bluuebunny/crossref_metadata_2025_split huggingface dataset:
Plasma metabolomics of primary open-angle glaucoma in three prospective US cohorts and the UK Biobank
Authors: Zeleznik Oana , Kang Jae H. , Lasky-Su Jessica , Eliassen A. Heather , Frueh Lisa , Clish Clary , Rosner Bernard A. , Elze Tobias , Hysi Pirro , Khawaja Anthony , Wiggs Janey L. , Pasquale Louis R. 
Published: March 2022

ABSTRACTPurposeTo better understand the etiologic pathways in glaucoma, we aimed to identify pre-diagnostic plasma metabolites associated with glaucoma risk.MethodsIn a case-control study from the Nurses’ Health Study (NHS), NHSII and Health Professionals Follow-Up Study (HPFS), 599 incident primary open-angle glaucoma (POAG) cases (mean time between blood draw and diagnosis was 10.3 years) were 1:1 matched to 599 controls. Plasma metabolites were measured with LC-MS/MS at the Broad Institute (Cambridge, MA, USA); 367 metabolites from 17 metabolite classes passed quality control analyses. For comparison, in a cross-sectional study in the UK Biobank, 168 NMR metabolites (Nightingale, Finland; version 2020) were measured in serum samples from 2,238 prevalent glaucoma cases and 44,723 controls. Metabolites were probit-score transformed for normality; multiple logistic regression was used to identify metabolites associated with POAG in NHS/NHSII/HPFS and glaucoma in UK Biobank. In NHS/NHSII/HPFS, we also used Metabolite Set Enrichment Analysis to identify metabolite classes associated with POAG. All analyses adjusted for established glaucoma risk factors. False discovery rate (FDR) and number of effective tests (NEF) were used to adjust for multiple comparisons.ResultsNine metabolite classes were associated (FDR<0.05) with POAG in NHS/NHSII/HPFS: triglycerides, diglycerides, two lysophospholipids classes [lysophosphatidylcholines and lysophosphatidylethanolamines], and two phospholipid class [phosphatidylethanolamines and phosphatidylcholines] were positively associated, while cholesteryl esters, carnitines, and organic acids and derivatives were inversely associated with POAG risk; further adjustment for covariates minimally altered the results. These associations were particularly stronger for POAG with paracentral visual field loss. In the UK Biobank, notably, triglycerides and phospholipids (from which lysophospholipids are derived through hydrolysis), were confirmed to be associated (p<0.05) with higher glaucoma risk. Also, in the UK Biobank, the metabolites of tyrosine, glucose, and glutamine were positively associated (NEF<0.2) while 3-hydroxybutyrate, acetate, citrate, pyruvate, and lactate (the latter 4 being anionic organic acids) were inversely associated with glaucoma (NEF<0.05).ConclusionsHigher levels of glycerides (diglycerides and triglycerides) and phospholipids were adversely associated with glaucoma in both the NHS/NHSII/HPFS and the UK Biobank, suggesting that they play an important role in glaucoma pathogenesis.PRÉCISHigher glyceride and phospholipid levels in pre-diagnostic plasma was associated with glaucoma risk in three cohorts and were associated with prevalent glaucoma in the UK Biobank. Altered lipid metabolism may be etiologically important in glaucoma.
The role of liver fat in cardiometabolic diseases is highlighted by genome-wide association study of MRI-derived measures of body composition
Authors: van der Meer Dennis , Gurholt Tiril P. , Sønderby Ida E. , Shadrin Alexey A. , Hindley Guy , Rahman Zillur , de Lange Ann-Marie G. , Frei Oleksandr , Leinhard Olof D. , Linge Jennifer , Simon Rozalyn , Westlye Lars T. , Halvorsen Sigrun , Dale Anders M. , Karlsen Tom H. , Kaufmann Tobias , Andreassen Ole A. 
Published: March 2022

