Mutant huntingtin actively crosses neuromuscular synapses and causes transmission-selective pathology in human myotubes A potential explanation for the spatiotemporal accumulation of pathological lesions in the brain of patients with neurodegenerative protein misfolding diseases (PMDs) is cell-to-cell transmission of aggregation-prone, misfolded proteins. Little is known about central to peripheral transmission and its contribution to pathology. We show that transmission of Huntingtons disease- (HD-) associated mutant HTT exon 1 (mHTTEx1) occurs across the neuromuscular junctions in human iPSC cultures and in vivo in wild-type mice. We found that transmission is an active and dynamic process, that happens prior to aggregate formation and is regulated by synaptic activity. Furthermore, we find that transmitted mHTTEx1 causes HD-relevant pathology at a molecular and functional level in human muscle cells, even in the presence of ubiquitous expression mHTTEx1. With this work we uncover a casual-link between mHTTEx1 synaptic transmission and pathology, highlighting the therapeutic potential in blocking toxic protein transmission in PMDs.
Distinct Synaptic Transfer Functions in Same-Type Photoreceptors Many sensory systems use ribbon-type synapses to transmit their signals to downstream circuits. The properties of this synaptic transfer fundamentally dictate which aspects in the original stimulus will be accentuated or suppressed, thereby partially defining the detection limits of the circuit. Accordingly, sensory neurons have evolved a wide variety of ribbon geometries and vesicle pool properties to best support their diverse functional requirements. However, the need for diverse synaptic functions does not only arise across neuron types, but also within. Here we show that UV-cones, a single type of photoreceptor of the larval zebrafish eye, exhibit striking differences in their synaptic ultrastructure and consequent calcium to glutamate transfer function depending on their location in the eye. We arrive at this conclusion by combining serial section electron microscopy and simultaneous "dual-colour" 2-photon imaging of calcium and glutamate signals from the same synapse in vivo. We further use the functional dataset to fit a cascade-like model of the ribbon synapse with different vesicle pool sizes, transfer rates and other synaptic properties. Exploiting recent developments in simulation-based inference, we obtain full posterior estimates for the parameters and compare these across different retinal regions. The model enables us to extrapolate to new stimuli and to systematically investigate different response behaviours of various ribbon configurations. We also provide an interactive, easy-to-use version of this model as an online tool. Overall, we show that already on the synaptic level of single neuron types there exist highly specialized mechanisms which are advantageous for the encoding of different visual features.
Phylogenetic analyses for orthogroup-based classification of GDSL-type esterase/lipase (GELP) family in angiosperm representative species GDSL-type esterase/lipase (GELP) enzymes have multiple functions in plants, spanning from developmental processes to the response to biotic and abiotic stresses. Genes encoding GELP belong to a large gene family with several tens to more than hundred members per angiosperm species.

Here, we applied iterative phylogenetic analyses to identify 10 main clusters subdivided into 44 expert-curated reference orthogroups (OGs) using three monocot and five dicot genomes. Our results show that some GELP OGs expanded while others were maintained as single copy genes.

This semi-automatic approach proves to be effective to characterize large gene families and provides a solid classification framework for the GELP members in angiosperms. The orthogroup-based reference will be useful to perform comparative studies, infer gene functions and better understand the evolutionary history of this gene family. The initial response of females towards congeneric males matches the propensity to hybridise in Ophthalmotilapia. AO_SCPLOWBSTRACTC_SCPLOWCichlid radiations often harbour closely related species with overlapping niches and distribution ranges. Such species sometimes hybridise in nature, which raises the question how can they coexist. This also holds for the Tanganyika mouthbrooders Ophthalmotilapia ventralis and O. nasuta. Earlier studies found indications of asymmetrical hybridisation with females of O. ventralis accepting males of O. nasuta, but not the other way around. We hypothesised that this was due to differences in the capacity for species recognition. Given the higher propensity of O. ventralis females towards hybridisation, we expect a reduced ability for species recognition in O. ventralis females, compared to O. nasuta females. We staged two experiments, one focusing on 22 female O. nasuta and one on 21 female O. ventralis. These fish were placed in one half of a tank and briefly exposed to a conspecific or a heterospecific male, a conspecific female, or nothing (control). Female response was evaluated by scoring six tracking parameters and by noting the occurrence of ten discrete behaviours before