bluuebunny/crossref_metadata_2025_split huggingface dataset:
Powerful gene-based testing by integrating long-range chromatin interactions and knockoff genotypes
Authors: Ma Shiyang , Dalgleish James L. , Lee Justin , Wang Chen , Liu Linxi , Gill Richard , Buxbaum Joseph D. , Chung Wendy , Aschard Hugues , Silverman Edwin K. , Cho Michael H. , He Zihuai , Ionita-Laza Iuliana 
Published: July 2021

AbstractGene-based tests are valuable techniques for identifying genetic factors in complex traits. Here we propose a novel gene-based testing framework that incorporates data on long-range chromatin interactions, several recent technical advances for region-based tests, and leverages the knockoff framework for synthetic genotype generation for improved gene discovery. Through simulations and applications to GWAS and whole-genome sequencing data for multiple diseases and traits we show that the proposed test increases the power over state-of-the-art gene-based tests in the literature, identifies genes that replicate in larger studies, and can provide a more narrow focus on the possible causal genes at a locus by reducing the confounding effect of linkage disequilibrium. Furthermore, our results show that incorporating genetic variation in distal regulatory elements tends to improve power over conventional tests. Results for UK Biobank and BioBank Japan traits are also available in a publicly accessible database that allows researchers to query gene-based results in an easy fashion.SignificanceGene-based tests are important tools for elucidating the genetic basis of complex traits. Despite substantial recent efforts in this direction, the existing tests are still limited owing to low power and detection of false positive signals due to the confounding effects of linkage disequilibrium. In this paper we describe a novel gene-based test that attempts to address these limitations by incorporating data on long-range chromatin interactions, several recent technical advances for region-based testing, and the knockoff framework for synthetic genotype generation. Through extensive simulations and applications to multiple diseases and traits, we show that the proposed test increases the power over state-of-the-art gene-based tests and provides a narrower focus on the possible causal genes involved at a locus.
Lives saved and hospitalizations averted by COVID-19 vaccination in New York City
Authors: Shoukat Affan , Vilches Thomas N. , Moghadas Seyed M. , Sah Pratha , Schneider Eric C. , Shaff Jaimie , Zucker Jane , Quinn Celia , Chokshi Dave A. , Galvani Alison P. 
Published: July 2021

AbstractDespite the emergence of highly transmissible variants, the number of cases in NYC has fallen from over 5,500 average daily cases in January, 2020 to less than 350 average daily cases in July, 2021. The impact of vaccination in saving lives and averting hospitalizations in NYC has not been formally investigated yet. We used an age-stratified agent-based model calibrated to COVID-19 transmission and vaccination in NYC to evaluate the impact of the vaccination campaign in suppressing the COVID-19 burden. We found that the vaccination campaign has prevented over 250,000 COVID-19 cases, 44,000 hospitalizations and 8,300 deaths from COVID-19 infection since the start of vaccination through July 1, 2021. Notably, the swift vaccine rollout suppressed another wave of COVID-19 that would have led to sustained increase in cases, hospitalizations and deaths during spring triggered by highly transmissible variants. As the Delta variant sweeps across the city, the findings of this study underscore the urgent need to accelerate vaccination and close the vaccine coverage gaps across the city.
The integration of genetically-regulated transcriptomics and electronic health records highlights a pattern of medical outcomes related to increased hepaticTransthyretinexpression
Authors: Pathak Gita A. , De Lillo Antonella , Wendt Frank R. , De Angelis Flavio , Koller Dora , Mendoza Brenda Cabrera , Jacoby Daniel , Miller Edward J. , Buxbaum Joel N. , Polimanti Renato 
Published: July 2021

