bluuebunny/crossref_metadata_2025_split huggingface dataset:
The HERV-K(HML-2) Transcriptome in Non-Diseased Tissue
Authors: Burn Aidan , Roy Farrah , Freeman Michael , Coffin John M 
Published: June 2022

AbstractHuman endogenous retrovirus (HERV) transcripts are known to be highly expressed in cancers, yet their activity in non-diseased tissue is largely unknown. Using the GTEx RNA-seq dataset from normal tissue sampled at autopsy, we characterized individual expression of the recent HERV-K(HML-2) provirus group across 13,000 different samples of 54 different tissues from 948 individuals. HML-2 transcripts could be identified in every tissue sampled, and were elevated in the cerebellum, pituitary, testis, and thyroid. 37 different individual proviruses were expressed in one or more tissues, representing all three LTR5 subgroups. 9 proviruses were identified as having LTR-driven transcription, 7 of which belonged to the most recent LTR5HS subgroup. Proviruses of different subgroups displayed a bias in tissue expression which may be associated with differences in transcription factor binding sites in their LTRs. Provirus expression was greater in evolutionarily older proviruses with an earliest shared ancestor of gorilla or older. HML-2 expression was significantly affected by biological sex in one tissue, while age and timing of death (Hardy score) had little effect. Proviruses containing intact gag, pro and env ORFs were expressed in the dataset, with almost every tissue measured potentially expressing at least one intact ORF (gag).
Structure and Flexibility of the Yeast NuA4 Histone Acetyltransferase Complex
Authors: Zukin Stefan A. , Marunde Matthew R. , Popova Irina K. , Nogales Eva , Patel Avinash B. 
Published: June 2022

AbstractThe NuA4 protein complex acetylates histones H4 and H2A to activate both transcription and DNA repair. We report the 3.0 Å-resolution cryo-electron microscopy structure of the central hub of NuA4, which flexibly tethers the HAT and TINTIN modules. The hub contains the large Tra1 subunit and a core that includes Swc4, Arp4, Act1, Eaf1 and the C-terminal region of Epl1. Eaf1 stands out as the primary scaffolding factor that interacts with the Tra1, Sw4 and Epl1 subunits and contributes the conserved HSA helix to the Arp module. Using nucleosome binding assays, we find that the HAT module, which is anchored to the core through Epl1, recognizes H3K4me3 nucleosomes with hyperacetylated H3 tails, while the TINTIN module, anchored to the core via Eaf1, recognizes nucleosomes that have hyperacetylated H2A and H4 tails. Together with the known interaction of Tra1 with site-specific transcription factors, our data suggests a model in which Tra1 recruits NuA4 to specific genomic sites then allowing the flexible HAT and TINTIN modules to select nearby nucleosomes for acetylation.
Mitochondrial interactome remodeling in aging mouse skeletal muscle associated with functional decline
Authors: Bakhtina Anna A. , Pharaoh Gavin , Keller Andrew D. , Stuppard Rudy , Marcinek David J. , Bruce James E. 
Published: June 2022

AbstractGenomic, transcriptomic, and proteomic approaches have been employed to gain insight into molecular underpinnings of aging in laboratory animals and in humans. However, protein function in biological systems is under complex regulation and includes factors in addition to abundance levels, such as modifications, localization, conformation, and protein-protein interactions. We have applied new robust quantitative chemical cross-linking technologies to uncover changes muscle mitochondrial interactome contributing to functional decline in aging. Statistically significant age-related changes in protein cross-link levels relating to assembly of electron transport system complexes I and IV, activity of glutamate dehydrogenase, and coenzyme-A binding in fatty acid beta-oxidation and TCA enzymes were observed. These changes showed remarkable correlation with measured CI based respiration differences within the same young-old animal pairs, indicating these cross-link levels offer new molecular insight on commonly observed age-related phenotypic differences. Overall, these system-wide quantitative mitochondrial interactome data provide the first molecular-level insight on ETS complex and substrate utilization enzyme remodeling that occur during age-related mitochondrial dysfunction. Each observed cross-link can serve as a protein conformational or protein-protein interaction probe in future studies making this dataset a unique resource for many additional in-depth molecular studies that are needed to better understand complex molecular changes that occur with aging.
Diverse thermosensory receptors and neurons mediate the neural coding of oral cooling in the mouse trigeminothalamic tract
Authors: Li Jinrong , Lemon Christian H. 
Published: June 2022

