signaling regulations between the vv16- and 32-cell stages are slightly different.

Roles and regulations of Hippo signaling during preimplantation mouse development. Sasaki H1 Dev Growth Differ. 59(1):12-20. doi: 10.1111/dgd.12335

The known -not the unknown- clearly points to complex functionally specified informational complexity. Dionisio

@128-129 addendum

[...] self-organizing mechanisms, which involve intercellular communications, play central roles in specification of cell fates and spatial arrangements of the two cell types in embryos. The mechanism by which the Par-aPKC system controls subcellular distribution of Amot in preimplantation embryos remains to be elucidated. How the cells select between the fates of internalization and re-polarization is an important question to be addressed in the future. While Hippo signaling plays a central role in the regulation of cell fate specification, other signaling pathways may also contribute to this process. The exact mechanisms that restrict Notch signaling to the outer cells and the relationship between Notch and Hippo signaling remain to be elucidated. [...] the Hippo signaling pathway is a central player in the regulation of the first cell fate specifications [...]

Roles and regulations of Hippo signaling during preimplantation mouse development. Sasaki H1 Dev Growth Differ. 59(1):12-20. doi: 10.1111/dgd.12335

The known -not the unknown- clearly points to complex functionally specified informational complexity. Dionisio

The rapid progress in the field of developmental biology in the past three decades has uncovered the near complete list of evolutionally conserved genes used for specification of animal body plan. [...] select reviews on some of the main symposium topics are discussed in depth. We hope those reviews help stimulate ideas and further investigation to provide fresh insight to revisit the century old problem of growth, shape and allometry in development.

Size in development Shigeo Hayashi, Mitsuru Morimoto, Hidehiko Inomata, Stefano Piccolo DOI: 10.1111/dgd.12339   Volume 59, Issue 1, Page 3 Development, Growth & Differentiation © Japanese Society of Developmental Biologists

The known -not the unknown- clearly points to complex functionally specified informational complexity. Dionisio

[...] the present study provides us with considerable insight into the molecular barriers behind the first cell-fate decision and the mechanisms governing cell plasticity, characteristic of totipotency. [...] several interesting questions remain unanswered [...]

Moving towards totipotency without a single miR-acle Noam Maoz & Yosef Buganim Cell Research (2017) 27, 600–601 (2017) doi:10.1038/cr.2017.30 http://www.nature.com/articles/cr201730

The known -not the unknown- clearly points to complex functionally specified informational complexity. Dionisio

When a sperm fertilizes an egg, a single-cell embryo termed a zygote is formed. The zygote, and its progeny in the first cell division, called the two-cell (2C) stage, are totipotent cells which are able to form the entire embryo and have an unrestricted developmental potential which allows differentiation into all embryonic and extraembryonic lineages. At later cell divisions of the pre-implantation embryo (4C, 8C, morula and blastocyst), cells start to lose totipotency. Developmental potential is gradually being restricted to inner cells forming the inner cell mass (ICM), which will generate the embryo, and to outer cells forming the trophectoderm (TE), which will generate extraembryonic tissues such as the placenta1.

Moving towards totipotency without a single miR-acle Noam Maoz & Yosef Buganim Cell Research (2017) 27, 600–601 (2017) doi:10.1038/cr.2017.30 http://www.nature.com/articles/cr201730

The known -not the unknown- clearly points to complex functionally specified informational complexity. Dionisio

Totipotency is the ability of a single cell to form an entire embryo, including extraembryonic tissues [...] [...] pluripotent stem cells lacking microRNA miR-34a, have an expanded cell fate potential allowing differentiation into not only embryonic but also extraembryonic lineages.

Moving towards totipotency without a single miR-acle Noam Maoz & Yosef Buganim Cell Research (2017) 27, 600–601 (2017) doi:10.1038/cr.2017.30 http://www.nature.com/articles/cr201730

The known -not the unknown- clearly points to complex functionally specified informational complexity. Dionisio

After a spermatozoon enters an oocyte, maternal factors accumulated in the oocyte reprogram the genomes of the terminally differentiated oocyte and spermatozoon epigenetically and turn the zygote into a totipotent cell, with the capacity to differentiate into all types of somatic cells in a highly organized manner and generate the entire organism, a feature referred to as totipotency. Differentiation of the first lineage begins after three cleavages, when the early embryo compacts and becomes polarized, followed by segregation of the first lineages--the inner cell mass (ICM) and the trophectoderm (TE). To date, a full understanding of the molecular mechanisms that underlie the establishment of totipotency and the ICM/TE lineage segregation remains unclear.

Lineage Segregation in the Totipotent Embryo. Wu G, Schöler HR Curr Top Dev Biol. 117:301-17. doi: 10.1016/bs.ctdb.2015.10.014

The known -not the unknown- clearly points to complex functionally specified informational complexity. Dionisio

The very first decisions in the life of a mammal are made even before the embryo implants into the womb. During this time, as the number of cells in the embryo increases from one to two to four and so on, the cells start to specialize to form distinct lineages. The first choice a cell faces is whether to join a cell population called the inner cell mass and become part of the embryo, or to join the trophectoderm lineage and become part of the placenta.

A developmental insurance policy. Saiz N, Hadjantonakis AK. Elife. 2017 Mar 28;6. pii: e26260. doi: 10.7554/eLife.26260.

The known -not the unknown- clearly points to complex functionally specified informational complexity. Dionisio

At the 32-cell stage, E-cadherin-mediated cell-cell adhesion and cell polarization by the Par-aPKC system activates and inactivates the Hippo pathway, respectively. Both mechanisms involve regulation of angiomotin, and cooperation of these mechanisms establishes cell position-dependent activation of Hippo signaling. At the 16-cell stage, however, asymmetric cell division produces the initial differences in Hippo signaling. At this stage, cell polarity is controlled by both Par-aPKC-dependent and -independent mechanisms. [...] the differences in Hippo signaling among blastomeres is first produced by asymmetric cell division and then enhanced and stabilized by cell position-dependent mechanisms until their fates are fixed.

Roles and regulations of Hippo signaling during preimplantation mouse development. Sasaki H1 Dev Growth Differ. 59(1):12-20. doi: 10.1111/dgd.12335

The known -not the unknown- clearly points to complex functionally specified informational complexity. Dionisio

During preimplantation development, mouse embryos form two types of cells, the trophoectoderm (TE) and inner cell mass (ICM), by the early blastocyst stage. This process does not require maternal factors localized in the zygotes, and embryos self-organize at the blastocyst stage through intercellular communications. [...] the intercellular Hippo signaling pathway plays a central role in the specification of the first cell fates. Hippo signaling is active in the inner cells but inactive in the outer cells. The Hippo-active inner and Hippo-inactive outer cells take the fates of the ICM and the TE, respectively.

Roles and regulations of Hippo signaling during preimplantation mouse development. Sasaki H1 Dev Growth Differ. 59(1):12-20. doi: 10.1111/dgd.12335

The known -not the unknown- clearly points to complex functionally specified informational complexity. Dionisio

[...] resolving the molecular mechanisms by which Ca2+ controls endomembrane trafficking remains one of the major open questions in plant cell biology.

The ins and outs of Ca2+ in plant endomembrane trafficking Ellie Himschoot 1, 2, 4, Roman Pleskot 1, 2, 3, 4, Daniël Van Damme 1, 2, Steffen Vanneste 1 Current Opinion in Plant Biology Volume 40, December 2017, Pages 131-137 https://doi.org/10.1016/j.pbi.2017.09.003

The known -not the unknown- clearly points to complex functionally specified informational complexity. Dionisio

@120 follow-up

The flexibility of plant growth and development depends largely on its ability to integrate numerous environmental stimuli and endogenous cues. This involves a tight coupling with endomembrane trafficking as illustrated by the modulation of cellular signal transduction and transport capacities in the plasma membrane through endocytic regulation of receptors and transporters [70–74].

The ins and outs of Ca2+ in plant endomembrane trafficking Ellie Himschoot 1, 2, 4, Roman Pleskot 1, 2, 3, 4, Daniël Van Damme 1, 2, Steffen Vanneste 1 Current Opinion in Plant Biology Volume 40, December 2017, Pages 131-137 https://doi.org/10.1016/j.pbi.2017.09.003

The known -not the unknown- clearly points to complex functionally specified informational complexity. Dionisio

During pre-implantation development, the mammalian zygote transforms into the blastocyst, the structure that will implant the embryo in the maternal uterus. Consisting of a squamous epithelium enveloping a fluid-filled cavity and the inner cell mass, the blastocyst is sculpted by a succession of morphogenetic events. These deformations result from the changes in the forces and mechanical properties of the tissue composing the embryo.

Mechanics of blastocyst morphogenesis Jean-Léon Maître DOI: 10.1111/boc.201700029 Biology of the Cell Wiley Online Library

The known -not the unknown- clearly points to complex functionally specified informational complexity. Dionisio

Directional cell-to-cell transport of functional molecules, called polar transport, enables plants to sense and respond to developmental and environmental signals. Transporters that localize to plasma membranes (PMs) in a polar manner are key components of these systems. PIN-FORMED (PIN) auxin efflux carriers, which are the most studied polar-localized PM proteins, are implicated in the polar transport of auxin that in turn regulates plant development and tropic growth.

Polar transport in plants mediated by membrane transporters: focus on mechanisms of polar auxin transport Satoshi Naramoto Current Opinion in Plant Biology Volume 40, December 2017, Pages 8-14

The known -not the unknown- clearly points to complex functionally specified informational complexity. Dionisio

Among the many organelles in eukaryotic cells, chloroplasts have the most complex structure, with multiple suborganellar membranes, making protein targeting to chloroplasts, particularly to various suborganellar membranes, highly challenging. Multiple mechanisms function in the biogenesis of chloroplast membrane proteins.

Sorting of nuclear-encoded chloroplast membrane proteins Dong Wook Lee 1, 3, Junho Lee 2, 3, Inhwan Hwang 1, 2 Current Opinion in Plant Biology Volume 40, December 2017, Pages 1-7 https://doi.org/10.1016/j.pbi.2017.06.011

The known -not the unknown- clearly points to complex functionally specified informational complexity. Dionisio

During plant–microbe interactions, host cells need to keep stringent control over the approaching pathogens and symbionts. This requires specific spatio-temporal assemblies of pattern recognition receptors and other complex constituents and a strict physical separation of genetically overlapping pathways. [...] this is, at least partially, achieved by the formation of nanometer scale membrane platforms that might act as signaling hubs. These and other larger-scale sub-compartments have been termed ‘membrane rafts’, ‘nanodomains’ and ‘microdomains’.

Membrane nanodomains and microdomains in plant–microbe interactions Thomas Ott Current Opinion in Plant Biology Volume 40, December 2017, Pages 82-88 https://doi.org/10.1016/j.pbi.2017.08.008

The known -not the unknown- clearly points to complex functionally specified informational complexity. Dionisio

Plant receptor complexes at the cell surface perceive many different external and internal signalling molecules and relay these signals into the cell to regulate development, growth and immunity. [...] receptor complex formation and composition are dynamic and take place at specific microdomains at the plasma membrane.

Dynamic complexity: plant receptor complexes at the plasma membrane Rebecca C Burkart, Yvonne Stahl Current Opinion in Plant Biology Volume 40, December 2017, Pages 15-21

The known -not the unknown- clearly points to complex functionally specified informational complexity. Dionisio

Trafficking of proteins and lipids within the plant endomembrane system is essential to support cellular functions and is subject to rigorous regulation. Despite this seemingly strict regulation, endomembrane trafficking needs to be dynamically adjusted to ever-changing internal and environmental stimuli, while maintaining cellular integrity. Although often overlooked, the versatile second messenger Ca2+ is intimately connected to several endomembrane-associated processes.

The ins and outs of Ca2+ in plant endomembrane trafficking Ellie Himschoot 1, 2, 4, Roman Pleskot 1, 2, 3, 4, Daniël Van Damme 1, 2, Steffen Vanneste 1 Current Opinion in Plant Biology Volume 40, December 2017, Pages 131-137 https://doi.org/10.1016/j.pbi.2017.09.003

The known -not the unknown- clearly points to complex functionally specified informational complexity. Dionisio

Note that some questions asked in the comments on the referenced papers open new cans of worms or Pandora boxes. As outstanding questions get answered, new interrogations are raised. The most fascinating discoveries are still ahead. The known -not the unknown- clearly points to complex functionally specified informational complexity. Dionisio

[...] the 3D shape of the horn of the Japanese rhinoceros beetle, Trypoxylus dichotomus, can be explained by the coordinated unfolding of furrows that are present at the surface of the horn primordia. Formation of the 3D shape in most animals involves the summation of many different cellular events, such as cell shape changes, proliferation and cell migration. [...] it is difficult to assess the contribution of each event and its integration into a coordinated developmental program that ultimately defines 3D structure [...]

Complex furrows in a 2D epithelial sheet code the 3D structure of a beetle horn. Matsuda K1, Gotoh H2, Tajika Y3, Sushida T4, Aonuma H4, Niimi T5, Akiyama M4, Inoue Y6, Kondo S1. Sci Rep. 7(1):13939. doi: 10.1038/s41598-017-14170-w.

Did somebody say 'coordinated developmental program'? Coordinated? program? The known -not the unknown- clearly points to complex functionally specified informational complexity. Dionisio

[...] complexity significantly hampers the elucidation of the mechanisms involved, preventing a thorough understanding of the principles that guide 3D morphogenesis in insects. [...] massive body transformations exclusively occur as the result of epithelial sheet unfolding [...] [...] drastic shape changes can be simulated by computer algorithms, allowing predictions of a 3D shape based solely upon information concerning the initial furrow pattern. [...] the furrow pattern of the beetle horn primordia possesses all the necessary information to instruct the formation of the pupal horn.

