bluuebunny/crossref_metadata_2025_split huggingface dataset:
Functional genomics implicates natural killer cells in the pathogenesis of ankylosing spondylitis
Authors: Chiñas Marcos , Fernandez-Salinas Daniela , Aguiar Vitor R. C. , Nieto-Caballero Victor E. , Lefton Micah , Nigrovic Peter A. , Ermann Joerg , Gutierrez-Arcelus Maria 
Published: September 2023

AbstractObjectiveMultiple lines of evidence indicate that ankylosing spondylitis (AS) is a lymphocyte-driven disease. However, which lymphocyte populations are critical in AS pathogenesis is not known. In this study, we aimed to identify the key cell types mediating the genetic risk in AS using an unbiased functional genomics approach.MethodsWe integrated genome-wide association study (GWAS) data with epigenomic and transcriptomic datasets of human immune cells. To quantify enrichment of cell type-specific open chromatin or gene expression in AS risk loci, we used three published methods that have successfully identified relevant cell types in other diseases. We performed co-localization analyses between GWAS risk loci and genetic variants associated with gene expression (eQTL) to find putative target genes.ResultsNatural killer (NK) cell-specific open chromatin regions are significantly enriched in heritability for AS, compared to other immune cell types such as T cells, B cells, and monocytes. This finding was consistent between two AS GWAS. Using RNA-seq data, we validated that genes in AS risk loci are enriched in NK cell-specific gene expression. Using the human Space-Time Gut Cell Atlas, we also found significant upregulation of AS-associated genes predominantly in NK cells. Co-localization analysis revealed four AS risk loci affecting regulation of candidate target genes in NK cells: two known loci,ERAP1 and TNFRSF1A, and two under-studied loci,ENTR1(akaSDCCAG3) andB3GNT2.ConclusionOur findings suggest that NK cells may play a crucial role in AS development and highlight four putative target genes for functional follow-up in NK cells.
Muscle cell atrophy induced by miR-155-5p reveals molecular targets in skeletal muscle disorders
Authors: Lopes Letícia , Cury Sarah Santiloni , de Moraes Diogo , Oliveira Jakeline Santos , de Oliveira Grasieli , Cabral-Marques Otavio , Fernandez Geysson Javier , Hirata Mario Hiroyuki , Wang Da-Zhi , Dal-Pai-Silva Maeli , Carvalho Robson Francisco , Freire Paula Paccielli 
Published: September 2023

AbstractMicroRNAs are small regulatory molecules that control gene expression. An emerging property of muscle miRNAs is the cooperative regulation of transcriptional and epitranscriptional events controlling muscle phenotype. miR-155 has been related to muscular dystrophy and muscle cell atrophy. However, the function of miR-155 and its molecular targets in muscular dystrophies remain poorly understood. Throughin silicoandin vitroapproaches we identify distinct transcriptional profile of muscle cell atrophy induced by miR-155-5p. The atrophic myotubes changed the expression of 359 genes (166 up-regulated and 193 down-regulated). We reanalyzed muscle transcriptomic data from dystrophin-deficient patients and detected overlap with gene expression patterns in miR-155-treated myotubes. Our analysis indicated that miR-155 regulates a set of transcripts, including Aldh1l, Nek2, Bub1b, Ramp3, Slc16a4, Plce1, Dync1i1, and Nr1h3. Enrichment analysis demonstrates 20 targets involved in metabolism, cell cycle regulation, muscle cell maintenance, and immune system. Moreover, digital cytometry confirmed a significant increase in M2 macrophages, indicating miR-155 effects on immune response in dystrophic muscles. We highlight a critical miR-155 associated with disease-related pathways in skeletal muscle disorders.
Attendance at remote versus face-to-face outpatient appointments in an NHS Trust
Authors: Kerr Gabriele , Greenfield Geva , Hayhoe Benedict , Gaughran Fiona , Halvorsrud Kristoffer , da Costa Mariana Pinto , Rehill Nirandeep , Raine Rosalind , Majeed Azeem , Costelloe Ceire , Neves Ana Luisa , Beaney Thomas 
Published: September 2023

