bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fibrin is a critical regulator of neutrophil effector function at mucosal barrier sites
Authors: Silva Lakmali M , Doyle Andrew D , Tran Collin L , Greenwell-Wild Teresa , Dutzan Nicolas , Lum Andrew G , Agler Cary S , Sibree Megan , Jani Priyam , Martin Daniel , Kram Vardit , Castellino Francis J , Flick Matthew J , Divaris Kimon , Bugge Thomas H , Moutsopoulos Niki M 
Published: January 2021

AbstractTissue-specific cues are critical for homeostasis at mucosal barriers. Here, we document that the clotting factor fibrin is a critical regulator of neutrophil function at mucosal barriers. We demonstrate that fibrin engages neutrophils through the αMβ2integrin receptor and activates effector functions, including the production of reactive oxygen species and NET formation. These immune-protective neutrophil functions become tissue damaging in the context of impaired plasmin-mediated fibrinolysis. Indeed, the accumulation of fibrin due to Mendelian genetic defects in plasmin leads to severe oral mucosal immunopathology in mice and humans. Concordantly, genetic polymorphisms in the humanPLGgene, encoding plasminogen, are associated with common forms of the oral mucosal disease periodontitis. Our work uncovers fibrin as a critical regulator of neutrophil effector function within the mucosal tissue microenvironment and suggests fibrin-neutrophil engagement as a pathogenic instigator and therapeutic target in common mucosal disease.
Human antibody immune responses are personalized by selective removal of MHC-II peptide epitopes
Authors: Gutiérrez-González Matias , Fahad Ahmed S. , Ardito Matt , Nanaware Padma , Lu Liying , Normandin Erica , Madan Bharat , Tivin Jacob , Coates Emily , Henry Amy R. , Laboune Farida , Graham Barney S. , Douek Daniel C. , Ledgerwood Julie E. , Mascola John R. , Martin William D. , Stern Lawrence J. , De Groot Annie S. , DeKosky Brandon J. 
Published: January 2021

SummaryHuman antibody responses are established by the generation of combinatorial sequence diversity in antibody variable domains, followed by iterative rounds of mutation and selection via T cell recognition of antigen peptides presented on MHC-II. Here, we report that MHC-II peptide epitope deletion from B cell receptors (BCRs) correlates with antibody developmentin vivo. Large-scale antibody sequence analysis and experimental validation of peptide binding revealed that MHC-II epitope removal from BCRs is linked to genetic signatures of T cell help, and donor-specific antibody repertoire modeling demonstrated that somatic hypermutation selectively targets the personalized MHC-II epitopes in antibody variable regions. Mining of class-switched sequences and serum proteomic data revealed that MHC-II epitope deletion is associated with antibody class switching and long-term secretion into serum. These data suggest that the MHC-II peptide epitope content of a BCR is an important determinant of antibody maturation that shapes the composition and durability of humoral immunity.HighlightsAntibody somatic hypermutation selectively removes MHC-II peptide epitopes from B cell receptors.Antibodies with lower MHC-II epitope content show evidence of greater T cell help, including class-switching.MHC-II peptide epitope removal from a BCR is linked to long-term antibody secretion in serum.MHC-II genotype provides a personalized selection pressure on human antibody development.
Optimal strategies for learning multi-ancestry polygenic scores vary across traits
Authors: Lehmann B.C.L. , Mackintosh M. , McVean G. , Holmes C.C. 
Published: January 2021

AbstractPolygenic scores (PGSs) are individual-level measures that aggregate the genome-wide genetic predisposition to a given trait. As PGS have predominantly been developed using European-ancestry samples, trait prediction using such European ancestry-derived PGS is less accurate in non-European ancestry individuals. Although there has been recent progress in combining multiple PGS trained on distinct populations, the problem of how to maximize performance given a multiple-ancestry cohort is largely unexplored. Here, we investigate the effect of sample size and ancestry composition on PGS performance for fifteen traits in UK Biobank. For some traits, PGS estimated using a relatively small African-ancestry training set outperformed, on an African-ancestry test set, PGS estimated using a much larger European-ancestry only training set. We observe similar, but not identical, results when considering other minority-ancestry groups within UK Biobank. Our results emphasise the importance of targeted data collection from underrepresented groups in order to address existing disparities in PGS performance.
Pathological turret mutations in the cardiac sodium channel cause long-range pore disruption
Authors: Habib Zaki F , Kohli Manas , Salvage Samantha C , Rahman Taufiq , Huang Christopher L-H , Jackson Antony P 
Published: January 2021