Complex furrows in a 2D epithelial sheet code the 3D structure of a beetle horn. Matsuda K1, Gotoh H2, Tajika Y3, Sushida T4, Aonuma H4, Niimi T5, Akiyama M4, Inoue Y6, Kondo S1. Sci Rep. 7(1):13939. doi: 10.1038/s41598-017-14170-w.

Did somebody say "information to instruct the formation"? The known -not the unknown- clearly points to complex functionally specified informational complexity. Dionisio

Elucidating the mechanisms that generate the characteristic 3D body shape of an animal is one of the major issues in the biological sciences. During the past three decades, our understanding of embryonic development has deepened remarkably. The mechanisms that guide morphogenetic processes at later stages, however, remain largely unknown.

Complex furrows in a 2D epithelial sheet code the 3D structure of a beetle horn. Matsuda K1, Gotoh H2, Tajika Y3, Sushida T4, Aonuma H4, Niimi T5, Akiyama M4, Inoue Y6, Kondo S1. Sci Rep. 7(1):13939. doi: 10.1038/s41598-017-14170-w.

There yet? :) The known -not the unknown- clearly points to complex functionally specified informational complexity. Dionisio

[...] horn formation in beetles occurs by two distinct processes: formation of the furrows and subsequently unfolding them. [...] this developmental simplicity offers an inherent advantage to understanding the principles that guide 3D morphogenesis in insects.

Complex furrows in a 2D epithelial sheet code the 3D structure of a beetle horn. Matsuda K1, Gotoh H2, Tajika Y3, Sushida T4, Aonuma H4, Niimi T5, Akiyama M4, Inoue Y6, Kondo S1. Sci Rep. 7(1):13939. doi: 10.1038/s41598-017-14170-w.

The known -not the unknown- clearly points to complex functionally specified informational complexity. Dionisio

The external organs of holometabolous insects are generated through two consecutive processes: the development of imaginal primordia and their subsequent transformation into the adult structures. During the latter process, many different phenomena at the cellular level (e.g. cell shape changes, cell migration, folding and unfolding of epithelial sheets) contribute to the drastic changes observed in size and shape. Because of this complexity, the logic behind the formation of the 3D structure of adult external organs remains largely unknown.

Complex furrows in a 2D epithelial sheet code the 3D structure of a beetle horn. Matsuda K1, Gotoh H2, Tajika Y3, Sushida T4, Aonuma H4, Niimi T5, Akiyama M4, Inoue Y6, Kondo S1. Sci Rep. 7(1):13939. doi: 10.1038/s41598-017-14170-w.

The known -not the unknown- clearly points to complex functionally specified informational complexity. Dionisio

Maybe we should go back to school to learn biology 101, then perhaps someday we could somehow understand the evo-devo stuff. Those who would like to learn basic biology concepts associated with development, may benefit from watching MIT free courses by professor Hazel Sive. Lecture 21 Development 1 Lecture 22 Development 2 Lecture 23 Stem Cells Lecture 24 Nervous System 1 Lecture 25 Nervous System 2 Lecture 26 Nervous System 3 https://ocw.mit.edu/courses/biology/7-013-introductory-biology-spring-2013/video-lectures/lecture-21-development-1/ Dionisio

[...] the dual role of Dpp in growth and patterning requires that it is expressed in a stripe. Late inactivation of Dpp impairs patterning, suggesting that the gradient information could be read at the end of the growth period. It remains to be determined how the two processes - growth and patterning - are coordinated to ensure the reproducible formation of the adult wing.

Dpp controls growth and patterning in Drosophila wing precursors through distinct modes of action. Bosch PS, Ziukaite R, Alexandre C, Basler K, Vincent JP. Elife. 6. pii: e22546. doi: 10.7554/eLife.22546.

Work in progress... stay tuned. Complex functionally specified informational complexity. Dionisio

Better tools to tune the level of Dpp signalling will be needed to assess the relationship between signalling activity and growth at all stages. [...] Dpp must originate from the pouch for this tissue to grow [...] [...] growth is normally sustained by Dpp produced at the A/P boundary. [...] the signalling gradient is essential for patterning as it specifies the domains of salm and omb expression and thus the positions of veins.

Dpp controls growth and patterning in Drosophila wing precursors through distinct modes of action. Bosch PS, Ziukaite R, Alexandre C, Basler K, Vincent JP. Elife. 6. pii: e22546. doi: 10.7554/eLife.22546.

Complex functionally specified informational complexity. Dionisio

Dpp behaves as a classic morphogen in wing imaginal discs of Drosophila. It is produced from a stripe of cells along the A/P boundary and spreads from there to activate the nested expression of target genes, which in turn position longitudinal veins. In addition to providing patterning information in the prospective wing, Dpp also promotes growth via repression of brinker.

Dpp controls growth and patterning in Drosophila wing precursors through distinct modes of action. Bosch PS, Ziukaite R, Alexandre C, Basler K, Vincent JP. Elife. 6. pii: e22546. doi: 10.7554/eLife.22546.

Complex functionally specified informational complexity. Dionisio

As a morphogen, Dpp is a pattern organiser. [...] graded Dpp signalling determines the position of wing veins, particularly veins 2 and 5, through regulation of salm and omb [...] The pro-growth role of Dpp is in part mediated through regulation of Myc [...] [...] a comprehensive understanding of growth regulation by Dpp signalling remains lacking.

Dpp controls growth and patterning in Drosophila wing precursors through distinct modes of action. Bosch PS, Ziukaite R, Alexandre C, Basler K, Vincent JP. Elife. 6. pii: e22546. doi: 10.7554/eLife.22546.

Complex functionally specified informational complexity. Dionisio

Segregation of wing imaginal discs into the territories that give rise to these three structures is controlled by a series of signalling events involving EGFR, JAK/STAT, Notch, and Hedgehog signalling, culminating in sustained expression of Wingless and Dpp in orthogonal stripes until the end of the third instar [...]

Dpp controls growth and patterning in Drosophila wing precursors through distinct modes of action. Bosch PS, Ziukaite R, Alexandre C, Basler K, Vincent JP. Elife. 6. pii: e22546. doi: 10.7554/eLife.22546.

Complex functionally specified informational complexity. Dionisio

During development, tissue growth must be precisely coupled with patterning to ensure that the right number of cells can contribute to the various substructures within each organ [...] [...] many signalling molecules that specify positional information also control growth [...]

Dpp controls growth and patterning in Drosophila wing precursors through distinct modes of action. Bosch PS, Ziukaite R, Alexandre C, Basler K, Vincent JP. Elife. 6. pii: e22546. doi: 10.7554/eLife.22546.

Do molecules themselves control or are part of controlling mechanisms? Complex functionally specified informational complexity. Dionisio

With two independent conditional alleles of dpp, we find that the stripe of Dpp is essential for wing growth. We then show that this requirement, but not patterning, can be fulfilled by uniform, low level, Dpp expression. Thus, the stripe of Dpp ensures that signalling remains above a pro-growth threshold, while at the same time generating a gradient that patterns cell fates.

Dpp controls growth and patterning in Drosophila wing precursors through distinct modes of action. Bosch PS, Ziukaite R, Alexandre C, Basler K, Vincent JP. Elife. 6. pii: e22546. doi: 10.7554/eLife.22546.

Complex functionally specified informational complexity. Dionisio

Dpp, a member of the BMP family, is a morphogen that specifies positional information in Drosophila wing precursors. In this tissue, Dpp expressed along the anterior-posterior boundary forms a concentration gradient that controls the expression domains of target genes, which in turn specify the position of wing veins. Dpp also promotes growth in this tissue. The relationship between the spatio-temporal profile of Dpp signalling and growth has been the subject of debate, which has intensified recently with the suggestion that the stripe of Dpp is dispensable for growth.

Dpp controls growth and patterning in Drosophila wing precursors through distinct modes of action. Bosch PS, Ziukaite R, Alexandre C, Basler K, Vincent JP. Elife. 6. pii: e22546. doi: 10.7554/eLife.22546.

Complex functionally specified informational complexity. Dionisio

[...] the anterior dpp stripe is critical for growth as well as patterning of the wing imaginal disc. [...] it remains an open question whether the requirement of the dpp stripe on wing disc growth changes over time. It would be important to acutely manipulate the endogenous morphogen gradient at the protein level to address the precise temporal requirement of the dpp stripe on wing disc growth [...]

Dpp from the anterior stripe of cells is crucial for the growth of the Drosophila wing disc. Matsuda S1, Affolter M1 Elife. 6. pii: e22319. doi: 10.7554/eLife.22319.

Work in progress... stay tuned. Complex functionally specified informational complexity. Dionisio

Morphogens are thought to disperse and form concentration gradients to control tissue patterning and growth [...] [...] decapentagplegic (dpp), a homologue of vertebrate bone morphogenetic protein 2/4 (BMP2/4), is expressed in a stripe of cells in the anterior compartment along the anterior-posterior compartmental boundary of the wing imaginal disc. From this source, Dpp protein is thought to spread and form a concentration gradient to control patterning and growth of the wing imaginal disc [...]

Dpp from the anterior stripe of cells is crucial for the growth of the Drosophila wing disc. Matsuda S1, Affolter M1 Elife. 6. pii: e22319. doi: 10.7554/eLife.22319.

Complex functionally specified informational complexity. Dionisio

Further work will be needed to explain how the Dpp signal regulates the growth of the wing. The answer to this question will contribute to a better understanding of the role of morphogens in regulating the size of human organs and how a failure to do so might cause developmental disorders.

Dpp from the anterior stripe of cells is crucial for the growth of the Drosophila wing disc. Matsuda S1, Affolter M1 Elife. 6. pii: e22319. doi: 10.7554/eLife.22319.

Complex functionally specified informational complexity. Dionisio

From the wings of a butterfly to the fingers of a human hand, living tissues often have complex and intricate patterns. Developmental biologists have long been fascinated by the signals – called morphogens – that guide how these kinds of pattern develop. Morphogens are substances that are produced by groups of cells and spread to the rest of the tissue to form a gradient. Depending on where they sit along this gradient, cells in the tissue activate different sets of genes, and the resulting pattern of gene activity ultimately defines the position of the different parts of the tissue. However, how the morphogens regulate tissue size and what role their gradients play in this process remain topics of intense debate in the field of developmental biology.

Dpp from the anterior stripe of cells is crucial for the growth of the Drosophila wing disc. Matsuda S1, Affolter M1 Elife. 6. pii: e22319. doi: 10.7554/eLife.22319.

Complex functionally specified informational complexity. Dionisio

The Dpp morphogen gradient derived from the anterior stripe of cells is thought to control growth and patterning of the Drosophila wing disc. However, the spatial-temporal requirement of dpp for growth and patterning remained largely unknown. [...] growth control by the Dpp morphogen gradient remains under debate. [...] the dpp stripe source is indeed required for wing disc growth, also during third instar larval stages.

Dpp from the anterior stripe of cells is crucial for the growth of the Drosophila wing disc. Matsuda S1, Affolter M1 Elife. 6. pii: e22319. doi: 10.7554/eLife.22319.

Complex functionally specified informational complexity. Dionisio

Many proteins localize to specific membrane domains or organelles within a cell, and it has been shown in several cases that correct protein localization plays a vital role in cell homeostasis [...] [...] the functional implication and the necessity of proper localization, as well as the consequences of distinct mislocalization of a given protein, are less well understood. In future studies, the GrabFP system will help to better understand the requirements for polarized distribution of signaling pathway components in different developmental contexts.

A nanobody-based toolset to investigate the role of protein localization and dispersal in Drosophila Stefan Harmansa,1,† Ilaria Alborelli,1,† Dimitri Bieli,1 Emmanuel Caussinus,1,2 and Markus Affolter1,* eLife. 2017; 6: e22549. doi: 10.7554/eLife.22549

Complex functionally specified informational complexity. Dionisio

[...] Dpp is prominently detected within the lateral plane of the DP epithelium. [...] basolateral Dpp spreading is required for proper Dpp signaling range and patterning [...] [...] basolateral, not apical/luminal Dpp dispersal is important for patterning and size control of the wing disc and the adult wing. [...] apical Dpp spreading plays a minor role in wing development.

A nanobody-based toolset to investigate the role of protein localization and dispersal in Drosophila Stefan Harmansa,1,† Ilaria Alborelli,1,† Dimitri Bieli,1 Emmanuel Caussinus,1,2 and Markus Affolter1,* eLife. 2017; 6: e22549. doi: 10.7554/eLife.22549

Complex functionally specified informational complexity. Dionisio

In the developing wing imaginal disc, Dpp is expressed and secreted from a central stripe of anterior cells adjacent to the anterior/posterior (A/P) compartment boundary from where it forms a concentration gradient into the surrounding target tissue. [...] the routes of Dpp dispersal remain controversial.

A nanobody-based toolset to investigate the role of protein localization and dispersal in Drosophila Stefan Harmansa,1,† Ilaria Alborelli,1,† Dimitri Bieli,1 Emmanuel Caussinus,1,2 and Markus Affolter1,* eLife. 2017; 6: e22549. doi: 10.7554/eLife.22549

What determines the initial location of Dpp sources, the starting / ending time and the rate of Dpp production and secretion? Complex functionally specified informational complexity. Dionisio

[...] the Dpp gradient forming in the lateral plane of the Drosophila wing disc epithelium is essential for patterning of the wing imaginal disc. [...] the role of protein localization and the effects of forced protein mislocalization have not been studied extensively and hence remain in many cases not well understood. [...] the functional Dpp morphogen gradient forms in the lateral plane of the wing disc epithelium.

A nanobody-based toolset to investigate the role of protein localization and dispersal in Drosophila Stefan Harmansa,1,† Ilaria Alborelli,1,† Dimitri Bieli,1 Emmanuel Caussinus,1,2 and Markus Affolter1,* eLife. 2017; 6: e22549. doi: 10.7554/eLife.22549

Complex functionally specified informational complexity. Dionisio

[...] future studies will need to investigate the localization and the effect of forced mislocalization of Dpp receptors and interaction partners on Dpp dispersal and gradient formation. [...] the Dpp ligand and the Dpp receptors or interaction partners could be localized to different compartments and the effect of such altered localization could confirm or refute emerging hypotheses. Of course, it will be of critical importance to complement the results obtained using the GrabFP system with functional studies interfering with trafficking and secretion of Dpp.

