bluuebunny/crossref_metadata_2025_split huggingface dataset:
MarcoPolo: a clustering-free approach to the exploration of differentially expressed genes along with group information in single-cell RNA-seq data
Authors: Kim Chanwoo , Lee Hanbin , Jeong Juhee , Jung Keehoon , Han Buhm 
Published: November 2020

AbstractA common approach to analyzing single-cell RNA-sequencing data is to cluster cells first and then identify differentially expressed genes based on the clustering result. However, clustering has an innate uncertainty and can be imperfect, undermining the reliability of differential expression analysis results. To overcome this challenge, we present MarcoPolo, a clustering-free approach to exploring differentially expressed genes. To find informative genes without clustering, MarcoPolo exploits the bimodality of gene expression to learn the group information of the cells with respect to the expression level directly from given data. Using simulations and real data analyses, we showed that our method puts biologically informative genes at high ranks more robustly than other existing methods. As our method provides information on how cells can be grouped for each gene, it can help identify cell types that are not separated well in the standard clustering process. Our method can also be used as a feature selection method to improve the robustness of the dimension reduction against changes in the parameters involved in the process.
Axon-secreted chemokine-like Orion is a signal for astrocyte infiltration during neuronal remodeling
Authors: Boulanger Ana , Thinat Camille , Züchner Stephan , Fradkin Lee G. , Lortat-Jacob Hugues , Dura Jean-Maurice 
Published: November 2020

SummaryThe remodeling of neurons is a conserved fundamental mechanism underlying nervous system maturation and function. Glial cells are known to clear neuronal debris but also to have an active role in the remodeling process. Developmental axon pruning ofDrosophilamemory center neurons occurs by a degenerative process mediated by infiltrating astrocytes. However, how these glial processes are recruited by the axons is unknown. In an unbiased screen, we identified a new gene (orion) which is necessary for both the pruning of some axons and removal of the resulting debris. Orion is secreted from the neurons and bears some features common to the chemokines, a family of chemoattractant cytokines. Thus, chemokine involvement in neuron/glial cell interaction is an evolutionarily ancient mechanism. We propose that Orion is the neuronal signal that elicits astrocyte infiltration required for developmental neuronal remodeling.
DisA limits RecA- and RadA/Sms-mediated replication fork remodelling to prevent genome instability
Authors: Torres Rubén , Alonso Juan C. 
Published: November 2020

AbstractThe DisA diadenylate cyclase (DAC), the DNA helicase RadA/Sms and the RecA recombinase are required to prevent a DNA replication stress during the revival of haploidBacillus subtilisspores. Moreover,disA, radAandrecAare epistatic among them in response to DNA damage. We show that DisA inhibits the ATPase activity of RadA/Sms C13A by competing for single-stranded (ss) DNA. In addition, DisA inhibits the helicase activity of RadA/Sms. RecA filamented onto ssDNA interacts with and recruits DisA and RadA/Sms onto branched DNA intermediates. In fact, RecA binds a reversed fork and facilitates RadA/Sms-mediated unwinding to restore a 3′-fork intermediate, but DisA inhibits it. Finally, RadA/Sms inhibits DisA DAC activity, but RecA counters this negative effect. We propose that RecA, DisA and RadA/Sms interactions, which are mutually exclusive, limit remodelling of stalled replication forks. DisA, in concert with RecA and/or RadA/Sms, indirectly contributes to template switching or lesion bypass, prevents fork breakage and facilitates the recovery of c-di-AMP levels to re-initiate cell proliferation.Subject CategoriesGenomic stability & Dynamics
find-tfbs: a tool to identify functional non-coding variants associated with complex human traits using open chromatin maps and phased whole-genome sequences
Authors: de Bellefon Sébastian Méric , Thibord Florian , Auer Paul L. , Blangero John , Coban-Akdemir Zeynep H , Floyd James S. , Fornage Myriam , Johnsen Jill M. , Lange Leslie A. , Lewis Joshua P. , Mathias Rasika A. , McHugh Caitlin P. , Moon Jee-Young , Reiner Alex P. , Stilp Adrienne M. ,   NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Lettre Guillaume 
Published: November 2020