AbstractBackground & AimsObesity and associated morbidities, metabolic associated liver disease (MAFLD) included, constitute some of the largest public health threats worldwide. Body composition and related risk factors are known to be heritable and identification of their genetic determinants may aid in the development of better prevention and treatment strategies. Recently, large-scale whole-body MRI data has become available, providing more specific measures of body composition than anthropometrics such as body mass index. Here, we aimed to elucidate the genetic architecture of body composition, by conducting the first genome-wide association study (GWAS) of these MRI-derived measures.MethodsWe ran both univariate and multivariate GWAS on fourteen MRI-derived measurements of adipose and muscle tissue distribution, derived from scans from 34,036 White European UK Biobank participants (mean age of 64.5 years, 51.5% female).ResultsThrough multivariate analysis, we discovered 108 loci with distributed effects across the body composition measures and 256 significant genes primarily involved in immune system functioning. Liver fat stood out, with a highly discoverable and oligogenic architecture and the strongest genetic associations. Comparison with 21 common cardiometabolic traits revealed both shared and specific genetic influences, with higher mean heritability for the MRI measures (h2=.25 vs. .16, p=1.4×10−6). We found substantial genetic correlations between the body composition measures and a range of cardiometabolic diseases, with the strongest correlation between liver fat and type 2 diabetes (rg=.48, p=1.6×10−22).ConclusionsThese findings show that MRI-derived body composition measures complement conventional body anthropometrics and other biomarkers of cardiometabolic health, highlighting the central role of liver fat, and improving our knowledge of the genetic architecture of body composition and related diseases.
Impact of a sanitation intervention on quality of life and mental wellbeing in low-income urban neighbourhoods of Maputo, Mozambique
Authors: Ross Ian , Greco Giulia , Adriano Zaida , Nala Rassul , Brown Joe , Opondo Charles , Cumming Oliver 
Published: March 2022

AbstractObjectivesToilet users often report valuing privacy and safety more highly than reduced disease, but effects of urban sanitation interventions on such outcomes have never been assessed quantitatively. In this study, we evaluate the impact of a shared sanitation intervention on quality of life (QoL) and mental wellbeing.DesignWe interviewed individuals living in intervention and control clusters of a recent non-randomised controlled trial, and used generalised linear mixed regression models to make an observational comparison of outcomes.Settinglow-income unsewered areas of Maputo City, MozambiqueParticipantsWe interviewed 424 participants, 222 from the prior trial’s intervention group, and 202 from the control group.InterventionsThe control group used low-quality pit latrines. The intervention group received high-quality shared toilets, contributing 10-15% of capital cost.OutcomesOur primary outcome was the sanitation-related quality of life (SanQoL) index, which applies respondent-derived weights to combine toilet users’ perceptions of sanitation-related disgust, privacy, safety, health, and shame. Secondary outcomes were the WHO-5 mental wellbeing index and a sanitation visual analogue scale.ResultsThe intervention group experienced a 1.6 standard deviation gain in SanQoL compared to the control group. This adjusted SanQoL gain was 0.34 (95% CI: 0.29-0.38) on a 0-1 scale with control mean 0.49. Effect sizes were largest for safety and privacy attributes. Intervention respondents also experienced a 0.2 standard deviation gain in mental wellbeing. The adjusted gain was 6.2 (95% CI: 0.3-12.2) on a 0-100 scale with control mean 54.4.ConclusionsQuality of life outcomes highly valued by toilet users and can be improved by sanitation interventions. Such outcomes should be measured in future sanitation trials, to help identify interventions which most improve people’s lives. Since SanQoL weights are derived from respondent valuation, the measure can also be used in economic evaluation.
The ITPRIPL1- CD3ε axis: a novel immune checkpoint controlling T cells activation
Authors: Deng Shouyan , Wang Yiting , Brosseau Jean-Philippe , Wang Yungang , Xu Jie 
Published: March 2022

