bluuebunny/crossref_metadata_2025_split huggingface dataset:
Resolving the insertion sites of polymorphic duplications reveals aHERC2haplotype under selection
Authors: Saitou M. , Gokcumen O. 
Published: December 2018

ABSTRACTPolymorphic duplications in humans have been shown to contribute to phenotypic diversity. However, the evolutionary forces that maintain variable duplications across the human genome are largely unexplored. To understand the haplotypic architecture of the derived duplications, we developed a linkage-disequilibrium based method to detect insertion sites of polymorphic duplications not represented in reference genomes. This method also allows resolution of haplotypes harboring the duplications. Using this approach, we conducted genome-wide analyses and identified the insertion sites of 22 common polymorphic duplications. We found that the majority of these duplications are intrachromosomal and only one of them is an interchromosomal insertion. Further characterization of these duplications revealed significant associations to blood and skin phenotypes. Based on population genetics analyses, we found that the partial duplication of a well-characterized pigmentation-related gene,HERC2, may be selected against in European populations. We further demonstrated that the haplotype harboring the partial duplication significantly affects the expression of theHERC2P9gene in multiple tissues. Our study sheds light onto the evolutionary impact of understudied polymorphic duplications in human populations and presents methodological insights for future studies.
Effect of diapause on cold-resistance in different life-stages of an aphid parasitoid wasp
Authors: Tougeron Kevin , Blanchet Leslie , van Baaren Joan , Le Lann Cecile , Brodeur Jacques 
Published: December 2018

To overwinter, insects from mild temperate areas can either enter diapause or remain active. Both strategies involve costs and benefits depending on the environment. In the first case, the emerging individuals will resist winter but have a reduced fitness because diapause entails physiological and ecological costs. In the second case, individuals need to be cold-resistant enough to withstand winter temperatures during their immature and adult stages, but could avoid diapause-associated costs. In mild temperate areas, the cost-benefit balance between the diapause and the non-diapause strategy would likely change in response to climate warming. A trade-off between these two strategies should lead to reduction of diapause expression in some populations. We explored the importance of such trade-off through the comparison of cold resistance capacities among different life stages in diapause and non-diapause individuals in a population of the aphid parasitoid Aphidius ervi (Hymenoptera: Braconidae) originating from western France where a decrease of diapause incidence was recently observed. As a proxy measure of insect physiological cold resistance, the Super Cooling Point (SCP) was determined for non-diapausing and diapausing prepupae and adults that went through prepupal diapause or not. Diapausing and non-diapausing prepupae were equally cold-resistant (-24.20	±0.30°C vs. -24.74	±0.36°C, respectively), and overall more resistant than adults. Adults that went through diapause as prepupae were less cold resistant (-17.85	±1.10°C) than adults that have not undergone through diapause (-21.10	±0.54°C). We also found that diapausing prepupae and adults that have undergone diapause were lighter than their non-diapausing counterparts, at a comparable size, suggesting higher energetic expenses during diapause. These results suggest a trade-off between diapause expression in prepupae and cold resistance and life-history-traits in adults. We conclude that selection could favor insects that do not enter diapause and thus avoid its associated costs while taking advantage at exploiting the mild winter environment.
The genomic and proteomic landscape of the rumen microbiome revealed by comprehensive genome-resolved metagenomics
Authors: Stewart Robert D. , Auffret Marc D. , Warr Amanda , Walker Alan W. , Roehe Rainer , Watson Mick 
Published: December 2018

AbstractRuminants provide essential nutrition for billions of people worldwide. The rumen is a specialised stomach adapted to the breakdown of plant-derived complex polysaccharides, and collectively the rumen microbiota encode the thousands of enzymes responsible. Here we present a comprehensive analysis of over 6.5 terabytes of Illumina and Nanopore sequence data, including assembly of 4941 metagenome-assembled genomes, and several single-contig, whole-chromosome assemblies of novel rumen bacteria. We also present the largest dataset of predicted proteins from the rumen, and provide rich annotation against public datasets. Together these data will form an essential part of future studies of rumen microbiome structure and function.
Generating closed bacterial genomes from long-read nanopore sequencing of microbiomes
Authors: Moss Eli L. , Bhatt Ami S. 
Published: December 2018

AbstractWe present the first method for efficient recovery of complete, closed genomes directly from microbiomes using nanopore long-read sequencing and assembly. We apply our approach to three healthy human gut communities and compare results to short read and read cloud approaches. We obtain nine finished genomes including the first reported closed genome of Prevotella copri, an organism with highly repetitive genome structure prevalent in non-western human gut microbiomes.
Pseudozyma saprotrophic yeasts have retained a large effector arsenal, including functional Pep1 orthologs
Authors: Sharma Rahul , Ökmen Bilal , Doehlemann Gunther , Thines Marco 
Published: December 2018