AbstractBackgroundTransthyretin (TTR) is a multi-function protein involved in the systemic transport of retinol and thyroxine. It also participates in the neuronal response to stress and proteolysis of few specific substrates. TTR is also the precursor of the fibrils that compromise organ function in the familial and sporadic systemic amyloidoses (ATTR). RNA-interference and anti-sense therapeutics targetingTTRhepatic transcription have been shown to reduce TTR amyloid formation. The goal of our study was to investigate the role of genetic regulation ofTTRtranscriptomic variation in human traits and diseases.Methods and FindingsWe leveraged genetic and phenotypic information from the UK Biobank and transcriptomic profiles from the GTEx (Genotype-Tissue Expression) project to test the association of genetically regulatedTTRgene expression with 7,149 traits assessed in 420,531 individuals. We conducted a joint multi-tissue analysis ofTTRtranscription regulation and identified an association with a specific operational procedure related to secondary open reduction of fracture of bone (p=5.46×10−6, false discovery rate q=0.039). Using tissue-specificTTR cisexpression quantitative trait loci, we demonstrated that the association is driven by the genetic regulation ofTTRhepatic expression (odds ratio [OR] = 3.46, 95% confidence interval [CI] = 1.85-6.44, p = 9.51×10−5). Although there is an established relationship of retinol and thyroxine abnormalities with bone loss and the risk of bone fracture, this is the first evidence of a possible effect ofTTRtranscriptomic regulation. Investigating the UK Biobank electronic health records available, we investigated the comorbidities affecting individuals undergoing the specific surgical procedure. Excluding medical codes related to bone fracture events, we identified a pattern of health outcomes that have been previously associated with ATTR manifestations. These included osteoarthritis (OR=3.18, 95%CI=1.93-4.25, p=9.18×10−8), carpal tunnel syndrome (OR=2.15, 95%CI=1.33-3.48, p=0.002), and a history of gastrointestinal diseases (OR=2.01, 95%CI=1.33-3.01, p=8.07×10−4).ConclusionsThe present study supports the notion thatTTRhepatic expression can affect health outcomes linked to physiological and pathological processes presumably related to the encoded protein. Our findings highlight how the integration of omics information and electronic health records can successfully dissect the complexity of multi-function proteins such as TTR.
Benefit-finding and self-compassion promote psychological well-being in caregivers of individuals with mental illness: a cross-sectional study
Authors: Tan Edina Yi-Qin , Yip Vania T. , Rolles-Abraham Kim Lian 
Published: July 2021

AbstractBackgroundResilience factors that promote psychological well-being amongst caregivers of individuals with a mental illness are understudied. Coping strategies (problem-focused coping, emotion-focused coping and benefit-finding) have been found to influence the relation between stress and psychological outcomes, but their relative contribution to psychological well-being has not been tested. Self-compassion reduces caregiver burden in caregivers, yet no research has examined its contribution to psychological well-being nor the mechanisms via which it could do so. The aim of this study was to examine benefit-finding and self-compassion as resilience factors that could promote psychological well-being amongst caregivers of individuals with mental illnesses.MethodsThis cross-sectional study was conducted between June 2019 to October 2019 in Singapore. 107 informal caregivers of individuals with various diagnosed mental illnesses completed an online questionnaire. COPE, General Benefit Finding Scale (GBFS), Self-Compassion Scale -Short (SCS-SF), Psychological Well-Being Scale -Brief (PWBS-B), and Hospital Anxiety and Depression Scale (HADS) were used. Hierarchical multiple regression and mediation analyses were conducted.ResultsBenefit-finding was a more important predictor of psychological well-being compared to problem-focused and emotion-focused coping. Self-compassion was positively associated with psychological well-being amongst caregivers, and this is partially due to an increased use of problem-focused coping strategies.ConclusionsFuture interventions should cultivate caregivers’ benefit-finding and self-compassion and consider using psychological well-being as an additional outcome measure.
microRNAs Over-expressed in Diabetic Foot Ulcers Healing - Computational Modeling of Molecular Structure
Authors: de Oliveira Andrade Luis Jesuino , Vinhaes Bittencourt Alcina Maria , Matos de Oliveira Luís , Matos de Oliveira Gabriela Correia 
Published: July 2021

