bluuebunny/crossref_metadata_2025_split huggingface dataset:
Variation inERAP2has opposing effects on severe respiratory infection and autoimmune disease
Authors: Hamilton Fergus , Mentzer Alexander , Parks Tom , Baillie J Kenneth , Davey Smith George , Ghazal Peter , Timpson Nicholas J 
Published: November 2022

IntroductionERAP2is an aminopeptidase involved in immunological antigen presentation. Genotype data in human samples from before and after the Black Death, an epidemic due toYersinia pestis, have marked changes in population allele frequency of the common single nucleotide polymorphism (SNP) rs2549794. This SNP in strong linkage disequilibrium with a key splicing SNP inERAP2(rs2248374) and this suggests that variation atERAP2may be relevant for protection from infection. rs2549794 is also associated with Crohn’s disease and findings imply balancing selection between infection and autoimmune disease at this locus. There have been no large-scale prospective case-control studies of variation atERAP2and infection.MethodsThis study aimed to explore the association between variation atERAP2and a) infection, b) autoimmune disease, and c) parental longevity as a proxy for lifespan. Genome Wide Association Studies (GWAS) of these outcomes were identified in contemporary cohorts (UK Biobank, FinnGen, and GenOMICC). Effect estimates were extracted for rs2549794 and rs2248374. Additionally,cisexpression and protein quantitative trait loci (QTLs) forERAP2were used in Mendelian randomisation analyses.ResultsAcross all cohorts, the T allele (minor allele frequency of 0.4-0.5) of rs2549794 showed evidence of association with respiratory infection (odds ratio; OR for pneumonia 1.03; 95% CI 1.01-1.05; p = 0.014). Effect estimates were larger in bacterial rather than viral infection and larger for more severe phenotypes (OR for critical care admission with pneumonia 1.08; 95% CI 1.02-1.14, p = 0.008, OR for death from pneumonia 1.07; 95% CI 1.01-1.12; p = 0.014). In contrast, opposing effects were identified for Crohn’s disease (OR 0.86; 95% CI 0.82-0.90, p = 8.6 × 10−9) and type 1 diabetes (OR 0.95; 95% CI 0.90-0.99, p = 0.02). No strong evidence for association was identified for sepsis. Carriage of the T allele was associated with increased age of parental death (beta in Z-scored years across both parents age at death 0.01, 95% CI 0.004-0.017, p = 0.002). Similar results were identified for rs2248374.In Mendelian randomisation analyses, increasing transcription or protein levels ofERAP2were strongly associated with protection from respiratory infection, with opposing effects identified on Crohn’s disease and type 1 diabetes. Increased expression ofERAP2was associated with reduced parental longevity.ConclusionsVariation atERAP2is associated with severe respiratory infection in modern societies, with an opposing association with Crohn’s disease and type 1 diabetes. These data support the hypothesis that changes in allele frequencies inERAP2observed at the time of the Black Death reflect protection from infection, and suggest ongoing balancing selection at this locus driven by autoimmune and infectious disease
Charting the Fourth Wave: Geographic, Temporal, Race/Ethnicity, and Demographic Trends in Polysubstance Fentanyl Overdose Deaths in the United States, 2010-2021
Authors: Friedman Joseph , Shover Chelsea 
Published: November 2022

ABSTRACTAimsTo characterize polysubstance death in the United States during the transition to the fourth wave of the overdose crisis. To characterize co-involved substances in fatal overdose involving synthetic opioids (mainly illicitly manufactured fentanyl analogs) by year, state, and intersectional sociodemographic groups.DesignPopulation-based cohort study of national death records.SettingUnited States.Participants/CasesPeople who died from drug overdose in the United States between 2010-2021.MeasurementsPercentage of all fatal overdose involving fentanyls, stimulants, and other drugs. Most commonly co-involved substances in fentanyl overdose by state and year. Percentage of fatal fentanyl overdose co-involving stimulants by state and year. Percentage of fatal fentanyl overdose co-involving stimulants by intersectional region, race/ethnicity, age, and sex.FindingsThe percent of US overdose deaths involving both fentanyl and stimulants concurrently rose nearly 60-fold, from 0.6% (n=235) in 2010 to 32.3% (n=34,424) in 2021. In 2010, fentanyl was most commonly found alongside prescription opioids, benzodiazepines, and alcohol. In the Northeast this shifted to heroin-fentanyl co-involvement in the mid-2010s, and nearly universally to cocaine-fentanyl co-involvement by 2021. Universally in the West, and in the majority of states in the South and Midwest, methamphetamine-fentanyl co-involvement predominated by 2021. The proportion of stimulant involvement in fentanyl-involved overdose deaths rose in virtually every state 2015-2021. Cluster analysis reveals particularly high rates for older Black and African American individuals living in the West.ConclusionsBy 2021 stimulants were the most common drug class found in fentanyl-involved overdoses in every state in the US. The rise of deaths involving cocaine and methamphetamine must be understood in the context of a drug market dominated by illicit fentanyls, which have made polysubstance use more desirable and commonplace. The widespread concurrent use of fentanyl and stimulants, as well as other polysubstance formulations, presents novel health risks and public health challenges. Ongoing nuanced surveillance is needed to track this rapidly shifting phenomenon.
Development of risk prediction models for preterm delivery in a rural setting in Ethiopia
Authors: Pons-Duran Clara , Wilder Bryan , Hunegnaw Bezawit Mesfin , Haneuse Sebastien , Goddard Frederick G. B. , Bekele Delayehu , Chan Grace J. 
Published: November 2022

