bluuebunny/crossref_metadata_2025_split huggingface dataset:
Alpha-1 antitrypsin inhibits SARS-CoV-2 infection
Authors: Wettstein Lukas , Conzelmann Carina , Müller Janis A. , Weil Tatjana , Groß Rüdiger , Hirschenberger Maximilian , Seidel Alina , Klute Susanne , Zech Fabian , Bozzo Caterina Prelli , Preising Nico , Fois Giorgio , Lochbaum Robin , Knaff Philip , Mailänder Volker , Ständker Ludger , Thal Dietmar Rudolf , Schumann Christian , Stenger Steffen , Kleger Alexander , Lochnit Günter , Sparrer Konstantin , Kirchhoff Frank , Frick Manfred , Münch Jan 
Published: July 2020

AbstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19). To identify factors of the respiratory tract that suppress SARS-CoV-2, we screened a peptide/protein library derived from bronchoalveolar lavage, and identified α1-antitrypsin (α1-AT) as specific inhibitor of SARS-CoV-2. α1-AT targets the viral spike protein and blocks SARS-CoV-2 infection of human airway epithelium at physiological concentrations. Our findings show that endogenous α1-AT restricts SARS-CoV-2 and repurposes α1-AT-based drugs for COVID-19 therapy.
Variability in carbapenemase activity of intrinsic OxaAb (OXA-51-like) beta-lactamase enzymes inAcinetobacter baumannii
Authors: Takebayashi Yuiko , Findlay Jacqueline , Heesom Kate J. , Warburton Philip J. , Avison Matthew B. , Evans Benjamin A. 
Published: July 2020

ABSTRACTObjectivesThis study aimed to measure the variability in carbapenem susceptibility conferred by different OxaAb variants, characterise the molecular evolution ofoxaAband elucidate the contribution of OxaAb and other possible carbapenem resistance factors in the clinical isolates using WGS and LC-MS/MS.MethodsDisc susceptibility and MIC broth microdilution tests were performed on ten clinicalA. baumanniiisolates and interpreted according to CLSI guidelines. Imipenem and meropenem MICs were evaluated for alloxaAbvariants cloned into susceptibleA. baumanniiCIP70.10 and increasedadeABCefflux pump gene expression BM4547 backgrounds, with and without their natural promoters. Molecular evolution analysis of theoxaAbvariants was performed using FastTree and SplitsTree4. Resistance determinants were studied in the clinical isolates using WGS and LC-MS/MS analysis.ResultsOxaAb(82), OxaAb(83), OxaAb(107), and OxaAb(110) carrying I129L and L167V substitutions increased carbapenem MICs when transferred into susceptibleA. baumanniibackgrounds without an upstream IS element. Carbapenem resistance was conferred with the addition of their natural upstream ISAba1promoter. LC-MS/MS analysis on the original clinical isolates showed no differences in expression levels of proteins commonly associated with carbapenem resistance.ConclusionsISAba1-driven overexpression of OxaAb variants with substitutions I129L and L167V confers carbapenem resistance with no need for additional resistance mechanisms.
Common genetic variants with fetal effects on birth weight are enriched for proximity to genes implicated in rare developmental disorders
Authors: Beaumont Robin N. , Mayne Isabelle K. , Freathy Rachel M. , Wright Caroline F. 
Published: July 2020

AbstractBirth weight is an important factor in newborn and infant survival, and both low and high birth weights are associated with adverse later life health outcomes. Genome-wide association studies (GWAS) have identified 190 loci associated with either maternal or fetal effects on birth weight. Knowledge of the underlying causal genes and pathways is crucial to understand how these loci influence birth weight, and the links between infant and adult morbidity. Numerous monogenic developmental syndromes are associated with birth weights at the extreme upper or lower ends of the normal distribution, and genes implicated in those syndromes may provide valuable information to help prioritise candidate genes at GWAS loci. We examined the proximity of genes implicated in developmental disorders to birth weight GWAS loci at which a fetal effect is either likely or cannot be ruled out. We used simulations to test whether those genes fall disproportionately close to the GWAS loci. We found that birth weight GWAS single nucleotide polymorphisms (SNPs) fall closer to such genes than expected by chance. This is the case both when the developmental disorder gene is the nearest gene to the birth weight SNP and also when examining all genes within 258kb of the SNP. This enrichment was driven by genes that cause monogenic developmental disorders with dominant modes of inheritance. We found several examples of SNPs located in the intron of one gene that mark plausible effects via different nearby genes implicated in monogenic short stature, highlighting the closest gene to the SNP not necessarily being the functionally relevant gene. This is the first application of this approach to birth weight loci, which has helped identify GWAS loci likely to have direct fetal effects on birth weight which could not previously be classified as fetal or maternal due to insufficient statistical power.
Serine 165 Phosphorylation of SHARPIN regulates the Activation of NF-κB
Authors: Thys An , Trillet Kilian , Rosinska Sara , Gayraud Audrey , Douanne Tiphaine , Danger Yannic , Renaud Clotilde , Antigny Luc , Lavigne Régis , Pineau Charles , Com Emmanuelle , Vérité Franck , Gavard Julie , Bidère Nicolas 
Published: July 2020