and during the encounter. Females always responded to the presence of another fish by approaching it. Remarkably, for both O. nasuta and O. ventralis, we did not find a different response between encounters with conspecific males and females. However, in agreement with our hypothesis, O. nasuta females behaved differently towards conspecific or heterospecific males, whereas O. ventralis females did not. When presented with a heterospecific male, O. nasuta females performed a lower number of  ram behaviours. Additionally, they never displayed the  flee behaviour, a component of the species mating repertoire that was seen in all but one of the presentations with a conspecific male. Our findings show that differences in species recognition at first encounter predict to a large degree the outcome of the mating process, even in the absence of mating behaviour. Mitochondrial F1FO ATP synthase determines the local proton motive force in cristae tips The classical view of oxidative phosphorylation is that a proton motive force PMF generated by the respiratory chain complexes fuels ATP synthesis. Under glycolytic conditions, ATP synthase in its reverse mode also can contribute to the PMF. Here, we dissected the two functions of ATP synthase and the role of its inhibitory factor 1 (IF1) under different metabolic conditions in detail. pH profiles of mitochondrial sub-compartments were recorded with high spatial resolution in live mammalian cells by positioning a pH-sensor directly at F1 and FO of ATP synthase, complex IV and in the matrix. Our results clearly show that ATP synthase activity is substantially controlling the PMF and that IF1 is essential under OXPHOS conditions to prevent reverse ATP synthase activity due to an almost negligible {Delta}pH.

GRAPHICAL ABSTRACT

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=183 SRC="FIGDIR/small/430746v2_ufig1.gif" ALT="Figure 1">
View larger version (50K):
org.highwire.dtl.DTLVardef@1a975eforg.highwire.dtl.DTLVardef@7ddb49org.highwire.dtl.DTLVardef@c7a128org.highwire.dtl.DTLVardef@2559e8_HPS_FORMAT_FIGEXP  M_FIG C_FIG HIGHLIGHTSO_LIThe {Delta}pH along and across the inner mitochondrial membrane is not homogeneous
C_LIO_LIThe proton motive force at cristae tips is controlled by F1 FO ATP synthase
C_LIO_LIUnder OXPHOS conditions, the pH difference between FO and F1 of active ATP synthase is almost negligible (1.2 proton vs. 1 proton equivalent)
C_LIO_LIIF1 is required to prevent the onset of ATP hydrolysis under OXPHOS conditions
C_LI In vitro evolution of uracil glycosylase towards DnaKJ and GroEL binding evolves different misfolded states Natural evolution is driven by random mutations that improve fitness. In vitro evolution mimics this process, however, on a short time-scale and is driven by the given bait. Here, we used directed in vitro evolution of a random library of Uracil glycosylase (eUNG) displayed on yeast surface to select for binding to chaperones GroEL, DnaK+DnaJ+ATP (DnaKJ) or E.coli cell extract (CE). Using binding to the eUNG inhibitor Ugi as probe for native foldedess, the CE selected population was further divided to Ugi binders (+U) (native) or non-binders (-U). We found that GroEL, DnaKJ and CE-U select and enrich for mutations causing eUNG to misfold, with the three being enriched in mutations in buried and conserved positions, with a tendency to increase positive charge. Still, each selection, as well as CE+U and natural evolution of eUNG has its own trajectory. While GroEL and CE-U selected for mutants highly sensitive to protease cleavage, DnaKJ selected for partially structured misfolded species with a tendency to refold, making them less sensitive to proteases. CE+U selected for more neutral mutations than natural evolution. In a more general context, our results show that GroEL has a higher tendency to purge promiscuous misfolded protein mutants from the system, while DnaKJ binds mutants misfolding-prone species that are, upon chaperone release, more likely to natively refold. CE-U shares some of the properties of GroEL and DnaKJ selected populations, while harboring also unique properties, explained by the existence of additional chaperones in CE, such as Tig, HtpG and ClpB. Temporal and Spatial Dynamics of Hepatic Stellate Cell Activation in Intrahepatic Cholangiocarcinoma Intrahepatic cholangiocarcinoma (iCCA) is an aggressive type of primary liver cancer characterized by its highly desmoplastic stroma. Compared to the ample knowledge on cancer-associated fibroblast residing within iCCA tumor mass, little is known about the fibrotic response from the tumor-surrounding liver and its role in iCCA development. In this study, we find a significant accumulation of peritumoral myofibroblasts (pMFs) in both patient iCCA and tumors from an iCCA orthotopic allograft mouse model. Using tumor and liver spheroid coculture we show that iCCA-liver interaction induces rapid pMF accumulation at the interface. We find pMFs placed around iCCA spheroids exert a strong suppressive effect on tumor cells growth, in contrast to the pro-proliferative effect of MFs mixed within tumor spheroids. However, prolonged iCCA-pMF interaction elicits tumor cell dissemination in vitro. We find an upregulation