AbstractThe voltage-gated sodium channel Nav1.5 initiates the cardiac action potential. Germline mutations that disrupt Nav1.5 activity predispose affected individuals to inherited cardiopathologies. Some of these Nav1.5 mutations alter amino acids in extracellular turret domains DII and DIII. Yet the mechanism is unclear. In the rat Nav1.5 structure determined by cryogenic electron microscopy, the wild-type residues corresponding to these mutants form a complex salt-bridge between the DII and DIII turret interface. Furthermore, adjacent aromatic residues form cation-π interactions with the complex salt-bridge. Here, we examine this region using site-directed mutagenesis, electrophysiology andin silicomodeling. We confirm functional roles for the salt-bridges and the aromatic residues. We show that their disruption perturbs the geometry of both the DEKA selectivity ring and the inner pore vestibule that are crucial for sodium ion permeability. Our findings provide insights into a class of pathological mutations occurring not only in Nav1.5 but also in other sodium channel isoforms too. Our work illustrates how the sodium channel structures now being reported can be used to formulate and guide novel functional hypotheses.
The sensitivity of ECG contamination to surgical implantation site in adaptive neurostimulation
Authors: Neumann Wolf-Julian , Sorkhabi Majid Memarian , Benjaber Moaad , Feldmann Lucia K. , Saryyeva Assel , Krauss Joachim K. , Contarino Maria Fiorella , Sieger Tomas , Jech Robert , Tinkhauser Gerd , Pollo Claudio , Palmisano Chiara , Isaias Ioannis U. , Cummins Daniel , Little Simon J. , Starr Philip A. , Kokkinos Vasileios , Gerd-Helge Schneider , Herrington Todd , Brown Peter , Richardson R. Mark , Kühn Andrea A. , Denison Timothy 
Published: January 2021

AbstractBackgroundBrain sensing devices are approved today for Parkinson’s, essential tremor, and epilepsy therapies. Clinical decisions for implants are often influenced by the premise that patients will benefit from using sensing technology. However, artifacts, such as ECG contamination, can render such treatments unreliable. Therefore, clinicians need to understand how surgical decisions may affect artifact probability.ObjectivesInvestigate neural signal contamination with ECG activity in sensing enabled neurostimulation systems, and in particular clinical choices such as implant location that impact signal fidelity.MethodsElectric field modelling and empirical signals from 85 patients were used to investigate the relationship between implant location and ECG contamination.aResultsThe impact on neural recordings depends on the difference between ECG signal and noise floor of the electrophysiological recording. Empirically, we demonstrate that severe ECG contamination was more than 3.2x higher in left-sided subclavicular implants (48.3%), when compared to right-sided implants (15.3%). Cranial implants did not show ECG contamination.ConclusionsGiven the relative frequency of corrupted neural signals, we conclude that implant location will impact the ability of brain sensing devices to be used for “closed-loop” algorithms. Clinical adjustments such as implant location can significantly affect signal integrity and need consideration.HighlightsChronic embedded brain sensing promises algorithm-based neurostimulationAlgorithms for closed-loop stimulation can be impaired by artifactsThe relationship of implant location to cardiac dipole has relevant impact on neural signal fidelity; simple models can provide guidance on the sensitivityECG artifacts are present in up to 50% of neural signals from left subclavicular DBS systemsImplanting DBS in a right subclavicular location significantly reduces frequency of ECG artifactsCranial-mounted implants are relatively immune to artifacts
Optimizing viral genome subsampling by genetic diversity and temporal distribution (TARDiS) for Phylogenetics
Authors: Marini Simone , Mavian Carla , Riva Alberto , Salemi Marco , Magalis Brittany Rife 
Published: January 2021