SummaryThe basidiomycete smut fungi are predominantly plant parasitic, causing severe losses in some crops. Most species feature a saprotrophic haploid yeast stage, and several smut fungi are only known from this stage, with some isolated from habitats without suitable hosts, e.g. from Antarctica. Thus, these species are generally believed to be apathogenic, but recent findings that some of these might have a plant pathogenic sexual counterpart, casts doubts on the validity of this hypothesis. Here, four Pseudozyma genomes were re-annotated and compared to published smut pathogens and the well-characterised effector gene Pep1 from these species was checked for its ability to complement a Pep1 deletion strain of Ustilago maydis. It was found that 113 high-confidence putative effector proteins were conserved among smut and Pseudozyma genomes. Among these were several validated effector proteins, including Pep1. By genetic complementation we show that Pep1 homologs from the supposedly apathogenic yeasts restore virulence in Pep1-deficient mutants Ustilago maydis. Thus, it is concluded that Pseudozyma species have retained a suite of effectors. This hints at the possibility that Pseudozyma species have kept an unknown plant pathogenic stage for sexual recombination or that these effectors have positive effects when colonising plant surfaces.
Inhibition of Notch signaling rescues cardiovascular development in Kabuki Syndrome
Authors: de los Angeles Serrano Maria , Demarest Bradley L. , Tone-Pah-Hote Tarlynn , Tristani-Firouzi Martin , Yost H. Joseph 
Published: December 2018

AbstractKabuki Syndrome patients have a spectrum of congenital disorders, including congenital heart defects, the primary determinant of mortality. Seventy percent of Kabuki Syndrome patients have mutations in the histone methyl-transferase KMT2D. However, the underlying mechanisms that drive these congenital disorders are unknown. Here, we generated and characterized a zebrafish kmt2d null mutant that recapitulates the cardinal phenotypic features of Kabuki Syndrome, including microcephaly, palate defects, abnormal ear development and cardiac defects. The cardiovascular defects consist of abnormal aortic arches and hypoplastic ventricle, driven by previously unknown aberrant endocardial and endothelial vasculogenesis. We identify a regulatory link between the Notch pathway and Kmt2d during vasculogenesis and show that pharmacological inhibition of Notch signaling rescues the cardiovascular phenotype in zebrafish Kabuki Syndrome. Taken together these findings demonstrate that Kmt2d regulates vasculogenesis, provide evidence for interactions between Kmt2d and Notch signaling in Kabuki Syndrome, and suggest future directions for clinical research.
Cellular multifunctionality in the muscle activity ofHydra vulgaris
Authors: Szymanski John , Yuste Rafael 
Published: December 2018

SummaryAs a cnidarian,Hydrahas an anatomically simple neuromuscular system likely similar to those of ancestral species, and its study could provide insights on the design logic and function of animal body plans throughout evolution. Here we have used calcium imaging to map the activity of the entire epitheliomuscular system of livingHydrain mounted preparations. We find seven basic spatiotemporal patterns of activation, with fast and slow kinetics of initiation and propagation. Contrary to previous assumptions, both endodermal and ectodermal epitheliomuscular tissues are systematically activated jointly during contractions, in spite of their muscle fibers being orthogonally arranged. We also find that individual cells surprisingly participate in multiple patterns, using different kinetics of activation. Our results reveal thatHydra’sepitheliomuscular tissue is a multifunctional system that can be flexibly reconfigured to generate different spatiotemporal activity patterns, enabling a structurally simple design to implement a varied behavior output.
Automated detection of the HER2 gene amplification status in Fluorescencein situhybridization images for the diagnostics of cancer tissues
Authors: Zakrzewski Falk , Back Walter de , Weigert Martin , Wenke Torsten , Zeugner Silke , Mantey Robert , Sperling Christian , Friedrich Katrin , Roeder Ingo , Aust Daniela E. , Baretton Gustavo , Hönscheid Pia 
Published: December 2018

AbstractThe human epidermal growth factor receptor 2 (HER2) gene amplification status is a crucial marker for evaluating clinical therapies of breast or gastric cancer. We propose a deep learning-based pipeline for the detection, localization and classification of interphase nuclei depending on their HER2 gene amplification state in Fluorescence in situ hybridization (FISH) images. Our pipeline combines two RetinaNet-based object localization networks which are trained (1) to detect and classify interphase nuclei into distinct classes normal, low-grade and high-grade and (2) to detect and classify FISH signals into distinct classes HER2 or centromere of chromosome 17 (CEN17). By independently classifying each nucleus twice, the two-step pipeline provides both robustness and interpretability for the automated detection of the HER2 amplification status. The accuracy of our deep learning-based pipeline is on par with that of three pathologists and FISH images on a set of 57 validation images containing several hundreds of nuclei are accurately classified. The automatic pipeline is a first step towards assisting pathologists in evaluating the HER2 status of tumors using FISH images, for analyzing FISH images in retrospective studies, and for optimizing the documentation of each tumor sample by automatically annotating and reporting of the HER2 gene amplification specificities.
The distribution of epistasis on simple fitness landscapes
Authors: Fraïsse Christelle , Welch John J. 
Published: December 2018