of Vcam1 in tumor cells in the early phase of iCCA-pMF interaction both in vitro and in vivo which is downregulated when tumor cells disseminate. Blocking Vcam1 activity in iCCA allograft mouse models slows primary tumor growth but lead to increased tumor metastasis. Our data suggest that pMFs are beyond simple pro- or anti-tumorigenic in iCCA, with the ability to suppress tumor growth but elicit tumor cell dissemination. "Adopt a Microorganism" methodology enhances the discourse richness of high school students in both hybrid learning and remote education The Internet has changed the way teachers and students access information and build knowledge. The recent COVID-19 pandemic has created challenges for both teachers and students and a demand for new methodologies of remote learning. In the life sciences, mixing online content with practical activities represents an even greater challenge. In microbiology, the implementation of an active teaching methodology, the #Adopt project, based on the social network Facebook(R), represents an excellent option for connecting remote education with classroom activities. In 2020, the version applied in high school, "Adopt a Microorganism", was adapted to meet the demands of emergency remote education owing to the suppression of face-to-face activities caused by the pandemic. In the present study, we assessed how the change in methodology impacted the discourse richness of students from high school integrated with technical education in the Business Administration program of the Federal Institute of Sao Paulo, Sorocaba Campus. Three questionnaires related to the groups of microorganisms (Archaea, Bacteria, Virus, Fungi, and Protozoan) were applied. The students responses in the 2019 and 2020 classes were compared concerning content richness and multiplicity of concepts through the application of the Shannon diversity index, an approach that is generally used to assess biodiversity in different environments. The observed results suggest that remote learning provided students with a conceptual basis and richness of content equivalent to that achieved by students subjected to the hybrid teaching model. In conclusion, this study suggests that the #Adopt project methodology increases students discourse richness in microbiology even without face-to-face traditional classes. Hidden dynamics of proteasome autoregulation discovered by cryo-EM data-driven deep learning The cellular functions are executed by macromolecular complexes in nonequilibrium dynamic processes, which exhibit a vast diversity of conformational states. Solving conformational continuum of important complexes at atomic level remains a key challenge in the methodology of computational biophysics. Here we introduce a deep-learning framework, named AlphaCryo4D, which enables atomic-level cryogenic electron microscopy reconstructions of nonequilibrium conformational continuum. AlphaCryo4D integrates 3D deep residual learning with manifold embedding of energy landscapes, which simultaneously improves 3D classification accuracy and reconstruction resolution via an energy-based particle-voting algorithm. Applications of this methodology to six experimental datasets demonstrated its generality in breaking resolution barrier of visualizing dynamic components of functional complexes, in choreographing continuous inter-subunit motions and in exploring their  hidden conformational space. Importantly, AlphaCryo4D identified 64 conformers of the substrate-bound human 26S proteasome and reconstituted single-nucleotide-exchange dynamics of proteasomal AAA-ATPase motor during translocation initiation, which together illuminates a grand hierarchical allostery for proteasome autoregulation. E156G and Arg158, Phe-157/del mutation in NTD of spike protein in B.1.617.2 lineage of SARS-CoV-2 leads to immune evasion through antibody escape Emerging variants of SARS-CoV-2 with better immune escape mechanisms and higher transmissibility remains a persistent threat across the globe. B.1.617.2 (Delta) variant was first emerged from Maharashtra, India in December, 2020. This variant is classified to be a major cause and concern of the second wave of COVID-19 in India. In the present study, we explored the genomic and structural basis of this variant through computational analysis, protein modelling and molecular dynamics (MD) simulations approach. B.1.617.2 variant carried E156G and Arg158, Phe-157/del mutations in NTD of spike protein. These mutations in N-terminal domain (NTD) of spike protein of B.1.617.2 variant revealed more rigidity and reduced flexibility compared to spike protein of Wuhan isolate. Further, docking and MD simulation study with 4A8 monoclonal antibody which was reported to bind NTD of spike protein suggested reduced binding of B.1.617.2 spike protein compared to that of spike protein of Wuhan isolate. The results of the present study demonstrate the possible case of immune escape and thereby fitness advantage of the new variant and further warrants demonstration through experimental evidence. Our study identified the probable mechanism through which B.1.617.2 variant is more pathogenically evolved with higher transmissibility as compared to the wild-type.



