bluuebunny/crossref_metadata_2025_split huggingface dataset:
The burden of respiratory conditions in the emergency department of Muhimbili National Hospital in Tanzania in the first two years of the COVID-19 pandemic
Authors: Ndumwa Harrieth P , Mboya Erick A , Amani Davis Elias , Mashoka Ramadhani , Nicholaus Paulina , Haniffa Rashan , Beane Abi , Mfinanga Juma , Sunguya Bruno , Sawe Hendry R. , Baker Tim 
Published: June 2022

AbstractBackgroundGlobally, respiratory diseases cause 10 million deaths every year. With the COVID-19 pandemic, the burden of respiratory illness increased and led to significant morbidity and mortality in both high- and low-income countries. This study assessed the burden and trend of respiratory conditions among patients presenting to the emergency department of Muhimbili National Hospital in Tanzania and compared with national COVID-19 data to determine if this knowledge may be useful for the surveillance of disease outbreaks in settings of limited specific diagnostic testing.MethodsThe study used routinely collected data from the electronic information system in the Emergency Medical Department (EMD) of Muhimbili National Hospital in Tanzania. All patients presenting to the EMD in a 2-year period, 2020 and 2021 with respiratory conditions were included. Descriptive statistics and graphical visualizations were used to describe the burden of respiratory conditions and the trends over time and to compare to national Tanzanian COVID-19 data during the same period.ResultsOne in every four patients who presented to the EMD of the Muhimbili National Hospital had a respiratory condition – 1039 patients per month. Of the 24,942 patients, 52% were males, and the median age (IQR) was 34.7 (21.7, 53.7) years. The most common respiratory diagnoses were pneumonia (52%), upper respiratory tract infections (31%), asthma (4.8%) and suspected COVID-19 (2.5%). There were four peaks of respiratory conditions coinciding with the four waves in the national COVID-19 data.ConclusionsThere is a high burden of respiratory conditions among patients presenting to the EMD of Muhimbili National Hospital. The trend shows four peaks of respiratory conditions in 2020-2021 seen to coincide with the four waves in the national COVID-19 data. Real-time hospital-based surveillance tools may be useful for early detection of respiratory disease outbreaks and other public health emergencies in settings with limited diagnostic testing.
The influence of different exercise types on elderly depressed patients: protocol for an umbrella review
Authors: Liu Jie , Gao Shu-qing , Zhang Lian-cheng 
Published: June 2022

AbstractIntroductionAt present, there are a large number of studies confirming that exercise can improve the depression of the elderly, but there is no research to compare the effects of different exercise programs. Therefore, the purpose of this article is to compare the effects of different exercise programs on the mood improvement of elderly people with depression, and select suitable exercise programs., In order to provide guidance and suggestions for clinical practice.Methods and analysisDocument retrieval was carried out in 7 databases including CNKI, ebsco, PsycARTICLES, PsycINFO, PubMed, Cochrane Library and Google Scholar. The retrieval time was from January 1, 2000 to May 1, 2022.ResultsObtain the exact amount of effect of different exercise programs on the mood improvement of elderly depression patients. This study will provide more convincing evidence for the effect of physical exercise on improving the mood of the elderly with depression. In addition, by comparing the effects of different exercise programs, the best program for the depression of elderly people with depression can be obtained, and some specific exercise suggestions can be provided for clinical practice, so as to promote the successful aging of the elderly.Ethics and disseminationAs this research is a systematic review of published literature, ethical approval is not required. The results will be reported according to the latest guidelines for Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 statement, and will be submitted to a peer-reviewed journal.PROSPERO registration numberCRD42021250602.Strengths and limitations of this studyThe planned systematic review will systematically report on the improvement of different types of exercise in elderly patients with depression.This protocol describes a comprehensive search strategy and eligibility criteria, which have no geographical restriction.The systematic review might be limited by the presence of selection and/or attrition bias inherent in some of the selected studies.Find the best exercise prescription for older adults with depressionAs with many reviews, the results may yield significant heterogeneity among the included studies.
Analysis of 16S rRNA gene sequence of nasopharyngeal exudate from healthy donors reveals changes in key microbial communities associated with aging
Authors: Candel Sergio , Pérez-Sanz Fernando , Tyrkalska Sylwia D. , Moreno-Docón Antonio , Esteban Ángel , L. Cayuela María , Mulero Victoriano 
Published: June 2022