AbstractIntroductionWith the growing use of remote appointments within the National Health Service, there is a need to understand potential barriers of access to care for some patients. In this observational study we examined missed appointments rates, comparing remote and face-to-face appointments among different patient groups.MethodsWe analysed adult outpatient appointments at Imperial College Healthcare NHS Trust in Northwest London in 2021. Rates of missed appointments per patient were compared between remote vs. face-to-face appointments using negative binomial regression models. Models were stratified by appointment type (first or a follow-up).ResultsThere were 874,659 outpatient appointments for 189,882 patients, 29.5% of whom missed at least one appointment. Missed rates were 12.5% for remote first appointments and 9.2% for face-to-face first appointment. Remote and face-to-face follow-up appointments were missed at similar rates (10.4% and 10.7%, respectively). For remote and face-to-face appointments, younger patients, residents of more deprived areas, and patients of Black, Mixed, and ‘other’ ethnicities missed more appointments. Male patients missed more face-to-face appointments, particularly at younger ages, but gender differences were minimal for remote appointments. Patients with long-term conditions (LTCs) missed more first appointments, whether face-to-face or remote. In follow-up appointments, patients with LTCs missed more face-to-face appointments but fewer remote appointments.DiscussionRemote face-to-face appointments were missed more often than face-to-face first appointments, follow-ups appointments had similar attendance rates for both modalities. Sociodemographic differences in outpatient appointment attendance were largely similar between face-to-face and remote appointments, indicating no widening of inequalities in attendance due to appointment modality.
RCoV19: A One-stop Hub for SARS-CoV-2 Genome Data Integration, Variants Monitoring, and Risk Pre-warning
Authors: Li Cuiping , Ma Lina , Zou Dong , Zhang Rongqin , Bai Xue , Li Lun , Wu Gangao , Huang Tianhao , Zhao Wei , Jin Enhui , Bao Yiming , Song Shuhui 
Published: September 2023

AbstractThe Resource for Coronavirus 2019 (RCoV19,https://ngdc.cncb.ac.cn/ncov/) is an open-access information resource dedicated to providing valuable data on the genomes, mutations, and variants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this updated implementation of RCoV19, we have made significant improvements and advancements over the previous version. Firstly, we have implemented a highly refined genome data curation model. This model now features an automated integration pipeline and optimized curation rules, enabling efficient daily updates of data in RCoV19. Secondly, we have developed a global and regional lineage evolution monitoring platform, alongside an outbreak risk pre-warning system. These additions provide a comprehensive understanding of SARS-CoV-2 evolution and transmission patterns, enabling better preparedness and response strategies. Thirdly, we have developed a powerful interactive mutation spectrum comparison module. This module allows users to compare and analyze mutation patterns, assisting in the detection of potential new lineages. Furthermore, we have incorporated a comprehensive knowledgebase on mutation effects. This knowledgebase serves as a valuable resource for retrieving information on the functional implications of specific mutations. In summary, RCoV19 serves as a vital scientific resource, providing access to valuable data, relevant information, and technical support in the global fight against COVID-19.
Metabolic Phenotypes of Overweight/Obesity and Risk of Cardiovascular Diseases in Postmenopausal Women: Findings from the China PEACE Million Persons Project
Authors: Deng Danying , Nie Zhiqiang , Wang Jiabin , Chen Chaolei , Wang Wenbin , Zhu Yanchen , Guan Qingyu , Ou Yanqiu , Feng Yingqing 
Published: September 2023

