bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genome wide association analysis in dilated cardiomyopathy reveals two new key players in systolic heart failure on chromosome 3p25.1 and 22q11.23
Authors: Garnier Sophie , Harakalova Magdalena , Weiss Stefan , Mokry Michal , Regitz-Zagrosek Vera , Hengstenberg Christian , Cappola Thomas P , Isnard Richard , Arbustini Eloisa , Cook Stuart A. , van Setten Jessica , Callis Jörg , Hakonarson Hakon , Morley Michael P , Stark Klaus , Prasad Sanjay K. , Li Jin , O’Regan Declan P , Grasso Maurizia , Müller-Nurasyid Martina , Meitinger Thomas , Empana Jean-Philippe , Strauch Konstantin , Waldenberger Mélanie , Marguiles Kenneth B , Seidman Christine E. , Meder Benjamin , Boutouyrie Pierre , Lacolley Patrick , Jouven Xavier , Erdman Jeanette , Blankenberg Stefan , Wichter Thomas , Ruppert Volker , Tavazzi Luigi , Dubourg Olivier , Roizes Gerard , Dorent Richard , DeGroote Pascal , Fauchier Laurent , Trochu Jean-Noël , Aupetit Jean-François , Germain Marine , Völker Uwe , Daiane Hemerich , Raji Ibticem , Bacq-Daian Delphine , Proust Carole , Lehnert Kristin , Maas Renee , Olaso Robert , Saripella Ganapathivarma , Felix Stephan B. , Ginn Steven Mc , Duboscq-Bidot Laëtitia , van Mil Alain , Besse Céline , Fontaine Vincent , Blanché Hélène , Keating Brendan , Garcia-Pavia Pablo , Curjol Angélique , Boland Anne , Komajda Michel , Cambien François , Deleuze Jean-François , Dörr Marcus , Asselbergs Folkert W , Villard Eric , Trégouët David-Alexandre , Charron Philippe ,   On behalf of GENMED consortium
Published: February 2020

SummaryWe present the results of the largest genome wide association study (GWAS) performed so far in dilated cardiomyopathy (DCM), a leading cause of systolic heart failure and cardiovascular death, with 2,719 cases and 4,440 controls in the discovery population. We identified and replicated two new DCM-associated loci, one on chromosome 3p25.1 (lead SNP rs62232870, p = 8.7 × 10−11and 7.7 × 10−4in the discovery and replication step, respectively) and the second on chromosome 22q11.23 (lead SNP rs7284877, p = 3.3 × 10−8and 1.4 × 10−3in the discovery and replication step, respectively) while confirming two previously identified DCM loci on chromosome 10 and 1,BAG3andHSPB7. The genetic risk score constructed from the number of lead risk-alleles at these four DCM loci revealed that individuals with 8 risk-alleles were at a 27% increased risk of DCM compared to individuals with 5 risk alleles (median of the referral population). We estimated the genome wide heritability at 31% ± 8%.In silicoannotation and functional 4C-sequencing analysis on iPSC-derived cardiomyocytes strongly suggestSLC6A6as the most likely DCM gene at the 3p25.1 locus. This gene encodes a taurine and beta-alanine transporter whose involvement in myocardial dysfunction and DCM is supported by recent observations in humans and mice. Although less easy to discriminate the better candidate at the 22q11.23 locus,SMARCB1appears as the strongest one.This study provides both a better understanding of the genetic architecture of DCM and new knowledge on novel biological pathways underlying heart failure, with the potential for a therapeutic perspective.
Comparative Gene Essentiality across the Bacterial Domain
Authors: Shaw Daniel , Hermoso Antonio , Lluch-Senar Maria , Serrano Luis 
Published: February 2020

ABSTRACTComparative genomics among bacteria has been used to gain insight into the minimal number of conserved genes in biological pathways. Essentiality studies have provided information regarding which genes are non-dispensable (essential, E) for cell growth. Here, we integrated studies of gene conservation, essentiality and function, performed in 47 diverse bacterial species. We showed there is a modest positive correlation between genome size and number of essential genes. Interestingly, we observed a clear shift in the functions assigned to these essential genes as genome size increases. For instance, essential genes related to transcription and translation dominate small genomes. In contrast, in large genomes functions of essential genes are related with cellular processing and metabolism. Finally, and most intriguing, we found a group of genes that while being highly conserved are also typically non-essential. This suggests that some housekeeping genes confer a significant survival benefit in nature while being non-essentialin vitro.
Nested oscillations and brain connectivity during sequential stages of feature-based attention
Authors: Pagnotta Mattia F. , Pascucci David , Plomp Gijs 
Published: March 2020