O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=93 SRC="FIGDIR/small/447321v3_ufig1.gif" ALT="Figure 1">
View larger version (23K):
org.highwire.dtl.DTLVardef@b92cborg.highwire.dtl.DTLVardef@1d261f7org.highwire.dtl.DTLVardef@11da73eorg.highwire.dtl.DTLVardef@1cef6ca_HPS_FORMAT_FIGEXP  M_FIG C_FIG A novel two-generation approach to the population dynamics of gregarious parasitoids Parasitoids, as important natural enemies, help maintain balance in natural ecosystems. Their population dynamics is generally predicted from the number of individuals. Here, using gregarious parasitoids as models, we show that this traditional approach omits one important parameter: the mothers manipulation of offspring fertility due to the clutch size-body size- fertility correlation. As a result of this correlation, when females deliberately adjust the number of offspring laid in a host, they determine not only the number but also the body sizes and reproductive potentials of those offspring. For the first time in the model species Anaphes flavipes, we determined the parasitoids offspring fertility from clutch size. Using this, we experimentally clarified the advantage of specific clutch size combinations and we show that identical fertility in the F1 generation can lead to distinctly different fertility values in the F2 generation. Even with the same number of hosts, lower fertility in the F1 generation can cause higher fertility in the F2 generation. Based on these results, we propose a novel two-generation approach which includes the clutch size-body size-fertility correlation. Our novel approach provides a new perspective for determining the individual fitness levels of gregarious parasitoids with new options for the modelling of parasitoid population dynamics. Fatal COVID-19 and non-COVID-19 Acute Respiratory Distress Syndrome is Associated with Incomplete Alveolar Type 1 Epithelial Cell Differentiation from the Transitional State Without Fibrosis ARDS due to COVID-19 and other etiologies results from injury to the alveolar epithelial cell (AEC) barrier resulting in noncardiogenic pulmonary edema, which causes acute respiratory failure; clinical recovery requires epithelial regeneration. During physiologic regeneration in mice, AEC2s proliferate, exit the cell cycle, and transiently assume a transitional state before differentiating into AEC1s; persistence of the transitional state is associated with pulmonary fibrosis in humans. It is unknown whether transitional cells emerge and differentiate into AEC1s without fibrosis in human ARDS and why transitional cells differentiate into AEC1s during physiologic regeneration but persist in fibrosis. We hypothesized that incomplete but ongoing AEC1 differentiation from transitional cells without fibrosis may underlie persistent barrier permeability and fatal acute respiratory failure in ARDS. Immunostaining of postmortem ARDS lungs revealed abundant transitional cells in organized monolayers on alveolar septa without fibrosis. They were typically cuboidal or partially spread, sometimes flat, and occasionally expressed AEC1 markers. Immunostaining and/or interrogation of scRNAseq datasets revealed that transitional cells in mouse models of physiologic regeneration, ARDS, and fibrosis express markers of cell cycle exit but only in fibrosis express a specific senescence marker. Thus, in severe, fatal early ARDS, AEC1 differentiation from transitional cells is incomplete, underlying persistent barrier permeability and respiratory failure, but ongoing without fibrosis; senescence of transitional cells may be associated with pulmonary fibrosis. A Novel Proposal for an Index for Regional Cerebral Perfusion Pressure - A Theoretical Approach Using Fluid Dynamics Cerebral blood flow (CBF) / cerebral blood volume (CBV) ratio derived by [15O] H2O/ CO2 and CO positron emission tomography (PET) examination has been used empirically as an index for cerebral perfusion pressure (CPP). However, this equation lacks a theoretical basis and furthermore, has not been confirmed to be proportionate to CPP, as direct measurement of local CPP is not practical.