AbstractThe immune system is critical to fighting infections and disease. The molecular recognition of harmful entities takes place when antigen-presenting cells (APC) harboring major histocompatibility complex (MHC) molecules bound to peptides derived from harmful antigens (ligand) dock on specific T cell receptor (TCR)-CD3 complex (receptor) at the surface of CD8+ T cells. The discovery of a general immune checkpoint mechanism to avoid the harmful impact of T cell hyperactivation provoked a paradigm shift. The clinical relevance of this mechanism is highlighted by the fact that PD-1 and PD-L1 inhibitors are very effective at boosting immune reactions. Still, immune evasion frequently happens. The observation that some PD-1/PD-L1 negative tumors have a poor immune response opens the door to identifying a novel immune checkpoint mechanism. Here, we discovered that ITPRIPL1, a gene with unknown function, impairs T cell activation. Surprisingly, we found that CD3ε is the direct receptor of ITPRIPL1. This novel immune checkpoint was validated as a drug target using ITPRIPL1 KO mice and monoclonal antibodies. Thus, targeting the ITPRIPL1-CD3e axis, especially in PD-1 - PDL-1 negative patients, is a promising therapeutic strategy to reduce immune evasion.
An immunoPET probe to SARS-CoV-2 reveals early infection of the male genital tract in rhesus macaques
Authors: Madden Patrick J. , Thomas Yanique , Blair Robert V. , Samer Sadia , Doyle Mark , Midkiff Cecily C. , Doyle-Meyers Lara A. , Becker Mark E. , Arif Muhammad S. , McRaven Michael D. , Simons Lacy M. , Carias Ann M. , Martinelli Elena , Lorenzo-Redondo Ramon , Hultquist Judd F , Villinger Francois J. , Veazey Ronald S. , Hope Thomas J. 
Published: March 2022

AbstractThe systemic nature of SARS-CoV-2 infection is highly recognized, but poorly characterized. A non-invasive and unbiased method is needed to clarify whole body spatiotemporal dynamics of SARS-CoV-2 infection after transmission. We recently developed a probe based on the anti-SARS-CoV-2 spike antibody CR3022 to study SARS-CoV-2 pathogenesis in vivo. Herein, we describe its use in immunoPET to investigate SARS-CoV-2 infection of three rhesus macaques. Using PET/CT imaging of macaques at different times post-SARS-CoV-2 inoculation, we track the 64Cu-labelled CR3022-F(ab’)2 probe targeting the spike protein of SARS-CoV-2 to study the dynamics of infection within the respiratory tract and uncover novel sites of infection. Using this method, we uncovered differences in lung pathology between infection with the WA1 isolate and the delta variant, which were readily corroborated through computed tomography scans. The 64Cu-CR3022-probe also demonstrated dynamic changes occurring between 1- and 2-weeks post-infection. Remarkably, a robust signal was seen in the male genital tract (MGT) of all three animals studied. Infection of the MGT was validated by immunofluorescence imaging of infected cells in the testicular and penile tissue and severe pathology was observed in the testes of one animal at 2-weeks post-infection. The results presented here underscore the utility of using immunoPET to study the dynamics of SARS-CoV-2 infection to understand its pathogenicity and discover new anatomical sites of viral replication. We provide direct evidence for SARS-CoV-2 infection of the MGT in rhesus macaques revealing the possible pathologic outcomes of viral replication at these sites.Graphic AbstractPET/CT detected SARS-CoV-2 infection of 4 different tissues in the male genital tract illuminates the cause of COVID-19 clinical sequalae of male sexual health and fertility
Figure 1.Diagram shows schematic illustration of the male genital tract of the rhesus macaque. Virus icon shows sites of SARS-CoV-2 PET signal. Text highlighting the clinical sequalae associated with each sight of infection is shown in text adjacent to each infection site.
Automated, Reproducible Investigation of gene set Differential Enrichment via the AUTO-go framework
Authors: Sperandio Eleonora , Grassucci Isabella , D’Ambrosio Lorenzo , Pallocca Matteo 
Published: March 2022

AbstractReproducibility in Life Sciences is challenged in the analysis of large multi-omics datasets. One of the final steps of said processes is Gene Set enrichment, where web tools represent a valuable resource but not a reliable surrogate for standardized, high-quality visualizations. The AUTO-go framework proposes standardization of the Gene Functional Enrichment process along with an R framework able to produce high-quality visualization in an automated manner, improving the reproducibility of the whole analytical process. We present three use cases in Cancer Transcriptomics and Epigenomics datasets as a proof-of-concept to visualize Multiple Differential Expression and Single Sample Gene Set Enrichment Analysis.Author SummaryBioinformatics and Data Science are routinely challenged to distill intelligible results from huge amounts of data. These results, in turn, are conveyed through plots and visualizations that should be easily reproducible for scientific soundness and ethical reasons. A specific area in which these analyses are of critical importance is Genomics, where Genes functions need to be enriched when comparing pathological states or treatments. Here we present a software framework that aims at standardizing said differential analyses and visualizations when dealing with genomics data. Finally, we show how it can be employed to shear light on publicly available datasets, even in small casuistry of Rare Cancers.
Metabolomic profiles of chronic distress predict future cardiovascular disease risk
Authors: Balasubramanian Raji , Shutta Katherine H. , Guasch-Ferre Marta , Huang Tianyi , Jha Shaili C. , Zhu Yiwen , Shadyab Aladdin H. , Manson JoAnn E. , Hu Frank , Rexrode Kathryn M. , Clish Clary B. , Hankinson Susan E. , Kubzansky Laura D. 
Published: March 2022