A nanobody-based toolset to investigate the role of protein localization and dispersal in Drosophila Stefan Harmansa,1,† Ilaria Alborelli,1,† Dimitri Bieli,1 Emmanuel Caussinus,1,2 and Markus Affolter1,* eLife. 2017; 6: e22549. doi: 10.7554/eLife.22549

Still investigating morphogen gradient formation? Over two years ago someone here claimed to know exactly how that happens. Maybe the authors of this paper didn't get the memo. Complex functionally specified informational complexity. Dionisio

[...] future studies should seek to identify the vertebrate equivalents of Drosophila Numb that are critical Notch signaling regulators and which segregate unequally to NPC daughter cells. Understanding the roles of Mib1 in RPE-RPC interactions, however, will require the identification of additional targets of Mib1 in future studies.

The Retinal Pigment Epithelium Is a Notch Signaling Niche in the Mouse Retina Taejeong Ha 1, Kyeong Hwan Moon 1, Le Dai 1, Jun Hatakeyama 2, Keejung Yoon 3, Hee-Sae Park 4, Young-Yoon Kong 5, Kenji Shimamura 2, Jin Woo Kim Cell Reports Volume 19, Issue 2, Pages 351-363 https://doi.org/10.1016/j.celrep.2017.03.040

Complex functionally specified informational complexity. Dionisio

Neural progenitor cells (NPCs) not only produce a variety of neurons but also renew themselves, providing a mechanism for coupling neurogenesis with tissue growth. An NPC can produce two NPCs or two neurons after a division. Alternatively, an NPC can produce a neuron and an NPC through asymmetric cell division and is able to preserve the NPC population during neurogenesis. Cell-contact-dependent Notch signaling is known to play a key role in maintaining NPCs during development and in adulthood (Gaiano and Fishell, 2002; Louvi and Artavanis-Tsakonas, 2006). Moreover, this signaling can differentiate the fates of the two NPC daughter cells upon the asymmetric activation of Notch in these cells

The Retinal Pigment Epithelium Is a Notch Signaling Niche in the Mouse Retina Taejeong Ha 1, Kyeong Hwan Moon 1, Le Dai 1, Jun Hatakeyama 2, Keejung Yoon 3, Hee-Sae Park 4, Young-Yoon Kong 5, Kenji Shimamura 2, Jin Woo Kim Cell Reports Volume 19, Issue 2, Pages 351-363 https://doi.org/10.1016/j.celrep.2017.03.040

Complex functionally specified informational complexity. Dionisio

Notch signaling in neural progenitor cell is triggered by ligands expressed in adjacent cells. [...] one RPC daughter receives extra Notch signals from the RPE to become an RPC, whereas its sister cell receives only a subthreshold level of intra-retinal Notch signal and differentiates into a neuron.

The Retinal Pigment Epithelium Is a Notch Signaling Niche in the Mouse Retina Taejeong Ha 1, Kyeong Hwan Moon 1, Le Dai 1, Jun Hatakeyama 2, Keejung Yoon 3, Hee-Sae Park 4, Young-Yoon Kong 5, Kenji Shimamura 2, Jin Woo Kim Cell Reports Volume 19, Issue 2, Pages 351-363 https://doi.org/10.1016/j.celrep.2017.03.040

Complex functionally specified informational complexity. Dionisio

Rigorously testing these putative mechanisms warrants further investigation. [...] U1 snRNP can also interact directly or indirectly with the ESE2 motif, and these interactions can be modulated by small molecules in a coordinated fashion thus providing specificity towards regulation of SMN2 alternative splicing [...] As further findings highlight mis-splicing to be the cause of many disease-causing mutations, the work presented here has the potential to have widespread implications in the research and development of such RNA-targeting therapies.

Binding to SMN2 pre-mRNA-protein complex elicits specificity for small molecule splicing modifiers Manaswini Sivaramakrishnan, Kathleen D. McCarthy, Sébastien Campagne, Sylwia Huber, Sonja Meier, Angélique Augustin, Tobias Heckel, Hélène Meistermann, Melanie N. Hug, Pascale Birrer, Ahmed Moursy, Sarah Khawaja, Roland Schmucki, Nikos Berntenis, Nicolas Giroud, Sabrina Golling, Manuel Tzouros, Balazs Banfai, Gonzalo Duran-Pacheco, Jens Lamerz, Ying Hsiu Liu, Thomas Luebbers, Hasane Ratni, Martin Ebeling, Antoine Cléry, Sergey Paushkin, Adrian R. Krainer, Frédéric H.-T. Allain & Friedrich Metzger Nature Communications 8, Article number: 1476 (2017) doi:10.1038/s41467-017-01559-4

Complex functionally specified informational complexity. Dionisio

Small molecule splicing modifiers have been previously described that target the general splicing machinery and thus have low specificity for individual genes. Several potent molecules correcting the splicing deficit of the SMN2 (survival of motor neuron 2) gene have been identified and these molecules are moving towards a potential therapy for spinal muscular atrophy (SMA). [...] these molecules directly bind to two distinct sites of the SMN2 pre-mRNA, thereby stabilizing a yet unidentified ribonucleoprotein (RNP) complex that is critical to the specificity of these small molecules for SMN2 over other genes. [...] our work has wide-ranging implications in understanding how small molecules can interact with specific quaternary RNA structures.

Binding to SMN2 pre-mRNA-protein complex elicits specificity for small molecule splicing modifiers. Sivaramakrishnan M1,2, McCarthy KD1, Campagne S3, Huber S1, Meier S1,2, Augustin A1, Heckel T1, Meistermann H1, Hug MN1, Birrer P1, Moursy A3, Khawaja S3, Schmucki R1, Berntenis N1, Giroud N1, Golling S1, Tzouros M1, Banfai B1, Duran-Pacheco G1, Lamerz J1, Hsiu Liu Y2, Luebbers T1, Ratni H1, Ebeling M4, Cléry A3, Paushkin S5, Krainer AR2, Allain FH3, Metzger F6. Nat Commun. 8(1):1476. doi: 10.1038/s41467-017-01559-4.

Complex functionally specified informational complexity. Dionisio

Before being translated into proteins, mRNAs are subjected to a sequential and strict control by RBPs exerted by the recognition of AREs in their 3?-UTRs. Regulation of mRNA homeostasis through ARE-RBPs allows the fine tuning of responses by controlling mRNA translation, degradation, or storage in diverse eukaryotic cell compartments

RNA Binding Protein Regulation and Cross-Talk in the Control of AU-rich mRNA Fate. García-Mauriño SM1, Rivero-Rodríguez F1, Velázquez-Cruz A1, Hernández-Vellisca M1, Díaz-Quintana A1, De la Rosa MA1, Díaz-Moreno Front Mol Biosci. 4:71. doi: 10.3389/fmolb.2017.00071.

Did somebody say 'fine-tuning'? Complex functionally specified informational complexity. Dionisio

[...] the whole understanding of such a fine tuned regulation is a challenge for future research and requires the integration of all the available structural and functional data by in vivo, in vitro and in silico approaches.

RNA Binding Protein Regulation and Cross-Talk in the Control of AU-rich mRNA Fate. García-Mauriño SM1, Rivero-Rodríguez F1, Velázquez-Cruz A1, Hernández-Vellisca M1, Díaz-Quintana A1, De la Rosa MA1, Díaz-Moreno Front Mol Biosci. 4:71. doi: 10.3389/fmolb.2017.00071.

Did somebody say 'fine tuned regulation'? Complex functionally specified informational complexity. Dionisio

mRNA metabolism is tightly orchestrated by highly-regulated RNA Binding Proteins (RBPs) that determine mRNA fate, thereby influencing multiple cellular functions across biological contexts.

RNA Binding Protein Regulation and Cross-Talk in the Control of AU-rich mRNA Fate. García-Mauriño SM1, Rivero-Rodríguez F1, Velázquez-Cruz A1, Hernández-Vellisca M1, Díaz-Quintana A1, De la Rosa MA1, Díaz-Moreno Front Mol Biosci. 4:71. doi: 10.3389/fmolb.2017.00071.

Did somebody say 'orchestrated'? Complex functionally specified informational complexity. Dionisio

In this review, we describe how this is performed not only by the spliceosome but also with the assistance of other splicing regulators. However, a more comprehensive understanding of how these molecules and networks interact to regulate global and tissue-specific splicing programmes is still required. It is, therefore, imperative to unveil these regulatory mechanisms to be at the forefront of molecular characterisation of tissue function and disease.

Alternative splicing: the pledge, the turn, and the prestige : The key role of alternative splicing in human biological systems. Gallego-Paez LM1, Bordone MC1, Leote AC1, Saraiva-Agostinho N1, Ascensão-Ferreira M1, Barbosa-Morais NL2. Hum Genet. 136(9):1015-1042. doi: 10.1007/s00439-017-1790-y.

Did somebody say 'programmes'? Complex functionally specified informational complexity. Dionisio

In a cellular context, the spliceosome performs canonical intron excision. In this case, the spliceosome is able to carry out splicing in alternative ways. Indeed, AS has an outstanding ability to allow the expression of highly specialised condition- and tissue-specific isoforms that contribute to different essential functions in the complex human physiology.

Alternative splicing: the pledge, the turn, and the prestige : The key role of alternative splicing in human biological systems. Gallego-Paez LM1, Bordone MC1, Leote AC1, Saraiva-Agostinho N1, Ascensão-Ferreira M1, Barbosa-Morais NL2. Hum Genet. 136(9):1015-1042. doi: 10.1007/s00439-017-1790-y.

Complex functionally specified informational complexity. Dionisio

Consider a magic trick, [...] performed by a world-class magician known as the spliceosome. From a single gene, multiple RNA products emerge. The results are intriguing: some of these transcripts are almost identical, and others are so unique as to exert antagonising functions. However, the trick is straightforward: it is a simple unit rearrangement of the gene sequence. However, how is such a simple trick performed? Let us unravel the magic of alternative splicing.

Alternative splicing: the pledge, the turn, and the prestige : The key role of alternative splicing in human biological systems. Gallego-Paez LM1, Bordone MC1, Leote AC1, Saraiva-Agostinho N1, Ascensão-Ferreira M1, Barbosa-Morais NL2. Hum Genet. 136(9):1015-1042. doi: 10.1007/s00439-017-1790-y.

"Magic trick" is a gross understatement. "Amazing" seems more appropriate. Complex functionally specified informational complexity. Dionisio

Alternative pre-mRNA splicing is a tightly controlled process conducted by the spliceosome, with the assistance of several regulators, resulting in the expression of different transcript isoforms from the same gene and increasing both transcriptome and proteome complexity. The differences between alternative isoforms may be subtle but enough to change the function or localization of the translated proteins. A fine control of the isoform balance is, therefore, needed throughout developmental stages and adult tissues or physiological conditions and it does not come as a surprise that several diseases are caused by its deregulation. The final act of the spliceosome, however, is yet to be fully revealed, as more knowledge is needed regarding the complex regulatory network that coordinates alternative splicing and how its dysfunction leads to disease.

Alternative splicing: the pledge, the turn, and the prestige : The key role of alternative splicing in human biological systems. Gallego-Paez LM1, Bordone MC1, Leote AC1, Saraiva-Agostinho N1, Ascensão-Ferreira M1, Barbosa-Morais NL2. Hum Genet. 136(9):1015-1042. doi: 10.1007/s00439-017-1790-y.

Complex functionally specified informational complexity.

Dionisio

The spliceosome is undoubtedly one of the most complicated machines inside the cell. Unraveling spliceosome biochemistry given the machine’s complexity, malleability, and sheer number of splicing factors is a formidable challenge. [...] many outstanding questions yet remain. Understanding the dynamic transitions of U6 as it progresses between these various complexes will likely require single molecule approaches among many other methods. Single molecule tools will also prove valuable in testing hypotheses related to individual complexes as well. In the new era of spliceosome structures and NGS analysis of spliceosome activity, the future for single molecule studies of the spliceosome looks very bright. It is time for the spliceosome to shine!

Lights, camera, action! Capturing the spliceosome and pre-mRNA splicing with single-molecule fluorescence microscopy. DeHaven AC1,2, Norden IS1,2, Hoskins AA2. Wiley Interdiscip Rev RNA. 7(5):683-701. doi: 10.1002/wrna.1358.

Complex functionally specified informational complexity. Dionisio

The process of removing intronic sequences from a precursor to messenger RNA (pre-mRNA) to yield a mature mRNA transcript via splicing is an integral step in eukaryotic gene expression. Splicing is carried out by a cellular nanomachine called the spliceosome that is composed of RNA components and dozens of proteins. Despite decades of study, many fundamentals of spliceosome function have remained elusive. Recent developments in single-molecule fluorescence microscopy have afforded new tools to better probe the spliceosome and the complex, dynamic process of splicing by direct observation of single molecules. These cutting-edge technologies enable investigators to monitor the dynamics of specific splicing components, whole spliceosomes, and even cotranscriptional splicing within living cells.

Lights, camera, action! Capturing the spliceosome and pre-mRNA splicing with single-molecule fluorescence microscopy. DeHaven AC1,2, Norden IS1,2, Hoskins AA2. Wiley Interdiscip Rev RNA. 7(5):683-701. doi: 10.1002/wrna.1358.

Complex functionally specified informational complexity. Dionisio

Small molecule inhibitors that target components of the spliceosome have great potential as tools to probe splicing mechanism and dissect splicing regulatory networks in cells. Because the spliceosome is a complicated and dynamic macromolecular machine comprised of many RNA and protein components, a variety of compounds that interfere with different aspects of spliceosome assembly is needed to probe its function.