ABSTRACTBackgroundFunctional or compositional perturbations of the microbiome can occur at different sites of the body and this dysbiosis has been linked to various diseases. Changes in the nasopharyngeal microbiome are associated to patient’s susceptibility to multiple viral infections, including COVID-19, supporting the idea that the nasopharynx may be playing an important role in health and disease. Most studies on the nasopharyngeal microbiome have focused on a specific component in the lifespan, such as infanthood or the elderly, or have other limitations such as low sample sizes. Therefore, detailed studies analyzing the age- and sex-associated changes in the nasopharyngeal microbiome of healthy people across their whole life are essential to understand the relevance of the nasopharynx in the pathogenesis of multiple diseases, particularly viral infections such as COVID-19.Results120 nasopharyngeal samples from healthy subjects of all ages and both sexes were analyzed by 16s rRNA sequencing. Nasopharyngeal bacterial alpha diversity did not vary in any case between age or sex groups. Proteobacteria, Firmicutes, Actinobacteria, and Bacteroidetes were the predominant phyla in all the age groups, with several sex-associated differences probably due to the different levels of sex hormones between both sexes. Acinetobacter, Brevundimonas, Dolosigranulum, Finegoldia, Haemophilus, Leptotrichia, Moraxella, Peptoniphilus, Pseudomonas, Rothia, and Staphylococcus were the only 11 bacterial genera that presented significant age-associated differences. Other bacterial genera such as Anaerococcus, Burkholderia, Campylobacter, Delftia, Prevotella, Neisseria, Propionibacterium, Streptococcus, Ralstonia, Sphingomonas, and Corynebacterium appeared in the population with a very high frequency, suggesting that their presence might be biologically relevant.ConclusionsIn contrast to other anatomical areas such as the gut, bacterial diversity in the nasopharynx of healthy subjects remains very stable and resistant to perturbations throughout the whole life and in both sexes. Age-associated changes in taxonomic composition were observed at phylum, family, and genus levels, as well as several sex-associated changes probably due to the different levels of sex hormones present in both sexes at certain ages. Our results provide a complete and valuable dataset that will be useful for future research aiming for studying the relationship between changes in the nasopharyngeal microbiome and susceptibility to or severity of multiple diseases, including COVID-19.
Population genomic insights into the evolution of the SARS-CoV-2 Omicron variant
Authors: Garg Kritika M. , Lamba Vinita , Chattopadhyay Balaji 
Published: June 2022

ABSTRACTA thorough understanding of the patterns of population subdivision of a pathogen can prevent disease spread. For SARS-CoV-2, the availability of millions of genomes makes this task analytically challenging. Our study used population genomic methods and identified subtle subdivisions within the Omicron variant, in addition to that captured by the Pango lineage. Further, some of the identified clusters of the Omicron variant revealed statistically significant signatures of selection or expansion revealing the role of microevolutionary processes in the spread of the virus. These are crucial information for policy makers as preventive measures can be designed to mitigate further spread based on a holistic understanding of the variability of the virus and evolutionary processes aiding its spread.
Screening for Pathogenic Variants in Cardiomyopathy Genes Predicts Mortality and Composite Outcomes in UK Biobank
Authors: Asatryan Babken , Shah Ravi A. , Dabbagh Ghaith Sharaf , Landstrom Andrew P. , Darbar Dawood , Khanji Mohammed Y , Lopes Luis R. , Duijvenboden Stefan van , Muser Daniele , Lee Aaron Mark , Haggerty Christopher M. , Arora Pankaj , Semsarian Christopher , Reichlin Tobias , Somers Virend K. , Owens Anjali T. , Petersen Steffen E. , Deo Rajat , Munroe Patricia B , Aung Nay , Chahal C. Anwar A. 
Published: June 2022