AbstractThe adaptor SHARPIN composes, together with the E3 ligases HOIP and HOIL1, the linear ubiquitin chain assembly complex. This enzymatic complex catalyzes and stamps atypical linear ubiquitin chains onto substrates to modify their fate, and has been linked to the regulation of the NF-κB pathway downstream most immunoreceptors, inflammation and cell death. However, how this signaling complex is regulated is not fully understood. Here, we report that a portion of SHARPIN is constitutively phosphorylated on the serine in position 165 in lymphoblastoid cells, and can be further induced following antigen receptor stimulation. Analysis of a phosphorylation-resistant mutant of SHARPIN revealed that this mark is dispensable for the generation of linear ubiquitin chains. However, phosphorylation allows the optimal activation of NF-κB in response to TNFα and T-cell receptor engagement. These results identify a new layer of regulation of the LUBAC, and unveil new strategies to modulate its action.
A computational exploration of resilience and evolvability of protein-protein interaction networks
Authors: Klein Brennan , Holmér Ludvig , Smith Keith M. , Johnson Mackenzie M. , Swain Anshuman , Stolp Laura , Teufel Ashley I. , Kleppe April S. 
Published: July 2020

AbstractProtein-protein interaction (PPI) networks represent complex intra-cellular protein interactions, and the presence or absence of such interactions can lead to biological changes in an organism. Recent network-based approaches have shown that a phenotype’s PPI network’sresilienceto environmental perturbations is related to its placement in the tree of life; though we still do not know how or why certain intra-cellular factors can bring about this resilience. Here, we explore the influence of gene expression and network properties on PPI networks’ resilience. We use publicly-available data of PPIs forE. coli, S. cerevisiae, andH. sapiens, where we compute changes in network resilience as new nodes (proteins) are added to the networks under three node addition mechanisms—random, degree-based, and gene-expression-based attachments. By calculating the resilience of the resulting networks, we estimate the effectiveness of these node addition mechanisms. We demonstrate that adding nodes with gene-expression-based preferential attachment (as opposed to random or degree-based) preserves and can increase the original resilience of PPI network in all three species, regardless of gene expression distribution or network structure. These findings introduce a general notion ofprospective resilience, which highlights the key role of network structures in understanding the evolvability of phenotypic traits.
Analysis of Complex DNA Rearrangements During Early Stages of HAC Formation
Authors: Pesenti Elisa , Liskovykh Mikhail , Okazaki Koei , Mallozzi Alessio , Reid Caitlin , Abad Maria Alba , Jeyaprakash A. Arockia , Kouprina Natalay , Larionov Vladimir , Masumoto Hiroshi , Earnshaw William C. 
Published: July 2020

AbstractHuman Artificial Chromosomes (HACs) are important tools for epigenetic engineering, for measuring chromosome instability (CIN) and possible gene therapy. However, their use in the latter is potentially limited because the input HAC-seeding DNA can undergo an unpredictable series of rearrangements during HAC formation. As a result, after transfection and HAC formation, each cell clone contains a HAC with a unique structure that cannot be precisely predicted from the structure of the HAC-seeding DNA. Although it has been reported that these rearrangements can happen, the timing and mechanism of their formation has yet to be described. Here we synthesized a HAC-seeding DNA with two distinct structural domains and introduced it into HT1080 cells. We characterized a number of HAC-containing clones and subclones to track DNA rearrangements during HAC establishment. We demonstrated that rearrangements can occur early during HAC formation. Subsequently, the established HAC genomic organization is stably maintained across many cell generations. Thus, early stages in HAC formation appear to at least occasionally involve a process of DNA shredding and shuffling that resembles chromothripsis, an important hallmark of many cancer types. Understanding these events during HAC formation has critical implications for future efforts aimed at synthesizing and exploiting synthetic human chromosomes.
The molecular landscape of neural differentiation in the developingDrosophilabrain revealed by targeted scRNA-seq and a multi-informatic analysis paradigm
Authors: Michki Nigel S. , Li Ye , Sanjasaz Kayvon , Zhao Yimeng , Shen Fred Y. , Walker Logan A. , Lee Cheng-Yu , Cai Dawen 
Published: July 2020

