bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dying to make a care policy: Community perception of causes of deaths using standardized verbal autopsy method: Saudi type 2 diabetes mellitus register data
Authors: Alyazidi Faleh , Shakely Deler , Petzold Max , Alyazidi Fawaz , Hussain-Alkhateeb Laith 
Published: February 2023

AbstractDiabetes mellitus (DM) is a serious global health issue which significantly impacts public health and socioeconomic development. Exploring how the community perceives the causes of deaths and their associated risk factors is crucial for public health. This study combines verbal autopsy (VA) with the Type 2 Diabetes Mellitus (T2DM) register to explore community perceptions of causes of death and associated influential factors in the western region of Saudi Arabia. 302 VA interviews were conducted with relatives or caregivers of deceased who died between 2017 and 2021 based on T2DM medical register from Alnoor Specialist Hospital in Makkah city, Saudi Arabia. Cause-specific mortality fractions (CSMFs) obtained from the VA using the InterVA-5 model were utilized to assess community perception. We used a multivariable logistic regression model to determine factors influencing community perceptions of causes of death. Lin’s CCC with 95% CI was used to analyze the concordance for the CSMFs from verbal autopsy causes of death (VACoD) as a presumed reference standard and family-reported causes of death (FRCoD). The outcomes of this study demonstrate a generally broad spectrum of community perceived mortalities, with some critical misconceptions based on the type of death and the deceased’s background and characteristics, with an overall CCC of 0.60 (95% CI: 0.20-1.00; p=003). The study findings demonstrate that community perception is weak if the deceased was male compared to female (aOR: 0.52; 95% CI: 0.26 –1.03) and if the deceased was >=80 years compared to 34–59 years (aOR: 0.48; 95% CI: 0.16-1.38), but it significantly improves among married compared to single (aOR: 2.13; 95% CI: 1.02 –4.42). The Saudi community perception of causes of death with reported type 2 diabetes was relatively plausible but varied substantially based on the type of death, sex, age >=80 years, and other vital events like marital status. Higher or lower community perception is attributed to how people may perceive risk factors associated with the causes of death, which can guide public health planning and interventional programs. The study findings further emphasize the need to employ robust and standardized VA methods within the routine medical services for a systemized assessment of families’ reported causes of death.
Designing a protein with emergent function by combinedin silico, in vitroandin vivoscreening
Authors: Kohyama Shunshi , Frohn Béla P. , Babl Leon , Schwille Petra 
Published: February 2023

AbstractRecently, utilization of machine learning (ML) based methods has led to astonishing progress in protein design and, thus, the design of new biological functionality. However, emergent functions that require higher-order molecular interactions, such as the ability to self-organize, are still extremely challenging to implement. Here, we describe a comprehensivein silico, in vitro, andin vitroscreening pipeline (i3-screening) to develop and validate ML-designed artificial homologs of a bacterial protein that confers its role in cell division through the emergent function of spatiotemporal pattern formation. Moreover, we present complete substitution of a wildtype gene by an ML-designed artificial homolog inEscherichia coli. These results raise great hopes for the next level of synthetic biology, where ML-designed synthetic proteins will be used to engineer cellular functions.
Population genomics-guided engineering of phenazine biosynthesis inPseudomonas chlororaphis
Authors: Thorwall Sarah , Trivedi Varun , Wheeldon Ian 
Published: February 2023

AbstractThe emergence of next-generation sequencing (NGS) technologies has made it possible to not only sequence entire genomes, but also identify metabolic engineering targets across the pangenome of a microbial population. This study leverages NGS data as well as existing molecular biology and bioinformatics tools to identify and validate genomic signatures for improving phenazine biosynthesis inPseudomonas chlororaphis. We sequenced a diverse collection of 34Pseudomonasisolates using short- and long-read sequencing techniques and assembled whole genomes using the NGS reads. In addition, we assayed three industrially relevant phenotypes (phenazine production, biofilm formation, and growth temperature) for these isolates in two different media conditions. We then provided the whole genomes and phenazine production data to a unitig-based microbial genome-wide association study (mGWAS) tool to identify novel genomic signatures responsible for phenazine production inP. chlororaphis. Post-processing of the mGWAS analysis results yielded 330 significant hits influencing the biosynthesis of one or more phenazine compounds. Based on a quantitative metric (called the phenotype score), we elucidated the most influential hits for phenazine production and experimentally validated themin vivoin the most optimal phenazine producing strain. Two genes significantly increased phenazine-1-carboxamide (PCN) production: a histidine transporter (ProY_1), and a putative carboxypeptidase (PS__04251). A putative MarR-family transcriptional regulator decreased PCN titer when overexpressed in a high PCN producing isolate. Overall, this work seeks to demonstrate the utility of a population genomics approach as an effective strategy in enabling identification of targets for metabolic engineering of bioproduction hosts.
Remote Research Practices Enhance Acute Stroke Clinical Trial Enrollment
Authors: Streib Christopher D , Staugaitis Abbey , Tessmer Megan , Gaffney Denise , Khan Shayan , Broderick Joseph P. , Khatri Pooja , Sangha Navdeep S 
Published: February 2023