AbstractMotivationWhole-genome DNA sequencing (WGS) enables the discovery of non-coding variants, but tools are lacking to prioritize the subset that functionally impacts human phenotypes. DNA sequence variants that disrupt or create transcription factor binding sites (TFBS) can modulate gene expression. find-tfbs efficiently scans phased WGS in large cohorts to identify and count TFBSs in regulatory sequences. This information can then be used in association testing to find putatively functional non-coding variants associated with complex human diseases or traits.ResultsWe applied find-tfbs to discover functional non-coding variants associated with hematological traits in the NHLBI Trans-Omics for Precision Medicine (TOPMed) WGS dataset (Nmax=44,709). We identified >2000 associations atP<1×10−9, implicating specific blood cell-types, transcription factors and causal genes. The vast majority of these associations are captured by variants identified in large genome-wide association studies (GWAS) for blood-cell traits. find-tfbs is computationally efficient and robust, allowing for the rapid identification of non-coding variants associated with multiple human phenotypes in very large sample size.Availabilityhttps://github.com/Helkafen/find-tfbsandhttps://github.com/Helkafen/find-tfbs-demoContactssebastian.meric.de.bellefon@umontreal.caandguillaume.lettre@umontreal.caSupplementary informationSupplementary data are available.
The multidisciplinary nature of COVID-19 research
Authors: Arencibia-Jorge Ricardo , García-García Lourdes , Galbán-Rodríguez Ernesto , Carrillo-Calvet Humberto 
Published: November 2020

ABSTRACTObjectiveWe analyzed the scientific output after COVID-19 and contrasted it with studies published in the aftermath of seven epidemics/pandemics: Severe Acute Respiratory Syndrome (SARS), Influenza A virus H5N1 and Influenza A virus H1N1 human infections, Middle East Respiratory Syndrome (MERS), Ebola virus disease, Zika virus disease, and Dengue.Design/Methodology/ApproachWe examined bibliometric measures for COVID-19 and the rest of studied epidemics/pandemics. Data were extracted from Web of Science, using its journal classification scheme as a proxy to quantify the multidisciplinary coverage of scientific output. We proposed a novel Thematic Dispersion Index (TDI) for the analysis of pandemic early stages.Results/DiscussionThe literature on the seven epidemics/pandemics before COVID-19 has shown explosive growth of the scientific production and continuous impact during the first three years following each emergence or re-emergence of the specific infectious disease. A subsequent decline was observed with the progressive control of each health emergency. We observed an unprecedented growth in COVID-19 scientific production. TDI measured for COVID-19 (29,4) in just six months, was higher than TDI of the rest (7,5 to 21) during the first three years after epidemic initiation.ConclusionsCOVID-19 literature showed the broadest subject coverage, which is clearly a consecuence of its social, economic, and political impact. The proposed indicator (TDI), allowed the study of multidisciplinarity, differentiating the thematic complexity of COVID-19 from the previous seven epidemics/pandemics.Originality/ValueThe multidisciplinary nature and thematic complexity of COVID-19 research were successfully analyzed through a scientometric perspective.
Bio-Physical Modeling ofGalvanicHuman Body Communication in Electro-Quasistatic Regime
Authors: Modak Nirmoy , Nath Mayukh , Chatterjee Baibhab , Maity Shovan , Sen Shreyas 
Published: November 2020