BACKGROUNDObesity and metabolic abnormalities were associated with increased risk of cardiovascular diseases (CVD). However, much remains unknown about which metabolic weight phenotypes and how relate to CVD, especially in postmenopausal women.METHODS AND RESULTSWe included 15,575 postmenopausal women aged 35 to 75 years (median age, 60.6 [IQR: 55.0-65.7]) free of CVD at baseline from a subcohort of the China Patient-centered Evaluative Assessment of Cardiac Events Million Persons Project between 1 January 2016 and 31 December 2020 in Guangdong Province at 8 sites. Cox regression models were used to investigate the associations of metabolic and overweight/obese status with the risk of developing CVD. Over a median follow-up period of 3.32 years, a total of 1354 CVD events occurred. Overall, 30.3% were metabolically heathy among the 9404 overweight/obese participants, while 49.2% were metabolically unhealthy among the 6171 normal weight subjects. Compared with the metabolically healthy normal weight group, the remaining three groups of participants were all at higher risk of combined CVD, with multivariate-adjusted hazard ratios and 95% confidence intervals of 1.41 (1.16–1.71) for metabolically unhealthy normal weight, 1.42 (1.16–1.73) for metabolically healthy overweight/obesity, and 1.75 (1.47–2.07) for metabolically unhealthy overweight/obesity. When subdividing overweight/obesity separately into overweight and obesity, combined CVD risk was only greater in metabolically unhealthy individuals across different weight categories.CONCLUSIONSPostmenopausal women with metabolically healthy overweight/obesity and metabolically unhealthy normal weight had a higher risk of cardiovascular disease than those with metabolically healthy normal weight, and the association of metabolically unhealthy overweight/obesity was greatest among four categories, suggesting that metabolic abnormalities and overweight/obesity should be monitored and controlled.CLINICAL PERSPECTIVEWhat Is New?Postmenopausal women with metabolic abnormalities combined with overweight/obesity and even normal weight had a higher risk of cardiovascular disease (CVD) than those with metabolically healthy normal weight.Metabolically healthy overweight/obesity were associated with greater risk of CVD, indicating that overweight/obesity alone may contribute to CVD risk in postmenopausal women.What Are the Clinical Implications?Individuals who are metabolically unhealthy and overweight/obese warrant close clinical supervision, while those of normal weight should not be ignored.
Structural and functional insights into the enzymatic plasticity of the SARS-CoV-2 NiRAN Domain
Authors: Small Gabriel I. , Fedorova Olga , Olinares Paul Dominic B. , Chandanani Joshua , Banerjee Anoosha , Choi Young Joo , Molina Henrik , Chait Brian , Darst Seth A. , Campbell Elizabeth A. 
Published: September 2023

SUMMARYThe enzymatic activity of the SARS-CoV-2 nidovirus RdRp-associated nucleotidyltransferase (NiRAN) domain is essential for viral propagation, with three distinct activities associated with modification of the nsp9 N-terminus, NMPylation, RNAylation, and deRNAylation/capping via a GDP-polyribonucleotidyltransferase reaction. The latter two activities comprise an unconventional mechanism for initiating viral RNA 5’-cap formation, while the role of NMPylation is unclear. The structural mechanisms for these diverse enzymatic activities have not been properly delineated. Here we determine high-resolution cryo-electron microscopy structures of catalytic intermediates for the NMPylation and deRNAylation/capping reactions, revealing diverse nucleotide binding poses and divalent metal ion coordination sites to promote its repertoire of activities. The deRNAylation/capping structure explains why GDP is a preferred substrate for the capping reaction over GTP. Altogether, these findings enhance our understanding of the promiscuous coronaviral NiRAN domain, a therapeutic target, and provide an accurate structural platform for drug development.
Cost-effectiveness and budget impact of decentralising childhood tuberculosis diagnosis: a mathematical modelling study in six high tuberculosis incidence countries
Authors: d’Elbée Marc , Harker Martin , Mafirakureva Nyashadzaishe , Nanfuka Mastula , Huyen Ton Nu Nguyet Minh , Taguebue Jean-Voisin , Moh Raoul , Khosa Celso , Mustapha Ayeshatu , Mwanga-Amumpere Juliet , Borand Laurence , Kwedi Nolna Sylvie , Komena Eric , Cumbe Saniata , Mugisha Jacob , Natukunda Naome , Eang Mao Tan , Wittwer Jérôme , Bénard Antoine , Bernard Tanguy , Sohn Hojoon , Bonnet Maryline , Wobudeya Eric , Marcy Olivier , Dodd Peter J. ,   TB-Speed Health Economics Study Group
Published: September 2023