SUMMARYTheDrosophilatype-II neuroblast (NB) lineages present an attractive model to investigate the neural differentiation process. With only 16 stem cells, the type-II NB lineages generate many intermediate neural progenitors (INPs) to rapidly expand the neuron and glia pool, similar to those in the human outer subventricular zone (OSVZ). We performed targeted single-cell mRNA sequencing (scRNA-seq) in 3rd instar larval brains and created MiCV, an scRNA-seq data visualization web tool to integrate results from multiple bioinformatics analyses, display co-expression patterns of multiple genes simultaneously, and retrieve gene function and ortholog annotations. We identified novel markers that label distinct neural subsets using MiCV and subsequentlyin situprofiled them to recover the spatial information lacking in the scRNA-seq data. These new markers further enabled us to build novel neural developmental trajectories that lead to unique neuronal cell fates. Combining prior knowledge,in silicoanalyses, andin situevidence, this multi-informatic investigation describes the molecular landscape of neural differentiation from a single developmental snapshot inDrosophila, and provides an experimental and analytical roadmap for navigating the differentiation process of more complex brains.
Multiple Emulsions Able To Be Use For Oral Administration Of Actives Pharmaceutical Ingredients: Different Phases Physico-Chemical Parameters Study
Authors: Augustin Diaga D. L. , Rodrigue D. A. , Mamadou S. , Mouhamed D. S. , Mady S. P. , Gora M. , Mounibé D. 
Published: July 2020

ABSTRACTWhen formulating emulsions, the preliminary tests, also known as formulation tests, constitute a step which can be long and expensive because of the quantity of reagents that can be used. A rigorous methodology could thus be of great interest, that is at the aim of our study which consists of evaluating the physico-chemical parameters of different phases used to make thus multiple emulsions.In our study, physico chemical parameters such as conductivity, pH, density, viscosity, and surface tension have been studied by direct measurement using equipment and also by means of suitable mounting.The results showed that the pH and the surface tension have an important role in the prediction of the stability of emulsions, these latter must be of the same order of magnitude. For all phases conductivity does not have too much interest apart from helping to determine the type of the emulsion.STATEMENT OF SIGNIFICANCEMultiple emulsions are of great therapeutic interest especially in the administration of medicament which can be inactivated by digestive enzymes, moreover the researches of formulation not being often easy, a control of the physicochemical parameters of the different phases would be of great interest in rapid formulations and at low cost.
Metagenome-assembled genomes fromMonte CristoCave (Diamantina, Brazil) reveal prokaryotic lineages as functional models for life on Mars
Authors: Bendia Amanda G. , Callefo Flavia , Araújo Maicon N. , Sanchez Evelyn , Teixeira Verônica C. , Vasconcelos Alessandra , Battilani Gislaine , Pellizari Vivian H. , Rodrigues Fabio , Galante Douglas 
Published: July 2020

AbstractAlthough several studies have explored microbial communities in different terrestrial subsurface ecosystems, little is known about the diversity of their metabolic processes and survival strategies. The advance of bioinformatic tools is allowing the description of novel and not-yet cultivated microbial lineages in different ecosystems, due to the genome reconstruction approach from metagenomic data. The recovery of genomes has the potential of revealing novel lifestyles, metabolic processes and ecological roles of microorganisms, mainly in ecosystems that are largely unknown, and in which cultivation could be not viable. In this study, through shotgun metagenomic data, it was possible to reconstruct several genomes of cultivated and not-yet cultivated prokaryotic lineages from a quartzite cave, located in Minas Gerais state, Brazil, which showed to possess a high diversity of genes involved with different biogeochemical cycles, including reductive and oxidative pathways related to carbon, sulfur, nitrogen and iron. Tree genomes were selected, assigned asTruepera sp.,Ca. Methylomirabilis sp. andCa. Koribacter sp. based on their lifestyles (radiation resistance, anaerobic methane oxidation and potential iron oxidation) for pangenomic analysis, which exhibited genes involved with different DNA repair strategies, starvation and stress response. Since these groups have few reference genomes deposited in databases, our study adds important genomic information about these lineages. The combination of techniques applied in this study allowed us to unveil the potential relationships between microbial genomes and their ecological processes with the cave mineralogy, as well as to discuss their implications for the search for extant lifeforms outside our planet, in silica- and iron-rich environments, especially on Mars.
The transcriptional repressor Zfp125 modifies hepatic energy metabolism in response to fasting and insulin resistance
Authors: Fernandes Gustavo W. , Bocco Barbara M. L. C. , Fonseca Tatiana L. , Salas-Lucia Federico , Nickel Olivia , Russo Samuel C. , Gereben Balázs , Kettelhut Isis C. , Bianco Antonio C. 
Published: July 2020