Modulating splicing with small molecular inhibitors of the spliceosome. Effenberger KA1,2, Urabe VK1,2, Jurica MS1,2. Wiley Interdiscip Rev RNA. 8(2). doi: 10.1002/wrna.1381.

Complex functionally specified informational complexity. Dionisio

The supraspliceosome also harbor components for all pre-mRNA processing activities. Thus the supraspliceosome - the endogenous spliceosome - is a stand-alone complete macromolecular machine capable of performing splicing, alternative splicing, and encompass all nuclear pre-mRNA processing activities that the pre-mRNA has to undergo before it can exit from the nucleus to the cytoplasm to encode for protein. Further high-resolution cryo-electron microscopy studies of the endogenous spliceosome are required to decipher the regulation of alternative splicing, and elucidate the network of processing activities within it.

Structural studies of the endogenous spliceosome - The supraspliceosome. Sperling J1, Sperling R2. Methods. 125:70-83. doi: 10.1016/j.ymeth.2017.04.005.

Complex functionally specified informational complexity. Dionisio

Pre-mRNA splicing is executed in mammalian cell nuclei within a huge (21MDa) and highly dynamic molecular machine - the supraspliceosome - that individually package pre-mRNA transcripts of different sizes and number of introns into complexes of a unique structure, indicating their universal nature. Detailed structural analysis of this huge and complex structure requires a stepwise approach using hybrid methods.

Structural studies of the endogenous spliceosome - The supraspliceosome. Sperling J1, Sperling R2. Methods. 125:70-83. doi: 10.1016/j.ymeth.2017.04.005.

Complex functionally specified informational complexity. Dionisio

The complex life of pre-mRNA from transcription to the production of mRNA that can be exported from the nucleus to the cytoplasm to encode for proteins entails intricate coordination and regulation of a network of processing events. Coordination is required between transcription and splicing and between several processing events including 5' and 3' end processing, splicing, alternative splicing and editing that are major contributors to the diversity of the human proteome, and occur within a huge and dynamic macromolecular machine-the endogenous spliceosome. The challenge ahead is to elucidate the structure and function of the endogenous spliceosome and decipher the regulation and coordination of its network of processing activities.

The nuts and bolts of the endogenous spliceosome. Sperling R Wiley Interdiscip Rev RNA. 8(1). doi: 10.1002/wrna.1377.

Complex functionally specified informational complexity. Dionisio

[...] a subset of chromatin proteins is physically in interaction with the enzyme responsible for RNA splicing. In addition, several chromatin proteins not found directly associated with the splicing machinery were also able to influence RNA splicing, suggesting that chromatin compaction very globally plays a role in splicing. [...] assembling DNA with chromatin proteins influences the efficiency of splicing.

A Broad Set of Chromatin Factors Influences Splicing Eric Allemand, Michael P. Myers, Jose Garcia-Bernardo, Annick Harel-Bellan, Adrian R. Krainer, and Christian Muchardt PLoS Genet. 12(9): e1006318. doi: 10.1371/journal.pgen.1006318

Complex functionally specified informational complexity. Dionisio

Splicing is an RNA editing step allowing to produce multiple transcripts from a single gene. The gene itself is organized in chromatin, associating DNA and multiple proteins. Some proteins regulating the compaction of the chromatin also affect RNA splicing. Yet, it was unclear whether these chromatin proteins were exceptions or whether chromatin very generally affected the outcome of splicing.

A Broad Set of Chromatin Factors Influences Splicing Eric Allemand, Michael P. Myers, Jose Garcia-Bernardo, Annick Harel-Bellan, Adrian R. Krainer, and Christian Muchardt PLoS Genet. 12(9): e1006318. doi: 10.1371/journal.pgen.1006318

Complex functionally specified informational complexity. Dionisio

Several studies propose an influence of chromatin on pre-mRNA splicing, but it is still unclear how widespread and how direct this phenomenon is. [...] chromatin impacts nascent pre-mRNP in their competence for splicing. [...] numerous chromatin factors associated or not with the spliceosome can affect the outcome of splicing, possibly as a function of the local chromatin environment that by default interferes with the efficiency of splicing.

A Broad Set of Chromatin Factors Influences Splicing Eric Allemand, Michael P. Myers, Jose Garcia-Bernardo, Annick Harel-Bellan, Adrian R. Krainer, and Christian Muchardt PLoS Genet. 12(9): e1006318. doi: 10.1371/journal.pgen.1006318

Complex functionally specified informational complexity. Dionisio

[...] there are numerous target genes that control diverse cellular events. [...] selective activation [...] No specific signal activates all the target genes and no gene is activated by all the signals.

Protein Regulation in Signal Transduction Narayanan A, Laxmi S. R and Shashikant R ISBN 978-93-84502-47-8 In book: Concepts in Cell Signaling, Chapter: 2, Publisher: Prashant Publishing House New Delhi, Editors: S. Kumar & A. K. Sharma, pp.58-71

Did somebody say "selective activation"? Complex functionally specified informational complexity. Dionisio

The balance of protein synthesis and degradation is necessary to maintain the efficiency and accuracy of signal transduction in the cell.

Protein Regulation in Signal Transduction Narayanan A, Laxmi S. R and Shashikant R ISBN 978-93-84502-47-8 In book: Concepts in Cell Signaling, Chapter: 2, Publisher: Prashant Publishing House New Delhi, Editors: S. Kumar & A. K. Sharma, pp.58-71

Did somebody say "efficiency and accuracy"? Complex functionally specified informational complexity. Dionisio

Proteins [...] [...] get regulated at many stages such as protein synthesis, protein folding, post translational modifications (PTMs), and degradation. Protein-protein interactions are another key means of regulating the multicomponent networks. These, altogether, make signal transduction pathway a tightly regulated event.

Protein Regulation in Signal Transduction Narayanan A, Laxmi S. R and Shashikant R ISBN 978-93-84502-47-8 In book: Concepts in Cell Signaling, Chapter: 2, Publisher: Prashant Publishing House New Delhi, Editors: S. Kumar & A. K. Sharma, pp.58-71

Did somebody say "tightly regulated"? Complex functionally specified informational complexity. Dionisio

The major players in the signal transduction pathways are proteins. There are many levels of regulation in such a pathway- from receptors to effectors. Different external cues bring about a diverse array of changes in a cell, with multiple pathways operating with efficiency and specificity.

Protein Regulation in Signal Transduction Narayanan A, Laxmi S. R and Shashikant R ISBN 978-93-84502-47-8 In book: Concepts in Cell Signaling, Chapter: 2, Publisher: Prashant Publishing House New Delhi, Editors: S. Kumar & A. K. Sharma, pp.58-71

Did somebody say "operating with efficiency and specificity"? Complex functionally specified informational complexity. Dionisio

For a cellular function to be carried out, it is imperative that a protein is synthesized, properly folded to its functional form, appropriately modified and localized. It should also be present in appropriate quantity and degraded after its span. All the processes in the cells are subject to this protein quality control system which is mediated by several molecules and pathways. Signal transduction is no exception.

Protein Regulation in Signal Transduction Narayanan A, Laxmi S. R and Shashikant R ISBN 978-93-84502-47-8 In book: Concepts in Cell Signaling, Chapter: 2, Publisher: Prashant Publishing House New Delhi, Editors: S. Kumar & A. K. Sharma, pp.58-71

Did somebody say 'quality control system'? Complex functionally specified informational complexity. Dionisio

Do the book chapter referenced @67 and the paper referenced @62 share the same title? @67: Protein Regulation in Signal Transduction Narayanan A, Laxmi S. R and Shashikant R ISBN 978-93-84502-47-8 @62: Protein Regulation in Signal Transduction Michael J. Lee and Michael B. Yaffe doi: 10.1101/cshperspect.a005918 Cold Spring Harbor Perspectives in Biology Cold Spring Harbor Laboratory Press Dionisio

Signal transduction pathways are involved in responses of the cells to different environmental cues and hence, the regulation of these pathways is highly significant. Proteins are the major players in the signaling pathways that are regulated at different stages during their span- from synthesis to degradation. Transcriptional and translational control of the protein synthesis, regulation by protein folding machinery, post-translational modifications, protein localization, protein-protein interactions, and regulated proteolysis- all these regulations work in concert to maintain the specificity and efficiency of the signaling networks. [...] irregularities in signaling networks result in deleterious effects.

Protein Regulation in Signal Transduction Narayanan A, Laxmi S. R and Shashikant R ISBN 978-93-84502-47-8

Did somebody say 'work in concert'? Complex functionally specified informational complexity. Dionisio

Originally based on a graduate course taught by the author, this true classic has once again been extensively updated to incorporate key new findings in biological signaling. With over half of the content re-written, plus 70 brand new and 50 revised figures, this is the most up-to-date textbook on signaling available anywhere. Thanks to its clear structure, hundreds of illustrative drawings, as well as chapter introductions and newly added study questions, this text excels as a companion for a course on biological signaling, and equally as an introductory reference to the field for students and researchers. Generations of students and junior researchers have relied on "the Krauss" to find their way through the bewildering complexity of biological signaling pathways. Table of Contents Preface XXVII 1 Basics of Cell Signaling 1 1.1 Cell Signaling: Why, When, and Where? 1 1.2 Intercellular Signaling 3 1.3 Hormones in Intercellular Signaling 8 1.4 Intracellular Signaling: Basics 15 1.5 Molecular Tools for Intracellular Signaling 18 2 Structural Properties, Regulation and Posttranslational Modification of Signaling Proteins 27 2.1 Modular Structure of Signaling Proteins 27 2.2 Modular Signaling Complexes 31 2.3 Regulation of Signaling Enzymes by Effector Binding 34 2.4 Posttranslational Modifications (PTMs) in Cellular Signaling 36 2.5 Regulation by Protein Phosphorylation 51 2.6 Regulation by Protein Lysine Acetylation 55 2.7 Regulation by Protein Methylation 58 2.8 Ubiquitin Modification of Proteins 62 2.9 Lipidation of Signaling Proteins 90 3 Organization of Signaling 103 3.1 Scaffold Proteins 103 3.2 Signal Processing in Signaling Paths and Signaling Networks 108 3.3 Architecture of Signaling Pathways 113 4 The Regulation of Gene Expression 129 4.1 The Basic Steps of Gene Expression 129 4.2 The Components of the Eukaryotic Transcription Machinery 131 4.3 The Principles of Transcription Regulation 149 4.4 The Control of Transcription Factors 165 4.5 Chromatin Structure and Transcription Regulation 175 5 RNA Processing, Translational Regulation, and RNA Interference 209 5.1 Pre-mRNA Processing 209 5.2 Regulation at the Level of Translation 217 5.3 Regulation by RNA Silencing 229 6 Signaling by Nuclear Receptors 251 6.1 Ligands of Nuclear Receptors (NRs) 252 6.2 Principles of Signaling by Nuclear Receptors (NRs) 254 6.3 Structure of Nuclear Receptors (NRs) 257 6.4 Transcriptional Regulation by NRs 268 6.5 Regulation of Signaling by Nuclear Receptors 274 6.6 Subcellular Localization of NRs 280 6.7 Nongenomic Functions of NRs and their Ligands 284 7 G Protein-Coupled Signal Transmission Pathways 291 7.1 Transmembrane Receptors: General Structure and Classification 291 7.2 Structural Principles of Transmembrane Receptors 294 7.3 G Protein-Coupled Receptors 301 7.4 Regulatory GTPases 320 7.5 The Heterotrimeric G Proteins 327 7.6 Receptor-independent Functions of Heterotrimeric G Proteins 350 7.7 Effector Molecules of G Proteins 352 7.8 GPCR Signaling via Arrestin 363 8 Intracellular Messenger Substances: “Second Messengers” 369 8.1 General Properties of Intracellular Messenger Substances 369 8.2 Cyclic AMP 371 8.3 cGMP and Guanylyl Cyclases 375 8.4 Metabolism of Inositol Phospholipids and Inositol Phosphates 378 8.5 Storage and Release of Ca2þ 383 8.6 Functions of Phosphoinositides 392 8.7 Ca2þ as a Signal Molecule 394 8.8 Diacylglycerol as a Signal Molecule 401 8.9 Other Lipid Messengers: Ceramide, Sphingosine, and Lysophosphatidic Acid 401 8.10 The NO Signaling Molecule 404 9 Ser/Thr-Specific Protein Kinases and Protein Phosphatases 417 9.1 Classification, Structure, and Characteristics of Protein Kinases 417 9.2 Structure and Regulation of Protein Kinases 420 9.3 Protein Kinase A 431 9.4 The PI3 Kinase/Akt Pathway 439 9.5 Protein Kinase C 447 9.6 Ca2þ/Calmodulin-Dependent Protein Kinases, CaM Kinases 455 9.7 Ser/Thr-Specific Protein Phosphatases 461 10 Signal Transmission via Transmembrane Receptors with Tyrosine-Specific Protein Kinase Activity 473 10.1 Structure and Function of RTKs 474 10.2 Downstream Effector Proteins of RTKs 494 10.3 Nonreceptor Tyrosine-Specific Protein Kinases, Non-RTKs 507 10.4 Protein Tyrosine Phosphatases 519 11 Signal Transmission via Ras Proteins 535 11.1 The Ras Superfamily of Monomeric GTPases 535 11.2 GTPase-Activating Proteins (GAPs) of the Monomeric GTPases 539 11.3 Guanine Nucleotide Exchange Factors (GEFs) of the Monomeric GTPases 541 11.4 Guanine Nucleotide Dissociation Inhibitors (GDIs) 544 11.5 The Ras Family of Monomeric GTPases 545 11.6 Raf Kinase as an Effector of Signal Transduction by Ras Proteins 555 11.7 Further Ras Family Members: R-Ras, Ral, and Rap 561 11.8 Reception and Transmission of Multiple Signals by Ras Protein 562 11.9 The Further Branches of the Ras Superfamily 568 12 Intracellular Signal Transduction: The MAP Kinase Pathways 573 12.1 Organization and Components of MAPK Pathways 575 12.2 Regulation of MAPK Pathways by Protein Phosphatases and Inhibitor Proteins 579 12.3 Scaffolding in MAPK Signaling 583 12.4 The Major MAPK Pathways of Mammals 586 13 Membrane Receptors with Associated Tyrosine Kinase Activity 593 13.1 Cytokines and Cytokine Receptors 593 13.2 The Jak-STAT Pathway 608 13.3 T- and B-Cell Receptors 618 13.4 Signal Transduction via Integrins 623 14 Other Transmembrane Receptor Classes: Signaling by TGF-b Receptors, TNF Receptors, Toll Receptors, and Notch 631 14.1 Receptors with Intrinsic Ser/Thr Kinase Activity: The TGF-b Receptor and Smad Protein Signaling 631 14.2 Receptor Regulation by Intramembrane Proteolysis: The Notch Receptor 642 14.3 Tumor Necrosis Factor Receptor (TNFR) Superfamily 648 14.4 Toll-Like Receptor Signaling 653 15 Cell-Cycle Control by External Signaling Pathways 661 15.1 Principles of Cell-Cycle Control 661 15.2 Key Elements of the Cell-Cycle Apparatus 666 15.3 Regulation of the Cell Cycle by Proteolysis 681 15.4 G1 Progression and S Phase Entry 684 15.5 Transit Through S Phase and M Phase 699 15.6 DNA Damage and DNA Replication Checkpoints 702 16 Malfunction of Signaling Pathways and Tumorigenesis: Oncogenes and Tumor Suppressor Genes 715 16.1 Basic Characteristics of Tumor Cells 715 16.2 Mutations in Cancer Cells 715 16.3 Common Physiologic Changes in Tumor Cells: The Hallmarks of Cancer 725 16.4 Signaling Proteins Mutated in Cancer: Oncogenes 729 16.5 Tumor Suppressor Genes: General Functions 741 16.6 Tumor Suppressors: Rb and ARF Proteins 743 16.7 Tumor Suppressor Protein p53 747 16.8 Wnt/b-Catenin Signaling and the Tumor Suppressor APC 770 17 Apoptosis 777 17.1 Overview of Apoptotic Pathways 778 17.2 Caspases: Death by Proteolysis 779 17.3 The Family of Bcl-2 Proteins: Gatekeepers of Apoptosis 786 17.4 The Mitochondrial Pathway of Apoptosis 789 17.5 Death Receptor-Triggered Apoptosis 792 17.6 Links of Apoptosis to Cellular Signaling Pathways 795 Questions 799 References 799 Index 801

