bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prominent members of the human gut microbiota express endo-acting O-glycanases to initiate mucin breakdown
Authors: Crouch Lucy I. , Liberato Marcelo V. , Urbanowicz Paulina A. , Baslé Arnaud , Lamb Christopher A. , Stewart Christopher J. , Cooke Katie , Doona Mary , Needham Stephanie , Brady Richard R. , Berrington Janet E. , Madunic Katarina , Wuhrer Manfred , Chater Peter , Pearson Jeffery P. , Glowacki Robert , Martens Eric C. , Zhang Fuming , Linhardt Robert J. , Spencer Daniel I. R. , Bolam David N. 
Published: November 2019

AbstractThe human gut microbiota (HGM) are closely associated with health, development and disease. The thick intestinal mucus layer, especially in the colon, is the key barrier between the contents of the lumen and the epithelial cells, providing protection against infiltration by the microbiota as well potential pathogens. The upper layer of the colonic mucus is a niche for a subset of the microbiota which utilise the mucin glycoproteins as a nutrient source and mucin grazing by the microbiota appears to play a key role in maintaining barrier function as well as community stability. Despite the importance of mucin breakdown for gut health, the mechanisms by which gut bacteria access this complex glycoprotein are not well understood. The current model for mucin degradation involves exclusively exo-acting glycosidases that sequentially trim monosaccharides from the termini of the glycan chains to eventually allow access to the mucin peptide backbone by proteases. However, this model is in direct contrast to the Sus paradigm of glycan breakdown used by the Bacteroidetes which involves extracellular cleavage of glycans by surface located endo-acting enzymes prior to import of the oligosaccharide products. Here we describe the discovery and characterisation of endo-acting family 16 glycoside hydrolases (GH16s) from prominent mucin degrading gut bacteria that specifically target the oligosaccharide side chains of intestinal mucins from both animals and humans. These endo-acting O-glycanases display β1,4-glactosidase activity and in several cases are surface located indicating they are involved in the initial step in mucin breakdown. The data suggest a new paradigm for mucin breakdown by the microbiota and the endo-mucinases provide a potential tool to explore changes that occur in mucin structure in intestinal disorders such as inflammatory bowel disease and colon cancer.
Genome-wide association study for maize leaf cuticular conductance identifies candidate genes involved in the regulation of cuticle development
Authors: Lin Meng , Matschi Susanne , Vasquez Miguel , Chamness James , Kaczmar Nicholas , Baseggio Matheus , Miller Michael , Stewart Ethan L. , Qiao Pengfei , Scanlon Michael J. , Molina Isabel , Smith Laurie G. , Gore Michael A. 
Published: November 2019

AbstractThe cuticle, a hydrophobic layer of cutin and waxes synthesized by plant epidermal cells, is the major barrier to water loss when stomata are closed at night and under water-limited conditions. Elucidating the genetic architecture of natural variation for leaf cuticular conductance (gc) is important for identifying genes relevant to improving crop productivity in drought-prone environments. To this end, we conducted a genome-wide association study ofgcof adult leaves in a maize inbred association panel that was evaluated in four environments (Maricopa, AZ, and San Diego, CA in 2016 and 2017). Five genomic regions significantly associated withgcwere resolved to seven plausible candidate genes (ISTL1, two SEC14 homologs, cyclase-associated protein, a CER7 homolog, GDSL lipase, and β-D-XYLOSIDASE 4). These candidates are potentially involved in cuticle biosynthesis, trafficking and deposition of cuticle lipids, cutin polymerization, and cell wall modification. Laser microdissection RNA sequencing revealed that all these candidate genes, with the exception of the CER7 homolog, were expressed in the zone of the expanding adult maize leaf where cuticle maturation occurs. With direct application to genetic improvement, moderately high average predictive abilities were observed for whole-genome prediction ofgcin locations (0.46 and 0.45) and across all environments (0.52). The findings of this study provide novel insights into the genetic control ofgcand have the potential to help breeders more effectively develop drought-tolerant maize for target environments.Article summaryThe cuticle serves as the major barrier to water loss when stomata are closed at night and under water-limited conditions and potentially relevant to drought tolerance in crops. We performed a genome-wide association study to elucidate the genetic architecture of natural variation for maize leaf cuticular conductance. We identified epidermally expressed candidate genes that are potentially involved in cuticle biosynthesis, trafficking and deposition, cutin polymerization, and cell wall modification. Finally, we observed moderately high predictive abilities for whole-genome prediction of leaf cuticular conductance. Collectively, these findings may help breeders more effectively develop drought-tolerant maize.
Germline and somatic genetic variants in the p53 pathway interact to affect cancer risk, progression and drug response
Authors: Zhang Ping , Kitchen-Smith Isaac , Xiong Lingyun , Stracquadanio Giovanni , Brown Katherine , Richter Philipp , Wallace Marsha , Bond Elisabeth , Sahgal Natasha , Moore Samantha , Nornes Svanhild , De Val Sarah , Surakhy Mirvat , Sims David , Wang Xuting , Bell Douglas A. , Zeron-Medina Jorge , Jiang Yanyan , Ryan Anderson , Selfe Joanna , Shipley Janet , Kar Siddhartha , Pharoah Paul , Loveday Chey , Jansen Rick , Grochola Lukasz F. , Palles Claire , Protheroe Andrew , Millar Val , Ebner Daniel , Pagadala Meghana , Blagden Sarah P. , Maughan Tim , Domingo Enric , Tomlinson Ian , Turnbull Clare , Carter Hannah , Bond Gareth 
Published: November 2019