AbstractBrain mechanisms of visual selective attention involve both local and network-level activity changes at specific oscillatory rhythms, but their interplay remains poorly explored. Here, we investigate anticipatory and reactive effects of feature-based attention using separate fMRI and EEG recordings, while participants attended to one of two spatially overlapping visual features (motion and orientation). We focused on EEG source analysis of local nested oscillations and on graph analysis of connectivity changes in a network of fMRI-defined regions of interest, and characterized a cascade of attentional effects and their interplay at multiple spatial scales. We discuss how the results may reconcile several theories of selective attention, by showing how β rhythms support anticipatory information routing through increased network efficiency and β-γ coupling in functionally specialized regions (V1 for orientation, V5 for motion), while reactive α-band desynchronization patterns and increased α-γ coupling in V1 and V5 mediate stimulus-evoked processing of task-relevant signals.
Host “cleansing zone” at secondary contact: a new pattern in host-parasite population genetics
Authors: Martinů Jana , Štefka Jan , Poosakkannu Anbu , Hypša Václav 
Published: March 2020

AbstractWe introduce a new pattern of population genetic structure in a host-parasite system that can arise after secondary contact (SC) of previously isolated populations. Due to different generation time and therefore different tempo of molecular evolution the host and parasite populations reach different degrees of genetic differentiation during their separation (e.g. in refugia). Consequently, during the SC the host populations are able to re-establish a single panmictic population across the whole recolonized area, while the parasite populations stop their dispersal at the SC zone and create a narrow hybrid zone (HZ). From the host’s perspective, the parasite’s HZ functions on a microevolutionary scale as a “host-cleansing filter”: while passing from area A to area B, the hosts are rid of the area A parasites and acquire the area B parasites. We demonstrate this novel pattern on a model composed ofApodemusmice andPolyplaxlice by comparing maternally inherited markers (complete mitochondrial genomes, and complete genomes of vertically transmitted symbiontLegionella polyplacis) with SNPs derived from the louse genomic data. We discuss circumstances which may lead to this pattern and possible reasons why it has been overlooked in the studies on host-parasite population genetics.
Curvature domains in V4 of Macaque Monkey
Authors: Hu Jiaming , Song Xue Mei , Wang Qiannan , Roe Anna Wang 
Published: March 2020

AbstractAn important aspect of visual object recognition is the ability to perceive object shape. How the brain encodes fundamental aspects of shape information remains poorly understood. Models of object shape representation describe a multi-stage process that includes encoding of contour orientation and curvature. While modules encoding contour orientation are well established (orientation domains in V1 and V2 visual cortical areas), whether there are modules for curvature is unknown. In this study, we identify a module for curvature representation in area V4 of monkey visual cortex and illustrate a systematic representation of low to high curvature and of curvature orientation, indicative of curvature hypercolumns in V4. We suggest that identifying systematic modular organizations at each stage of the visual cortical hierarchy signifies the key computations performed.SignificanceWe use intrinsic signal optical imaging in area V4 of anesthetized macaque monkey to study the functional organization of curvature representation. We find a modular basis for cue-invariant curvature representation in area V4 of monkey visual cortex and illustrate a systematic representation from low to high curvature and of curvature orientation, replete with curvature pinwheels. This is the first report of systematic functional organization for curvature representation in the visual system. The use of optical imaging has revealed at a population level spatial details of cortical responses, something which has not been evident from previous studies of single neurons. These data support a representational architecture underlying a ‘curvature hypercolumn’ in V4.
Exploring the Pharmacological Mechanism of Bezoar on Cerebral Ischemic Stroke using a Network Pharmacology Approach
Authors: Du Xin , Li Changxiang , Ren Beida , Deng Nan , Chen Congai , Wang Xueqian , Cheng Fafeng , Qingguo Wang Min Liu 
Published: February 2020