ABSTRACTDifferent sets of peripheral and medullary trigeminal neurons respond across a cooling gradient applied to intraoral skin. Here we applied electrophysiology to anesthetized mice to study if different types of cool-driven trigeminothalamic neurons convey oral cooling information to the thalamus. We monitored spiking responses to oral stimulation with cold (≤13°C), cool (21°C to 28°C), neutral (35°C), and warm/hot (≥40°C) water in single trigeminal nucleus caudalis (Vc) neurons physiologically tested for projections to the thalamus. We also recorded oral thermal responses from Vc neurons in mice gene deficient for the cooling and menthol receptor TRPM8 to study afferent mechanisms of central oral thermosensory activity. We found that thalamic-projecting Vc neurons that respond to oral cooling comprise heterogeneous cell types. These cell types showed unique temporal response kinetics across cool and cold temperatures, with tuning to select ranges of a cooling gradient. The combined thermal activity of multiple, differently tuned types of trigeminothalamic cooling neurons offered greater contrast between cold, cool, and warm temperatures in multivariate analysis than the responses of the individual neural types alone, agreeing with a neural population code for cooling information. Compared to control, TRPM8 deficient mice demonstrated a loss of Vc neurons tuned to mild oral cooling, but maintained Vc cells responsive to intense cold. Notably, distinctions between Vc population responses to mild cool and warm temperatures were impaired in TRPM8 deficient mice, suggesting a role for TRPM8 in oral warmth recognition. Diverse receptors and neurons mediate oral cooling signals carried by the trigeminothalamic pathway.
Culture-Independent Detection and Identification of Leptospira Serovars
Authors: Matthias Michael A. , Lubar Aristea A. , Lanka Acharige Shalka S. , Chaiboonma Kira L. , Pilau Nicholas N. , Marroquin Alan S. , Jayasundara Dinesha , Agampodi Suneth , Vinetz Joseph M. 
Published: June 2022

AbstractPathogenic Leptospira, the causative agents of leptospirosis, comprise >200 serotypes (called serovars). Most have a restricted reservoir-host range, and some, e.g., serovar Copenhageni, are cosmopolitan and of public health importance owing to their propensity to produce severe, fatal disease in humans. Available serotyping approaches—such as multi-locus sequence typing, core genome sequence typing, pulsed-field gel electrophoresis, and the cross-agglutination absorption test—are tedious and expensive, and require isolation of the organisms in culture media—a protracted and incredibly inefficient process— precluding their use in prospective studies or outbreak investigations. The unavailability of culture-independent assays capable of distinguishing Leptospira serotypes remains a crucial gap in the field. Here, we have developed a simple yet specific real-time qPCR assay—targeting a Leptospira-unique gene encoding a putative polysaccharide flippase—that provides intra-species, serotype-defining (i.e., epidemiologically useful) information, and improves upon the sensitivity of preferred lipL32-based qPCR-based diagnostic tests. The assay, dubbed RAgI (“rage one”), is rapid and affordable, and reliably and specifically detects group I pathogenic Leptospira in culture, serum and urine, with no detectable off-target amplification—even of the genetically related but low virulence group II pathogenic (formerly “intermediate”) or non-pathogenic Leptospira. It retained 100% diagnostic specificity when tested against difficult sample types, including field-collected dog urine-samples and environmental samples containing varied and complex microbial species-consortia. And holds considerable promise in the clinical setting, and for routine epidemiological and environmental surveillance studies.
SARS-CoV-2 evolution and evasion from multiple antibody treatments in a cancer patient
Authors: Shapira Guy , Weiner Chen , Sorek Abramovich Reut , Gutwein Odit , Rainy Nir , Benveniste-Levkovitz Patricia , Gordon Ezra , Bar Chaim Adina , Shomron Noam 
Published: June 2022