AbstractTARDiS for Philogenetics is a novel tool for optimal genetic sub-sampling. It optimizes both genetic diversity and temporal distribution through a genetic algorithm. TARDiS, along with example data sets and a user manual, is available at https://github.com/smarini/tardis-phylogenetics
Rbec: a tool for analysis of amplicon sequencing data from synthetic microbial communities
Authors: Zhang Pengfan , Spaepen Stjin , Bai Yang , Hacquard Stephane , Garrido-Oter Ruben 
Published: January 2021

AbstractSummarySynthetic microbial communities (SynComs) constitute an emerging and powerful tool in biological, biomedical, and biotechnological research. Despite recent advances in algorithms for the analysis of culture-independent amplicon sequencing data from microbial communities, there is a lack of tools specifically designed for analysing SynCom data, where reference sequences for each strain are available. Here we present Rbec, a tool designed for the analysis of SynCom data that accurately corrects PCR and sequencing errors in amplicon sequences and identifies intra-strain polymorphic variation. Extensive evaluation using mock bacterial and fungal communities show that our tool outperforms current methods for samples of varying complexity, diversity, and sequencing depth. Furthermore, Rbec also allows accurate detection of contaminants in SynCom experiments.Availability and implementationRbec is freely available as an open-source multi-platform R package. Release versions can be obtained via Bioconductor. The developer version is maintained and can be downloaded at:https://github.com/PengfanZhang/Rbec.Contactgarridoo@mpipz.mpg.de
Investigating the impact of reference assembly choice on genomic analyses in a cattle breed
Authors: Lloret-Villas Audald , Bhati Meenu , Kadri Naveen Kumar , Fries Ruedi , Pausch Hubert 
Published: January 2021

AbstractBackgroundReference-guided read alignment and variant genotyping are prone to reference allele bias, particularly for samples that are greatly divergent from the reference genome. A Hereford-based assembly is the widely accepted bovine reference genome. Haplotype-resolved genomes that exceed the current bovine reference genome in quality and continuity have been assembled for different breeds of cattle. Using whole genome sequencing data of 161 Brown Swiss cattle, we compared the accuracy of read mapping and sequence variant genotyping as well as downstream genomic analyses between the bovine reference genome (ARS-UCD1.2) and a highly continuous Angus-based assembly (UOA_Angus_1).ResultsRead mapping accuracy did not differ notably between the ARS-UCD1.2 and UOA_Angus_1 assemblies. We discovered 22,744,517 and 22,559,675 high-quality variants from ARS-UCD1.2 and UOA_Angus_1, respectively. The concordance between sequence- and array-called genotypes was high and the number of variants deviating from Hardy-Weinberg proportions was low at segregating sites for both assemblies. More artefactual INDELs were genotyped from UOA_Angus_1 than ARS-UCD1.2 alignments. Using the composite likelihood ratio test, we detected 40 and 33 signatures of selection from ARS-UCD1.2 and UOA_Angus_1, respectively, but the overlap between both assemblies was low. Using the 161 sequenced Brown Swiss cattle as a reference panel, we imputed sequence variant genotypes into a mapping cohort of 30,499 cattle that had microarray-derived genotypes. The accuracy of imputation (Beagle R2) was very high (0.87) for both assemblies. Genome-wide association studies between imputed sequence variant genotypes and six dairy traits as well as stature produced almost identical results from both assemblies.ConclusionsThe ARS-UCD1.2 and UOA_Angus_1 assemblies are suitable for reference-guided genome analyses in Brown Swiss cattle. Although differences in read mapping and genotyping accuracy between both assemblies are negligible, the choice of the reference genome has a large impact on detecting signatures of selection using the composite likelihood ratio test. We developed a workflow that can be adapted and reused to compare the impact of reference genomes on genome analyses in various breeds, populations and species.
Patient-specific network connectivity combined with a next generation neural mass model to test clinical hypothesis of seizure propagation
Authors: Gerster Moritz , Taher Halgurd , Škoch Antonín , Hlinka Jaroslav , Guye Maxime , Bartolomei Fabrice , Jirsa Viktor , Zakharova Anna , Olmi Simona 
Published: January 2021