AbstractBackgroundIschemic stroke is a common clinical disease limited by its time window for treatment. In addition to its high mortality rate, only one treatment currently exists for ischemic stroke. Nonetheless, traditional Chinese medicine is often used as a reatment for the disease. Bezoar is a multi-functional drug that has been demonstrated to be effective for the treatment of ischemic stroke. However, its mechanism of action is yet to be fully elucidated. Based on network pharmacology, we explored the potential mechanism of action of bezoar. Symmap and literature data mining methods were used to obtain the target of bezoar. The mechanism of bezoar for the treatment of ischemic stroke was identified and ischemic stroke-related targets were retrieved using DrugBank, Online Mendelian Inheritance in Man, and Therapeutic Target Database. Protein-protein interaction networks were constructed using the Cytoscape plugin, BisoGenet, and analysed by topological methods. Gene Ontology and Kyoto Encyclopaedia of Genes and Genomes pathway enrichment were carried out via the Database for Annotation, Visualization, and Integrated Discovery server. We obtained 48 potential targets and 3 signalling pathways, including mitogen-activated protein kinase, hypoxia-inducible factor-1, and tumour necrosis factor signalling pathways. The mechanism of action of bezoar on ischemic stroke involves multiple targets and signalling pathways. Our research provides a network pharmacology framework for future Chinese medicinal research.
Altered B cells homeostasis in child-onset immunoglobulin A vasculitis
Authors: Liu Deying , Jiang Yanfang , Wang Jinghua , Liu Jinxiang , Xu Meng , Liu Congcong , Yang Sirui 
Published: February 2020

AbstractBackgroundImmunoglobulin A vasculitis (IgAV), also called Henoch–Schönlein purpura, is a systemic small vessels vasculitis with immunoglobulin A1-dominant immune deposits. B-cells are a heterogeneous population with unique subsets distinguished by their phenotypes and cytokine production. Here, we explored the status of B cell subsets in patients with IgAV.MethodsThirty IgAV patients and fifteen age- and sex-matched healthy individuals were enrolled in this study. Fresh blood samples were collected from both healthy and IgAV patients. Upon the distinct expressions of CD3, CD19, CD20, CD38, CD27 and IgD, peripheral blood mononuclear cells (PBMCs) were initially categorized into plasmablasts and memory B cells. Subsequently, using surface markers including CD138 and IgM, and intracellular markers containing IgM and IgG, plasmablasts and memory B cells were further divided into distinct subgroups. A total of eleven populations were detected using multiple flow cytometry.ResultsCD3-CD19+IgD+CD27-, CD3-CD19+CD20-CD38+, CD3-CD19+CD20-CD38+IgM+, and CD3-CD19+CD20-CD38+CD138+B cells were larger in patients with IgAV than in the HCs. Only CD3-CD19+IgD-CD27+IgM+B cell counts were reduced in IgAV. The elevated B cell numbers returned to normal after treatment. Plasma and plasmablast B cell numbers correlated with plasma IgA levels. On the contrary, CD3-CD19+IgD-CD27+IgM+B cell numbers were negatively proportional to the plasma IgA levels while naïve B cell numbers correlated with plasma and plasmablast B cell counts.ConclusionsWe hypothesized that immunoglobulin production was abnormally elevated in IgAV and could be explained by altered B-cell subset homeostasis.
Path sampling simulations reveal how the Q61L mutation restricts the dynamics of KRas
Authors: Roet Sander , Hooft Ferry , Bolhuis Peter G. , Swenson David W.H. , Vreede Jocelyne 
Published: February 2020

AbstractThe GTPase KRas is a signaling protein in networks for cell differentiation, growth, and division. KRas mutations can prolong activation of these networks, resulting in tumor formation. When active, KRas tightly binds GTP. Several oncogenic mutations affect the conversion between this rigid state and inactive, more flexible states. Detailed understanding of these transitions may provide valuable insights into how mutations affect KRas. Path sampling simulations, which focus on transitions, show KRas visiting several states, which are the same for wild type and the oncogenic mutant Q61L. Large differences occur when converting between these states, indicating the dramatic effect of the Q61L mutation on KRas dynamics. For Q61L a route to the flexible state is inaccessible, thus shifting the equilibrium to more rigid states. Our methodology presents a novel way to predict dynamical effects of KRas mutations, which may aid in identifying potential therapeutic targets.Author summaryCancer cells frequently contain mutations in the protein KRas. However, KRas is a challenging target for anti-cancer drugs, in part because the dynamic behavior of flexible regions in the protein is difficult to characterize experimentally, and occurs on timescales that are too long for straightforward molecular dynamics simulations. We have used path sampling, an advanced simulation technique that overcomes long timescales, to obtain atomistic insight into the dynamics of KRas. Comparing the oncogenic mutant Q61L to the wild type revealed that the mutation closes off one transition channel for deactivating KRas. Our approach opens up the way for predicting the dynamical effects of mutations in KRas, which may aid in identifying potential therapeutic targets.
STIG: Generation and simulated sequencing of synthetic T cell receptor repertoires
Authors: Woodcock Mark G. , Bortone Dante S. , Vincent Benjamin G. 
Published: February 2020