AbstractBackgroundThe burden of childhood tuberculosis remains high globally, largely due to under-diagnosis. Decentralising childhood tuberculosis diagnosis services to lower health system levels could improve case detection, but there is little empirically based evidence on cost-effectiveness or budget impact.MethodsWe assessed the cost-effectiveness and budget impact of decentralising a comprehensive diagnosis package for childhood tuberculosis to district hospitals (DH-focused) or primary health centres (PHC-focused) compared to standard of care (SOC) in Cambodia, Cameroon, Côte d’Ivoire, Mozambique, Sierra Leone, and Uganda (NCT04038632). A mathematical model was developed to assess the health and economic outcomes of the intervention from a health system perspective. Estimated outcomes were tuberculosis cases, deaths, disability- adjusted life years and incremental cost-effectiveness ratios (ICERs). We also calculated the budget impact of nationwide implementation.FindingsFor the DH-focused strategy versus SOC, ICERs ranged between $263 (Cambodia) and $342 (Côte d’Ivoire) per disability-adjusted life-year (DALY) averted. For the PHC-focused strategy versus SOC, ICERs ranged between $477 (Cambodia) and $599 (Côte d’Ivoire) per DALY averted. Results were sensitive to TB prevalence and the discount rate used. The additional costs of implementing the DH-focused strategy ranged between $13M (Cambodia) and $50M (Mozambique), and between $14M (Sierra Leone) and $135M (Uganda) for the PHC-focused strategy.InterpretationThe DH-focused strategy may be cost-effective in some countries, depending on the cost- effectiveness threshold used for policy making. Either intervention would require substantial early investment.FundingUnitaid
High-flow nasal cannula vs non-invasive ventilation in acute hypoxia: Propensity score matched study
Authors: Munroe Elizabeth S , Prevalska Ina , Hyer Madison , Meurer William J , Mosier Jarrod M , Tidswell Mark A. , Prescott Hallie C , Wei Lai , Wang Henry , Fung Christopher M 
Published: September 2023

AbstractRATIONALEThe optimal treatment for early hypoxemic respiratory failure is unclear, and both high-flow nasal cannula and non-invasive ventilation are used. Determining clinically relevant outcomes for evaluating non-invasive respiratory support modalities remains a challenge.OBJECTIVESTo compare the effectiveness of initial treatment with high-flow nasal cannula versus non-invasive ventilation for acute hypoxemic respiratory failure.METHODSWe conducted a retrospective cohort study of patients with acute hypoxemic respiratory failure treated with high-flow nasal cannula or non-invasive ventilation within 24 hours of Emergency Department arrival (1/2018-12/2022). We matched patients 1:1 using a propensity score for odds of receiving non-invasive ventilation. The primary outcome was major adverse pulmonary events (28-day mortality, ventilator-free days, non-invasive respiratory support hours) calculated using a Win Ratio.MEASUREMENTS AND MAIN RESULTS1,265 patients met inclusion criteria. 795 (62.8%) received high-flow oxygen and 470 (37.2%) received non-invasive ventilation. We propensity score matched 736/1,265 (58.2%) patients. There was no difference between non-invasive ventilation vs high-flow nasal cannula in 28-day mortality (17.7% vs 23.1%, p=0.08) or ventilator-free days (median [Interquartile Range]: 28 [25, 28] vs 28 [13, 28], p=0.50), but patients on non-invasive ventilation required treatment for fewer hours (median 7 vs 13, p< 0.001). Win Ratio for composite major adverse pulmonary events favored non-invasive ventilation (1.26, 95%CI 1.06-1.49, p< 0.001).CONCLUSIONSIn this observational study of patients with acute hypoxemic respiratory failure, initial treatment with non-invasive ventilation was superior to high-flow nasal cannula for major pulmonary adverse events. Evaluation of composite outcomes is important in the assessment of respiratory support modalities.
Indicators of Co-occurrence of Mood Disorder with Chronic Medical Conditions: Evidence from an Administrative Claims Data Analysis
Authors: Chhabria Karishma , Krause Trudy Millard , Hamden Randa , Jabbi Mbemba 
Published: September 2023

ABSTRACTObjectiveMood disorder (including major depression and bipolar disorder) prevalence is over 10% and accounts for a significant share of global disease burden. Mental and physical illness are related, however, the association between mood disorders and acute/chronic disease subclasses remains poorly understood.MethodsThis observational cross-sectional study used administrative claims data from 6,709,258 adult enrollees with a full-year enrollment in the 2018 OPTUM Clinformatics® database. Data of enrollees with/without diagnoses of a mood disorder co-occurring with chronic comorbid conditions (defined by the Elixhauser Comorbidity Index) using the International Classification of Diseases (ICD-10) were analyzed by accounting for age, race, and ethnicity.ResultsOverall, the sample was predominantly non-Hispanic Caucasians (64.56%), with 48.59% females and a mean age of 43.54 years±12.46 years. The prevalence of mood disorders was 3.71% (248,890), of which 0.61% (n=40,616) had bipolar disorders and 3.10% (n=208,274) had Major Depressive Disorder (MDD). Logistic regression odds ratios revealed a strong association between mood disorder diagnoses and peptic ulcers (2.11; CI=2.01-2.21), weight loss (2.53; CI, 2.46-2.61), renal failure (2.37, CI = 2.31-2.42), peripheral vascular disease (2.24; CI=2.19-2.30), and pulmonary circulation disorder (1.77; CI=1.70-1.84).ConclusionsOverall, mood disorders were associated with vascular and cardiac chronic medical conditions, suggesting a possible pathophysiological link between these conditions. The results highlight the importance of understanding the prevalence of co-occurring mood and medical conditions and may inform novel biological diagnostics and future identification of mechanisms for multimorbidity.
Macroevolutionary dynamics in micro-organisms: generalists give rise to specialists across biomes in the ubiquitous bacterial phylumMyxococcota
Authors: Padfield Daniel , Kay Suzanne , Vos Rutger , Quince Christopher , Vos Michiel 
Published: September 2023