AbstractBackgroundMany acute stroke clinical trials (ASCTs) are underpowered or terminated early due to poor recruitment. A pervasive challenge to ASCT recruitment is the physical separation of patients, their legally authorized representatives, research coordinators, and clinician investigators when trial-eligible patients are identified. Remote research practices (RRPs) can facilitate time-critical ASCT enrollment and follow-up assessments, however, the feasibility and effectiveness are unknown.MethodsThis case-control study retrospectively reviewed ASCT enrollment at two institutions. When conventional in-person clinical research was not possible, completion of study specific essential clinical trial events (ECTEs) were attempted via RRPs utilizing telemedicine evaluation or telephone communication. The primary outcome was successful execution of ECTEs by modality: in-person, telemedicine evaluation, or telephone communication. The secondary outcome was protocol violation rate by modality. We utilized Fisher’s Exact Test for primary and secondary outcomes and descriptive statistics to report RRP utilization.ResultsA total of 1603 individual ECTEs were attempted for 171 subjects. RRPs were utilized for 53.9% of ECTEs (19.3% telemedicine, 34.6% telephone communication). ECTEs were more likely to be completed successfully via telemedicine (100%) than in-person (98.2%) or telephone (92.3%), (p<0.01). Additionally, protocol deviations were less common with telemedicine (0.0%) than in-person (2.6%), or telephone (2.8%) (p=0.04). More than half (53.4%) of randomized ASCT enrollments were dependent upon RRPs. Randomization (94.7%) and outpatient assessments (84.6%) were more frequently completed via RRPs compared to eligibility screening (40.7%), informed consent (40.4%), supervision of study intervention (44.6%), and inpatient assessments (18.8%).ConclusionRemote research practices were effective and doubled randomized ASCT enrollments in comparison to conventional research models that are restricted to in-person interaction alone. Telemedicine was associated with the highest rate of successful ECTE execution and the lowest rate of protocol deviations. These findings may be confounded by indication and further definitive study is indicated.
Protocol for a cluster randomised controlled trial to evaluate the effectiveness of digital health interventions in improving non-communicable disease management during the pandemic in rural Pakistan
Authors: Wei Xiaolin , Khan Nida , Durrani Hammad , Muzaffar Naila , Haldane Victoria , Walley John D , Thorpe Kevin , Ge Erjia , Ge Shiliang , Dodd Warren , Wallace James , Aslanyan Garry , Laporte Audrey , Khan Muhammad Amir 
Published: February 2023

Background: The COVID-19 pandemic has revealed gaps in global health systems, especially in the low- and middle-income countries (LMICs). Evidence shows that patients with non-communicable diseases (NCDs) are at higher risk of contracting COVID-19 and suffering direct and indirect health consequences. Considering the future challenges such as environmental disasters and pandemics to the LMICs health systems, digital health interventions (DHI) are well poised to strengthen health care resilience. This study aims to implement and evaluate a comprehensive package of DHIs of integrated COVID-NCD care to manage NCDs in primary care facilities in rural Pakistan. Methods The study is designed as a pragmatic, parallel two-arm, multi-centre, cluster randomised controlled trial. We will randomise 30 primary care facilities in three districts of Punjab, where basic hypertension and diabetes diagnosis and treatment is provided, with a ratio of 1:1 between intervention and control. In each facility, we will recruit 50 patients who have uncontrolled hypertension. The intervention arm will receive training on an integrated COVID-NCD guideline, and will use a smartphone app-based telemedicine platform where patients can communicate with health providers and peer-supporters, along with a remote training and supervision system. Usual care will be provided in the control arm. Patients will be followed up for 10 months. Our primary indicator is systolic blood pressure measured at 10 months. A process evaluation guided by implementation science frameworks will be conducted to explore implementation questions. A cost-effectiveness evaluation will be conducted to inform future scale up in Pakistan and other LMICs. Discussion: Our study is one of the first randomised controlled trials to evaluate the effectiveness of DHIs to manage NCDs to strengthen health system resilience in LMICs. We will also evaluate the implementation process and cost-effectiveness to inform future scale-up in similar resource constrained settings.
Deciphering D4Z4 CpG methylation gradients in fascioscapulohumeral muscular dystrophy using nanopore sequencing
Authors: Butterfield Russell J , Dunn Diane M , Duval Brett , Moldt Sarah , Weiss Robert B 
Published: February 2023