AbstractT cell receptor repertoire inference from DNA and RNA sequencing experiments is frequently performed to characterize host immune responses to disease states. Existing tools for repertoire inference have been compared across publicly available biological datasets or unpublished simulated sequencing data. Evaluation and comparison of these tools is challenging without common data sets created from a known repertoire with well-defined biological and sequencing characteristics. Here we introduce STIG, a tool to create simulated T cell receptor sequencing data from a customizable virtual T cell repertoire, with clear attribution of individual reads back to locations within their respective T-cell receptor clonotypes. STIG allows for robust performance evaluation of T cell repertoire inference and downstream analysis methods. STIG is implemented in Python 3 and is freely available for download athttps://github.com/Benjamin-Vincent-Lab/stigAuthor summaryAs part of the acquired immune system, T cells are integral in the host response to microbes, tumors and autoimmune disease. These cells each have a semi-unique T cell receptor that serves to bind a set of antigens that will in turn stimulate that cell to perform its particular pro- (or anti) inflammatory role. This receptor is the product of DNA rearrangement of germline gene segments, similar to B cell receptor loci rearrangement, which provides a wide variety of potential T cell receptors to respond to antigens. At the site of an immune reaction, T cells can increase their number through clonal expansion and methods have been developed to analyze bulk genetic sequencing data to infer the individual receptors and the relative size of their clonal subpopulations present within a sample. To date, these methods and tools have been tested and compared using either biological samples (where the true quantitiy and types of T cells is unknown) or unshared synthetic datasets. In this paper I describe a new tool to generate biologically-inspired T-cell repertoires in-silico and generate simulated sequencing data from them.
SNCAE46KtransgenicDrosophilaModel of Parkinson’s Disease Confirmed the Causative Role of Oxidative Stress
Authors: Jahromi Samaneh Reiszadeh , Ramesh S R , Finkelstein David I , Haddadi Mohammad 
Published: February 2020

AbstractParkinson’s disease (PD) is a class of neurodegenerative disorders in which, complex interactions of genetic and environmental agents are involved in the etiology of both sporadic and familial PD cases. α-synuclein-encodingSNCAgene is known as one of the major genetic contributors of this disease.E46Kmutation inSNCAgene has not been investigated as intensive as otherSNCAgene mutations including A30P and A53T. In this study, to induce PD inDrosophilaflies,UAS-hSNCAWTandUAS-hSNCAE46Ktransgenic fly lines were constructed, whereSNCAgene was over-expressed in flies brains using GAL4-UAS genetic system. Western blot analysis of head samples ofSNCA-expressing flies verifiedSNCAexpression at protein level. Light and electron microscopy analysis of ommatidial structures were performed to verify neurodegeneration as a result of α-synuclein gene overexpression inDrosophilatransgenic flies. Confocal microscopy analysis of dopaminergic neuron clusters verified cell loss followingSNCAE46Kexpression in the flies’ brain.E46Kα-synuclein gene over-expression resulted in an evident decline in longevity as well as climbing ability of the flies. Biochemical studies of transgenic flies showed a remarkable decline in antioxidant enzymes activity and a significant increase in oxidative markers level as well as AchE enzyme activity. Oxidative stress has been known as a causal factor in PD pathogenesis, following expression ofE46Kmutant version of humanSNCAgene. ThisDrosophilamodel is able to facilitate comparative studies of both molecular and cellular assays implicated in the assessment of neurotoxicity of different α-synuclein mutations.
Improved reference genome of the arboviral vectorAedes albopictus
Authors: Palatini U. , Masri R.A. , Cosme L.V. , Koren S. , Thibaud-Nissen F. , Biedler J.K. , Krsticevic F. , Johnston J.S. , Halbach R. , Crawford J.E. , Antoshechkin I. , Failloux A. , Pischedda E. , Marconcini M. , Ghurye J. , Rhie A. , Sharma A. , Karagodin D.A. , Jenrette J. , Gamez S. , Miesen P. , Caccone A. , Sharakhova M.V. , Tu Z. , Papathanos P.A. , Van Rij R.P. , Akbari O. S. , Powell J. , Phillippy A. M. , M. Bonizzoni 
Published: February 2020