ABSTRACTBackgroundPreterm birth complications are the leading causes of death among children under five years. A key practical challenge, however, is the inability to accurately identify pregnancies that are at high risk of preterm delivery, especially in resource-limited settings where there is limited availability of biomarkers assessment.MethodsWe evaluated whether risk of preterm delivery can be predicted using available data from a pregnancy and birth cohort in Amhara region, Ethiopia. All participants were enrolled in the cohort between December 2018 and March 2020. The study outcome was preterm delivery, defined as any delivery occurring before week 37 of gestation regardless of vital status of the fetus or neonate. A range of sociodemographic, clinical, environmental, and pregnancy-related factors were considered as potential inputs. Cox and accelerated failure time models, and decision tree ensembles were used to predict risk of preterm delivery. Model discrimination was estimated using the area-under-the-curve (AUC). Additionally, the conditional distributions of cervical length (CL) and fetal fibronectin (FFN) were simulated to ascertain whether those factors could improve model performance.ResultsA total of 2493 pregnancies were included. Of those, 138 women were censored due to loss-to-follow-up before delivery. Overall, predictive performance of models was poor. The AUC was highest for the tree ensemble classifier (0.60, 95%CI [0.57, 0.63]). When models were calibrated so that 90% of women who experienced a preterm delivery were classified as high risk, at least 75% of those classified as high risk did not experience the outcome. The simulation of CL and FFN distributions did not significantly improve models’ performance.ConclusionsPrediction of preterm delivery remains a major challenge. In resource-limited settings, predicting high-risk deliveries would not only save lives, but also inform resource allocation. It may not be possible to accurately predict risk of preterm delivery without investing in novel technologies to identify genetic factors, immunological biomarkers or the expression of specific proteins.
Global transmission suitability maps for dengue virus transmitted byAedes aegyptifrom 1981 to 2019
Authors: Nakase Taishi , Giovanetti Marta , Obolski Uri , Lourenço José 
Published: November 2022

ABSTRACTMosquito-borne viruses increasingly threaten human populations due to accelerating changes in climate, human and mosquito migration, and land use practices. Over the last three decades, the global distribution of dengue has rapidly expanded, causing detrimental health and economic problems in many areas of the world. To develop effective disease control measures and plan for future epidemics, there is an urgent need to map the current and future transmission potential of dengue across both endemic and emerging areas. Expanding and applying Index P, a previously developed mosquito-borne viral suitability measure, we map the global climate-driven transmission potential of dengue virus transmitted byAedes aegyptimosquitoes from 1981 to 2019. This database of dengue transmission suitability maps and an R package for Index P estimations are offered to the public health community as resources towards the identification of past, current and future transmission hotspots. These resources and the studies they facilitate can contribute to the planning of disease control and prevention strategies, especially in areas where surveillance is unreliable or non-existent.
Wearable-Derived Maternal Heart Rate Variability As A Novel Digital Biomarker of Preterm Birth
Authors: Jasinski Summer R. , Rowan Shon , Presby David M. , Claydon Elizabeth A. , Capodilupo Emily R. 
Published: November 2022