ABSTRACTFascioscapulohumeral muscular dystrophy (FSHD) is caused by a unique genetic mechanism that relies on contraction and hypomethylation of the D4Z4 macrosatellite array on the chromosome 4q telomere allowing ectopic expression of theDUX4gene in skeletal muscle. Genetic analysis is difficult due to the large size and repetitive nature of the array, a nearly identical array on the 10q telomere, and the presence of divergent D4Z4 arrays scattered throughout the genome. Here, we combine nanopore long-read sequencing with Cas9-targeted enrichment of 4q and 10q D4Z4 arrays for comprehensive genetic analysis including determination of the length of the 4q and 10q D4Z4 arrays with base-pair resolution. In the same assay, we differentiate 4q from 10q telomeric sequences, determine A/B haplotype, identify paralogous D4Z4 sequences elsewhere in the genome, and estimate methylation for all CpGs in the array. Asymmetric, length-dependent methylation gradients were observed in the 4q and 10q D4Z4 arrays that reach a hypermethylation point at approximately 10 D4Z4 repeat units, consistent with the known threshold of pathogenic D4Z4 contractions. High resolution analysis of individual D4Z4 repeat methylation revealed areas of low methylation near the CTCF/insulator region and areas of high methylation immediately preceding theDUX4transcriptional start site. Within theDUX4exons, we observed a waxing/waning methylation pattern with a 180-nucleotide periodicity, consistent with phased nucleosomes. Targeted nanopore sequencing complements recently developed molecular combing and optical mapping approaches to genetic analysis for FSHD by adding precision of the length measurement, base-pair resolution sequencing, and quantitative methylation analysis.
Discovery of multi-state gene cluster switches determining the adaptive mitochondrial and metabolic landscape of breast cancer
Authors: Menegollo Michela , Bentham Robert B. , Henriques Tiago , Qi Ng Seow , Ren Ziyu , Esculier Clarinde , Agarwal Sia , Tong Emily , Lo Clement , Ilangovan Sanjana , Szabadkai Zorka , Suman Matteo , Patani Neill , Ghanate Avinash , Bryson Kevin , Stein Robert C. , Yuneva Mariia , Szabadkai Gyorgy 
Published: February 2023

AbstractAdaptive metabolic switches are proposed to underlie conversions between cellular states during normal development as well as in cancer evolution, where they represent important therapeutic targets. However, the full spectrum, characteristics and regulation of existing metabolic switches are unknown. We propose that metabolic switches can be recognised by locating large alternating gene expression patterns and associate them with specific metabolic states. We developed a method to identify interspersed genesets by massive correlated biclustering (MCbiclust) and to predict their metabolic wiring. Testing the method on major breast cancer transcriptome datasets we discovered a series of gene sets with switch-like behaviour, predicting mitochondrial content, activity and central carbon fluxes in tumours associated with different switch positions. The predictions were experimentally validated by bioenergetic profiling and metabolic flux analysis of13C-labelled substrates and were ultimately extended by geneset analysis to link metabolic alterations to cellular states, thus predicting tumour pathology, prognosis and chemosensitivity. The method is applicable to any large and heterogeneous transcriptome dataset to discover metabolic and associated pathophysiological states.Statement of significanceWe present a novel method to identify the transcriptomic signatures of metabolic switches underlying divergent routes of cellular transformation. We illustrate the power of the method by stratifying breast cancer into metabolic subtypes, predicting their biology, architecture and clinical outcome.
Spenito-dependent metabolic sexual dimorphism intrinsic to fat storage cells
Authors: Diaz Arely V. , Matheny Tyler , Stephenson Daniel , Nemkov Travis , D’Alessandro Angelo , Reis Tânia 
Published: February 2023