AbstractThe Asian tiger mosquitoAedes albopictusis globally expanding and has become the main vector for human arboviruses in Europe. Here we present AalbF2, a dramatically improved assembly of theAe. albopictusgenome that has revealed widespread viral insertions, novel microRNAs and piRNA clusters, the sex determining locus, new immunity genes, and has enabled genome-wide studies of geographically diverseAe. albopictuspopulations and analyses of the developmental and stage-dependent network of expression data. Additionally, we built the first physical map for this species with 75% of the assembled genome anchored to the chromosomes. These up-to-date resources of the genome provide a foundation to improve understanding of the adaptation potential and the epidemiological relevance of this species and foster the development of innovative control measures.One Sentence SummaryLong-read and Hi-C-basedde novoassembly of the arboviral vectorAedes albopictusgenome fosters deeper understanding of its biological features.
Coordination of asparagine uptake and asparagine synthetase expression is required for T cell activation
Authors: Hope Helen Carrasco , Brownlie Rebecca J. , Steele Lynette , Salmond Robert J. 
Published: March 2020

AbstractT cell receptor triggering by antigen results in metabolic reprogramming that, in turn, facilitates T cells’ exit from quiescence. The increased nutrient requirements of activated lymphocytes are met in part by upregulation of cell surface transporters and enhanced uptake of amino acids, fatty acids and glucose from the environment. However, the role of intracellular pathways of amino acid biosynthesis in T cell activation is relatively unexplored. Asparagine (Asn) is a non-essential amino acid that can be synthesized intracellularly through the glutamine-hydrolyzing enzyme asparagine synthetase (ASNS). We set out to define the requirements for uptake of extracellular Asn and ASNS activity in CD8+T cell activation. At early timepoints of activation, T cells expressed little or no ASNS and, as a consequence, viability and TCR-stimulated growth, activation and metabolic reprogramming were substantially impaired under conditions of Asn deprivation. At later timepoints (>48h of activation), TCR-induced mTOR-dependent signals resulted in upregulation of ASNS, that endowed T cells with the capacity to function independently of extracellular Asn. Thus, we have determined that the coordinated upregulation of ASNS expression and uptake of extracellular Asn is required for optimal T cell effector responses.
Manipulation of a Cation-π Sandwich Reveals Conformational Flexibility in Phenylalanine Hydroxylase
Authors: Arturo Emilia C. , Merkel George W. , Hansen Michael R. , Lisowski Sophia , Almeida Deeanne , Gupta Kushol , Jaffe Eileen K. 
Published: February 2020

ABSTRACTPhenylalanine hydroxylase (PAH) is an allosteric enzyme responsible for maintaining phenylalanine (Phe) below neurotoxic levels; its failure results in phenylketonuria. Wild type (WT) PAH equilibrates among resting-state (RS-PAH) and activated (A-PAH) conformations, whose equilibrium position depends upon allosteric Phe binding to the A-PAH conformation. The RS-PAH conformation of WT rat PAH (rPAH) contains a cation-π sandwich between Phe80, Arg123, and Arg420, which cannot exist in the A-PAH conformation. Phe80 variants F80A, F80D, F80L, and F80R were prepared; their conformational equilibrium was evaluated using native PAGE, size exclusion chromatography, ion exchange behavior, intrinsic protein fluorescence, enzyme kinetics, and limited proteolysis, each as a function of [Phe]. Like WT rPAH, F80A and F80D show allosteric activation by Phe while F80L and F80R are constitutively active. Maximal activity of all variants suggests relief of a rate-determining conformational change involving Phe80. Limited proteolysis of WT rPAH in the absence of Phe reveals facile cleavage within a C-terminal 4-helix bundle that is buried in the RS-PAH tetramer interface, reflecting dynamic dissociation of the RS-PAH conformation. This cleavage is not seen for the Phe80 variants, which all show proteolytic hypersensitivity in a linker that repositions during the RS-PAH to A-PAH conformational interchange. Hypersensitivity is corrected by addition of Phe such that all Phe80 variants become like WT rPAH and achieve the A-PAH conformation. Thus, manipulation of Phe80 perturbs the conformational space sampled by PAH, increasing the propensity to sample intermediates in the RS-PAH and A-PAH interchange, which are presumed on-pathway because they can readily achieve the A-PAH conformation by addition of Phe.