We have developed a new index for CPP using the Poiseuille equation based on a simple model. Our model suggests that CBF/CBV2 is proportionate to CPP and that it is mathematically a more accurate index than CBF/CBV. Cell-specific Bioorthogonal Tagging of Glycoproteins Altered glycosylation is an undisputed corollary of cancer development. Understanding these alterations is paramount but hampered by limitations underlying cellular model systems. For instance, the intricate interactions between tumour and host cannot be adequately recapitulated in monoculture of tumour-derived cell lines. More complex co-culture models usually rely on sorting procedures for proteome analyses and rarely capture the details of protein glycosylation. Here, we report a strategy termed Bio-Orthogonal Cell line-specific Tagging of Glycoproteins (BOCTAG). Cells are equipped by transfection with an artificial biosynthetic pathway that transforms bioorthogonally tagged sugars into the corresponding nucleotide-sugars. Only transfected cells incorporate bioorthogonal tags into glycoproteins in the presence of non-transfected cells. We employ BOCTAG as an imaging technique and to annotate cell-specific glycosylation sites in mass spectrometry-glycoproteomics. We demonstrate application in co-culture and mouse models, allowing for profiling of the glycoproteome as an important modulator of cellular function. Hepatic MIR20B promotes nonalcoholic fatty liver disease by suppressing PPARA BackgroundNon-alcoholic fatty liver disease (NAFLD) is characterized by excessive lipid accumulation and imbalances in lipid metabolism in the liver. Although nuclear receptors (NRs) play a crucial role in hepatic lipid metabolism, the underlying mechanisms of NR regulation in NAFLD remain largely unclear.

MethodsUsing network analysis and RNA-seq to determine the correlation between NRs and microRNA in human NAFLD patients, we revealed that MIR20B specifically targets PPARA. MIR20B mimic and anti-MIR20B were administered to human HepG2 and Huh-7 cells and mouse primary hepatocytes as well as high fat diet (HFD)- or methionine-deficient diet (MCD)-fed mice to verify the specific function of MIR20B in NAFLD. We tested the inhibition of the therapeutic effect of a PPAR agonist, fenofibrate, by MIR20B and the synergic effect of combination of fenofibrate with anti-MIR20B.

ResultsWe revealed that MIR20B specifically targets PPARA through miRNA regulatory network analysis of nuclear receptor genes in NAFLD. The expression of MIR20B was upregulated in free fatty acid (FA)- treated hepatocytes and the livers of both obesity-induced mice and NAFLD patients. Overexpression of MIR20B significantly increased hepatic lipid accumulation and triglyceride levels. Furthermore, MIR20B significantly reduced FA oxidation and mitochondrial biogenesis by targeting PPARA. In MIR20B-introduced mice, the effect of fenofibrate to ameliorate hepatic steatosis was significantly suppressed. Finally, inhibition of MIR20B significantly increased FA oxidation and uptake, resulting in improved insulin sensitivity and a decrease in NAFLD progression. Moreover, combination of fenofibrate and anti-MIR20B exhibited the synergic effect on improvement of NAFLD in MCD-fed mice.

ConclusionsTaken together, our results demonstrate that the novel MIR20B targets PPARA, plays a significant role in hepatic lipid metabolism, and present an opportunity for the development of novel therapeutics for NAFLD.

FundingThis research was funded by Korea Mouse Phenotyping Project (2016M3A9D5A01952411), the National Research Foundation of Korea (NRF) grant funded by the Korea government (2020R1F1A1061267, 2018R1A5A1024340, NRF-2021R1I1A2041463, 2020R1I1A1A01074940), and the Future-leading Project Research Fund (1.210034.01) of UNIST. Frameshift and wild-type proteins are highly similar because the genetic code and genomes were optimized for frameshift tolerance Frameshift protein sequences encoded by alternative reading frames of coding genes have been considered meaningless, and frameshift mutations have been considered of little importance for the molecular evolution of coding genes and proteins. However, functional frameshifts have been found widely existing. It was puzzling how a frameshift protein kept its structure and functionality while its amino-acid sequence was changed substantially. Here we show that frame similarities between frameshifts and wild types are higher than random similarities and are defined at the genetic code, gene, and genome levels. In the standard genetic code, frameshift codon substitutions are more conservative than random substitutions. The frameshift tolerability of the standard genetic code ranks in the top 2.0-3.5% of alternative genetic codes, showing that the genetic code is nearly optimal for frameshift tolerance. Furthermore, frameshift-resistant codons (codon pairs) appear more frequently than expected in many genes and certain genomes, showing that the frameshift optimality is reflected not only in the genetic code but more importantly, in its allowance of further optimizing the frameshift tolerance of a particular gene or genome, which shed light on the role of frameshift mutations in molecular and genomic evolution. Micro topographical instruction of bacterial attachment, biofilm