AbstractFitness interactions between mutations can influence a population’s evolution in many different ways. While epistatic effects are difficult to measure precisely, important information about the overall distribution is captured by the mean and variance of log fitnesses for individuals carrying different numbers of mutations. We derive predictions for these quantities from simple fitness landscapes, based on models of optimizing selection on quantitative traits. We also explore extensions to the models, including modular pleiotropy, variable effects sizes, mutational bias, and maladaptation of the wild-type. We illustrate our approach by reanalysing a large data set of mutant effects in a yeast snoRNA. Though characterized by some strong epistatic interactions, these data give a good overall fit to the non-epistatic null model, suggesting that epistasis might have little effect on the evolutionary dynamics in this system. We also show how the amount of epistasis depends on both the underlying fitness landscape, and the distribution of mutations, and so it is expected to vary in consistent ways between new mutations, standing variation, and fixed mutations.
Arp2/3 complex-driven spatial patterning of the BCR enhances immune synapse formation, BCR signaling and cell activation
Authors: Bolger-Munro Madison , Choi Kate , Scurll Joshua , Abraham Libin , Chappell Rhys , Sheen Duke , Dang-Lawson May , Wu Xufeng , Priatel John J , Coombs Daniel , Hammer John A , Gold Michael R 
Published: December 2018

AbstractWhen B cells encounter antigens on the surface of an antigen-presenting cell (APC), B cell receptors (BCRs) are gathered into microclusters that recruit signaling enzymes. These microclusters then move centripetally and coalesce into the central supramolecular activation cluster of an immune synapse. The mechanisms controlling BCR organization during immune synapse formation, and how this impacts BCR signaling, are not fully understood. We show that this coalescence of BCR microclusters depends on the actin-related protein 2/3 (Arp2/3) complex, which nucleates branched actin networks. Moreover, in murine B cells this dynamic spatial reorganization of BCR microclusters amplifies proximal BCR signaling reactions and enhances the ability of membrane-associated antigens to induce transcriptional responses and proliferation. Our finding that Arp2/3 complex activity is important for B cell responses to spatially-restricted membrane-bound antigens, but not for soluble antigens, highlights a critical role for Arp2/3 complex-dependent actin remodelling in B cell responses to APC-bound antigens.
A Chemical Kinetic Basis for Measuring Translation Initiation and Elongation Rates from Ribosome Profiling data
Authors: Sharma Ajeet K. , Sormanni Pietro , Ahmed Nabeel , Ciryam Prajwal , Friedrich Ulrike A. , Kramer Guenter , O’Brien Edward P. 
Published: December 2018

ABSTRACTAnalysis methods based on simulations and optimization have been previously developed to estimate relative translation rates from next-generation sequencing data. Translation involves molecules and chemical reactions; hence, bioinformatics methods consistent with the laws of chemistry and physics are more likely to produce accurate results. Here, we derive simple equations based on chemical kinetic principles to measure the translation-initiation rate, transcriptome-wide elongation rate, and individual codon translation rates from ribosome profiling experiments. Our methods reproduce the known rates from ribosome profiles generated from detailed simulations of translation. Applying our methods to data from S. cerevisiae and mouse embryonic stem cells we find that the extracted rates reproduce expected correlations with various molecular properties. A codon can exhibit up to 26-fold variability in its translation rate depending upon its context within a transcript. This broad distribution means that the average translation rate of a codon is not representative of the rate at which most instances of that codon are translated. We also find that mouse embryonic stem cells have a global translation speed of 5.2 AA/s, is similar to what has been previous reported using another analysis method. This large variability in translation rates suggests that translational regulation might be used by cells to a greater degree than previously thought.
Dynamic design: manipulation of millisecond timescale motions on the energy landscape of Cyclophilin A
Authors: Juárez-Jiménez Jordi , Gupta Arun A. , Karunanithy Gogulan , Mey Antonia S. J. S. , Georgiou Charis , Ioannidis Harris , De Simone Alessio , Barlow Paul N. , Hulme Alison N. , Walkinshaw Malcolm D. , Baldwin Andrew J. , Michel Julien 
Published: December 2018