AbstractHuman Body Communication (HBC) is an alternative to radio wave-based Wireless Body Area Network (WBAN) because of its low-loss, wide bandwidth leading to enhanced energy efficiency. HBC also shows better performance in terms of physical security as most of the signal is confined within the body. To obtain optimum performance and usability, modeling of the body channel plays a vital role. Out of two HBC modalities, Galvanic HBC has the promise to provide lower loss compare to Capacitive HBC for shorter channel length. In this paper, we present the first lumped element based detailed model of Galvanic HBC channel which is used to explain the dependency of channel loss on the material property of skin, fat and muscle tissue layer along with electrode size, electrode separation, geometrical position of the electrodes and return path capacitance. The model considers the impedance of skin and muscle tissue layers and the effect of various coupling capacitances between the body and Tx/Rx electrodes to the Earth-ground. A 2D planner structure is simulated in HFSS to prove the validity of the proposed model. The effect ofsymmetryandasymmetryat the transmitter and receiver end are also explained using the model. The experimental results show that, due to the mismatch at the transmitter and receiver side, the loss increases gradually with channel length and saturates to a finite value as channel length becomes significantly longer compare to the transmitting or receiving electrode pair separation.
Elevated cerebrospinal fluid cytokine levels in tuberculous meningitis predict survival in response to dexamethasone
Authors: Whitworth Laura , Troll Rajan , Pagán Antonio J. , Roca Francisco , Edelstein Paul H. , Troll Mark , Tobin David , Phu Nguyen Hoan , Bang Nguyen Duc , Thwaites Guy , Thuong Nguyen Thuy Thuong , Sewell Roger , Ramakrishnan Lalita 
Published: November 2020

ABSTRACTAdjunctive treatment with anti-inflammatory corticosteroids like dexamethasone increases survival in tuberculosis meningitis. Dexamethasone responsiveness associates with a C/T variant inLeukotriene A4 Hydrolase (LTA4H), which regulates expression of the pro-inflammatory mediator leukotriene B4 (LTB4). TT homozygotes, with increased LTB4, have the highest survival when treated with dexamethasone and the lowest survival without. While the T allele is present in only a minority of the world’s population, corticosteroids confer modest survival benefit worldwide. Using Bayesian methods, we examined how pre-treatment levels of cerebrospinal fluid (CSF) pro-inflammatory cytokines affect survival in dexamethasone-treated tuberculous meningitis.LTA4HTT homozygosity was associated with global cytokine increases, including TNF. Association between higher cytokine levels and survival extended to non-TT patients, suggesting that other genetic variants may also induce dexamethasone-responsive pathological inflammation. These findings warrant studies that tailor dexamethasone therapy to pre-treatment CSF cytokine concentrations, while searching for additional genetic loci shaping the inflammatory milieu.
Development of a multiplexed targeted mass spectrometry assay for LRRK2-phosphorylated Rabs and Ser910/Ser935 biomarker sites
Authors: Nirujogi Raja S. , Tonelli Francesca , Taylor Matthew , Lis Pawel , Zimprich Alexander , Sammler Esther , Alessi Dario R 
Published: November 2020

AbstractMutations that increase the protein kinase activity of LRRK2 are one of the most common causes of familial Parkinson’s disease. LRRK2 phosphorylates a subset of Rab GTPases within their Switch-II motif, impacting interaction with effectors. We describe and validate a new, multiplexed targeted mass spectrometry assay to quantify endogenous levels of LRRK2-phosphorylated Rab substrates (Rab1, Rab3, Rab8, Rab10, Rab35 and Rab43) as well as total levels of Rabs, LRRK2 and LRRK2-phosphorylated at the Ser910 and Ser935 biomarker sites. Exploiting this assay, we quantify for the first time the relative levels of each of the pRab proteins in different cells (mouse embryonic fibroblasts, human neutrophils) and mouse tissues (brain, kidney, lung and spleen). We define how these components are impacted by Parkinson’s pathogenic mutations (LRRK2[R1441C] and VPS35[D620N]) and LRRK2 inhibitors. We find that the VPS35[D620N], but not LRRK2[R1441C] mutation, enhances Rab1 phosphorylation in a manner blocked by administration of an LRRK2 inhibitor, providing the first evidence that endogenous Rab1 is a physiological substrate for LRRK2. We exploit this assay to demonstrate that in Parkinson’s patients with VPS35[D620N] mutations, phosphorylation of multiple Rab proteins (Rab1, Rab3, Rab8, Rab10 and Rab43) is elevated. We highlight the benefits of this assay over immunoblotting approaches currently deployed to assess LRRK2 Rab signalling pathway.
SCReadCounts: Estimation of cell-level SNVs from scRNA-seq data
Authors: Prashant NM , Alomran Nawaf , Chen Yu , Liu Hongyu , Bousounis Pavlos , Movassagh Mercedeh , Edwards Nathan , Horvath Anelia 
Published: November 2020