formation and in vivo host response Bio-instructive materials that prevent bacterial biofilm formation and drive an appropriate host immune response have the potential to significantly reduce the burden of medical device-associated infections. As bacterial surface attachment is sensitive to surface topography, we experimentally surveyed 2,176 combinatorially generated shapes using an unbiased high-throughput micro topographical polystyrene polymer chip screen. This identified topographies that reduced colonization in vitro by up to 15-fold compared with a flat surface for both motile and non-motile bacterial pathogens. Equivalent reductions were achieved on polyurethane, a polymer commonly used in medical devices. Using machine learning methods, a set of design rules based on generalisable topo-descriptors was established for predicting bacteria-resistant micro topographies. In a murine foreign body infection model, anti-attachment topographies were shown to be refractory to P. aeruginosa colonization and serendipitously, the fibrotic response to the implant was reduced, offering control of foreign body response using simple topographical patterning of non-eluting implants. Intramolecular 13C signals inform about carbon allocation in plants Stable isotopes at natural abundance are key tools to study physiological processes occurring outside the temporal scope of manipulation and monitoring experiments. Whole-molecule carbon isotope ratios (13C/12C) enable assessments of plant carbon uptake yet conceal information about carbon allocation. Here, we identify an intramolecular 13C/12C signal at treering glucose C-5 and C-6 and develop experimentally testable theories on its origin. More specifically, we assess the potential of processes within C3 metabolism for signal introduction based (inter alia) on constraints on signal propagation posed by metabolic networks. We propose that the intramolecular signal reports carbon allocation into major metabolic pathways in actively photosynthesising leaf cells including the anaplerotic, shikimate, and non-mevalonate pathway. We support our theoretical framework by linking it to previously reported whole-molecule 13C/12C increases in cellulose of ozone-treated Betula pendula and a highly significant relationship between the intramolecular signal and tropospheric ozone concentration. Our theory postulates a pronounced preference of leaf-cytosolic triose-phosphate isomerase to catalyse the forward reaction in vivo (dihydroxyacetone phosphate to glyceraldehyde 3-phosphate). In conclusion, intramolecular 13C/12C analysis resolves information about carbon uptake and allocation enabling more comprehensive assessments of carbon metabolism than whole-molecule 13C/12C analysis.

HighlightIntramolecular 13C/12C analysis resolves information about carbon uptake and allocation (and associated environmental controls) enabling more comprehensive assessments of carbon metabolism, plant-environment interactions, and environmental variability than whole-molecule 13C/12C analysis. Uncovering non-random binary patterns within sequences of intrinsically disordered proteins Sequence-ensemble relationships of intrinsically disordered proteins (IDPs) are governed by binary patterns such as the linear clustering or mixing of specific residues or residue types with respect to one another. To enable the discovery of potentially important, shared patterns across sequence families, we describe a computational method referred to as NARDINI for Non-random Arrangement of Residues in Disordered Regions Inferred using Numerical Intermixing. This work was partially motivated by the observation that parameters that are currently in use for describing different binary patterns are not interoperable across IDPs of different amino acid compositions and lengths. In NARDINI, we generate an ensemble of scrambled sequences to set up a composition-specific null model for the patterning parameters of interest. We then compute a series of pattern-specific z-scores to quantify how each pattern deviates from a null model for the IDP of interest. The z-scores help in identifying putative non-random linear sequence patterns within an IDP. We demonstrate the use of NARDINI derived z-scores by identifying sequence patterns in three well-studied IDP systems. We also demonstrate how NARDINI can be deployed to study archetypal IDPs across homologs and orthologs. Overall, NARDINI is likely to aid in designing novel IDPs with a view toward engineering new sequence-function relationships or uncovering cryptic ones. We further propose that the z-scores introduced here are likely to be useful for theoretical and computational descriptions of sequence-ensemble relationships across IDPs of different compositions and lengths. Notch signaling via Hey1 and Id2b regulates Muller glia's regenerative response to retinal injury Zebrafish Muller glia (MG) respond to retinal injury by suppressing Notch signaling and producing progenitors for retinal repair. A certain threshold of injury-derived signal must be exceeded in order to engage MG in a regenerative response (MGs injury-response threshold). Pan-retinal Notch inhibition expands the zone of injury-responsive MG at the site of focal injury, suggesting that Notch signaling regulates