AbstractDespite considerable health consequences from preterm births, their incidence remains unchanged over recent decades, due partially to limited screening methods and limited use of extant methods. Wearable technology offers a novel, noninvasive, and acceptable way to track vital signs, such as maternal heart rate variability (mHRV). Previous research observed that mHRV declines throughout the first 33 weeks of gestation in term, singleton pregnancies, after which it improves. The aim of this study was to explore whether mHRV inflection is a feature of gestational age or an indication of time to delivery. This retrospective case-control study considered term and preterm deliveries. Remote data collection via non-invasive wearable technology enabled diverse participation with subjects representing 42 US states and 16 countries. Participants (N=241) were recruited from the WHOOP (Whoop, Inc.) userbase and wore WHOOP straps during singleton pregnancies between March 2021 and October 2022. Mixed effect spline models by gestational age and time until birth were fit for within-person mHRV, grouped into preterm and term births. For term pregnancies, gestational age (AIC = 26627.6, R2m = 0.0109, R2c= 0.8571) and weeks until birth (AIC =26616.3, R2m = 0.0112, R2c = 0.8576) were representative of mHRV trends, with significantly stronger fit for weeks until birth (relative log-likelihood ratio = 279.5). For preterm pregnancies, gestational age (AIC =1861.9, R2m = 0.0016, R2c = 0.8582) and time until birth (AIC = 1848.0, R2m = 0.0100, R2c = 0.8676) were representative of mHRV trends, with significantly stronger fit for weeks until birth (relative log-likelihood ratio= 859.4). This study suggests that wearable technology, such as the WHOOP strap, may provide a digital biomarker for preterm delivery by screening for changes in nighttime mHRV throughout pregnancy that could in turn alert to the need for further evaluation and intervention.
Multimodal and spatially resolved profiling identifies distinct patterns of T-cell infiltration in nodal B-cell lymphoma entities
Authors: Roider Tobias , Baertsch Marc A. , Fitzgerald Donnacha , Voehringer Harald , Brinkmann Berit J. , Czernilofsky Felix , Knoll Mareike , Llaó-Cid Laura , Bruch Peter-Martin , Liebers Nora , Schürch Christian M. , Passerini Verena , Brobeil Alexander , Mechtersheimer Gunhild , Müller-Tidow Carsten , Weigert Oliver , Seiffert Martina , Nolan Garry P. , Huber Wolfgang , Dietrich Sascha 
Published: November 2022

SummaryT-cell-engaging immunotherapies have improved the treatment of nodal B-cell lymphoma, but responses vary highly. Future improvements of such therapies require better understanding of the variety of lymphoma-infiltrating T-cells. We employed single-cell RNA and T-cell receptor sequencing alongside quantification of surface proteins, flow cytometry and multiplexed immunofluorescence on 101 lymph nodes from healthy controls, and patients with diffuse large B-cell, mantle cell, follicular, or marginal zone lymphoma. This multimodal resource revealed entity-specific quantitative and spatial aberrations of the T-cell microenvironment. Clonal PD1+TCF7-but not PD1+TCF7+cytotoxic T-cells converged into terminally exhausted T-cells, the proportions of which were variable across entities and linked to inferior prognosis. In follicular and marginal zone lymphoma, we observed expansion of follicular helper and IKZF3+regulatory T-cells, which were clonally related and inversely associated with tumor grading. Overall, we portray lymphoma-infiltrating T-cells with unprecedented comprehensiveness and decipher both beneficial and adverse dimensions of T-cell response.
Improving annotation propagation on molecular networks through random walks: Introducing ChemWalker
Authors: Borelli Tiago C. , Arini Gabriel Santos , Feitosa Luís G. P. , Dorrestein Pieter C. , Lopes Norberto P. , da Silva Ricardo R. 
Published: November 2022

AbstractAnnotation of the mass signals is still the biggest bottleneck for the untargeted mass spectrometry analysis of complex mixtures. Molecular networks are being increasingly adopted by the mass spectrometry community as a tool to annotate large scale experiments. We have previously shown that the process of propagating annotations from spectral library matches on molecular networks can be automated using Network Annotation Propagation (NAP). One of the limitations of NAP is that the information for the spectral matches is only propagated locally, to the first neighbor of a spectral match. Here we show that annotation propagation can be expanded to nodes not directly connected to spectral matches using random walks on graphs, introducing the ChemWalker python library. Similarly to NAP, ChemWalker relies on combinatorial in silico fragmentation results, performed by MetFrag, searching biologically relevant databases. Departing from the combination of a spectral network and the structural similarity among candidate structures, we have used MetFusion Scoring function to create a weight function, producing a weighted graph. This graph was subsequently used by the random walk to calculate the probability of ‘walking’ through a set of candidates, departing from seed nodes (represented by spectral library matches). This approach allowed the information propagation to nodes not directly connected to the spectral library match. Compared to NAP, ChemWalker has a series of improvements, on running time, scalability and maintainability and is available as a stand alone python package. ChemWalker is freely available athttps://github.com/computational-chemical-biology/ChemWalker.
CTCF mediates the Activity-by-contact derived cis-regulatory hubs
Authors: Lee Mick , Mangnier Loïc , Padilla Cory C. , Lee Dominic Paul , Tan Wilson , Li Peter Yiqing , Zheng Wen Hao , Gan Louis , Chen Ching Kit , Lim Yee Phong , Qin Wang Rina Miao , Bilodeau Steve , Bureau Alexandre , Foo Roger Sik-Yin , Anene-Nzelu Chukwuemeka George 
Published: November 2022