Biochemistry of Signal Transduction and Regulation, 5th Edition Gerhard Krauss ISBN: 978-3-527-33366-0

Given the fast pace biology research is going at these days, an over 3 year old textbook might be slightly outdated on some details? Maybe another rewrite is due? Did somebody say 'the bewildering complexity of biological signaling pathways'? Complex functionally specified informational complexity. Dionisio

Trpm2 channels are pro-survival by modulating HIF-1? expression, preserving mitochondrial bioenergetics, decreasing mitochondrial ROS production, and increasing ROS scavenging in cells subjected to oxidative stress. Trpm2 channels protected hearts against I/R injury and tumor cells from doxorubicin toxicity. Targeting Trpm2 channels in the treatment of diseases may result in benefit, e.g., ameliorating cardiac ischemia-reperfusion injury (friend), or harm, e.g., aggravating doxorubicin cardiotoxicity (foe). Therapy with Trpm2 inhibitors may require specific targeting to cancer cells. More detailed investigation needs to be performed before thoughtful and safe therapy centering on Trpm2 channels can be devised.

Transient Receptor Potential-Melastatin Channel Family Member 2: Friend or Foe. Cheung JY, Miller BA1. Trans Am Clin Climatol Assoc. 2017;128:308-329. PMID: 28790515 PMCID: PMC5525431

Complex functionally specified informational complexity. Dionisio

We have shown that Trpm2 channels protect the heart from oxidative stress, specifically I/R injury (36,60) and doxorubicin cardiotoxicity (37). Thus therapy designed to promote Trpm2 activation may be beneficial in acute coronary syndromes, ischemic cardiomyopathy, and doxorubicin cardiotoxicity. On the other hand, Trpm2 channels are involved in cell proliferation and differentiation and sustained indiscriminate Trpm2 activation may not only protect cells from injury including chemotherapy but also promote survival of occult malignant cells. Therefore, therapy must be thoughtful and designed to be organ- and tissue-specific. An in-depth study of Trpm2 is thus warranted in the emerging field of onco-cardiology.

Transient Receptor Potential-Melastatin Channel Family Member 2: Friend or Foe. Cheung JY, Miller BA1. Trans Am Clin Climatol Assoc. 2017;128:308-329. PMID: 28790515 PMCID: PMC5525431

Complex functionally specified informational complexity. Dionisio

Transient receptor potential melastatin 2 (Trpm2) channels are nonvoltage-activated channels permeable to monovalent and divalent cations, and are expressed in heart, brain, kidney, vasculature, and hematopoietic cells. Trpm2 is overexpressed in bladder, lung, breast, liver, head, and neck cancers. Classically, Trpm2 activation induces cell injury and death by Ca2+ overload or enhanced inflammatory response. Recent studies show that Trpm2 protects lungs from endotoxin-induced injury by reducing reactive oxygen species production in phagocytes; and improves cardiac function after ischemia-reperfusion injury by preserving mitochondrial respiration and cellular adenosine triphosphate levels while decreasing reactive oxygen species levels. In neuroblastoma xenografts, Trpm2 overexpression promotes tumor growth through modulation of hypoxia-inducible transcription factor expression and cellular bioenergetics; whereas Trpm2 inhibition results in enhanced sensitivity to doxorubicin. The robust expression in cancer cells and its pro-survival and proliferative properties make Trpm2 a rational target for cancer therapy. Indiscriminate Trpm2 inhibition, however, may engender serious untoward side effects in other vital organs.

Transient Receptor Potential-Melastatin Channel Family Member 2: Friend or Foe. Cheung JY, Miller BA1. Trans Am Clin Climatol Assoc. 2017;128:308-329. PMID: 28790515 PMCID: PMC5525431

Complex functionally specified informational complexity. Dionisio

Cells must respond to a diverse, complex, and ever-changing mix of signals, using a fairly limited set of parts. Changes in protein level, protein localization, protein activity, and protein–protein interactions are critical aspects of signal transduction, allowing cells to respond highly specifically to a nearly limitless set of cues and also to vary the sensitivity, duration, and dynamics of the response. Signal-dependent changes in levels of gene expression and protein synthesis play an important role in regulation of protein levels, whereas posttranslational modifications of proteins regulate their degradation, localization, and functional interactions. Protein ubiquitylation, for example, can direct proteins to the proteasome for degradation or provide a signal that regulates their interactions and/or location within the cell. Similarly, protein phosphorylation by specific kinases is a key mechanism for augmenting protein activity and relaying signals to other proteins that possess domains that recognize the phosphorylated residues.

Protein Regulation in Signal Transduction Michael J. Lee and Michael B. Yaffe doi: 10.1101/cshperspect.a005918 Cold Spring Harbor Perspectives in Biology Cold Spring Harbor Laboratory Press

Complex functionally specified informational complexity. Dionisio

A final intriguing case is that of cotranslational interaction between human mitochondrially encoded COX1 and C12ORF62 [...] The mechanistic details of this process are not yet fully understood, but it has a fascinating implication, [...] [...] to further understand the role of cotranslational assembly in normal biological function, as well as its potential implications mitigating the DN effect in inherited and de novo genetic disorders, there is a need for new tools and much more experimental characterization cotranslational processes.

Regulation, evolution and consequences of cotranslational protein complex assembly Eviatar Natan 1, Jonathan N Wells 2, Sarah A Teichmann 3, Joseph A Marsh 2 Science Direct Current Opinion in Structural Biology Volume 42, Pages 90-97 DOI: https://doi.org/10.1016/j.sbi.2016.11.023

Did somebody say 'intriguing'? Did somebody say 'fascinating'? Complex functionally specified informational complexity. Dionisio

Clearly, other factors such as chaperones may participate in ensuring correct assembly both for homomers and heteromers. Chaperones play an essential role in avoiding misfolding or aggregation, thus promoting the formation of native tertiary and quaternary protein structure. The mechanistic details of how they act vary dramatically, and chaperones as a whole encompass a wide variety of unrelated protein families The action of chaperones is particularly important for eukaryotic proteins, which are typically longer than those from prokaryotes, often comprise multiple domains, and have a higher incidence of intrinsically disordered and flexible regions [...]

Regulation, evolution and consequences of cotranslational protein complex assembly Eviatar Natan 1, Jonathan N Wells 2, Sarah A Teichmann 3, Joseph A Marsh 2 Science Direct Current Opinion in Structural Biology Volume 42, Pages 90-97 DOI: https://doi.org/10.1016/j.sbi.2016.11.023

Complex functionally specified informational complexity. Dionisio

[...] the exact frequency at which cotranslational folding occurs in either prokaryotes or eukaryotes is unknown [...] There are several reasons why proteins might acquire secondary structure during translation, sometimes even while still inside the ribosome exit tunnel [...] The cell broadly regulates both cis and trans mechanisms.

Regulation, evolution and consequences of cotranslational protein complex assembly Eviatar Natan 1, Jonathan N Wells 2, Sarah A Teichmann 3, Joseph A Marsh 2 Science Direct Current Opinion in Structural Biology Volume 42, Pages 90-97 DOI: https://doi.org/10.1016/j.sbi.2016.11.023

Complex functionally specified informational complexity. Dionisio

[...] there are still unanswered questions about how the cell regulates protein complex assembly, and where assembly actually occurs within the cell. A logical place to begin addressing this is in the initial stages of protein synthesis and folding.

Regulation, evolution and consequences of cotranslational protein complex assembly Eviatar Natan 1, Jonathan N Wells 2, Sarah A Teichmann 3, Joseph A Marsh 2 Science Direct Current Opinion in Structural Biology Volume 42, Pages 90-97 DOI: https://doi.org/10.1016/j.sbi.2016.11.023

Complex functionally specified informational complexity. Dionisio

Proteins are synthesized as linear polymers and have to fold into their native structure to fulfil various functions in the cell. Folding can start co-translationally when the emerging peptide is still attached to the ribosome and is guided by the environment of the polypeptide exit tunnel and the kinetics of translation. Major questions are: When does co-translational folding begin? What is the role of the ribosome in guiding the nascent peptide towards its native structure? How does translation elongation kinetics modulate protein folding? Here we suggest how novel structural and biophysical approaches can help to probe the interplay between the ribosome and the emerging peptide and present future challenges in understanding co-translational folding.

Co-translational protein folding: progress and methods Michael Thommen, Wolf Holtkamp, Marina V Rodnina Current Opinion in Structural Biology Volume 42, Pages 83-89 DOI: https://doi.org/10.1016/j.sbi.2016.11.020

Did somebody say 'future challenges'? Complex functionally specified informational complexity. Dionisio

Contemporary protein structure is a result of the trade off between the laws of physics and the evolutionary selection. The polymer nature of proteins played a decisive role in establishing the basic structural and functional units of soluble proteins. We discuss how these elementary building blocks work in the hierarchy of protein domain structure, co-translational folding, as well as in enzymatic activity and molecular interactions. Next, we consider modulators of the protein function, such as intermolecular interactions, disorder-to-order transitions, and allosteric signaling, acting via interference with the protein's structural dynamics. We also discuss the post-translational modifications, which is a complementary intricate mechanism evolved for regulation of protein functions and interactions. In conclusion, we assess an anticipated contribution of discussed topics to the future advancements in the field.

Protein function machinery: from basic structural units to modulation of activity Igor N Berezovsky 1, 2, Enrico Guarnera 1, Zejun Zheng 1, Birgit Eisenhaber 1, Frank Eisenhaber 1, 3 Current Opinion in Structural Biology Volume 42, Pages 67-74 DOI: https://doi.org/10.1016/j.sbi.2016.10.021

Parole, parole, parole... Where's the beef? Complex functionally specified informational complexity. Dionisio

@46-47: https://www.researchgate.net/profile/Igor_Berezovsky/publication/308912133_Basic_units_of_protein_structure_folding_and_function/links/597efbdfaca272d56817fa17/Basic-units-of-protein-structure-folding-and-function.pdf Complex functionally specified informational complexity. Dionisio

Cichlids encompass one of the most diverse groups of fishes in South and Central America, and show extensive variation in life history, morphology, and colouration. [...] a key amino acid substitution present in some Central American cichlids accelerates the rate of decay of active rhodopsin, which may mediate adaptation to clear water habitats.

Accelerated Evolution and Functional Divergence of the Dim Light Visual Pigment Accompanies Cichlid Colonization of Central America. Hauser FE1, Ilves KL2,3, Schott RK1, Castiglione GM4, López-Fernández H1,2, Chang BSW1,4, Mol Biol Evol. 34(10):2650-2664. doi: 10.1093/molbev/msx192.

Fish remains fish? Isn’t this all about microevolutionary changes? Where’s the beef? Another example of the Embedded Variability Framework (EVF) designed within the biological systems. Complex functionally specified informational complexity. Dionisio

@51-52 Isn’t this all about microevolutionary changes? Where’s the beef? Another example of the Embedded Variability Framework (EVF) designed within the biological systems. Complex functionally specified informational complexity. Dionisio

[...] unique amino acid substitutions occur at sites under positive selection in high-altitude catfishes, located at opposite ends of the RH1 intramolecular hydrogen-bonding network. Natural high-altitude variants introduced into these sites via mutagenesis have limited effects on spectral tuning, yet decrease the stability of dark-state and light-activated rhodopsin, accelerating the decay of ligand-bound forms. As found in cold-adapted enzymes, this phenotype likely compensates for a cold-induced decrease in kinetic rates-properties of rhodopsin that mediate rod sensitivity and visual performance. Our results support a role for natural variation in enhancing the performance of GPCRs in response to cold temperatures.