AbstractInsights into oncogenesis derived from cancer susceptibility loci could facilitate better cancer management and treatment through precision oncology. However, therapeutic applications have thus far been limited by our current lack of understanding regarding both their interactions with somatic cancer driver mutations and their influence on tumorigenesis. Here, by integrating germline datasets relating to cancer susceptibility with tumour data capturing somatically-acquired genetic variation, we provide evidence that single nucleotide polymorphism (SNPs) and somatic mutations in the p53 tumor suppressor pathway can interact to influence cancer development, progression and treatment response. We go on to provide human genetic evidence of a tumor-promoting role for the pro-survival activities of p53, which supports the development of more effective therapy combinations through their inhibition in cancers retaining wild-type p53.SignificanceWe describe significant interactions between heritable and somatic genetic variants in the p53 pathway that affect cancer susceptibility, progression and treatment response. Our results offer evidence of how cancer susceptibility SNPs can interact with cancer driver genes to affect cancer progression and identify novel therapeutic targets.
GNMFLMI: Graph Regularized Nonnegative Matrix Factorization for Predicting LncRNA-MiRNA Interactions
Authors: Wang Mei-Neng , You Zhu-Hong , Li Li-Ping , Wong Leon , Chen Zhan-Heng , Gan Cheng-Zhi 
Published: November 2019

AbstractLong non-coding RNAs (lncRNAs) and microRNAs (miRNAs) have been involved in various biological processes. Emerging evidence suggests that the interactions between lncRNAs and miRNAs play an important role in regulating of genes and the development of many diseases. Due to the limited scale of known lncRNA-miRNA interactions, and expensive time and labor costs for identifying them by biological experiments, more accurate and efficient lncRNA-miRNA interactions computational prediction approach urgently need to be developed. In this work, we proposed a novel computational method, GNMFLMI, to predict lncRNA-miRNA interactions using graph regularized nonnegative matrix factorization. More specifically, the similarities both lncRNA and miRNA are calculated based on known interaction information and their sequence information. Then, the affinity graphs for lncRNAs and miRNAs are constructed using thep-nearest neighbors, respectively. Finally, a graph regularized nonnegative matrix factorization model is developed to accurately identify potential interactions between lncRNAs and miRNAs. To evaluate the performance of GNMFLMI, five-fold cross validation experiments are carried out. GNMFLMI achieves the AUC value of 0.9769 which outperforms the compared methods NMF and CNMF. In the case studies for lncRNA nonhsat159254.1 and miRNA hsa-mir-544a, 20 and 16 of the top-20 associations predicted by GNMFLMI are confirmed, respectively. Rigorous experimental results demonstrate that GNMFLMI can effectively predict novel lncRNA-miRNA interactions, which can provide guidance for relevant biomedical research.
Unblended Disjoint Tree Merging using GTM improves species tree estimation
Authors: Smirnov Vladimir , Warnow Tandy 
Published: November 2019