AbstractBackgroundInherited cardiomyopathies can present with broad variation of phenotype. Data are limited regarding genetic screening strategies and outcomes associated with putative pathogenic variants (PuPV) in cardiomyopathy-associated genes in the general population.ObjectiveWe aimed to determine the risk of mortality and cardiomyopathy-related outcomes associated with PuPV in cardiomyopathy-associated genes in UK Biobank.MethodsUsing whole exome sequencing data, variants in dilated, hypertrophic and arrhythmogenic cardiomyopathy-associated genes with at least limited evidence of disease causality according to ClinGen Expert Panel curations, were annotated using REVEL (≥0.65) and ANNOVAR (predicted loss of function) to identify PuPVs. Individuals with PuPV comprised the genotype-positive (G+) and those without PuPV the genotype-negative (G-) cohorts. Group comparisons were made using time-to-event analyses for the primary (all-cause mortality) and secondary outcomes (diagnosis of cardiomyopathy; composite outcome of diagnosis of cardiomyopathy, heart failure, arrhythmia, stroke, and death).ResultsAmong 200,619 participants, 22,401 (11.2%) were found to host ≥1 PuPV in cardiomyopathy-associated genes (G+). After adjusting for age and sex, G+ individuals had increased all-cause mortality [HR 1.07 (95%CI 1.02-1.13; p=0.011)] and increased rates of diagnosis of cardiomyopathy later in life [HR 2.37 (95%CI 1.98-2.85; p<0.0001)], which further increased in those with PuPV in definitive/strong evidence ClinGen genes [3.25 (95%CI 2.63-4.00; p<0.0001)]. G+ individuals had a higher risk of developing the composite outcome [HR 1.11 (95%CI 1.06-1.15; p<0.0001)].ConclusionsAdults with PuPV in cardiomyopathy-associated genes have higher all-cause mortality and increased risk of developing cardiomyopathy-associated features and complications, compared to genotype-negative controls.Condensed AbstractLeveraging the UK Biobank prospective cohort, we analyzed whole exome sequencing data in dilated, hypertrophic and arrhythmogenic cardiomyopathy-associated genes using a population screening ‘genotype-first’ approach. Individuals with putative pathogenic variants in genes implicated in cardiomyopathies showed an increased risk of all-cause mortality, higher risk of developing clinical cardiomyopathy later in life, and higher risk of a composite outcome (cardiomyopathy, heart failure, arrhythmia, stroke, and death) compared to genotype-negative controls. These findings highlight the potential role of ‘genotype-first’ approach in elevating personalized medicine into population level precision health in the future.
Sparse Parallel Independent Component Analysis and Its Application to Identify Stable and Replicable Imaging-genomic Association Patterns in UK Biobank
Authors: Duan Kuaikuai , Chen Jiayu , Fu Zening , Silva Rogers F. , Calhoun Vince D. , Dell’Orco Michela , Perrone-Bizzozero Nora I , Du Yuhui , Jiang Wenhao , Liu Jingyu 
Published: June 2022

AbstractData fusion analyses of brain imaging and genomics enable the linking of genomic factors to brain patterns. Due to the small to modest effect sizes of common genetic variants, it is usually challenging to reliably identify relevant genetic factors from the rest of the genome with the typical sample size in neuroimaging studies. To alleviate this problem, we propose sparse parallel independent component analysis (spICA) to leverage the sparsity of individual genomic sources, building upon the existing parallel independent component analysis (pICA) algorithm. Sparsity is enforced by performing Hoyer projection on the estimated independent sources. Simulation results demonstrate that spICA yields improved recovery of imaging-genomic associations and sources compared to pICA. We applied spICA to whole-brain gray matter volume (GMV) and whole-genome single nucleotide polymorphisms (SNPs) data of five different sets of 24,985 discovery samples in the UK Biobank. We identified three GMV sources significantly and stably associated with one SNP source and replicated these associations. GMV sources highlighted frontal, parietal, and temporal regions. Their corresponding loadings on individuals were related to multiple cognitive measures, and the temporal region interacts with age influencing cognition. The SNP component underscored SNPs in chromosome 17 that were enriched in the inflammation response pathway and in regulation effect in the prefrontal cortex via gene expression, methylation, transcription expression, and isoform percentage.
System-wide profiling by proteome integral solubility alteration assay of drug residence times for target characterization
Authors: Sabatier Pierre , Beusch Christian M. , Meng Zhaowei , Zubarev Roman A. 
Published: June 2022

AbstractMost drugs used in the clinic and drug candidates target multiple proteins, and thus detailed characterization of their efficacy targets is required. While current methods rely on quantitative measurements at thermodynamic equilibrium, kinetic parameters such as the residence time of a drug on its target provide a better proxy for efficacy in vivo. Here, we present Residence Time Proteome Integral Solubility Alteration (ResT-PISA) assay which provides monitoring temporal protein solubility profiles after drug removal (“off-curve”) in cell lysate or intact cells, quantifying the lifetime of drug-target interaction. A compressed version of the assay measures the integral under the off-curve enabling the multiplexing of binding affinity and residence time assessments into a single proteomic analysis. We introduce a combined scoring system for three parametric dimensions to improve prioritization of targets. By providing complementary information to other characteristics of drug-target interaction, ResT-PISA approach will be useful in drug development and precision medicine.
The RNA demethylase FTO controls m6A marking on SARS-CoV-2 and classifies COVID-19 severity in patients
Authors: Malbec Lionel , Celerier Margot , Bizet Martin , Calonne Emilie , Hofmann-Winkler Heike , Boeckx Bram , Abdelnabi Rana , Putmans Pascale , Hassabi Bouchra , Naesens Lieve , Lambrechts Diether , Pöhlmann Stefan , Deplus Rachel , Delang Leen , Jeschke Jana , Fuks François 
Published: June 2022