SummaryZfp125 is a transcriptional repressor that inhibits hepatic VLDL secretion. Here we show that mice with liver-specific Zfp125 knockdown exhibited lower respiratory quotient, reduced glycemia and pyruvate-stimulated liver glucose output, and higher levels of β-hydroxyl-butyrate. Microarray and ChIP-seq studies identified Zfp125 peaks in the promoter of 135 metabolically relevant genes, including genes involved in fatty acid oxidation and ketogenesis, e.g. Ppara, Cpt1a, Bdh1 and Hmgcs2. Repression by Zfp125 involved recruitment of the corepressors Kap1 and the histone methyl transferase Setdb1, increasing the levels of H3K9me3, a heterochromatin marker of gene silencing. The resulting increase in acetyl-CoA levels accelerated gluconeogenesis through allosteric activation of pyruvate carboxylase. Zfp125 knockdown in isolated mouse hepatocytes amplified the induction of ketogenesis by glucagon or insulin resistance, whereas the expression of key gluconeogenic genes Pck1 and G6pc was amplified by Zfp125. These findings place Zfp125 at the center of fuel dysregulation of type 2 diabetes.
Mendelian imputation of parental genotypes for genome-wide estimation of direct and indirect genetic effects
Authors: Young Alexander I. , Nehzati Seyed Moeen , Lee Chanwook , Benonisdottir Stefania , Cesarini David , Benjamin Daniel J. , Turley Patrick , Kong Augustine 
Published: July 2020

AbstractAssociations between genotype and phenotype derive from four sources: direct genetic effects, indirect genetic effects from relatives, population stratification, and correlations with other variants affecting the phenotype through assortative mating. Genome-wide association studies (GWAS) of unrelated individuals have limited ability to distinguish the different sources of genotype-phenotype association, confusing interpretation of results and potentially leading to bias when those results are applied – in genetic prediction of traits, for example. With genetic data on families, the randomisation of genetic material during meiosis can be used to distinguish direct genetic effects from other sources of genotype-phenotype association. Genetic data on siblings is the most common form of genetic data on close relatives. We develop a method that takes advantage of identity-by-descent sharing between siblings to impute missing parental genotypes. Compared to no imputation, this increases the effective sample size for estimation of direct genetic effects and indirect parental effects by up to one third and one half respectively. We develop a related method for imputing missing parental genotypes when a parent-offspring pair is observed. We provide the imputation methods in a software package, SNIPar (single nucleotide imputation of parents), that also estimates genome-wide direct and indirect effects of SNPs. We apply this to a sample of 45,826 White British individuals in the UK Biobank who have at least one genotyped first degree relative. We estimate direct and indirect genetic effects for ∼5 million genome-wide SNPs for five traits. We estimate the correlation between direct genetic effects and effects estimated by standard GWAS to be 0.61 (S.E. 0.09) for years of education, 0.68 (S.E. 0.10) for neuroticism, 0.72 (S.E. 0.09) for smoking initiation, 0.87 (S.E. 0.04) for BMI, and 0.96 (S.E. 0.01) for height. These results suggest that GWAS based on unrelated individuals provides an inaccurate picture of direct genetic effects for certain human traits.
“A transient heritable memory regulates HIV reactivation from latency”
Authors: Lu Yiyang , Singh Abhyudai , Dar Roy D. 
Published: July 2020