AbstractPhylogeny estimation is an important part of much biological research, but large-scale tree estimation is infeasible using standard methods due to computational issues. Recently, an approach to large-scale phylogeny has been proposed that divides a set of species into disjoint subsets, computes trees on the subsets, and then merges the trees together using a computed matrix of pairwise distances between the species. The novel component of these approaches is the last step: Disjoint Tree Merger (DTM) methods. We present GTM (Guide Tree Merger), a polynomial time DTM method that adds edges to connect the subset trees, so as to provably minimize the topological distance to a computed guide tree. Thus, GTM performs unblended mergers, unlike the previous DTM methods. Yet, despite the potential limitation, our study shows that GTM has excellent accuracy, generally matching or improving on two previous DTMs, and is much faster than both. Thus, the GTM approach to the DTM problem is a useful new tool for large-scale phylogenomic analysis, and shows the surprising potential for unblended DTM methods. The software for GTM is available at https://github.com/vlasmirnov/GTM.
Themacrophage-expressed gene(mpeg)1identifies a subpopulation of B cells in the adult zebrafish
Authors: Ferrero Giuliano , Gomez Etienne , Iyer Sowmya , Rovira Mireia , Miserocchi Magali , Langenau David M. , Bertrand Julien Y. , Wittamer Valérie 
Published: November 2019

ABSTRACTThe mononuclear phagocytic system (MPS) consists of many cells, in particular macrophages, scattered throughout the body. However, there is increasing evidence for the heterogeneity of tissue-resident macrophages, leading to a pressing need for new tools to discriminate MPS subsets from other hematopoietic lineages.Mpeg1.1is an evolutionary conserved gene encodingperforin-2, a pore-forming protein associated with host defense against pathogens. Zebrafishmpeg1.1:GFPandmpeg1.1:mCherryreporters were originally established to specifically label macrophages. Since, more than 100 peer-reviewed publications have made use ofmpeg1.1-driven transgenics forin vivostudies, providing new insights into key aspects of macrophage ontogeny, activation and function. However, while the macrophage-specific expression pattern of thempeg1.1promoter has been firmly established in the zebrafish embryo, it is currently not known whether this specificity is maintained through adulthood. Here we report direct evidence that beside macrophages, a subpopulation of B-lymphocytes is marked bympeg1.1reporters in most adult zebrafish organs. Thesempeg1.1+lymphoid cells endogenously expressmpeg1.1and can be separated frommpeg1.1+macrophages by virtue of their light-scatter characteristics using FACS. Remarkably, our analyses also revealed that B-lymphocytes, rather than mononuclear phagocytes, constitute the mainmpeg1.1-positive population inirf8nullmyeloid-defective mutants, which were previously reported to recover tissue-resident macrophages in adulthood. One notable exception are skin macrophages, whose development and maintenance appear to be independent fromirf8, similar to mammals. Collectively, our findings demonstrate thatirf8functions in myelopoiesis are evolutionary conserved and highlight the need for alternative macrophage-specific markers to study the MPS in adult zebrafish.SUMMARY SENTENCEMpeg1 is not a restricted macrophage marker, but also labels B cells in the adult zebrafish. Therefore, previously identifiedirf8-independent macrophages likely consist of B lymphocytes.Graphical Abstract
Balancing control: a Bayesian interpretation of habitual and goal-directed behavior
Authors: Schwöbel Sarah , Markovic Dimitrije , Smolka Michael N. , Kiebel Stefan J. 
Published: November 2019