ABSTRACTThe 3D chromatin architecture establishes a complex network of genes and regulatory elements necessary for transcriptomic regulation in development and disease. This network can be modeled by cis-regulatory hubs (CRH) which underscore the local functional interactions between enhancers and promoter regions and differ from other higher order chromatin structures such as topological associated domains (TAD). The Activity-by-contact (ABC) model of enhancer-promoter regulation has been recently used in the identification of these CRHs, but little is known about the role of CTCF on the ABC scores and the consequent impact on CRHs. Here we show that the loss of CTCF leads to a reorganization of the enhancer-promoter interactions resulting in a re-distribution of ABC scores of the putative enhancers in C57/bl6 mouse hearts. The loss of CTCF also leads to a global reduction of the total number of CRHs, and an increase in the size of the CRHs due to increase in the number of elements within each hub. In addition, CTCF loss led to more CRHs that cross TAD boundaries. These results provide another layer of evidence to support the importance of CTCF in the formation of regulatory networks necessary for gene regulation.
GHB degradation via TCA cycle is the major metabolic route inArabidopsis thaliana
Authors: Mekonnen Dereje W. 
Published: November 2022

AbstractGamma-hydroxybutyric acid (GHB) is a reduced product of the chemically reactive succinic semi-aldehyde (SSA), which itself is produced from the degradation of GABA. It is regarded as a short chain fatty acid. Despite our understanding of the synthesis of GHB, little is known about its fate. Exogenous application of 0.1 mM GHB topop2 x ssadh, a double mutant incapable of catabolizing GABA, increased the endogenous GHB level by 13-fold compared to the wild type. The GHB dynamic studies by feeding and relieving from treatments showed that GHB is rapidly metabolized in wild type plants compared to thepop2 x ssadhdouble mutant. Although regarded as a short chain fatty acid, GHB level was not altered in mutants of the beta oxidation pathway following exogenous feeding. Therefore, the metabolism back to SSA and then TCA cycle appears to be the major route for GHB degradation. However, the presence of another catabolic route such as secondary modifications cannot be ruled out.
DNA Methylation in Cocaine Use Disorder – An Epigenome-wide Approach in the Human Prefrontal Cortex
Authors: Poisel Eric , Zillich Lea , Streit Fabian , Frank Josef , Friske Marion M , Foo Jerome C , Mechawar Naguib , Turecki Gustavo , Hansson Anita C , Nöthen Markus M , Rietschel Marcella , Spanagel Rainer , Witt Stephanie H 
Published: November 2022

AbstractCocaine use disorder (CUD) is characterized by a loss of control over drug intake and is associated with structural, functional, and molecular alterations in the brain. At the molecular level, epigenetic alterations are hypothesized to contribute to the higher-level functional and structural brain changes as observed in CUD. Most evidence of cocaine-associated epigenetic changes comes from animal studies while only a few studies have been performed using human tissue. We investigated epigenome-wide DNA methylation signatures of CUD in human postmortem brain tissue of Brodmann Area 9 (BA9). A total of N = 42 BA9 brain samples were obtained from N = 21 individuals with CUD and N = 21 individuals without a CUD diagnosis. We performed an epigenome-wide association study and analyzed CUD-associated differentially methylated regions (DMRs). To assess the functional role of CUD-associated differential methylation, we performed Gene Ontology enrichment analyses and characterized co-methylation networks using a weighted correlation network analysis. We further investigated epigenetic age in CUD using epigenetic clocks for the assessment of biological age. While no CpG site was associated with CUD at epigenome-wide significance in BA9, we detected a total of 20 CUD-associated DMRs. After annotation of DMRs to genes, we identifiedNPFFR2andKALRNfor which a previous role in the behavioral response to cocaine in rodents is known. Three of the four identified CUD-associated co-methylation modules were functionally related to neurotransmission and neuroplasticity. Protein-protein interaction networks derived from module hub genes revealed several addiction-related genes as highly connected nodes such asCACNA1C, NR3C1, andJUN. In BA9, we observed a trend toward epigenetic age acceleration in individuals with CUD remaining stable even after adjustment for covariates. Results from our study highlight that CUD is associated with epigenome-wide differences in DNA methylation levels in BA9 particularly related to synaptic signaling and neuroplasticity. This supports findings from previous studies that report on the strong impact of cocaine on neurocircuits in the human prefrontal cortex. Further studies are needed to follow up on the role of epigenetic alterations in CUD focusing on the integration of epigenetic signatures with transcriptomic and proteomic data.
The MuSK-BMP pathway maintains myofiber size in slow muscle through regulation of Akt-mTOR signaling
Authors: Jaime Diego , Fish Lauren A. , Madigan Laura A. , Ewing Madison D. , Fallon Justin R. 
Published: November 2022