AbstractReactivation of human immunodeficiency virus 1 (HIV-1) from latently infected T cells is a critical barrier to successfully eradicate HIV-1 from patients. Latency models in Jurkat T-cells reveal that individual cells reactivate in an all-or-none fashion when exposed to latency reversal agents (LRAs). Remarkably, this heterogeneity arises within a clonal cell population of genetically identical cells containing a single copy of the provirus integrated at the same genomic site. To characterize these single-cell responses, we leverage the classical Luria-Delbrück fluctuation test where single cells are isolated from a clonal population, and exposed to LRAs after a period of colony expansion. If cellular responses are purely random, then the fraction of reactivating cells should have minimal colony-to-colony fluctuations given the large number of cells present after weeks of colony growth. In contrast, data shows considerable colony-to-colony fluctuations with the fraction of reactivating cells following a skewed distribution. Systematic measurements of fluctuations over time in combination with mathematical modeling uncovers the existence of a heritable memory that regulates HIV-1 reactivation, where single cells are in a LRA-responsive state for a few weeks before switching back to an irresponsive state. These results have enormous implications for designing therapies to purge the latent reservoir and illustrate the utility of fluctuation-based assays to uncover hidden transient cellular states underlying phenotypic heterogeneity.
RhoA effectors LOK/SLK activate ERM proteins to locally inhibit RhoA and define apical morphology
Authors: Zaman Riasat , Lombardo Andrew , Sauvanet Cécile , Viswanatha Raghuvir , Awad Valerie , Bonomo Locke Ezra-Ros , McDermitt David , Bretscher Anthony 
Published: July 2020

AbstractActivated Ezrin-Radixin-Moesin (ERM) proteins link the plasma membrane to the actin cytoskeleton to generate apical structures, including microvilli. Among many kinases implicated in ERM activation are the homologs LOK and SLK. CRISPR/Cas9 was used to knockout all ERM proteins or LOK/SLK in human cells. LOK/SLK knockout eliminates all ERM activating phosphorylation. The apical domain of cells lacking LOK/SLK or ERMs is strikingly similar and selectively altered, with loss of microvill, and junctional actin replaced by ectopic myosin-II containing apical stress-fiber-like structures. Constitutively active ezrin can reverse the phenotypes of either ERMs or LOK/SLK knockouts, showing that the major function of LOK/SLK is to activate ERMs. Both knockout lines have elevated active RhoA with concomitant enhanced myosin light chain phosphorylation, revealing that active ERMs are negative regulators of RhoA. As RhoA-GTP activates LOK/SLK to activate ERM proteins, the ability of active ERMs to negatively regulate RhoA-GTP represents a novel local feedback loop necessary for the proper apical morphology of epithelial cells.
Long-read genome sequencing for the diagnosis of neurodevelopmental disorders
Authors: Hiatt Susan M. , Lawlor James M.J. , Handley Lori H. , Ramaker Ryne C. , Rogers Brianne B. , Partridge E. Christopher , Boston Lori Beth , Williams Melissa , Plott Christopher B. , Jenkins Jerry , Gray David E. , Holt James M. , Bowling Kevin M. , Bebin E. Martina , Grimwood Jane , Schmutz Jeremy , Cooper Gregory M. 
Published: July 2020

AbstractPurposeExome and genome sequencing have proven to be effective tools for the diagnosis of neurodevelopmental disorders (NDDs), but large fractions of NDDs cannot be attributed to currently detectable genetic variation. This is likely, at least in part, a result of the fact that many genetic variants are difficult or impossible to detect through typical short-read sequencing approaches.MethodsHere, we describe a genomic analysis using Pacific Biosciences circular consensus sequencing (CCS) reads, which are both long (>10 kb) and accurate (>99% bp accuracy). We used CCS on six proband-parent trios with NDDs that were unexplained despite extensive testing, including genome sequencing with short reads.ResultsWe identified variants and createdde novoassemblies in each trio, with global metrics indicating these data sets are more accurate and comprehensive than those provided by short-read data. In one proband, we identified a likely pathogenic (LP),de novoL1-mediated insertion inCDKL5that results in duplication of exon 3, leading to a frameshift. In a second proband, we identified multiple largede novostructural variants, including insertion-translocations affectingDGKBandMLLT3, which we show disruptMLLT3transcript levels. We consider this extensive structural variation likely pathogenic.ConclusionThe breadth and quality of variant detection, coupled to finding variants of clinical and research interest in two of six probands with unexplained NDDs strongly support the value of long-read genome sequencing for understanding rare disease.