MGs injury-response threshold. We found that Notch signaling enhanced chromatin accessibility and gene expression at a subset of regeneration-associated genes in the uninjured retina. Two Notch effector genes, hey1 and id2b, were identified that reflect bifurcation of the Notch signaling pathway, and differentially regulate MGs injury-response threshold and proliferation of MG-derived progenitors. Furthermore, Notch signaling component gene repression in the injured retina suggests a role for Dll4, Dlb, and Notch3 in regulating Notch signaling in MG and epistasis experiments confirm that the Dll4/Dlb-Notch3-Hey1/Id2b signaling pathway regulates MGs injury-response threshold and proliferation. Fitness-related traits are maximized in recently introduced, slow-growing populations of a global invasive clam Many species are shifting their ranges being forced to rapidly respond to novel stressful environmental conditions. Colonizing individuals experience strong selective forces that favor the expression of life history traits notably affecting dispersal and reproductive rates in newly invaded habitats. Limited information is currently available on trait variation within the invasive range despite being critical for understanding ecological and evolutionary factors that drive the process of range expansion of invasive species. Here we evaluated life history shifts of the widely introduced Asian clam Corbicula, within its invaded range. Through an exhaustive literature search, we obtained data for 17 invasive Corbicula populations from different ecosystems worldwide. We tested the relationship between population and individual parameters relevant to the process of range expansion. Our main results are that recently introduced Corbicula populations were characterized by (i) low density and low rate of population increase, (ii) clams reproduced earlier in slow-growing populations, and (iii) density had no effect on population increase. All Corbicula populations analyzed in this study, which are fixed for one genotype (lineage Form A/R), experienced different selective environments in the introduced range. These findings support the perspective that adaptive phenotypic plasticity favored the expression of traits that maximize fitness in recently established populations, which faced stronger r-selective forces relative to long-established ones. We discuss the role of plasticity in facilitating rapid adaptation and increasing the likelihood of populations to overcome difficulties associated with low densities and low population increase in newly invaded areas. Cell Cycle Delay, Pro-metaphase Arrest and C-metaphase Inducing Effects of Petroleum Ether Fraction of Leaf Aqueous Extract of Clerodendrum viscosum Vent. Clerodendrum viscosum is a traditionally used medicinal plant. The present study aimed to analyze cell cycle delay, pro-metaphase arrest, and c-metaphase inducing effects of the petroleum ether fraction (AQPEF) of leaf aqueous extract of C. Viscosum (LAECV). The LAECV was fractionated with petroleum ether and its metaphase arrest, cell cycle delay, and c-metaphase inducing activities were tested on A. cepa root tip cells. The AQPEF induced cell cycle delay, and colchicine like metaphase, c-metaphase, in A. cepa root tip cells. Thus, the present study explores AQPEF as an active fraction of LAECV having metaphase arresting, cell cycle delay, and c-metaphase inducing potentials. Diverse stem-chondrichthyan oral structures and evidence for an independently acquired acanthodid dentition The teeth of sharks famously form a series of transversely-organised files with conveyor-belt replacement that are borne directly on the jaw cartilages, in contrast to the dermal plate-borne dentition of bony fishes that undergoes site-specific replacement. A major obstacle in understanding how this system evolved is the poorly understood relationships of the earliest chondrichthyans and the profusion of morphologically and terminologically diverse bones, cartilages, splints and whorls that they possess. Here we use tomographic methods to investigate mandibular structures in several early branching  acanthodian-grade stem-chondrichthyans. We show that the dentigerous jaw bones of disparate genera of ischnacanthids are united by a common construction, being growing bones with non-shedding dentition. Mandibular splints, which support the ventro-lateral edge of the Meckels cartilage in some taxa, are formed from dermal bone and may be an acanthodid synapomorphy. We demonstrate that the teeth of Acanthodopsis are borne directly on the mandibular cartilage and that this taxon is deeply nested within an edentulous radiation, representing an unexpected independent origin of teeth. Many or even all of the range of unusual oral structures may be apomorphic, but they should nonetheless be considered when building hypotheses of tooth and jaw evolution, both in chondrichthyans and more broadly. Improving epigenetic clock performance and interpretation with deep learning Several age predictors based on DNA methylation, dubbed epigenetic clocks, have been created in recent years, with the vast majority based on regularized linear regression. This study explores the improvement in the performance and interpretation of epigenetic clocks using deep