AbstractInfection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in immunocompromised patients may lead to accelerated viral mutation rate, immune evasion and persistent viral shedding over many months. Here we report the case of a severely immunocompromised cancer patient infected with the Delta variant of SARS-CoV-2 for over 8 months. Genome sequencing of samples taken after repeated monoclonal antibody treatments reveal the emergence and accumulation of mutations enabling escape from neutralization by antibodies. Mutations emerging in accessory and non-structural viral proteins target specific residues of immunomodulatory domains, potentially leading to loss of some functions, while preserving others. The mutated virus managed to completely overcome neutralization by monoclonal antibodies while remaining viable and infective. Our results suggest that the loss of specific immunomodulatory viral functions might confer a selective advantage in immunocompromised hosts. We also compare between mutations emerging in the presence and absence of neutralizing antibodies.HighlightsSARS-CoV-2 undergoes rapid evolution in an immunocompromised, chronically infected cancer patient, overcoming neutralization by two monoclonal antibody cocktail treatmentsReceptor binding domain (RBD) mutations emerging after monoclonal antibody treatment enable effective escape from neutralization in the absence of adaptive immunitySome emerging mutations are predicted to disrupt immunomodulatory viral proteins, including prevention of ORF8 homodimerization, mis-localization of ORF3a in host cells and alteration of the host-suppressive function of NSP1
Omega-3 supplements in the prevention and treatment of youth depression and anxiety: A scoping review
Authors: Reily Natalie M. , Tang Samantha , Negrone Ashlee , Gan Daniel Z. Q. , Sheanoda Veronica , Christensen Helen 
Published: June 2022

AbstractIntroductionEmerging evidence suggests that omega-3 supplements may be efficacious in reducing symptoms of depression and anxiety in adults, particularly as an adjunct to antidepressant medication. However, research on its efficacy in young people is limited. Thus, this scoping review aimed to summarise existing evidence on the efficacy of omega-3 supplementation in treating depression and anxiety in young people aged 14-24.MethodFour databases (Cochrane CENTRAL, EmBASE, PsycINFO and PubMed) were searched from inception to 4th August 2021. Eligible peer-reviewed studies were empirical studies which examined the efficacy of omega-3 supplements in preventing/treating anxiety and/or depression in young people aged 14-24. Risk of bias was assessed for randomised studies using the Cochrane Risk of Bias Tool. Selected grey literature databases were also searched, with eligible sources assessed for quality. A group of stakeholders consisting of young people with lived experience of anxiety/depression, parents/carers and mental health professionals informed the research questions and data interpretation. Findings were summarised using narrative synthesis.Results17 empirical studies (N = 1240 participants) meeting inclusion criteria were identified. Studies varied in treatment and participant characteristics. In general, the data did not support the view that omega-3 supplements were efficacious in improving symptoms of anxiety or depression. In contrast, most grey literature sources recommended the use of omega-3 supplements despite the lack of supporting evidence.DiscussionEvidence for efficacy of omega-3 supplementation in reducing symptoms of depression and anxiety was inconclusive. More research is needed to identify potential mechanisms and moderators of the effect of omega-3 supplements on depression and anxiety symptoms in young people.
An Economic Evaluation of a virtual Covid Ward in Leicester, Leicestershire, and Rutland
Authors: Swift Jim , O’Kelly Noel , Barker Chris , Woodward Alex , Ghosh Sudip 
Published: June 2022

AbstractObjectiveThe objective of this study was to demonstrate the impact of a virtual Covid—19 ward on NHS resource use.MethodsDifferent methods were used to derive comparators for the observational data on acute length of stay versus the actual lengths of stay of 310 patients on acute wards and differences estimated. The resource use associated with delivering care in the virtual ward were collected on an ongoing basis.ResultsThe virtual ward delivered estimated health care system savings of 1,103 bed days, £529,719 in net financial savings across two key groups of patients; those who had been on oxygen and required weaning off it while within the virtual ward and those not requiring oxygen therapy with less severe acute Covid disease. The costs of the intervention were 9.7% of the estimated gross savings and the mean net saving per patient was £1,709 in the base case without including the savings associated with a likely reduction in re-admissions. The 30-day re-admission rate was 2.9%, which was substantially beneath alternative comparative data. The mean cost of the intervention was £184.38 per patient.ConclusionThe virtual ward delivered significant financial savings in both groups of patients, did so with a high degree of confidence, whilst doing so at a very low absolute and relative cost.
BNT162b2 effectiveness against Delta & Omicron variants in teens by dosing interval and duration
Authors: Ionescu Iulia G. , Skowronski Danuta M. , Sauvageau Chantal , Chuang Erica , Ouakki Manale , Kim Shinhye , De Serres Gaston 
Published: June 2022