Evolution of nonspectral rhodopsin function at high altitudes. Castiglione GM1,2, Hauser FE2, Liao BS1, Lujan NK2,3,4, Van Nynatten A1, Morrow JM2, Schott RK2, Bhattacharyya N1, Dungan SZ2, Chang BSW5 Proc Natl Acad Sci U S A. 114(28):7385-7390. doi: 10.1073/pnas.1705765114

Complex functionally specified informational complexity. Dionisio

High-altitude environments present a range of biochemical and physiological challenges for organisms through decreases in oxygen, pressure, and temperature relative to lowland habitats. Protein-level adaptations to hypoxic high-altitude conditions have been identified in multiple terrestrial endotherms; however, comparable adaptations in aquatic ectotherms, such as fishes, have not been as extensively characterized. In enzyme proteins, cold adaptation is attained through functional trade-offs between stability and activity, often mediated by substitutions outside the active site. Little is known whether signaling proteins [e.g., G protein-coupled receptors (GPCRs)] exhibit natural variation in response to cold temperatures. Rhodopsin (RH1), the temperature-sensitive visual pigment mediating dim-light vision, offers an opportunity to enhance our understanding of thermal adaptation in a model GPCR.

Evolution of nonspectral rhodopsin function at high altitudes. Castiglione GM1,2, Hauser FE2, Liao BS1, Lujan NK2,3,4, Van Nynatten A1, Morrow JM2, Schott RK2, Bhattacharyya N1, Dungan SZ2, Chang BSW5 Proc Natl Acad Sci U S A. 114(28):7385-7390. doi: 10.1073/pnas.1705765114

Complex functionally specified informational complexity. Dionisio

Like many aquatic vertebrates, whales have blue-shifting spectral tuning substitutions in the dim-light visual pigment, rhodopsin, that are thought to increase photosensitivity in underwater environments. We have discovered that known spectral tuning substitutions also have surprising epistatic effects on another function of rhodopsin, the kinetic rates associated with light-activated intermediates. [...] killer whale rhodopsin is unusually resilient to pleiotropic effects on retinal release from key blue-shifting substitutions (D83N and A292S), largely due to a surprisingly specific epistatic interaction between D83N and the background residue, S299.

Epistatic interactions influence terrestrial-marine functional shifts in cetacean rhodopsin. Dungan SZ1, Chang BS2,3,4. Proc Biol Sci. 284(1850). pii: 20162743. doi: 10.1098/rspb.2016.2743.

Isn't this all about microevolutionary changes? Where's the beef? Did somebody say 'surprising'? Did somebody say 'surprisingly'? Complex functionally specified informational complexity. Dionisio

Biological systems are complex and consist of many proteins and other molecules. Genes are the sections of DNA that provide the instructions needed to produce these molecules, and some genes encode proteins that can bind to DNA to control whether other genes are switched on or off. [...] the nature of the interaction between mutations can be explained through biophysical laws, combined with the basic knowledge of the logic of how genes regulate each other’s activities. The interaction between individual mutations – epistasis – determines how a genotype maps onto a phenotype [...]

On the mechanistic nature of epistasis in a canonical cis-regulatory element Mato Lagator,1,† Tiago Paixão,1,† Nicholas H Barton,1 Jonathan P Bollback,1,2 and C?lin C Guet1,* eLife. 2017; 6: e25192. doi: 10.7554/eLife.25192

Complex functionally specified informational complexity. Dionisio

Understanding the relation between genotype and phenotype remains a major challenge. The difficulty of predicting individual mutation effects, and particularly the interactions between them, has prevented the development of a comprehensive theory that links genotypic changes to their phenotypic effects. [...] a predictive theory for the effects of cis-regulatory mutations is possible from first principles, as long as the essential molecular mechanisms and the constraints these impose on a biological system are accounted for.

On the mechanistic nature of epistasis in a canonical cis-regulatory element Mato Lagator,1,† Tiago Paixão,1,† Nicholas H Barton,1 Jonathan P Bollback,1,2 and C?lin C Guet1,* eLife. 2017; 6: e25192. doi: 10.7554/eLife.25192

Complex functionally specified informational complexity. Dionisio

Despite now a days wealth of structural data in the Protein Data Bank (Bermanetal.,2000) and decades of protein studies, some of the very fundamentals of protein structure are still under intense discussion. [...] the exhaustive catalogs with detail description of all relevant characteristics are yet to be produced. The catalog will be instrumental in the high-throughput annotation / prediction of protein function on the basis of its building blocks - elementary functions [...] Further development of the concept of descriptor of elementary function (Goncearenco and Berezovsky,2015;Zheng et al.,2016), construction of the comprehensive library of descriptors, and implementation of the computational protocol for descriptor - based design of required catalytic functions are also the first priority, future tasks.

Basic units of protein structure, folding, and function Igor N. Berezovsky a, b, Enrico Guarnera a, Zejun Zheng a Progress in Biophysics and Molecular Biology ScienceDirect Volume 128, Pages 85-99 DOI: https://doi.org/10.1016/j.pbiomolbio.2016.09.009

Complex functionally specified informational 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. 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 Igor N. Berezovsky a, b, Enrico Guarnera a, Zejun Zheng a Progress in Biophysics and Molecular Biology ScienceDirect Volume 128, Pages 85-99 DOI: https://doi.org/10.1016/j.pbiomolbio.2016.09.009

Complex functionally specified informational complexity. Dionisio

The 20 naturally occurring amino acids have different environmental preferences of where they are likely to occur in protein structures. Environments in a protein can be classified by their proximity to solvent by the residue depth measure. Since the frequencies of amino acids are different at various depth levels, the substitution frequencies should vary according to depth. To quantify these substitution frequencies, we built depth dependent substitution matrices. Further developments in these substitution matrices could help in improving structure-sequence alignment for protein 3D structure modeling.

Depth dependent amino acid substitution matrices and their use in predicting deleterious mutations Nida Farheen a, 1, Neeladri Sen a, 1, Sanjana Nair a, Kuan Pern Tan b, c, M.S. Madhusudhan a, b Progress in Biophysics and Molecular Biology Volume 128, Pages 14-23 DOI: https://doi.org/10.1016/j.pbiomolbio.2017.02.004

Complex functionally specified informational complexity. Dionisio

Complete maps of PPI networks annotated with biological pathway and protein structural information, will provide a platform from which to understand the molecular nature of PPI networks, in turn guiding predictions of the impacts of mutations on disease biology. Structural understanding and quantification of effects of mutations at PPIs will enable the design of better PPI inhibitors and stabilisers that can target specific disease states, and address cases where further interface mutations lead to drug resistance.

Mutations at protein-protein interfaces: Small changes over big surfaces have large impacts on human health Harry C. Jubb a, b, 1, Arun P. Pandurangan a, 1, Meghan A. Turner a, c, 1, Bernardo Ochoa-Montaño a, 1, Tom L. Blundell a, David B. Ascher a, d Progress in Biophysics and Molecular Biology Volume 128, Pages 3-13 DOI: https://doi.org/10.1016/j.pbiomolbio.2016.10.002

Work in progress... stay tuned. Complex functionally specified informational complexity. Dionisio

Interactions between proteins mediate many biological processes, especially with respect to cell regulatory events requiring high signal-to-noise ratios to transduce information within and between cells [...] Understanding how mutations modulate protein interactions and thus biological functions raises potential for developing therapeutic interventions targeting interaction mutants. Protein interactions impart selectivity and sensitivity to biological processes, and may occur either through the co-operative assembly of specific multi-protein assemblies or through the co-operative folding and binding of one binding protomer onto another.

Mutations at protein-protein interfaces: Small changes over big surfaces have large impacts on human health Harry C. Jubb a, b, 1, Arun P. Pandurangan a, 1, Meghan A. Turner a, c, 1, Bernardo Ochoa-Montaño a, 1, Tom L. Blundell a, David B. Ascher a, d Progress in Biophysics and Molecular Biology Volume 128, Pages 3-13 DOI: https://doi.org/10.1016/j.pbiomolbio.2016.10.002

Complex functionally specified informational complexity. Dionisio

Many essential biological processes including cell regulation and signalling are mediated through the assembly of protein complexes. Changes to protein-protein interaction (PPI) interfaces can affect the formation of multiprotein complexes, and consequently lead to disruptions in interconnected networks of PPIs within and between cells, further leading to phenotypic changes as functional interactions are created or disrupted. [...] a better understanding of how these mutations affect the structure, function, and formation of multiprotein complexes provides novel opportunities for tackling them, including the development of small-molecule drugs targeted specifically to mutated PPIs.

Mutations at protein-protein interfaces: Small changes over big surfaces have large impacts on human health Harry C. Jubb a, b, 1, Arun P. Pandurangan a, 1, Meghan A. Turner a, c, 1, Bernardo Ochoa-Montaño a, 1, Tom L. Blundell a, David B. Ascher a, d Progress in Biophysics and Molecular Biology Volume 128, Pages 3-13 DOI: https://doi.org/10.1016/j.pbiomolbio.2016.10.002

Complex functionally specified informational complexity. Dionisio

[...] the follicular epithelium represents a beautiful example of how the combination of diverse signalling pathways creates cell diversity by using morphogen gradients. These gradients initiate spatially restricted gene expression domains that become stabilized by negative cross-regulation of their downstream targets. Finding out how the temporal- and spatial-specific information provided by these signalling pathways converge on their downstream targets and particularly how their activating and repressing inputs are integrated on the target gene enhancers is a fundamental area of research [...]

Cell Signalling: Combining Pathways for Diversification and Reproducibility James Castelli-Gair Hombría, Acaimo González-Reyes Current Biology Volume 26, Issue 21, pR1153–R1155 DOI: http://dx.doi.org/10.1016/j.cub.2016.08.070

Complex functionally specified informational complexity. Dionisio

[...] posterior follicle cells with an activated STAT pathway signal back to the oocyte, reorganizing its £cytoskeleton [...]. The nature of this signal from the posterior follicle cells to the oocyte is unknown [...]

Cell Signalling: Combining Pathways for Diversification and Reproducibility James Castelli-Gair Hombría, Acaimo González-Reyes Current Biology Volume 26, Issue 21, pR1153–R1155 DOI: http://dx.doi.org/10.1016/j.cub.2016.08.070

Complex functionally specified informational complexity. Dionisio

Intriguingly, the EGFR pathway is responsible for setting both the A–P and D–V axes. [...] it is the combination of the EGFR pathway with either the JAK/STAT or the BMP pathways that ultimately determines different follicle cell fates.

Cell Signalling: Combining Pathways for Diversification and Reproducibility James Castelli-Gair Hombría, Acaimo González-Reyes Current Biology Volume 26, Issue 21, pR1153–R1155 DOI: http://dx.doi.org/10.1016/j.cub.2016.08.070

Complex functionally specified informational complexity. Dionisio

How a given signalling pathway can generate diverse outcomes is an open question. A new study shows that EGFR signalling in combination with JAK/STAT or BMP pathways induces different cell fates. Antagonistic interactions between downstream targets further stabilizes epithelial patterning.

Cell Signalling: Combining Pathways for Diversification and Reproducibility James Castelli-Gair Hombría, Acaimo González-Reyes Current Biology Volume 26, Issue 21, pR1153–R1155 DOI: http://dx.doi.org/10.1016/j.cub.2016.08.070

Complex functionally specified informational complexity. Dionisio

What coordinates the internal leading and trailing edges in collectively migrating cells is largely unknown.

Fat2 and Lar Dance a Pas de Deux during Collective Cell Migration Qiyan Mao 1, Jules Lavalou 1, Thomas Lecuit Developmental Cell Volume 40, Issue 5, Pages 425-426 DOI: https://doi.org/10.1016/j.devcel.2017.02.025

Complex functionally specified informational complexity. Dionisio

Collective migration of epithelial cells underlies diverse tissue-remodeling events, but the mechanisms that coordinate individual cell migratory behaviors for collective movement are largely unknown. [...] the cadherin Fat2 and the receptor tyrosine phosphatase Lar function in a planar signaling system that coordinates leading and trailing edge dynamics between neighboring cells. Fat2 signals from each cell's trailing edge to induce leading edge protrusions in the cell behind, in part by stabilizing Lar's localization in these cells. Conversely, Lar signals from each cell's leading edge to stimulate trailing edge retraction in the cell ahead. Fat2/Lar signaling is similar to planar cell polarity signaling in terms of sub-cellular protein localization; however, Fat2/Lar signaling mediates short-range communication between neighboring cells instead of transmitting long-range information across a tissue. This work defines a key mechanism promoting epithelial migration and establishes a different paradigm for planar cell-cell signaling.

Fat2 and Lar Define a Basally Localized Planar Signaling System Controlling Collective Cell Migration Kari Barlan 1, Maureen Cetera 2, 3, Sally Horne-Badovinac Developmental Cell Volume 40, Issue 5, Pages 467-477.e5 DOI:0https://doi.org/10.1016/j.devcel.2017.02.003

Did somebody say 'coordinate'? Complex functionally specified informational complexity. Dionisio

Basement membranes (BMs) are specialized types of extracellular matrix (ECM) that coat the basal side of epithelial and endothelial tissues, surround muscles and fat cells, and play an active role in tissue and organ morphogenesis [...] [...] the specific functions of the different BM components during morphogenesis remain uncertain. [...] our knowledge of the molecular details behind the initiation of collective cell migration is scarce. [...] the finding that collective migration is regulated by linked cellular and environmental properties broadens our understanding of the cellular basis of development and disease.