ABSTRACTDynamics underlying epileptic seizures span multiple scales in space and time, therefore, understanding seizure mechanisms requires identifying the relations between seizure components within and across these scales, together with the analysis of their dynamical repertoire. In this view, mathematical models have been developed, ranging from single neuron to neural population.In this study we consider a neural mass model able to exactly reproduce the dynamics of heterogeneous spiking neural networks. We combine the mathematical modelling with structural information from non-invasive brain imaging, thus building large-scale brain network models to explore emergent dynamics and test clinical hypothesis. We provide a comprehensive study on the effect of external drives on neuronal networks exhibiting multistability, in order to investigate the role played by the neuroanatomical connectivity matrices in shaping the emergent dynamics. In particular we systematically investigate the conditions under which the network displays a transition from a low activity regime to a high activity state, which we identify with a seizure-like event. This approach allows us to study the biophysical parameters and variables leading to multiple recruitment events at the network level. We further exploit topological network measures in order to explain the differences and the analogies among the subjects and their brain regions, in showing recruitment events at different parameter values.We demonstrate, along the example of diffusion-weighted magnetic resonance imaging (MRI) connectomes of 20 healthy subjects and 15 epileptic patients, that individual variations in structural connectivity, when linked with mathematical dynamic models, have the capacity to explain changes in spatiotemporal organization of brain dynamics, as observed in network-based brain disorders. In particular, for epileptic patients, by means of the integration of the clinical hypotheses on the epileptogenic zone (EZ), i.e. the local network where highly synchronous seizures originate, we have identified the sequence of recruitment events and discussed their links with the topological properties of the specific connectomes. The predictions made on the basis of the implemented set of exact mean-field equations turn out to be in line with the clinical pre-surgical evaluation on recruited secondary networks.
Traumatic Brain Injury Impairs Systemic Vascular Function Through Altered Lipid Metabolism and Disruption of Inward-Rectifier Potassium (Kir2.1) Channels
Authors: Sackheim Adrian M. , Villalba Nuria , Sancho Maria , Harraz Osama F. , Bonev Adrian D. , D’Alessandro Angelo , Nemkov Travis , Nelson Mark T. , Freeman Kalev 
Published: January 2021

AbstractBACKGROUND AND PURPOSETrauma can lead to widespread vascular endothelial dysfunction, but the underlying mechanisms remain largely unknown. Strong inward-rectifier potassium channels (Kir2.1) play a critical role in the dynamic regulation of regional perfusion and blood flow. Kir2.1 channel activity is modulated by phosphatidylinositol 4,5-bisphosphate (PIP2), a minor membrane phospholipid that is degraded by phospholipase A2(PLA2) in conditions of oxidative stress or severe inflammation. We hypothesized that PLA2–induced depletion of PIP2impairs Kir2.1 channel function.METHODSA fluid percussion injury model of traumatic brain injury (TBI) in rats was used to study mesenteric resistance arteries 24 hours after injury. Patch-clamp electrophysiology in freshly isolated endothelial and smooth muscle cells was performed to monitor Kir2.1 conductance, and the functional responses of intact arteries were assessed using pressure myography. We analyzed circulating PLA2, hydrogen peroxide (H2O2), and metabolites to identify alterations in signaling pathways associated with PIP2in TBI.RESULTSElectrophysiology analysis of endothelial and smooth muscle cells revealed a significant reduction of Ba2+-sensitive Kir2.1 currents after TBI. Additionally, dilations to elevated extracellular potassium and BaCl2- or ML 133-induced constrictions in pressurized arteries were significantly decreased following TBI, consistent with an impairment of Kir2.1 channel function. The addition of a PIP2analog to the patch pipette successfully rescued endothelial Kir2.1 currents after TBI. Both H2O2and PLA2activity were increased after injury. Metabolomics analysis demonstrated altered lipid metabolism signaling pathways, including increased arachidonic acid, and fatty acid mobilization after TBI.CONCLUSIONSOur findings support a model in which increased H2O2-induced PLA2activity after trauma hydrolyzes endothelial PIP2, resulting in impaired Kir2.1 channel function.
Phospholipase A2inhibitor-loaded micellar nanoparticles attenuate inflammation and mitigate osteoarthritis progression
Authors: Wei Yulong , Yan Lesan , Luo Lijun , Gui Tao , Amirshaghaghi Ahmad , You Tianyan , Tsourkas Andrew , Qin Ling , Cheng Zhiliang 
Published: January 2021