ABSTRACTMyofiber size regulation is critical in health, disease, and aging. MuSK (muscle-specific kinase) is a BMP (bone morphogenetic protein) co-receptor that promotes and shapes BMP signaling. MuSK is expressed at all neuromuscular junctions and is also present extrasynaptically in the slow soleus muscle. To investigate the role of the MuSK-BMP pathway in vivo we generated mice lacking the BMP-binding MuSK Ig3 domain. These ΔIg3-MuSK mice are viable and fertile with innervation levels comparable to wild type. In 3-month-old mice myofibers are smaller in the slow soleus, but not in the fast tibialis anterior (TA). Transcriptomic analysis revealed soleus-selective decreases in RNA metabolism and protein synthesis pathways as well as dysregulation of IGF1-Akt-mTOR pathway components. Biochemical analysis showed that Akt-mTOR signaling is reduced in soleus but not TA. We propose that the MuSK-BMP pathway acts extrasynaptically to maintain myofiber size in slow muscle by promoting protein synthetic pathways including IGF1-Akt-mTOR signaling. These results reveal a novel mechanism for regulating myofiber size in slow muscle and introduce the MuSK-BMP pathway as a target for promoting muscle growth and combatting atrophy.
Single-cell microencapsulation improves lung retention of endothelial colony forming cells after intravascular delivery and unmasks therapeutic benefit in severe pulmonary arterial hypertension
Authors: Cober Nicholas D. , Chaudhary Ketul R. , Deng Yupu , Lee Chyan-Jang , Rowe Katelynn , Courtman David W. , Stewart Duncan J. 
Published: November 2022

AbstractBackgroundPulmonary arterial hypertension (PAH) is triggered by pulmonary vascular endothelial cell apoptosis and microvascular loss; therefore, therapies that can regenerate lost vasculature may offer therapeutic benefit. Endothelial colony forming cells (ECFCs) can directly repair damaged blood vessels and may have therapeutic potential for the treatment of PAH. However, poor retention of ECFCs in the lungs following intravenous delivery greatly limits their therapeutic application. Therefore, we studied whether cellular microencapsulation could enhance ECFCs viability and retention in the lung after systemic delivery and improve therapeutic efficacy of ECFCs in a rat monocrotaline (MCT) PAH model.MethodsECFCs were encapsulated by vortex-emulsion using various concentrations of agarose, and capsule size and initial cell viability were assessed. Encapsulated and free ECFCs were transduced with luciferase and administered to Sprague-Dawley rats three days after injection of MCT. ECFCs were trackedin vivoby bioluminescence imaging (BLI) to assess cell persistence and bio-distribution. At end-study, right ventricular systolic pressure (RVSP) and right ventricular hypertrophy were assessed for therapeutic efficacy.ResultsMicrogel encapsulation using 3.5% agarose improved cells survival and supported cell migration from capsules. At 15 minutes after delivery, BLI radiance were similar for free and microencapsulated ECFCs; however, only encapsulated cells could be detected by BLI at 4 and 24 hours. Transplantation of microencapsulated ECFCs led to significant improvement in RVSP three weeks after delivery compared to non-encapsulated ECFCs.ConclusionTogether, microencapsulation increased retention of ECFCs within the lungs. Furthermore, even a modest increase in ECFCs persistence over 24 hours can provide an important therapeutic benefit in the rat MCT model of PAH.