Laminin Levels Regulate Tissue Migration and Anterior-Posterior Polarity during Egg Morphogenesis in Drosophila María C. Díaz de la Loza 1, 4, Alfonsa Díaz-Torres 1, Federico Zurita 2, Alicia E. Rosales-Nieves 1, Emad Moeendarbary 3, 5, Kristian Franze 3, María D. Martín-Bermudo 1, Acaimo González-Reyes Cell Reports Volume 20, Issue 1, Pages 211-223 DOI: https://doi.org/10.1016/j.celrep.2017.06.031

Complex functionally specified informational complexity. Dionisio

Epithelial structures are foundational for tissue organization in all metazoans. Sheets of epithelial cells form lateral adhesive junctions and acquire apico-basal polarity perpendicular to the surface of the sheet. Epithelial follicle cells progress through tightly choreographed phases of proliferation, patterning, reorganization and migrations, before they differentiate to form the elaborate structures of the eggshell. Distinct structural domains are organized by differential adhesion, within which lateral junctions are remodeled to further shape the organized epithelia. During collective cell migrations, adhesive interactions mediate supracellular organization of planar polarized macromolecules, and facilitate crawling over the basement membrane or traction against adjacent cell surfaces. Technological advances will keep this tissue at the leading edge for interrogating the precise spatiotemporal regulation of normal epithelial reorganization events [...]

The repertoire of epithelial morphogenesis on display: Progressive elaboration of Drosophila egg structure Juan Carlos Duhart, Travis T. Parsons, Laurel A. Rafters Mechanisms of Development DOI: https://doi.org/10.1016/j.mod.2017.04.002

Did somebody say 'tightly choreographed'? Did somebody say 'elaborate structures'? Did somebody say 'precise spatiotemporal regulation'? Complex functionally specified informational complexity. Dionisio

Understanding the mechanisms driving tissue and organ formation requires knowledge across scales. How do signaling pathways specify distinct tissue types? How does the patterning system control morphogenesis? [...] The Drosophila egg chamber, where EGF and BMP signaling intersect to specify unique cell types that construct epithelial tubes for specialized eggshell structures, has provided a tractable system to ask these questions. Work there has elucidated connections between scales of development [...]

Epithelial Patterning, Morphogenesis, and Evolution: Drosophila Eggshell as a Model Author links open overlay panel Miriam Osterfield 1, Celeste A. Berg 2, Stanislav Y. Shvartsman 3 Developmental Cell Volume 41, Issue 4, Pages 337-348 DOI: https://doi.org/10.1016/j.devcel.2017.02.018

Complex functionally specified informational complexity. Dionisio

How confident could we be on the validity of the rationale for the origins of the metabolic maze? The path from simple to complex is not to be considered ‘the’ paradigm of evolution, but it is appealing in view of having been reached here as a result, not having been taken as a premise or assumption. [...] In this possibly highly conflictive area, we remain.

Self-Referential Encoding on Modules of Anticodon Pairs—Roots of the Biological Flow System Romeu Cardoso Guimarães Life (Basel). 2017 Jun; 7(2): 16. doi: 10.3390/life7020016

parole, parole, parole... Where's the beef? :) Complex functionally specified informational complexity. Dionisio

We are not committed with the RNA World proposition and cannot offer a justified alternative. Some of the commonly accepted pre-biotic supports and guides for oligomerization reactions, e.g., from mineral surfaces such as clays [125], would be non-specific enough to accept diverse kinds of monomers. Any choice among the possibilities would have to rely upon robust experimentation.

Self-Referential Encoding on Modules of Anticodon Pairs—Roots of the Biological Flow System Romeu Cardoso Guimarães Life (Basel). 2017 Jun; 7(2): 16. doi: 10.3390/life7020016

parole, parole, parole... Where's the beef? :) Complex functionally specified informational complexity. Dionisio

In view of the difficulties in taking sides with respect to the RNA World proposition and together with the possibility of the lack of hydropathy correlation with the dinucleotides being derived only from the poorness of the encoded amino acid set—just two, probably amidst other amino acids or other compounds polymerized together with them due to catalytic non-specificity—we prefer to say of an unknown constitution of the carriers.

Self-Referential Encoding on Modules of Anticodon Pairs—Roots of the Biological Flow System Romeu Cardoso Guimarães Life (Basel). 2017 Jun; 7(2): 16. doi: 10.3390/life7020016

parole, parole, parole... Where's the beef? :) Complex functionally specified informational complexity. Dionisio

In face of the persisting doubts on the feasibility of a pure RNA world—in spite of the beauty in the RNA technology, our studies are plainly consistent with an early RNP world, late DNP. The nucleic acid and the protein component structures would have coevolved.

Self-Referential Encoding on Modules of Anticodon Pairs—Roots of the Biological Flow System Romeu Cardoso Guimarães Life (Basel). 2017 Jun; 7(2): 16. doi: 10.3390/life7020016

parole, parole, parole... Where's the beef? :) Complex functionally specified informational complexity. Dionisio

I think there are two basic flaws of the paper. The first is more philosophic, the second more phylogenetic (incl. EVO-DEVO). [Zoltán Varga] The survey of causality is incomplete! [Zoltán Varga] These are insufficiently disentangled in the paper. [Zoltán Varga] [...] both the whole body and the infra-individual level structures act as biological entities reacting to the forces of their environment. Furthermore, both are built on the basis of genetic programs, which follow a linear order of activation. [author's response]

Demystification of animal symmetry: symmetry is a response to mechanical forces Gábor Holló Biol Direct. 2017; 12: 11. doi: 10.1186/s13062-017-0182-5

Did somebody say 'programs'? This paper seems to beg the question “where’s the beef?” It seems to draw pseudoscientific conclusions prematurely. Work in progress... stay tuned. They ain’t seen nothin’ yet. The most revealing discoveries are still ahead. Complex functionally specified informational complexity. Dionisio

[...] there is very little concrete, let alone quantitative, argument here as how, specifically, physical factors produce symmetry. [Eugene Koonin] Regrettably, I do not have the impression that direct and [in]direct causes, and biological and physical factors are disentangled here in a satisfactory manner. [Eugene Koonin] [...] the paper lacks specific descriptions as to the precise extent physical factors determine symmetrical patterns in the animal body. However, please let me first underline that this hypothesis paper tries to give a general framework for thinking about symmetry, and not to offer exact explanations for individual cases for the specific animal taxa. [author's response] I am open to conducting further investigations; in this case, please, give more specific details on how to proceed. [author's response]

Demystification of animal symmetry: symmetry is a response to mechanical forces Gábor Holló Biol Direct. 2017; 12: 11. doi: 10.1186/s13062-017-0182-5

This paper seems to beg the question “where’s the beef?” It seems to draw pseudoscientific conclusions prematurely. Work in progress... stay tuned. They ain’t seen nothin’ yet. The most revealing discoveries are still ahead. Complex functionally specified informational complexity. Dionisio

The exact mechanisms by which internal bilateral symmetry builds have been in part elucidated, although several aspects remain unclear. [...] the whole process of the formation of the symmetry plane, probably also including the factors which direct the interaction of the molecules mentioned, remains elusive. How the cells exactly sense the midline and how they stop there, however, remains a mystery [...] [...] a cellular community effect stemming from external physical forces may also play an important role in the process. [...] the answer to the bigger question of what the indirect causes of the two main symmetries are, is still missing. Bilateral symmetry is a major enigma in biology. Other potential ultimate factors which favour bilaterality remain to be discovered. Hopefully, our picture of animal symmetry will be further clarified when we will eventually be able to identify the ultimate causes behind the very origin of either radial or bilateral symmetry, long-sought answers to fundamental problems in evolutionary biology.

Demystification of animal symmetry: symmetry is a response to mechanical forces Gábor Holló Biol Direct. 2017; 12: 11. doi: 10.1186/s13062-017-0182-5

This paper seems to beg the question “where’s the beef?” It seems to draw pseudoscientific conclusions prematurely. Work in progress... stay tuned. They ain’t seen nothin’ yet. The most revealing discoveries are still ahead. Complex functionally specified informational complexity. Dionisio

Symmetry is an eye-catching feature of animal body plans, yet its causes are not well enough understood. Symmetry is a frequent pattern in nature, often perceived as a source of beauty, and is also a salient property of animal body plans. The concept of the body plan can be defined as an ontogenetic pattern-organising algorithm, thanks to which the body develops in a specific order.

Demystification of animal symmetry: symmetry is a response to mechanical forces Gábor Holló Biol Direct. 2017; 12: 11. doi: 10.1186/s13062-017-0182-5

This paper seems to beg the question “where’s the beef?” It seems to draw pseudoscientific conclusions prematurely. They ain’t seen nothin’ yet. The most revealing discoveries are still ahead. Complex functionally specified informational complexity. Dionisio

[...] the conceptions that view morphogenetic phenomena as processes directed strictly by genes and morphogenes alone must be abandoned, and substituted by a view which also includes the role of mechanical forces.

Demystification of animal symmetry: symmetry is a response to mechanical forces Gábor Holló Biol Direct. 2017; 12: 11. doi: 10.1186/s13062-017-0182-5

Abandon previous conceptions? What guarantees that the newly proposed conception won't have to be abandoned too? This paper seems to beg the question "where's the beef?" It seems to draw pseudoscientific conclusions prematurely. They ain't seen nothin' yet. The most revealing discoveries are still ahead. Complex functionally specified informational complexity. Dionisio

[...] the probability of membrane fusion increases when external tension is applied to one of the participating membranes. It is clear that mechanical tension plays a pivotal role in vesicle trafficking and it will be interesting to see in the future how cells regulate tension to adjust the energy landscape of these processes in order to control their kinetics. [...] at intermediate tension, SNARE-mediated fusion efficiency is indeed increased substantially, which we attribute to facilitation of lipid splaying and assisted fusion pore expansion. [...] membrane tension steers membrane fusion and might therefore be an essential prerequisite for fast fusion as observed for the release of neurotransmitters at the neuronal synapse. [...] local tension needs to be substantial, even close to bilayer lysis to increase fusion efficiency with unstressed vesicles.

Membrane tension increases fusion efficiency of model membranes in the presence of SNAREs Torben-Tobias Kliesch,1 Jörn Dietz,1 Laura Turco,2 Partho Halder,3 Elena Polo,1 Marco Tarantola,2 Reinhard Jahn,3 and Andreas Janshoffcorresponding author1 Sci Rep. 2017; 7: 12070. doi: 10.1038/s41598-017-12348-w

Complex functionally specified informational complexity. Dionisio

The large gap in time scales between membrane fusion occurring in biological systems during neurotransmitter release and fusion observed between model membranes has provoked speculations over a large number of possible factors that might explain this discrepancy. One possible reason is an elevated lateral membrane tension present in the presynaptic membrane. Fusion of small membranous organelles inside a cell and fusion of vesicles with the plasma membrane are the key steps in the secretory pathway for the transport of lipids, proteins and signalling molecules in eukaryotic cells.

Membrane tension increases fusion efficiency of model membranes in the presence of SNAREs Torben-Tobias Kliesch,1 Jörn Dietz,1 Laura Turco,2 Partho Halder,3 Elena Polo,1 Marco Tarantola,2 Reinhard Jahn,3 and Andreas Janshoffcorresponding author1 Sci Rep. 2017; 7: 12070. doi: 10.1038/s41598-017-12348-w

Complex functionally specified informational complexity. Dionisio

Surprisingly, scission of the intercellular bridge after the first mitotic division in C. elegans does not appear to exhibit an absolute requirement for the ESCRT machinery, arguing instead for the existence of a parallel, potentially actin-dependent pathway that supports this process. How membrane removal orchestrated by the ESCRT 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. König J1, Frankel EB2, Audhya A3, Müller-Reichert T4. J Cell Biol. 2017 May 1;216(5):1277-1286. doi: 10.1083/jcb.201607030.

Did somebody say 'Surprisingly'? Did somebody say 'orchestrated'? Did somebody say 'timing'? Did somebody say 'machinery'? Work in progress... stay tuned. Complex functionally specified informational 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 [...] Our findings highlight conserved mechanisms that contribute to the abscission process but also demonstrate unique features that distinguish cytokinesis in an embryonic system from that observed in mammalian cells in culture.

Membrane remodeling during embryonic abscission in Caenorhabditis elegans. König J1, Frankel EB2, Audhya A3, Müller-Reichert T4. J Cell Biol. 2017 May 1;216(5):1277-1286. doi: 10.1083/jcb.201607030.

Complex functionally specified informational 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 [...] [...] 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 ESCRT (endosomal sorting complex required for transport) machinery. Surprisingly, in the absence of ESCRT 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. König J1, Frankel EB2, Audhya A3, Müller-Reichert T4. J Cell Biol. 2017 May 1;216(5):1277-1286. doi: 10.1083/jcb.201607030.

Did somebody say 'Surprisingly'? Complex functionally specified informational complexity. Dionisio

@3 addendum

In the future, advanced imaging techniques, novel biosensors and use of conditional mutants should further enhance our understanding of cellular contractile responses to stretch within tubular tissues in vivo. Further studies are also required to better understand the assembly and organization of the contractile machinery within in vivo tubes. Basic questions include how actin bundles are aligned within cells and what determines their dominant orientation, which proteins contribute to the development and maintenance of stress fiber-like structures and how forces might contribute to these processes [...] knowledge of the mechanotransduction pathways involved in regulating tubular contractility might suggest novel therapeutic targets.

Stretch-induced actomyosin contraction in epithelial tubes: Mechanotransduction pathways for tubular homeostasis. Sethi K1, Cram EJ2, Zaidel-Bar R3. Semin Cell Dev Biol. 2017 Nov;71:146-152. doi: 10.1016/j.semcdb.2017.05.014.

Work in progress... stay tuned. Complex functionally specified informational complexity. Dionisio

@3 addendum

Tubular structures, such as blood vessels, exocrine glands, and airway passages, are a common feature of the animal body plan. Though each tubular structure in the body is anatomically distinct, they all experience external forces that influence their structure and function. [...] much less is known about regulation of contractile stress fiber-like structures in epithelial tubes. [...] very few studies have addressed the cellular responses to stretching in vivo. [...] multiple mechanical cues influence cells in vivo [...] [...] multiple biochemical path-ways also regulate contractility [...]