AbstractIn everyday life, our behavior varies on a continuum from automatic and habitual to deliberate and goal-directed. Recent evidence suggests that habit formation and relearning of habits operate in a context-dependent manner: Habit formation is promoted when actions are performed in a specific context, while breaking off habits is facilitated after a context change. It is an open question how one can computationally model the brain’s balancing between context-specific habits and goal-directed actions. Here, we propose a hierarchical Bayesian approach for control of a partially observable Markov decision process that enables conjoint learning of habits and reward structure in a context-specific manner. In this model, habit learning corresponds to an updating of priors over policies and interacts with the learning of the outcome contingencies. Importantly, the model is solely built on probabilistic inference, which effectively provides a simple explanation of how the brain may balance contributions of habitual and goal-directed control. We illustrated the resulting behavior using agent-based simulated experiments, where we replicated several findings of devaluation, extinction, and renewal experiments, as well as the so-called two-step task which is typically used with human participants. In addition, we show how a single parameter, the habitual tendency, can explain individual differences in habit learning and the balancing between habitual and goal-directed control. Finally, we discuss the link of the proposed model to other habit learning models and implications for understanding specific phenomena in substance use disorder.
Functional characterisation of gut microbiota and metabolism in Type 2 diabetes indicates thatClostridialesandEnterococcuscould play a key role in the disease
Authors: Mora-Ortiz Marina , Oregioni Alain , Claus Sandrine P. 
Published: November 2019

AbstractThere is growing evidence indicating that gut microbiota contributes to the development of metabolic syndrome and Type 2 Diabetes (T2D). The most widely-used model for T2D research is the leptin deficientdb/dbmouse model. Yet, a characterisation of the gut microbial composition in this model in relationship with the metabolism is lacking. The objectives of this study were to identify metabolomics and microbial modulations associated with T2D in thedb/dbmouse model. The majority of microbial changes observed included an increase of Enterobacteriaceae and a decrease of Clostridiales in diabetics. The metabolomics interrogation of caecum indicated a lower proteolytic activity in diabetics, who also showed higher Short-Chain Fatty Acid (SCFA) levels. In the case of faeces, the model identified 9 metabolites, the main ones were acetate, butyrate and Branched Chain Amino Acids (BCAAs). Finally, liver was the organ with more metabolic links with gut-microbiota followed by the Gut-Brain Axis (GBA). In conclusion, the interaction between Clostridiales and Enterococcus with caecal metabolism could play a key role in the onset and development of diabetes. Further studies should investigate whether the role of these bacteria is causal or co-occurring.
Spatial and temporal patterns of nitric oxide diffusion and degradation drive emergent cerebrovascular dynamics
Authors: Haselden William , Kedarasetti Ravi Teja , Drew Patrick J. 
Published: November 2019

AbstractNitric oxide (NO) is a gaseous signaling molecule that plays an important role in neurovascular coupling. NO produced by neurons diffuses into the smooth muscle surrounding cerebral arterioles, driving vasodilation. However, the rate of NO degradation in hemoglobin is orders of magnitude higher than in brain tissue, though how this might impact NO signaling dynamics is not completely understood. We used simulations to investigate how the spatial and temporal patterns of NO generation and degradation impacted dilation of a penetrating arteriole in cortex. We found that the spatial location of NO production and the size of the vessel both played an important role in determining its responsiveness to NO. The much higher rate of NO degradation and scavenging of NO in the blood relative to the tissue drove emergent vascular dynamics. Large vasodilation events could be followed by post-stimulus constrictions driven by the increased degradation of NO by the blood, and vasomotion-like 0.1-0.3 Hz oscillations could also be generated. We found that these dynamics could be enhanced by elevation of free hemoglobin in the plasma, which occurs in diseases such as malaria and sickle cell anemia, or following blood transfusions. Finally, we show that changes in blood flow during hypoxia or hyperoxia could be explained by altered NO degradation in the parenchyma. Our simulations suggest that many common vascular dynamics may be emergent phenomenon generated by NO degradation by the blood or parenchyma.
Mass spectrometry based immunopeptidomics leads to robust predictions of phosphorylated HLA class I ligands
Authors: Solleder Marthe , Guillaume Philippe , Racle Julien , Michaux Justine , Pak HuiSong , Müller Markus , Coukos George , Bassani-Sternberg Michal , Gfeller David 
Published: November 2019