ABSTRACTBackgroundVasculopathy associated with diabetic neuropathy are important risk factors for the diabetic foot ulcers development. Diabetic foot ulcers is severe complication that occur in about 15% of people with diabetes, being able require hospitalization and amputation in its treatment.ObjectiveDesign in silico the molecular structure of micro-ribonucleic acid (miRNA) overexpressed in diabetic foot ulcers healing.MethodWe performed a careful search of the nucleotide sequence of 8 miRNAs over-expressed in diabetic foot ulcers, designing in silico the molecular structure of following miRNAs: miRNA-146a, miRNA-155, miRNA-132, miRNA-191, miRNA-21, miRNA-203a, miRNA-203b, and miRNA-210. The nucleotides were taken from GenBank of National Center for Biotechnology Information genetic sequence database. The sequences acquired were aligned with the Clustal W multiple alignment algorithms. The molecular modeling of structures was built using the RNAstructure, an automated miRNAs structure modelling server.ResultsWe showed a search for nucleotide sequence and the design of the molecular structure of following miRNA over-expressed in diabetic foot ulcers healing: miRNA-146a, miRNA-155, miRNA-132, miRNA-191, miRNA-21, miRNA-203a, miRNA-203b, and miRNA-210. We produced a tutorial on a molecular model of the 8 miRNAs overexpressed in the diabetic foot by processing in silico projection of their molecular structures.ConclusionWe show in silico secondary structures design of selected of 8 miRNAs over-expressed in diabetic foot ulcers healing by means of computational biology.
TREM2 impacts brain microglia, oligodendrocytes and endothelial co-expression modules revealing genes and pathways important in Alzheimer’s disease
Authors: Carbajosa Guillermo , Malki Karim , Lawless Nathan , Wang Hong , Ryder John W. , Wozniak Eva , Wood Kristie , Mein Charles A. , Hodgkinson Alan , Dobson Richard J.B. , Collier David A. , O’Neill Michael J. , Newhouse Stephen J. , Hodges Angela K. 
Published: July 2021

AbstractA microglia response to pathogenic signals in diseases such as Alzheimer’s disease (AD) has long been recognised, but recent genetic findings have cemented their direct causal contribution to AD and thus the potential to target them or their effector pathways as a possible treatment strategy. TREM2 is a highly penetrant microglia risk gene for AD, which appears central to the coordination of the damage response by microglia in AD. Its absence has a negative impact on Tau and amyloid symptoms and pathologies. Full knowledge of its pathway and relationships with other brain cells in AD has not been fully characterised, but will be essential to fully evaluate the impact of manipulating this pathway for treatment development and to establish the best targets for achieving this. We used whole genome RNA sequencing of hippocampus and cortical brain samples from control, AD, and AD TREM2 risk carriers to identify TREM2-dependent genes driving changes in pathways, processes and cell types in AD. Through highly influential intra and intermodular hub genes and overall changes in the levels of gene expression, TREM2-DAP12 was found to strongly influence a number of other microglia, oligodendrocyte and endothelial genes, notably those involved in complement and Fcγ receptor function, microglia-associated ribosomal genes and oligodendrocyte genes, particularly proteosomal subunits. These strong TREM2 centred co-expression relationships were significantly disrupted in AD cases with a TREM2 risk variant, revealing for the first time genes and pathways directly impacted by TREM2 in the brains of AD patients. Consistent with its function as a lipid sensor, our data supports a role for TREM2 in mediating oligodendrocyte and/or myelin clearance in AD which may be essential not only for preserving healthy tissue homeostasis but may also serve to minimise the persistence of antigenic peptides and lipids which may lead to detrimental pro-inflammatory sequelae. Further work should expand our knowledge of TREM2 on complement and Fcγ receptor function and its impact on oligodendcrotye and myelin integrity and further evaluate the genes and pathways we have identified as possible treatment targets for AD.
Quantification ofMyxococcus xanthusAggregation and Rippling Behaviors: Deep-learning Transformation of Phase-contrast into Fluorescence Microscopy Images
Authors: Zhang Jiangguo , Comstock Jessica A. , Cotter Christopher R. , Murphy Patrick A. , Nie Weili , Welch Roy D. , Patel Ankit B. , Igoshin Oleg A. 
Published: July 2021

AbstractMyxococcus xanthusbacteria are a model system for understanding pattern formation and collective cell behaviors. When starving, cells aggregate into fruiting bodies to form metabolically inert spores. During predation, cells self-organize into traveling cell-density waves termed ripples. Both phase-contrast and fluorescence microscopy are used to observe these patterns but each has its limitations. Phase-contrast images have higher contrast, but the resulting image intensities lose their correlation with cell density. The intensities of fluorescence microscopy images, on the other hand, are well correlated with cell density, enabling better segmentation of aggregates and better visualization of streaming patterns in between aggregates. However, fluorescence microscopy requires the engineering of cells to express fluorescent proteins and can be phototoxic to the cells. To combine the advantages of both imaging methodologies, we develop a generative adversarial network that converts phase-contrast into fluorescent images. By including an additional histogram-equalized output to the state-of-art pix2pixHD algorithm, our model generates accurate images of aggregates and streams, enabling the estimation of aggregate positions and sizes, but with small shifts of their boundaries. Further training on ripple patterns enables accurate estimation of the rippling wavelength. Our methods are thus applicable for many other phenotypic behaviors and pattern formation studies.
Proximity interactome analysis of Lassa polymerase reveals eRF3a/GSPT1 as a druggable target for host directed antivirals
Authors: Fang Jingru , Pietzsch Colette , Witwit Haydar , Tsaprailis George , Crynen Gogce , Cho Kelvin Frank , Ting Alice Y. , Bukreyev Alexander , Saphire Erica Ollmann , de la Torre Juan Carlos 
Published: July 2021