AbstractBackground and ObjectivesTwo- and three-dose BNT162b2 (Pfizer-BioNTech) mRNA vaccine effectiveness (VE) against SARS-CoV-2 infection, including Delta and Omicron variants, was assessed among adolescents in two Canadian provinces where first and second doses were spaced longer than the manufacturer-specified 3-week interval.MethodsTest-negative design estimated VE against laboratory-confirmed SARS-CoV-2 infection among adolescents 12-17 years old in Quebec and British Columbia, Canada between September 5, 2021 (epi-week 36), and April 30, 2022 (epi-week 17). Delta-dominant and Omicron-dominant periods spanned epi-weeks 36-47 and 51-17, respectively. VE was assessed from 14 days and explored by interval between first and second doses, time since second dose, and with administration of a third dose.ResultsMedian first-second dosing-interval was ∼8 weeks and second-third dosing-interval was ∼28-31 weeks. Median follow-up post-second-dose was ∼10-11 weeks for Delta-dominant and ∼21-22 weeks for Omicron-dominant periods, and ∼3-9 weeks post-third dose. VE against Delta was ≥90% to at least the 5th month post-second dose. VE against Omicron declined from ∼65-75% at weeks to ≤50% by the 3rd month post-vaccination, restored to ∼60-65% shortly following a third dose. VE exceeded 90% against Delta regardless of dosing-interval but appeared improved against Omicron with ≥8 weeks between first and second doses.ConclusionIn adolescents, two BNT162b2 doses provided strong and sustained protection against Delta but reduced and rapidly-waning VE against Omicron. Longer interval between first and second doses and a third dose improved Omicron protection. Updated vaccine antigens, increased doses and/or dosing-intervals may be needed to improve adolescent VE against immunological-escape variants.
An Occupational Health Survey for Port Employees in Shenzhen and A Dataset Management System based on R
Authors: Wang Jinlin , Mo Chunbao , Huang Yuehong , Lin Dafeng , Situ Jie , Zhang Ming , Zhang Naixing 
Published: June 2022

AbstractBackgroundPort employees is a huge occupational group in industrial economy but the occupational health problem does not receive enough attention and the relative data is still deficient. Hence, the aim of the study was to survey the occupational health condition for port employees and to construct a relative dataset.MethodA cross-sectional study was implemented among the population in a Shenzhen port, they were required to undergo occupational physical examination and questionnaires to learn about physical condition and other information. Description analysis were used to describe the data, and missing value analysis and Cronbach’s alpha coefficient were utilized to evaluated the data quality. And management system based on Shiny was constructed to manage and analyze the dataset.ResultA total of 5245 participants involved in this study, 3211 of them received occupational physical examinations, 3946 participants received the questionnaire, and 1912 received the both. Quality analysis suggested that the total missing rate of these three datasets were 10.76%, 0% and 4.78%, respectively. And the total Cronbach’s alpha confidence of Effort-Reward Imbalance Questionnaire and National Health Literacy Monitoring Questionnaire was 0.808. Furthermore, a dataset management system with preview overview, selection, output and summary functions was constructed.ConclusionOccupational Health Survey for Port Employees is a reliable survey and it’s system can be used to manage and analyze the dataset, however, further optimization and improvement are still required.
Combining Machine Learning with Cox models for identifying risk factors for incident post-menopausal breast cancer in the UK Biobank
Authors: Liu Xiaonan , Morelli Davide , Littlejohns Thomas J , Clifton David A , Clifton Lei 
Published: June 2022

1.AbstractBreast cancer is the most common cancer in women. A better understanding of risk factors plays a central role in disease prediction and prevention. We aimed to identify potential novel risk factors for breast cancer among post-menopausal women, with pre-specified interest in the role of polygenic risk scores (PRS) for risk prediction.We designed an analysis pipeline combining both machine learning (ML) and classical statistical models with emphasis on necessary statistical considerations (e.g. collinearity, missing data). Extreme gradient boosting (XGBoost) machine with Shapley (SHAP) feature importance measures were used for risk factor discovery among ∼1.7k features in 104,313 post-menopausal women from the UK Biobank cohort. Cox models were constructed subsequently for in-depth investigation.Both PRS were significant risk factors when fitted simultaneously in both ML and Cox models (p< 0.001). ML analyses identified 11 (excluding the two PRS) novel predictors, among which five were confirmed by the Cox models: plasma urea (HR=0.95, 95% CI 0.92−0.98,p< 0.001) and plasma phosphate (HR=0.67, 95% CI 0.52−0.88,p= 0.003) were inversely associated with risk of developing post-menopausal breast cancer, whereas basal metabolic rate (HR=1.15, 95% CI 1.08−1.22,p< 0.001), red blood cell count (HR=1.20, 95% CI 1.08−1.34,p= 0.001), and creatinine in urine (HR=1.05, 95% CI 1.01−1.09,p= 0.008) were positively associated.Our final Cox model demonstrated a slight improvement in risk discrimination when adding novel features to a simpler Cox model containing PRS and the established risk factors (Harrell’s C-index = 0.670 vs 0.665).
Cardiovascular disease and subsequent risk of psychiatric disorders: a nationwide sibling-controlled study
Authors: Shen Qing , Song Huan , Aspelund Thor , Yu Jingru , Lu Donghao , Jakobsdóttir Jóhanna , Bergstedt Jacob , Yi Lu , Sullivan Patrick F. , Sjölander Arvid , Ye Weimin , Fall Katja , Fang Fang , Valdimarsdóttir Unnur 
Published: June 2022