AbstractProkaryotes dominate the Tree of Life, but our understanding of the macroevolutionary processes generating this diversity is still limited. Habitat transitions are thought to be a key driver of prokaryote diversity, but we still know relatively little about how prokaryotes successfully transition and persist across environments, and how this varies between biomes and lineages. Here, we investigate biome transitions and specialisation in natural populations of a focal bacterial phylum, theMyxococcota, sampled across a range of replicated soils and freshwater and marine sediments in Cornwall (UK). By targeted deep sequencing of the protein-coding generpoB, we found >2000 uniqueMyxococcotalineages, with the majority (77%) being biome specialists and <5% able to live across the salt barrier. Discrete character evolution models revealed that biome specialists very rarely transitioned to specialising in another biome. Instead, generalists mediated transitions between biome specialists. Multistate hidden-state speciation and extinction models found variation in speciation rate across the tree, but this variation was independent of biome association and specialisation. Overall, our results help explain how microbes transition between biomes and are consistent with “the jack-of-all-trades” trade-off, where generalists suffer a cost in any individual environment, resulting in rapid evolution of niche specialists.
RNA-based sensitive fungal pathogen detection
Authors: Micheel Julia , Aron Franziska , Kelani Abdulrahman A. , Girbardt Christian , Blango Matthew G. , Walther Grit , Wollny Damian 
Published: September 2023

AbstractDetecting fungal pathogens, a major cause of severe systemic infections, remains challenging due to the difficulty and time-consuming nature of diagnostic methods. This delay in identification hinders targeted treatment decisions and may lead to unnecessary use of broad-spectrum antibiotics. To expedite treatment initiation, one promising approach is to directly detect pathogen nucleic acids such as DNA, which is often preferred to RNA because of its inherent stability. However, a higher number of RNA molecules per cell makes RNA a more promising diagnostic target which is particularly prominent for highly expressed genes such as rRNA. Here, we investigated the utility of a minimal input-specialized reverse transcription protocol to increase diagnostic sensitivity. This proof-of-concept study demonstrates that fungal rRNA detection by the minimal input protocol is drastically more sensitive compared to detection of genomic DNA even with high levels of human RNA background. This approach can detect several of the most relevant human pathogenic fungal genera, such asAspergillus, Candida, andFusariumand thus represents a powerful, cheap, and easily adaptable addition to currently available diagnostic assays.
LanTERN: a fluorescent sensor that specifically binds lanthanides
Authors: Jones Ethan , Su Yang , Sander Chris , Justman Quincey A. , Springer Michael , Silver Pamela A. 
Published: September 2023

AbstractLanthanides, a series of fifteen f-block elements, are crucial in modern technology, and their purification by conventional chemical means comes at a significant environmental cost. Synthetic biology offers promising solutions. However, the lack of biochemical tools to measure lanthanide binding is a bottleneck to progress. Here, we introduce LanTERN, a lanthanide-responsive fluorescent protein rationally engineered from the lanmodulin-binding protein, LanM. LanTERN was designed based on GCaMP, a genetically encoded calcium indicator that couples the ion binding of four EF hand motifs to increased GFP fluorescence. We engineered seven mutations across the parent construct’s four EF hand motifs to switch specificity from calcium to lanthanides. The resulting protein, LanTERN, directly converts the binding of 10 measured lanthanides to 14-fold or greater increased fluorescence. LanTERN development opens new avenues for creating improved lanthanide-binding proteins and bio-sensing systems.