learning. First, we gathered 143 publicly available data sets from several human tissues to develop AltumAge, a neural network framework that is a highly accurate and precise age predictor. Compared to ElasticNet, AltumAge performs better for within-data set and cross-data set age prediction, being particularly more generalizable in older ages and new tissue types. We then used deep learning interpretation methods to learn which methylation sites contributed to the final model predictions. We observe that while most important CpG sites are linearly related to age, some highly-interacting CpG sites can influence the relevance of such relationships. Using chromatin annotations, we show that the CpG sites with the highest contribution to the model predictions were related to gene regulatory regions in the genome, including proximity to CTCF binding sites. We also found age-related KEGG pathways for genes containing these CpG sites. Lastly, we perform downstream analyses of AltumAge to explore its applicability and compare its age acceleration with Horvaths model. We show that our neural network approach predicts higher age acceleration for tumors and for cells that exhibit age-related changes in vitro, such as replicative senescence and mitochondrial dysfunction. Altogether, our neural network approach provides significant improvement and flexibility to current epigenetic clocks for both performance and model interpretability. Coronavirus-associated molecular mimicry through homology to a SARS-CoV-2 peptide could be leading to susceptibility in patients with HLA-A*02:01 and HLA-A*24:02 serotypes This study aims to predict autoimmunity-related pathological mechanisms that possess risk for individuals with specific human leukocyte antigen (HLA) serotypes and shared by certain coronaviruses including SARS-CoV-2, based on homology to a SARS-CoV-2 peptide. With the given aim, 1-) coronavirus-associated sequences, which are homologous to the 15mer SARS-CoV-2 peptide CFLGYFCTCYFGLFC, are obtained. 2-) Human peptides that have at least 7 residue matches with those coronavirus sequences, and the SARS-CoV-2 15mer, are found. 3-) Epitope pairs, which are sourced by those aligned coronavirus and human sequences are identified. 4-) Epitope pairs that are predicted to bind strongly not only to the same HLA allele with each other but also to the same HLA allele as those of the respective alignment of the SARS-CoV-2 peptide are selected. Following are the identified proteins or peptides (with HLA-A*02:01 or HLA-A*24:02 epitopes), as described in 1-to-4: Immunoglobulin heavy chain junction regions, CRB1 isoform I precursor, slit homolog 2 protein, hCG1995581, hCG2028737, phospholipid phosphatase-related protein type 2. Among those, CRB1 isoform I precursor sequence with the predicted HLA-A*24:02 epitope aligns with the highest number of different sequences. Results imply autoimmunity risk in COVID-19 patients with HLA-A*02:01 and HLA-A*24:02 serotypes, through molecular mimicry, as a shared pathogenicity risk that can be prevalent upon getting infected with certain coronaviruses. These can pave way to improved risk groups assessment and autoimmunity treatment options, for COVID-19 and its associated diseases. Also, the approach in this study can be used to predict prospective pathologies of the transmissible variants in susceptible humans. Reducing phenotypic instabilities of microbial population during continuous cultivation based on cell switching dynamics Predicting the fate of a microbial population (i.e., growth, gene expression...) remains a challenge, especially when this population is exposed to very dynamic environmental conditions, such as those encountered during continuous cultivation. Indeed, the dynamic nature of continuous cultivation process implies the potential deviation of the microbial population involving genotypic and phenotypic diversification. This work has been focused on the induction of the arabinose operon in Escherichia coli as a model system. As a preliminary step, the GFP level triggered by an arabinose-inducible ParaBAD promoter has been tracked by flow cytometry in chemostat with glucose-arabinose co-feeding. For a large range of glucose-arabinose co-feeding, the simultaneous occurrence of GFP positive and negative subpopulation was observed. In a second set of experiments, continuous cultivation was performed by adding either glucose or arabinose, based on the ability of individual cells for switching from low GFP to high GFP states, according to a technology called segregostat. In segregostat mode of cultivation, on-line flow cytometry analysis was used for adjusting the arabinose/glucose transitions based on the phenotypic switching capabilities of the microbial population. This strategy allowed finding an appropriate arabinose pulsing frequency, leading to a prolonged maintenance of the induction level with limited impact on phenotypic diversity for more than 60 generations. This result suggests that constraining individual cells into a given phenotypic trajectory is maybe not the best strategy for directing cell population. Instead, allowing individual cells switching around a predefined threshold seems to be a robust strategy leading to oscillating, but predictable, cell population behavior.