Stretch-induced actomyosin contraction in epithelial tubes: Mechanotransduction pathways for tubular homeostasis. Sethi K1, Cram EJ2, Zaidel-Bar R3. Semin Cell Dev Biol. 2017 Nov;71:146-152. doi: 10.1016/j.semcdb.2017.05.014.

Complex functionally specified informational complexity. Dionisio

The mechanisms of extrusion of epithelial cells are now being unraveled though it remains unclear what the determinants are of an individual epithelial cell being shed. There is now also an increasing understanding that epithelial cell shedding can be a protective mechanism against infection through expulsion of invading pathogens. Further studies are likely to reveal therapeutic targets for inflammatory and infective bowel disease.

Deciphering the Complex Signaling Systems That Regulate Intestinal Epithelial Cell Death Processes and Shedding. Patterson AM1,2, Watson AJM1,2. Front Immunol. 2017 Jul 18;8:841. doi: 10.3389/fimmu.2017.00841.

Work in progress… stay tuned. Complex functionally specified informational complexity. Dionisio

Intestinal epithelial cells play a fundamental role in maintaining homeostasis. Shedding of intestinal cells in a controlled manner is critical to maintenance of barrier function. Barrier function is maintained during this shedding process by a redistribution of tight junctional proteins to facilitate closure of the gap left by the shedding cell. However, despite the obvious importance of epithelial cell shedding to gut health, a central question is how the extrusion of epithelial cells is achieved, enabling barrier integrity to be maintained in the healthy gut and restored during inflammation remains largely unanswered.

Deciphering the Complex Signaling Systems That Regulate Intestinal Epithelial Cell Death Processes and Shedding. Patterson AM1,2, Watson AJM1,2. Front Immunol. 2017 Jul 18;8:841. doi: 10.3389/fimmu.2017.00841.

Complex functionally specified informational complexity. Dionisio

[...] the subsequent construction of individual neuronal circuits relies on the concerted action of many different signaling pathways [...] [...] presence of other effectors of the Nodal pathway that contribute to L/R nerve asymmetries independently of MMP processing [...] [...] co-expression of several MMPs acting with partial redundancies with each other [...] [...] MMPs have many different substrates with potentially opposite effects on the same biological process. The MMP substrates that are responsible for asymmetric phrenic nerve patterning remain to be determined [...] [...] the in vivo assessment of these hypotheses will be challenging.

Genetic specification of left-right asymmetry in the diaphragm muscles and their motor innervation. Charoy C1, Dinvaut S1, Chaix Y1, Morlé L1, Sanyas I1, Bozon M1, Kindbeiter K1, Durand B1, Skidmore JM2,3, De Groef L4, Seki M5, Moons L4, Ruhrberg C6, Martin JF7, Martin DM2,3,8, Falk J1, Castellani V1. Elife. 2017 Jun 22;6. pii: e18481. doi: 10.7554/eLife.18481

Work in progress… stay tuned. Complex functionally specified informational complexity. Dionisio

Future work should aim to address how and at which stage phrenic motoneurons are imprinted. The resulting L/R imprints could occur early on during neurogenesis or later on during motoneuron differentiation. [...] a L/R imprint confers specific axon behaviors to the left and right phrenic motoneurons. Further investigations are thus needed to assess with more specific tools Robo protein dynamics and distribution along phrenic axons and in the growth cones. This work will provide a better characterization of the functional outcome determined by the balance of short and long Robo forms in the establishment of phrenic nerve patterns.

Genetic specification of left-right asymmetry in the diaphragm muscles and their motor innervation. Charoy C1, Dinvaut S1, Chaix Y1, Morlé L1, Sanyas I1, Bozon M1, Kindbeiter K1, Durand B1, Skidmore JM2,3, De Groef L4, Seki M5, Moons L4, Ruhrberg C6, Martin JF7, Martin DM2,3,8, Falk J1, Castellani V1. Elife. 2017 Jun 22;6. pii: e18481. doi: 10.7554/eLife.18481

Work in progress... stay tuned. Complex functionally specified informational complexity. Dionisio

The diaphragm is the main respiratory muscle of mammalian organisms, separating the thoracic and abdominal cavities. [...] a genetic program that establishes other differences between the left and right sides of the embryo also gives rise to the differences between the left and right sides of the diaphragm. This program switches on different genes in the left and right phrenic nerves, which activate different molecular pathways in the left and right sides of the diaphragm muscle. [...] the first asymmetry instruction in diaphragm patterning is provided by early Nodal signaling, which sets the L/R axis and visceral asymmetry of the embryo. Beyond this early mechanism, phrenic motoneurons have an intrinsic, genetically encoded L/R asymmetry that manifests itself in the differential activation of molecules that have key roles in axon guidance, including Robo1 and MMP2.

Genetic specification of left-right asymmetry in the diaphragm muscles and their motor innervation. Charoy C1, Dinvaut S1, Chaix Y1, Morlé L1, Sanyas I1, Bozon M1, Kindbeiter K1, Durand B1, Skidmore JM2,3, De Groef L4, Seki M5, Moons L4, Ruhrberg C6, Martin JF7, Martin DM2,3,8, Falk J1, Castellani V1. Elife. 2017 Jun 22;6. pii: e18481. doi: 10.7554/eLife.18481

Did somebody say 'program'? Did somebody say 'instruction'? Complex functionally specified informational complexity. Dionisio

The diaphragm is a dome-shaped muscle that forms the floor of the rib cage, separating the lungs from the abdomen. As we breathe in, the diaphragm contracts. This causes the chest cavity to expand, drawing air into the lungs. A pair of nerves called the phrenic nerves carry signals from the spinal cord to the diaphragm to tell it when to contract. These nerves project from the left and right sides of the spinal cord to the left and right sides of the diaphragm respectively.

Genetic specification of left-right asymmetry in the diaphragm muscles and their motor innervation. Charoy C1, Dinvaut S1, Chaix Y1, Morlé L1, Sanyas I1, Bozon M1, Kindbeiter K1, Durand B1, Skidmore JM2,3, De Groef L4, Seki M5, Moons L4, Ruhrberg C6, Martin JF7, Martin DM2,3,8, Falk J1, Castellani V1. Elife. 2017 Jun 22;6. pii: e18481. doi: 10.7554/eLife.18481

Complex functionally specified informational complexity. Dionisio

The diaphragm muscle is essential for breathing in mammals. Its asymmetric elevation during contraction correlates with morphological features suggestive of inherent left-right (L/R) asymmetry. Whether this asymmetry is due to L versus R differences in the muscle or in the phrenic nerve activity is unknown. [...] both the diaphragm muscle and phrenic nerves have asymmetries, which can be established independently of each other during early embryogenesis in pathway instructed by Nodal, a morphogen that also conveys asymmetry in other organs. [...] phrenic motoneurons receive an early L/R genetic imprint, with L versus R differences both in Slit/Robo signaling and MMP2 activity and in the contribution of both pathways to establish phrenic nerve asymmetry. Our study therefore demonstrates L-R imprinting of spinal motoneurons and describes how L/R modulation of axon guidance signaling helps to match neural circuit formation to organ asymmetry.

Genetic specification of left-right asymmetry in the diaphragm muscles and their motor innervation. Charoy C1, Dinvaut S1, Chaix Y1, Morlé L1, Sanyas I1, Bozon M1, Kindbeiter K1, Durand B1, Skidmore JM2,3, De Groef L4, Seki M5, Moons L4, Ruhrberg C6, Martin JF7, Martin DM2,3,8, Falk J1, Castellani V1. Elife. 2017 Jun 22;6. pii: e18481. doi: 10.7554/eLife.18481

Complex functionally specified informational complexity. Dionisio

Slits are secreted proteins that bind to Roundabout (Robo) receptors. Slit-Robo signaling is best known for mediating axon repulsion in the developing nervous system. However, in recent years the functional repertoire of Slits and Robo has expanded tremendously and Slit-Robo signaling has been linked to roles in neurogenesis, angiogenesis and cancer progression among other processes. Likewise, our mechanistic understanding of Slit-Robo signaling has progressed enormously.

The role of Slit-Robo signaling in the regulation of tissue barriers. Wu MF1,2, Liao CY3, Wang LY3, Chang JT Development. 2016 Sep 1;143(17):3037-44. doi: 10.1242/dev.132829

Complex functionally specified informational complexity. Dionisio

Mechanical, Electronic and Control Systems Engineering Design on exceedingly large doses of steroids? We ain't seen nothin' yet. The most fascinating discoveries are still ahead. Dionisio

Epithelial tissues are defined by polarized epithelial cells that are integrated into tissues and exhibit barrier function in order to regulate what is allowed to pass between cells. Cell-cell junctions must be stable enough to promote barrier function and tissue integrity, yet plastic enough to remodel when necessary. This remarkable ability to dynamically sense and respond to changes in cell shape and tissue tension allows cell-cell junctions to remain functional during events that disrupt epithelial homeostasis including morphogenesis, wound healing, and cell division. In order to achieve this plasticity, both tight junctions and adherens junctions are coupled to the underlying actomyosin cytoskeleton. Together, Rho GTPases, their regulators, and effectors form compartmentalized signaling modules that regulate actomyosin structure and contractility to achieve proper cell-cell adhesion and tissue barriers.

Rho GTPases and actomyosin: Partners in regulating epithelial cell-cell junction structure and function. Arnold TR1, Stephenson RE1, Miller AL2. Exp Cell Res. 2017 Sep 1;358(1):20-30. doi: 10.1016/j.yexcr.2017.03.053

Complex functionally specified informational complexity. Dionisio

[...] it is tempting to speculate that asymmetric distributions of mechanical tension might guide both actin and septin filament systems to self-assemble into polarized networks during cytokinesis. Mechanical forces have has been suggested to shape other actin-based structures [...] [...] the actomyosin ring of vertebrate cells responds to intrinsically generated forces. [...] it will be interesting to further investigate the intricate relationship between contractile forces and actin network organization.

Cytokinesis in vertebrate cells initiates by contraction of an equatorial actomyosin network composed of randomly oriented filaments. Spira F1, Cuylen-Haering S1, Mehta S2, Samwer M1, Reversat A3, Verma A2, Oldenbourg R2, Sixt M3, Gerlich DW1. Elife. 2017 Nov 6;6. pii: e30867. doi: 10.7554/eLife.30867.

Complex functionally specified informational complexity. Dionisio

Animal cells divide by contracting the cell cortex in an equatorial zone between the two poles of the mitotic spindle, resulting in the ingression of a cleavage furrow. This is initiated by activation of the small GTPase RhoA at the equatorial cell cortex, which induces polymerization of unbranched actin filaments and activation of non-muscle myosin II [...]

Cytokinesis in vertebrate cells initiates by contraction of an equatorial actomyosin network composed of randomly oriented filaments. Spira F1, Cuylen-Haering S1, Mehta S2, Samwer M1, Reversat A3, Verma A2, Oldenbourg R2, Sixt M3, Gerlich DW1. Elife. 2017 Nov 6;6. pii: e30867. doi: 10.7554/eLife.30867.

Complex functionally specified informational complexity. Dionisio

The actomyosin ring generates force to ingress the cytokinetic cleavage furrow in animal cells, yet its filament organization and the mechanism of contractility is not well understood. [...] cleavage furrow ingression initiates by contraction of an equatorial actin network with randomly oriented filaments. The network subsequently gradually reoriented actin filaments along the cell equator. This strictly depended on myosin II activity, suggesting local network reorganization by mechanical forces. Cortical laser microsurgery revealed that during cytokinesis progression, mechanical tension increased substantially along the direction of the cell equator, while the network contracted laterally along the pole-to-pole axis without a detectable increase in tension. [...] an asymmetric increase in cortical tension promotes filament reorientation along the cytokinetic cleavage furrow, which might have implications for diverse other biological processes involving actomyosin rings.

Cytokinesis in vertebrate cells initiates by contraction of an equatorial actomyosin network composed of randomly oriented filaments. Spira F1, Cuylen-Haering S1, Mehta S2, Samwer M1, Reversat A3, Verma A2, Oldenbourg R2, Sixt M3, Gerlich DW1. Elife. 2017 Nov 6;6. pii: e30867. doi: 10.7554/eLife.30867.

Complex functionally specified informational complexity. Dionisio

Many tissues in our body have a tubular shape and are constantly exposed to various stresses. Luminal pressure imposes tension on the epithelial and myoepithelial or smooth muscle cells surrounding the lumen of the tubes. Contractile forces generated by actomyosin assemblies within these cells oppose the luminal pressure and must be calibrated to maintain tube diameter homeostasis and tissue integrity. In this review, we discuss mechanotransduction pathways that can lead from sensation of cell stretch to activation of actomyosin contractility, providing rapid mechanochemical feedback for proper tubular tissue function.

Stretch-induced actomyosin contraction in epithelial tubes: Mechanotransduction pathways for tubular homeostasis. Sethi K1, Cram EJ2, Zaidel-Bar R3. Semin Cell Dev Biol. 2017 Nov;71:146-152. doi: 10.1016/j.semcdb.2017.05.014.

Complex functionally specified informational complexity. Dionisio

Interesting topic. Thanks. Dionisio

The nervous system uses a LOT of mechanical engineering. An example I encountered today while building courseware: The outer hair cells in the cochlea serve partly as sensors, mainly as an adaptive automatic gain control to insure that our attention stays focused on new and important info. Some of the AGC is in software and some is purely mechanical. Here's a purely mechanical mechanism: Each hair cell handles one frequency. Each has a long cilium that is yanked back and forth by the acoustic wave in the tectorial membrane. The long cilium pulls its shorter partners with a rope-like link. As the wave at this frequency continues, the rope reels out of a little ratchet in the long cilium, so that the overall impulse from all the cilia grows weaker. When the wave stops, the ratchet winches the rope back to its original tension. image polistra