AbstractCompletion of the Lassa virus (LASV) life cycle critically depends on the activities of the virally encoded RNA-dependent RNA polymerase in replication and transcription of the viral RNA genome in the cytoplasm of infected cells. The contribution of cellular proteins to these processes remains unclear. Here, we applied proximity proteomics to define the interactome of LASV polymerase in cells, under conditions that recreate LASV RNA synthesis. We engineered a LASV polymerase-biotin ligase (TurboID) fusion protein that retained polymerase activity and successfully biotinylated the proximal proteome, which allowed the identification of 42 high-confidence LASV polymerase interactors. We subsequently performed an siRNA screen to identify those interactors that have functional roles in authentic LASV infection. As proof-of-principle, we characterized eukaryotic peptide chain release factor subunit 3a (eRF3a/GSPT1), which we found to be a proviral factor that physically associates with LASV polymerase. Targeted degradation of GSPT1 by a small molecule drug candidate, CC-90009, resulted in strong inhibition of LASV infection in cultured cells. Our work demonstrates the feasibility of using proximity proteomics to illuminate and characterize yet to be defined, host-pathogen interactome, which can reveal new biology and uncover novel targets for the development of antivirals against highly pathogenic RNA viruses.Significance StatementLassa virus (LASV), the causative agent of Lassa fever (LF), represents an important public health problem in Western Africa. There is no FDA-approved therapeutic intervention to treat LF. Due to its limited genome coding capacity, LASV proteins are often multifunctional and orchestrate complex interactions with cellular factors to execute steps required to complete the viral life cycle. LASV polymerase is essential for replication and expression of the viral genome, and thus is an attractive target for antiviral intervention. Here we present the first host interactome of the LASV polymerase, which can guide identification of novel druggable host cellular targets for the development of cost-effective antiviral therapies for LF.
Identification of leptospiral protein antigens recognized by WC1+γδ T cell subsets as target for development of recombinant vaccines
Authors: Teixeira Aline F. , Gillespie Alexandria , Yirsaw Alehegne , Britton Emily , Telfer Janice C. , do Nascimento Ana Lucia , Baldwin Cynthia L. 
Published: July 2021

AbstractPathogenic Leptospira species cause leptospirosis, a neglected zoonotic disease recognized as a global public health problem. It is also the cause of the most common cattle infection that results in major economic losses due to reproductive problems. γδ T cells play a role in the protective immune response in livestock species against Leptospira while human γδ T cells also respond to Leptospira. Thus, activation of γδ T cells has emerged as a potential component for optimization of vaccine strategies. Bovine γδ T cells proliferate and produce IFN-γ in response to vaccination with inactivated leptospires and this response is mediated by a specific subpopulation of the WC1-bearing γδ T cells. WC1 molecules are members of the group B scavenger receptor cysteine rich (SRCR) superfamily and are composed of multiple SRCR domains, of which particular extracellular domains act as ligands for Leptospira. Since WC1 molecules function as both pattern recognition receptors and γδ TCR coreceptors, the WC1 system has been proposed as a novel target to engage γδ T cells. Here, we demonstrate the involvement of leptospiral protein antigens in the activation of WC1+ γδ T cells and identified two leptospiral outer membrane proteins able to interact directly with them. Interestingly, we show that the protein-specific γδ T cell response is composed of WC1.1+ and WC1.2+ subsets, although a greater number of WC1.1+γδ T cells respond. Identification of protein antigens will enhance our understanding of the role γδ T cells play in the leptospiral immune response and in recombinant vaccine development.
A strategy to suppress STAT1 signalling conserved in pathogenic poxviruses and paramyxoviruses
Authors: Talbot-Cooper Callum , Pantelejevs Teodors , Shannon John P. , Cherry Christian R. , Au Marcus T. , Hyvönen Marko , Hickman Heather D. , Smith Geoffrey L. 
Published: July 2021