AbstractBackgroundThe association between cardiovascular disease (CVD) and selected psychiatric disorders has frequently been suggested while inadequate control of familial factors and comorbidities has halted causal inferences.MethodsWe identified 869 056 patients newly diagnosed with CVD from 1987 to 2016 in Sweden while no history of psychiatric disorders, and 910 178 full siblings of these patients and 10 individually age- and sex-matched unrelated population controls (N=8 690 560). Adjusting for multiple comorbid conditions, we used flexible parametric models and Cox regression to estimate the association of CVD with risk of all subsequent psychiatric disorders, comparing rates of first incident psychiatric disorder among CVD patients with rates among unaffected full siblings and population controls.ResultsThe median age at diagnosis was 60 years for patients with cardiovascular disease and 59.2% were male. During up to thirty years of follow-up, the crude incidence rates of psychiatric disorder were 7.1, 4.6 and 4.0 per 1000 person-years for patients with cardiovascular disease, their siblings and population controls. In the sibling comparison, we observed an increased risk of psychiatric disorder during the first year after cardiovascular diagnosis (hazard ratio [HR], 2.74; 95% confidence interval [CI], 2.62-2.87) and thereafter (1.45; 95% CI, 1.42-1.48). Increased risks were observed for all types of psychiatric disorders and among all diagnoses of cardiovascular disease. We observed similar associations in the population comparison. Cardiovascular patients who developed a comorbid psychiatric disorder during the first year after diagnosis were at increased risk of subsequent cardiovascular death compared to patients without such comorbidity (HR 1.55; 95% CI 1.44-1.67).ConclusionsPatients diagnosed with cardiovascular disease are at an elevated risk for subsequent psychiatric disorders independent of familial factors and comorbid conditions. Cardiovascular patients with comorbid psychiatric disorders are at increased risk of cardiovascular mortality suggesting that surveillance and treatment of psychiatric comorbidities should be considered as an integral part of clinical management of newly diagnosed patients with cardiovascular disease.Fundingthis work was supported by the EU Horizon 2020 Research and Innovation Action Grant (CoMorMent, Grant nr. 847776 to UV, PFS and FF), Grant of Excellence, Icelandic Research Fund (grant no. 163362-051 to UV), ERC Consolidator Grant (StressGene, grant no: 726413 to UV), Swedish Research Council (Vetenskapsrådet, award D0886501 to PFS) and US NIMH R01 MH123724 (to PFS).
Human PRPS1 filaments stabilize allosteric sites to regulate activity
Authors: Hvorecny Kelli L. , Hargett Kenzee A. , Quispe Joel , Kollman Justin M. 
Published: June 2022

AbstractThe universally conserved enzyme phosphoribosyl pyrophosphate synthetase (PRPS) assembles filaments in evolutionarily diverse organisms. PRPS is a key regulator of nucleotide metabolism, and mutations in the human enzyme PRPS1 lead to a spectrum of diseases. Here, we determine structures of PRPS1 filaments in active and inhibited states, with fixed assembly contacts accommodating both conformations. The conserved assembly interface stabilizes the binding site for the essential activator phosphate, increasing activity in the filament. Some disease mutations alter assembly, supporting the link between filament stability and activity. Structures of active PRPS1 filaments turning over substrate also reveal coupling of catalysis in one active site with product release in an adjacent site. PRPS1 filaments therefore provide an additional layer of allosteric control, conserved throughout evolution, with likely impact on metabolic homeostasis. Stabilization of allosteric binding sites by polymerization adds to the growing diversity of assembly-based enzyme regulatory mechanisms.