BackgroundChronic psychological distress has been associated with increased risk of cardiovascular disease (CVD). However, mechanistic evidence explaining the observed associations remains limited and, with data are particularly sparse among women. This study examined if a metabolite profile linked with distress would be associated with increased risk of CVD.MethodsA plasma metabolite-based distress score (MDS) of twenty metabolites was derived in a cross-sectional, 1:1 matched case-control dataset (n=558 women) in the Nurses’ Health Study (NHS). We then calculated this score in two other cohorts, the Women’s Health Initiative Observational Cohort (WHI-OS) and the Prevención con Dieta Mediterránea (PREDIMED) trial, and tested association with risk of developing adjudicated measures of CVD in each cohort. We considered incident coronary heart disease (CHD) in the WHI-OS dataset which included 944 postmenopausal women (472 CHD cases; mean time to event of 5.8 years), and incident CVD (including stroke, myocardial infarction, CVD death) in the PREDIMED dataset which included 980 men and women (224 CVD cases, mean time to event of 3.1 years).ResultsIn the WHI-OS, a 1-SD increase in the plasma MDS was associated with a 14% increased risk of incident CHD (odds ratio [OR]=1.14, 95% CI: 1.03 – 1.26), adjusting for known CVD risk factors excluding total and HDL cholesterol. This association was attenuated after including total and HDL cholesterol (OR=1.09; 95% CI: 0.98 – 1.21). Of the component metabolites in the MDS, tryptophan and threonine were inversely associated with incident CHD risk. In PREDIMED, each one SD increase in the MDS was associated with a 17% increased incident CVD risk (OR=1.17, 95% CI: 1.00 – 1.38), after adjusting for risk factors including total and HDL cholesterol. Similar associations were observed in men and women. Four individual metabolites in the MDS were associated with incident CVD risk in fully adjusted models in PREDIMED. Biliverdin and C36:5 PC plasmalogen had inverse associations, whereas C16:0 ceramide and C18:0 LPE each had positive associations with CVD risk.ConclusionsOur study sheds light on the key molecular alterations that characterize chronic distress and are predictive of subsequent CVD risk in men and women. These findings provide additional evidence for the role of distress in CVD development.
Human MAIT cells show clonal diversity but transcriptional and functional homogeneity
Authors: Garner Lucy C. , Amini Ali , FitzPatrick Michael E.B. , Provine Nicholas M. , Klenerman Paul 
Published: March 2022

AbstractMucosal-associated invariant T (MAIT) cells are considered to have limited clonal diversity. In contrast, recent studies suggest the presence of functionally distinct subsets. We investigated this model through single-cell analysis of the MAIT cell TCR repertoire and transcriptional profile in human blood and liver. Further, we developed functional RNA-sequencing (fRNA-seq), an approach to integrate cellular function and TCR clonotype at a single-cell level following differential stimulation. MAIT cells showed surprising clonal diversity, with TCR repertoires shared across tissues but unique to individuals. Functional diversity within resting MAIT cells was low and largely related to tissue site. MAIT cells displayed distinct transcriptional responses to in vitro TCR and cytokine stimulation, with cells positioned along gradients of activation. Clonal origin influenced both resting and activated transcriptional profiles. Overall, MAIT cells exhibit diverse donor-specific TCR repertoires which, along with tissue and activation context, influence their phenotype and function.
Early Childhood Reading for Pleasure: Evidence from the ABCD Study for Benefits to Cognitive Performance and Mental Health and Associated Changes in Brain Structure
Authors: Sun Yunjun , Sahakian Barbara J. , Langley Christelle , Yang Anyi , Jiang Yuchao , Zhao Xingming , Li Chunhe , Cheng Wei , Feng Jianfeng 
Published: March 2022