SummaryThe induction of interferon-stimulated genes by signal transducer and activator of transcription (STAT) proteins, is a critical host defence to fight virus infections. Here, a highly expressed poxvirus protein 018 is shown to inhibit IFN-induced signalling by binding the SH2 domain of STAT1 to prevent STAT1 association with an activated IFN receptor. Despite the presence of additional inhibitors of IFN-induced signalling, a poxvirus lacking 018 was attenuated in mice. The 2.0 Å crystal structure of the 018:STAT1 complex reveals a mechanism for a high-affinity, pTyr-independent mode of binding to an SH2 domain. Furthermore, the STAT1 binding motif of 018 shows sequence similarity to the STAT1-binding proteins from Nipah virus, which like 018, block the association of STAT1 with an IFN receptor. Taken together, these results provide detailed mechanistic insight into a potent mode of STAT1 antagonism, found to exist in genetically diverse virus families.
Deep deconvolution of the hematopoietic stem cell regulatory microenvironment reveals a high degree of specialization and conservation between mouse and human
Authors: Ye Jin , Calvo Isabel A. , Cenzano Itziar , Vilas Amaia , Martinez-de-Morentin Xabier , Lasaga Miren , Alignani Diego , Paiva Bruno , Viñado Ana C. , Martin-Uriz Patxi San , Romero Juan P. , Agreda Delia Quilez , Barrios Marta Miñana , González Ignacio Sancho , Todisco Gabriele , Malcovati Luca , Planell Nuria , Saez Borja , Tegner Jesper , Prosper Felipe , Gomez-Cabrero David 
Published: July 2021

ABSTRACTUnderstanding the regulation of normal and malignant human hematopoiesis requires comprehensive cell atlas of the hematopoietic stem cell (HSC) regulatory microenvironment. Here, we develop a tailored bioinformatic pipeline to integrate public and proprietary single-cell RNA sequencing (scRNA-seq) datasets. As a result, we robustly identify for the first time 14 intermediate cell states and 11 stages of differentiation in the endothelial and mesenchymal BM compartments, respectively. Our data provide the most comprehensive description to date of the murine HSC-regulatory microenvironment and suggests a higher level of specialization of the cellular circuits than previously anticipated. Furthermore, this deep characterization allows to infer conserved features in human, suggesting that the layers of microenvironmental regulation of hematopoiesis may also be shared between species. Our resource and methodology are a steppingstone towards a comprehensive cell atlas of the BM microenvironment.
A subcellular biochemical model for T6SS dynamics reveals winning competitive strategies
Authors: Lin Yuexia Luna , Smith Stephanie N. , Kanso Eva , Septer Alecia N. , Rycroft Chris H. 
Published: July 2021

AbstractThe Type VI secretion system (T6SS) is a broadly distributed interbacterial weapon that can be used to eliminate competing bacterial populations. Although unarmed target populations are typically used to study T6SS function, bacteria most likely encounter other T6SS-armed competitors in nature. The outcome of such battles is not well understood, neither is the connection between the outcomes with the subcellular details of the T6SS. Here, we incorporated new biological data derived from natural competitors of Vibrio fischeri light organ symbionts to build a biochemical model for T6SS function at the single cell level. The model accounts for activation of structure formation, structure assembly, and deployment. By developing an integrated agent-based model (IABM) that incorporates strain-specific T6SS parameters, we replicated outcomes of biological competitions, validating our approach. We used the IABM to isolate and manipulate strain-specific physiological differences between competitors, in a way that is not possible using biological samples, to identify winning strategies for T6SS-armed populations. We found that a tipping point exists where the cost of building more T6SS weapons outweighs their protective ability. Furthermore, we found that competitions between a T6SS-armed population and a unarmed target had different outcomes dependent on the geometry of the battlefield: target cells survived at the edges of a range expansion scenario where unlimited territory could be claimed, while competitions within a confined space, much like the light organ crypts where natural V. fischeri compete, resulted in the rapid elimination of the unarmed competitor.