ABSTRACTTreating osteoarthritis (OA) remains a major clinical challenge. Despite recent advances in drug discovery and development, no disease-modifying drug for knee OA has emerged with any significant clinical success, in part due to the lack of valid and responsive therapeutic targets and poor drug delivery within knee joints. In this work, we show that the amount of secretory phospholipase A2(sPLA2) enzyme increases in articular cartilage in human and mouse OA cartilage tissues. We hypothesize that inhibition of sPLA2activity may be an effective treatment strategy for OA. To develop a sPLA2-responsive and nanoparticle (NP)-based interventional platform for OA management, we incorporated a sPLA2inhibitor (sPLA2i) into the phospholipid membrane of micelles. The engineered sPLA2i-loaded micellar nanoparticles (sPLA2i-NPs) were able to penetrate deep into the cartilage matrix, prolong retention in the joint space, and mitigate OA progression. These findings suggest that sPLA2i-NPs can be promising therapeutic agents for OA treatment.
Chromosome size affects sequence divergence between species through the interplay of recombination and selection
Authors: Tigano Anna , Khan Ruqayya , Omer Arina D. , Weisz David , Dudchenko Olga , Multani Asha S. , Pathak Sen , Behringer Richard R. , Aiden Erez L. , Fisher Heidi , MacManes Matthew D. 
Published: January 2021

AbstractThe structure of the genome shapes the distribution of genetic diversity and sequence divergence. To investigate how the relationship between chromosome size and recombination rate affects sequence divergence between species, we combined empirical analyses and evolutionary simulations. We estimated pairwise sequence divergence among 15 species from three different Mammalian clades -Peromyscusrodents,Musmice, and great apes - from chromosome-level genome assemblies. We found a strong significant negative correlation between chromosome size and sequence divergence in all species comparisons within thePeromyscusand great apes clades, but not theMusclade, suggesting that the dramatic chromosomal rearrangements amongMusspecies may have masked the ancestral genomic landscape of divergence in many comparisons. Our evolutionary simulations showed that the main factor determining differences in divergence among chromosomes of different size is the interplay of recombination rate and selection, with greater variation in larger populations than in smaller ones. In ancestral populations, shorter chromosomes harbor greater nucleotide diversity. As ancestral populations diverge, diversity present at the onset of the split contributes to greater sequence divergence in shorter chromosomes among daughter species. The combination of empirical data and evolutionary simulations revealed that chromosomal rearrangements, demography, and divergence times may also affect the relationship between chromosome size and divergence, and deepen our understanding of the role of genome structure on the evolution of species divergence.
The statistics ofk-mers from a sequence undergoing a simple mutation process without spurious matches
Authors: Blanca Antonio , Harris Robert S. , Koslicki David , Medvedev Paul 
Published: January 2021

AbstractK-mer-based methods are widely used in bioinformatics, but there are many gaps in our understanding of their statistical properties. Here, we consider the simple model where a sequence S (e.g. a genome or a read) undergoes a simple mutation process whereby each nucleotide is mutated independently with some probability r, under the assumption that there are no spurious k-mer matches. How does this process affect the k-mers of S? We derive the expectation and variance of the number of mutated k-mers and of the number of islands (a maximal interval of mutated k-mers) and oceans (a maximal interval of non-mutated k-mers). We then derive hypothesis tests and confidence intervals for r given an observed number of mutated k-mers, or, alternatively, given the Jaccard similarity (with or without minhash). We demonstrate the usefulness of our results using a few select applications: obtaining a confidence interval to supplement the Mash distance point estimate, filtering out reads during alignment by Minimap2, and rating long read alignments to a de Bruijn graph by Jabba.