AbstractBACKGROUNDEarly childhood has increasingly been recognized as an important neurodevelopmental period. However, the links between specific forms of early educational activities and cognition and mental health remain unclear.METHODSA large-scale analysis on the attainments of childhood Reading for Pleasure (early RfP) and its relationship with young adolescent measures of cognition, mental health and brain structure was conducted, using linear mixed-effects model, structural equation and mediation analyses. Participants were from the Adolescent Brain and Cognitive Development (ABCD) study, a USA national cohort (n=11,878). A two-sample Mendelian randomization (MR) analysis using genetic instruments from two independent genome-wide association studies (GWAS) based on ABCD and GWAS meta-analyses including UK-biobank datasets were conducted to assess potential causal inference.RESULTSEarly RfP was positively associated with cognitive assessments, which in contrast, was negatively associated with dimensional psychiatric problems in young adolescents. MR analysis revealed a beneficial relationship between early RfP and later-life cognitive performance, and a trend towards a protective relationship between early RfP and later-life attention disorder. Brain regions in which larger cortical areas were positively associated with early RfP included the superior temporal, prefrontal, left angular, parahippocampal, right anterior cingulate (ACC), occipital, supramarginal and orbital regions and subcortical ventral diencephalon (DC), thalamus, and brainstem volumes. Mediation analysis indicated that the brain regions significantly mediated the effects of early RfP with better cognitive performance and lower psychiatric problems.INTERPRETATIONOur results highlight the importance of encouraging RfP in young children during the critical early childhood stage, as it was associated with beneficial outcomes for cognition, mental health, and brain structure later in life.
ARID1A maintains transcriptionally repressive H3.3 associated with CHD4-ZMYND8 chromatin interactions
Authors: Reske Jake J. , Wilson Mike R. , Armistead Brooke , Perez Cristina , Hrit Joel , Adams Marie , Rothbart Scott B. , Missmer Stacey A. , Fazleabas Asgerally T. , Chandler Ronald L. 
Published: March 2022

AbstractARID1A is a signature subunit of the mammalian SWI/SNF (BAF) chromatin remodeling complex and is mutated at a high rate in malignancies and benign diseases originating from the uterine endometrium. Through genome-wide analysis of human endometriotic epithelial cells, we show that more than half of ARID1A binding sites are marked by the variant histone H3.3, including active regulatory elements. ARID1A loss leads to H3.3 depletion at ARID1A bound active regulatory elements and a concomitant redistribution of H3.3 towards genic elements. ARID1A interactions with the repressive chromatin remodeler CHD4 (NuRD) are associated with H3.3-containing chromatin regulation. ZMYND8, the CHD4-interacting acetyl-histone H4 reader, specifies ARID1A-CHD4-H3.3 target regulatory activity towards histone H4 lysine 16 acetylation (H4K16ac) to repress super-enhancers. ARID1A, H3.3, CHD4, and ZMYND8 co-repress the expression of genes governing extracellular matrix, motility, adhesion, and epithelial-to-mesenchymal transition. Moreover, these gene expression alterations are observed in human endometriomas. Altogether, these studies demonstrate that cooperation among a histone reader and different types of chromatin remodelers safeguards the endometrium through transcriptionally repressive H3.3.
An Open-source, Cost-Efficient Excitation Module for Single-molecule Microscopy
Authors: George Dylan R. , Ambrose Benjamin , Cadby Ashley J. , Craggs Timothy D. 
Published: March 2022

AbstractIn fluorescence microscopy, scientific-grade laser diodes are key components and contribute a considerable expense to the total cost of the microscope setup. Existing open-source laser excitation modules are mainly designed for super-resolution imaging and have not been fully characterised to meet the requirements of single-molecule spectroscopy measurements. In this paper we introduce an open-source, cost-efficient excitation module that can be used for confocal, accurate single-molecule FRET, fluorescence correlation spectroscopy (FCS) and low-power super-resolution techniques. The module delivers two diode lasers (520 nm and 638 nm) via a single-mode fibre, with stable power output (<1% deviation), which can be modulated on the microsecond timescale. Here, we benchmark these lasers against smFRET standards, and recover consistent diffusion coefficients from FCS measurements, thereby demonstrating their suitability for a range of single-molecule spectroscopic experiments, whilst reducing the overall costs of our open-source smFRET instrument (the smfBox) by ~50%, making these types of experiments even more accessible to the widest possible userbase.