AbstractProteins need to interconvert between many conformations in order to function, many of which are formed transiently, and sparsely populated. Particularly when the lifetimes of these states approach the millisecond timescale, identifying the relevant structures and the mechanism by which they inter-convert remains a tremendous challenge. Here we introduce a novel combination of accelerated MD (aMD) simulations and Markov State modelling (MSM) to explore these ‘excited’ conformational states. Applying this to the highly dynamic protein CypA, a protein involved in immune response and associated with HIV infection, we identify five principally populated conformational states and the atomistic mechanism by which they interconvert. A rational design strategy predicted that the mutant D66A should stabilise the minor conformations and substantially alter the dynamics whereas the similar mutant H70A should leave the landscape broadly unchanged. These predictions are confirmed using CPMG and R1ρ solution state NMR measurements. By accurately and reliably exploring functionally relevant, but sparsely populated conformations with milli-second lifetimesin silico, our aMD/MSM method has tremendous promise for the design of dynamic protein free energy landscapes for both protein engineering and drug discovery.
Activation of oral epithelial EphA2-EFGR signaling by Candida albicans virulence factors
Authors: Swidergall Marc , Solis Norma V. , Millet Nicolas , Huang Manning Y. , Lin Jianfeng , Phan Quynh T. , Lazarus Michael D. , Wang Zeping , Mitchell Aaron P. , Filler Scott G. 
Published: December 2018

AbstractDuring oropharyngeal candidiasis (OPC), Candida albicans invades and damages oral epithelial cells, which respond by producing proinflammatory mediators that recruit phagocytes to foci of infection. The ephrin type-A receptor 2 (EphA2) detects β-glucan and plays a central role in stimulating epithelial cells to release proinflammatory mediators during OPC. The epidermal growth factor receptor (EGFR) also interacts with C. albicans and is known to be activated by the Als3 adhesin/invasin and the Ece1/Candidalysin pore-forming toxin. Here, we investigated the interactions among EphA2, EGFR, Als3 and Ece1/Candidalysin during OPC. We found that Als3 and Ece1/Candidalysin function in the same pathway to damage epithelial cells in vitro. They also work together to cause OPC in mice. EGFR and EphA2 constitutively associate with each other as part of a physical complex and are mutually dependent for C. albicans-induced activation. In vitro, either Als3 or Ece1/Candidalysin is required for C. albicans to activate EGFR, sustain EphA2 activation, and stimulate epithelial cells to secrete CXCL8/IL-8 and CCL20. In the mouse model of OPC, Ece1/Candidalysin alone activates EGFR and induces CXCL1/KC and CCL20 production. Ece1/Candidalysin is also necessary for the production of IL-1α and IL-17A independently of Als3 and EGFR. These results delineate the complex interplay between host cell receptors and C. albicans virulence factors during the induction of OPC and the resulting oral inflammatory response.Author summaryOropharyngeal candidiasis occurs when the fungus Candida albicans proliferates in the mouth. The disease is characterized by fungal invasion of the superficial epithelium and a localized inflammatory response. Two C. albicans virulence factors contribute to the pathogenesis of OPC, Als3 which enables the organisms to adhere to and invade host cells and Ece1/Candidalysin which is pore-forming toxin that damages host cells. Two epithelial cell receptors, ephrin type-A receptor 2 (EphA2) and the epidermal growth factor receptor (EGFR) are activated by C. albicans. Here, we show that EphA2 and EGFR form part of complex and that each receptor is required to activate the other. Als3 and Ece1/Candidalysin function in the same pathway to damage epithelial cells. In isolated epithelial cells, both of these virulence factors activate EphA2 and EGFR, and stimulate the production of inflammatory mediators. In the mouse model of OPC, Ece1/Candidalysin elicits of a subset of the oral inflammatory response. Of the cytokines and chemokines induced by this toxin, some require the activation of EGFR while others are induced independently of EGFR. This work provides a deeper understanding of the interactions among C. albicans virulence factors and host cell receptors during OPC.
Symmetry breaking in the embryonic skin triggers a directional and sequential front of competence during plumage patterning
Authors: Bailleul Richard , Dinh Carole Desmarquet-Trin , Hidalgo Magdalena , Curantz Camille , Touboul Jonathan , Manceau Marie 
Published: December 2018

ABSTRACTThe development of an organism involves the formation of patterns from initially homogeneous surfaces in a reproducible manner. Simulations of various theoretical models recapitulate final states of natural patterns1-4yet drawing testable hypotheses from those often remains difficult4,5. Consequently, little is known on pattern-forming events. Here, we extend modeling to reproduce not only the final plumage pattern of birds, but also the observed natural variation in its dynamics of emergence in five species. We built a unified model intrinsically generating the directionality, sequence, and duration of patterning, and usedin vivoexperiments to test its parameter-based predictions. We showed that while patterning duration is controlled by overall cell proliferation, its directional and sequential progression result from a pre-pattern: an initial break in surface symmetry launches a traveling front of increased cell density that defines domains with self-organizing capacity. These results show that universal mechanisms combining pre-patterning and self-organization govern the timely emergence of the plumage pattern in birds.