AbstractRecent studies have demonstrated the utility of scRNA-seq SNVs to distinguish tumor from normal cells, characterize intra-tumoral heterogeneity, and define mutation-associated expression signatures. In addition to cancer studies, SNVs from single cells have been useful in studies of transcriptional burst kinetics, allelic expression, chromosome X inactivation, ploidy estimations, and haplotype inference. To aid these types of studies, we have developed a tool, SCReadCounts, for cell-level tabulation of the sequencing read counts bearing SNV reference and variant alleles from barcoded scRNA-seq alignments. Provided genomic loci and expected alleles, SCReadCounts generates cell-SNV matrices with the absolute variant- and reference-harboring read counts, as well as cell-SNV matrices of expressed Variant Allele Fraction (VAFRNA) suitable for a variety of downstream applications. We demonstrate three different SCReadCounts applications on 59,884 cells from seven neuroblastoma samples: (1) estimation of cell-level expression of known somatic mutations and RNA-editing sites, (2) estimation of celllevel allele expression of germline heterozygous SNVs, and (3) a discovery mode assessment of the reference and each of the three alternative nucleotides at genomic positions of interest that does not require prior SNV information. For the later, we applied SCReadCounts on the coding regions ofKRAS, where it identified known and novel recurrent somatic mutations in a low-to-moderate proportion of cells. The SCReadCounts read counts module is benchmarked against the analogous modules of GATK and Samtools. SCReadCounts is freely available (https://github.com/HorvathLab/NGS) as 64-bit self-contained binary distributions for Linux and MacOS, in addition to Python source.
STREME: Accurate and versatile sequence motif discovery
Authors: Bailey Timothy L. 
Published: November 2020

AbstractSequence motif discovery algorithms can identify novel sequence patterns that perform biological functions in DNA, RNA and protein sequences—for example, the binding site motifs of DNA- and RNA-binding proteins. The STREME algorithm presented here advances the state-of-the-art inab initiomotif discovery in terms of both accuracy and versatility. Usingin vivoDNA (ChIP-seq) and RNA (CLIP-seq) data, and validating motifs with reference motifs derived fromin vitrodata, we show that STREME is more accurate, sensitive, thorough and rapid than several widely used algorithms (DREME, HOMER, MEME, Peak-motifs and Weeder). STREME’s capabilities include the ability to find motifs in datasets with hundreds of thousands of sequences, to find both short and long motifs (from 3 to 30 positions), to perform differential motif discovery in pairs of sequence datasets, and to find motifs in sequences over virtually any alphabet (DNA, RNA, protein and user-defined alphabets). Unlike most motif discovery algorithms, STREME accurately estimates and reports the statistical significance of each motif that it discovers. STREME is easy to use via its web server athttp://meme-suite.org, and is fully integrated with the widely-used MEME Suite of sequence analysis tools, which can be freely downloaded at the same web site for non-commercial use.
Universal constraints on protein evolution in the long-term evolution experiment withEscherichia coli
Authors: Maddamsetti Rohan 
Published: November 2020