AbstractThe presentation of peptides on class I human leukocyte antigen (HLA-I) molecules plays a central role in immune recognition of infected or malignant cells. In cancer, non-self HLA-I ligands can arise from many different alterations, including non-synonymous mutations, gene fusion, cancer-specific alternative mRNA splicing or aberrant post-translational modifications. Identifying HLA-I ligands remains a challenging task that requires either heavy experimental work forin-vivoidentification or optimized bioinformatics tools for accurate predictions. To date, no HLA-I ligand predictor includes post-translational modifications. To fill this gap, we curated phosphorylated HLA-I ligands from several immunopeptidomics studies (including six newly measured samples) covering 72 HLA-I alleles, and retrieved a total of 2,066 unique phosphorylated peptides. We then expanded our motif deconvolution tool to identify precise binding motifs of phosphorylated HLA-I ligands. Our results reveal a clear enrichment of phosphorylated peptides among HLA-C ligands and demonstrate a prevalent role of both HLA-I motifs and kinase motifs on the presentation of phosphorylated peptides. This data further enabled us to develop and validate the first predictor of interactions between HLA-I molecules and phosphorylated peptides.
Genome-wide association study of musical beat synchronization demonstrates high polygenicity
Authors: Niarchou Maria , Gustavson Daniel E. , Sathirapongsasuti J. Fah , Anglada-Tort Manuel , Eising Else , Bell Eamonn , McArthur Evonne , Straub Peter ,   The 23andMe Research Team, McAuley J. Devin , Capra John A. , Ullén Fredrik , Creanza Nicole , Mosing Miriam A. , Hinds David , Davis Lea K. , Jacoby Nori , Gordon Reyna L. 
Published: November 2019

AbstractMoving in synchrony to the beat is a fundamental component of musicality. Here, we conducted a genome-wide association study (GWAS) to identify common genetic variants associated with beat synchronization in 606,825 individuals. Beat synchronization exhibited a highly polygenic architecture, with sixty-nine loci reaching genome-wide significance (p<5×10−8) and SNP-based heritability (on the liability scale) of 13%-16%. Heritability was enriched for genes expressed in brain tissues, and for fetal and adult brain-specific gene regulatory elements, underscoring the role of central nervous system-expressed genes linked to the genetic basis of the trait. We performed validations of the self-report phenotype (through internet-based experiments) and of the GWAS (polygenic scores for beat synchronization were associated with patients algorithmically classified as musicians in medical records of a separate biobank). Genetic correlations with breathing function, motor function, processing speed, and chronotype suggest shared genetic architecture with beat synchronization and provide avenues for new phenotypic and genetic explorations.
Accelerating functional gene discovery in osteoarthritis
Authors: Butterfield Natalie C. , Curry Katherine F. , Steinberg Julia , Dewhurst Hannah , Komla-Ebri Davide , Mannan Naila S. , Adoum Anne-Tounsia , Leitch Victoria D. , Logan John G. , Waung Julian A. , Ghirardello Elena , Southam Lorraine , Youlten Scott E. , Mark Wilkinson J , McAninch Elizabeth A. , Vancollie Valerie E. , Kussy Fiona , White Jacqueline K. , Lelliott Christopher J. , Adams David J. , Jacques Richard , Bianco Antonio C. , Boyde Alan , Zeggini Eleftheria , Croucher Peter I. , Williams Graham R. , Duncan Bassett J. H. 
Published: November 2019

AbstractOsteoarthritis causes debilitating pain and disability, resulting in a huge socioeconomic burden, yet no drugs are available that prevent disease onset or progression. Here, we develop, validate and use rapid-throughput imaging techniques to identify abnormal joint phenotypes in unselected mutant mice generated by the International Knockout Mouse Consortium. We identify 14 genes with functional involvement in osteoarthritis pathogenesis, including the homeobox genePitx1, and functionally characterize 6 candidate human osteoarthritis genes in mouse models. We demonstrate sensitivity of the methods by identifying age-related degenerative joint damage in wild-type mice. Finally, we generate mutant mice with an osteoarthritis-associated polymorphism in theDio2gene byCrispr/Cas9genome editing and demonstrate a protective role in disease onset with public health implications. This expanding resource of unselected mutant mice will transform the field by accelerating functional gene discovery in osteoarthritis and offering unanticipated drug discovery opportunities for this common and incapacitating chronic disease.