AbstractThe RNA modification N6-methyladenosine (m6A) plays a key role in the life cycles of several RNA viruses. Whether this applies to SARS-CoV-2 and whether m6A affects the outcome of COVID-19 disease is still poorly explored. Here we report that the RNA demethylase FTO strongly affects both m6A marking of SARS-CoV-2 and COVID-19 severity. By m6A profiling of SARS-CoV-2, we confirmed in infected cultured cells and showed for the first time in vivo in hamsters that the regions encoding TRS_L and the nucleocapsid protein are multiply marked by m6A, preferentially within RRACH motifs that are specific to β-coronaviruses and well conserved across SARS-CoV-2 variants. In cells, downregulation of the m6A demethylase FTO, occurring upon SARS-CoV-2 infection, increased m6A marking of SARS-CoV-2 RNA and slightly promoted viral replication. In COVID-19 patients, a negative correlation was found between FTO expression and both SARS-CoV-2 expression and disease severity. FTO emerged as a classifier of disease severity and hence a potential stratifier of COVID-19 patients.
Constraints of vigilance-dependent noradrenergic signaling to mouse cerebellar Bergmann glia
Authors: Salinas-Birt Angelica , Zhu Xiangyu , Lim Eunice Y. , Santory Aryana J. Cruz , Ye Liang , Paukert Martin 
Published: June 2022

AbstractBehavioral state plays an important role in determining astroglia Ca2+signaling. In particular, locomotion-mediated elevated vigilance has been found to trigger norepinephrine-dependent whole cell Ca2+elevations in astroglia throughout the brain. For cerebellar Bergmann glia it has recently been found that locomotion-induced transient Ca2+elevations depend on their α1A-adrenergic receptors. With increasing availability and implementation of locomotion as behavioral parameter it becomes important to understand the constraints of noradrenergic signaling to astroglia. Here we evaluated the effect of speed, duration and interval of locomotion on Ca2+signals in Bergmann glia as well as cerebellar noradrenergic axon terminals. We found almost no dependence on locomotion speed, but following the initial Ca2+transient prolonged locomotion events revealed a steady-state Ca2+elevation. Comparison of time course and recovery of transient Bergmann glia and noradrenergic terminal Ca2+dynamics suggested that noradrenergic terminal Ca2+activity determines Bergmann glia Ca2+activation and does not require noradrenergic receptor desensitization to account for attenuation during prolonged locomotion. Further, analyzing the correlation among Ca2+dynamics within regions within the field of observation we found that coordinated activity among noradrenergic terminals accounts for fluctuations of steady-state Bergmann glia Ca2+activity. Together, our findings will help to better understand astroglia Ca2+dynamics during less controlled awake behavior and may guide the identification of behavioral contexts preferably dependent on astroglia Ca2+signaling.
Ancient brainstem inhibitory neurons control selective spatial attention
Authors: Kothari Ninad B. , Banerjee Arunima , Zhang Qingcheng , You Wen-Kai , Mysore Shreesh P. 
Published: June 2022

AbstractTo behave adaptively in complex environments, animals must selectively process the most important information in space while ignoring distractors. Contrary to the dominant cortico-centric view, we report that an evolutionarily old group of inhibitory neurons in the brainstem, called PLTi, is critical for this function of selective spatial attention. In freely behaving mice performing a human-like spatial attention task, we found that bilateral silencing of PLTi severely disrupted target selection without causing perceptual or motor impairments. PLTi’s effects depended necessarily on goal-relevant, rather than just physical salience-based signals, together revealing it as a dedicated brain site for priority-driven attentional target selection. PLTi’s core computational function is its explicit implementation of the abstract cognitive decision boundary separating target from distracters: it controlled the accuracy and categorical precision of this decision boundary, doing so by shaping neural representations of competing stimuli in the superior colliculus, a major sensorimotor hub. PLTi may, therefore, be a conserved brainstem engine across vertebrates for winner-take-all-like spatial decisions in goal-driven behavior.
CROP-Seq: a single-cell CRISPRi platform for characterizing candidate genes relevant to metabolic disorders in human adipocytes
Authors: Bielczyk-Maczynska Ewa , Sharma Disha , Blencowe Montgomery , Gustafsson Peter Saliba , Gloudemans Michael J. , Yang Xia , Carcamo-Orive Ivan , Wabitsch Martin , Svensson Katrin J. , Park Chong Y. , Quertermous Thomas , Knowles Joshua W. , Li Jiehan 
Published: June 2022