AbstractAlthough it is well known that abundant proteins evolve slowly across the tree of life, there is little consensus for why this is true. Here, I report that abundant proteins evolve slowly in the hypermutator populations of Lenski’s long-term evolution experiment withEscherichia coli(LTEE). Specifically, the density of all observed mutations per gene, as measured in metagenomic time series covering 60,000 generations of the LTEE, significantly anti-correlates with mRNA abundance, protein abundance, and degree of protein-protein interaction. The same pattern holds for nonsynonymous mutation density. However, synonymous mutation density, measured across the LTEE hypermutator populations, positively correlates with protein abundance. These results show that universal constraints on protein evolution are visible in data spanning three decades of experimental evolution. Therefore, it should be possible to design experiments to answer why abundant proteins evolve slowly.Significance StatementA universal evolutionary pattern is that highly abundant and highly interacting proteins evolve slowly. This pattern was discovered in analyses that cover millions of years’ worth of sequence variation, so it is not clear how long it takes (decades, centuries, millennia) for such patterns to emerge. Here, I report that this universal evolutionary pattern emerges in metagenomic data that cover just 30 years of experimental evolution.
Gene edited fluorescent cerebral organoids to study human brain function and disease
Authors: Bachmann Lisa , Villarejo Lucia Gallego , Heinen Natalie , Marks David , Müller Thorsten 
Published: November 2020

AbstractCerebral organoids are a promising model to study human brain function and disease, though the high inter-organoid variability of the mini-brains is still challenging. To overcome this limitation, we introduce the method of labeled mixed organoids generated from two different hiPSC lines, which enables the identification of cells from different origin within a single organoid. The method combines a gene editing workflow and subsequent organoid differentiation and offers a unique tool to study gene function in a complex human 3D tissue-like model. Using a CRISPR/Cas9 gene editing approach, different fluorescent proteins were fused to β-actin or lamin B1 in hiPSCs and subsequently used as a marker to identify each cell line. Mixtures of differently edited cells were seeded to induce embryoid body formation and cerebral organoid differentiation. As a consequence, the development of the 3D tissue was detectable by live confocal fluorescence microscopy and immunofluorescence staining in fixed samples. Analysis of mixed organoids allowed the identification and examination of specifically labeled cells in the organoid that belong to each of the two hiPSC donor lines. We demonstrate that a direct comparison of the individual cells is possible by having the edited and the control (or the two differentially labeled) cells within the same organoid, and thus the mixed organoids overcome the inter-organoid inhomogeneity limitations. The approach aims to pave the way for the reliable analysis of human genetic disorders by the use of organoids and to fundamentally understand the molecular mechanisms underlying pathological conditions.
Core self-evaluations and psychological well-being: the mediating role of work-to-family enrichment
Authors: Sahin Saiyada Ghzalah , Pal Suchitra , Hughes Brian M. 
Published: November 2020

PurposeHow or whether dimensions of work-to-family enrichment (WFE) mediate the relationship between an individual's core self-evaluations (CSEs) and their psychological well-being (PWB) is yet to be explained. The purpose of this study is to examine the role of three WFE dimensions in mediating between CSEs and PWB in Indian bank employees.Design/methodology/approachThe present study collected data from 222 full-time bank employees working in Indian nationalized banks. The authors tested the study hypotheses using parallel mediation analysis.FindingsThe result showed positive associations among CSEs, all WFE dimensions (development, affect and capital-based) and PWB. Parallel mediation analysis suggested that two WFE dimensions (affect and capital-based) mediated the relationship between CSEs and PWB.Research limitations/implicationsThe use of a single source of data (Indian nationalized banks) limits the generalizability of the findings.Practical implicationsSenior management at these banks may build a happier and more satisfied workforce by implementing appropriate training and personality development programs. Empowering and rewarding employees for the desired performances may help them appreciate their self-worth, enrich their quality of life (by gaining positive resources from work-family interactions) and ultimately improve their PWB.Originality/valueThe research literature has been relatively silent on the mediating role of individual dimensions of WFE. The present study adds to the existing body of knowledge by exploring the role of individual dimension-based WFE in the relationship between CSEs and PWB.