AbstractObjectiveCROP-Seq combines gene silencing using CRISPR interference (CRISPRi) with single-cell RNA sequencing (scRNA-Seq) to conduct a functional reverse genetic screen of novel gene targets associated with adipocyte differentiation or function, with single-cell transcriptomes as the readout.MethodsWe created a human preadipocyte SGBS cell line with stable expression of KRAB-dCas9 for CRISPRi-mediated gene knock-down. This line was transduced with a lentiviral library of sgRNAs targeting 6 genes of interest (3 sgRNAs / gene, 18 sgRNAs), 6 positive control genes (3 sgRNAs / gene, 18 sgRNAs), and non-targeting control sgRNAs (4 sgRNAs). Transduced cells were selected and differentiated, and individual cells were captured using microfluidics at day 0, 4 and 8 of adipogenic differentiation. Next, expression and sgRNA libraries were created and sequenced. Bioinformatic analysis of resulting scRNA-Seq expression data was used to determine the effects of gene knock-down and the dysregulated pathways, and to predict cellular phenotypes.ResultsSingle-cell transcriptomes obtained from SGBS cells following CRISPRi recapitulate different states of differentiation from preadipocytes to adipocytes. We confirmed successful knock-down of targeted genes. Transcriptome-wide changes were observed for all targeted genes, with over 400 differentially expressed genes identified per gene at least at one timepoint. Knock-down of known adipogenesis regulators PPARG and CEBPB inhibited adipogenesis. Gene set enrichment analyses revealed molecular processes for adipose tissue differentiation and function for novel genes. MAFF knock-down led to a downregulation of transcriptional response to proinflammatory cytokine TNF-α in preadipocytes. TIPARP knock-down resulted in an increase in the expression of a beiging marker UCP1 at D8 of adipogenesis.ConclusionsThe CROP-Seq system in SGBS cells can determine the consequences of target gene knock-down at the transcriptome level. This powerful, hypothesis-free tool can identify novel regulators of adipogenesis, preadipocyte and adipocyte function associated with metabolic disease.HighlightsCRISPR interference screen coupled with single-cell RNA sequencing (CROP-Seq)Parallel screening of 12 genes in human SGBS adipocytes and preadipocytesUncovered novel regulators of adipogenesis and adipocyte functionGraphical abstract
Structure-Uptake Relationship Studies of Oxazolidinones in Gram-negative ESKAPE Pathogens
Authors: Hu Ziwei , Leus Inga V. , Chandar Brinda , Sherborne Bradley , Avila Quentin P. , Rybenkov Valentin V. , Zgurskaya Helen I. , Duerfeldt Adam S. 
Published: June 2022

AbstractTo date, little is known about applicability and/or generality of molecular features and how they impact small molecule permeation into Gram-negative bacteria. Identifying motifs or structural trends that correlate with broad and/or species-specific permeation would enable the rational design of new antibacterials. The clinical success of linezolid for treating Gram-positive infections paired with the high conservation of bacterial ribosomes predicts that if oxazolidinones were engineered to accumulate in Gram-negative bacteria, then this pharmacological class would find broad utility in eradicating infections. Here we report an investigative study of a strategically designed library of oxazolidinones to determine the effects of molecular structure on accumulation and biological activity.E. coli, A. baumannii, andP. aeruginosastrains with varying degrees of compromise (in efflux and outer membrane) were used to identify motifs that hinder permeation across the outer-membrane and/or enhance efflux susceptibility broadly and specifically between species. The results of this study illustrate that small changes in molecular structure are enough to overcome the efflux and/or permeation issues of this scaffold. Three oxazolidinone analogs (3e,12f, and14) were identified from this study that exhibit activity against all three pathogens assessed, a biological profile not observed for linezolid.