AbstractMetabolism in males and females is distinct. Differences are usually linked to sexual reproduction, with circulating signals (e.g. hormones) playing major roles. By contrast, sex differences prior to sexual maturity and intrinsic to individual metabolic tissues are less understood. We analyzedDrosophila melanogasterlarvae and find that males store more fat than females, the opposite of the sexual dimorphism in adults. We show that metabolic differences are intrinsic to the major fat storage tissue, including many differences in the expression of metabolic genes. Our previous work identified fat storage roles for Spenito (Nito), a conserved RNA-binding protein and regulator of sex determination. Nito knockdown specifically in the fat storage tissue abolished fat differences between males and females. We further show that Nito is required for sex-specific expression of the master regulator of sex determination, Sex-lethal (Sxl). “Feminization” of fat storage cells via tissue-specific overexpression of a Sxl target gene made larvae lean, reduced the fat differences between males and females, and induced female-like metabolic gene expression. Altogether, this study supports a model in which Nito autonomously controls sexual dimorphisms and differential expression of metabolic genes in fat cells in part through its regulation of the sex determination pathway.
Speedy-PASEF: Analytical flow rate chromatography and trapped ion mobility for deep high-throughput proteomics
Authors: Szyrwiel Lukasz , Gille Christoph , Mülleder Michael , Demichev Vadim , Ralser Markus 
Published: February 2023

AbstractIncreased throughput in proteomic experiments can improve accessibility of proteomic platforms, reduce costs and facilitate new approaches in systems biology and biomedical research. Here we propose Speedy-PASEF, a combination of analytical flow rate chromatography with ion mobility separation of peptide ions, data-independent acquisition and data analysis with the DIA-NN software suite, for conducting fast, high-quality proteomic experiments that require only moderate sample amounts. For instance, using a 500-μl/min flow rate and a 3-minute chromatographic gradient, Speedy-PASEF quantified 5,211 proteins from 2 μg of a mammalian cell-line standard at high quantitative accuracy and precision. We further used Speedy-PASEF to analyze blood plasma samples from a cohort of COVID-19 inpatients, using a 3-minute chromatographic gradient and alternating column regeneration on a dual pump system, for processing 398 samples per day. Speedy-PASEF delivered a comprehensive view of the COVID-19 plasma proteome, allowing classification of the patients according to disease severity and revealing plasma biomarker candidates. Speedy-PASEF thus facilitates acquisition of high-quality proteomes in large numbers.
AC. elegansmale pheromone feminizes germline gene expression in hermaphrodites and imposes life-history costs
Authors: Angeles-Albores David , Aprison Erin Z. , Dzitoyeva Svetlana , Ruvinsky Ilya 
Published: February 2023

AbstractSex pheromones improve reproductive success, but also impose costs. Here we show that even brief exposure to physiological amounts of the dominantC. elegansmale pheromone, ascr#10, alters the expression of thousands of genes in hermaphrodites. The most dramatic effect on the transcriptome was the upregulation of genes expressed during oogenesis and downregulation of genes associated with male gametogenesis. Among the detrimental effects of ascr#10 on hermaphrodites is the increased risk of persistent infections caused by pathological pharyngeal hypertrophy. Our results reveal a way in which social signals help to resolve the inherent conflict between spermatogenesis and oogenesis in a simultaneous hermaphrodite, presumably to optimally align reproductive function to the presence of potential mating partners. They also show that the beneficial effects of the pheromone are accompanied by harmful consequences that reduce lifespan.
Integrated Cell Landscape and Dynamics in the Progression of Bone Repair
Authors: Shi Junfeng , Wang Jie , Yin Shi , Lin Sihan , Jiang Fei , Zhang Maolin , Wu Xiaolin , Shen Lijuan , Gu Xuefeng , Yang Ruomeng , Yang Jiawei , Wen Jin , Zhang Wenjie , Chang Qing , Jiang Xinquan 
Published: February 2023

AbstractBone homeostasis and repair is a systematic progress with spatiotemporal interaction of multiple cell types involved in skeletal and immune system. Precise spatiotemporal regulation of cell type-specific functions in bone repair contributes to further development of tissue engineering and regenerative medicine. Here, we utilized single-cell RNA sequencing to illustrate a map of cell landscape and dynamics in the progression of rodent bone self-healing and a perturbation by lymphoid cell-deficiency. We identified different functions of myeloid cell and lymphoid cell to osteogenesis and angiogenesis during bone repair and their mutual complementation under lymphoid cell-deficient condition. Additionally, we used CD34+humanized reconstituted mice to reveal further insights into the mechanism of human bone homeostasis and repair. Our integrated cellular analysis of bone repair explores the functional diversity and complementation between myeloid cells and lymphoid cells during bone healing process and provides further therapeutic implications for the treatment of bone disease and degeneration following ageing.
Repeatability of adaptation in sunflowers: genomic regions harbouring inversions also drive adaptation in species lacking an inversion
Authors: Soudi Shaghayegh , Jahani Mojtaba , Todesco Marco , Owens Gregory L. , Bercovich Natalia , Rieseberg Loren H. , Yeaman Sam 
Published: February 2023

AbstractLocal adaptation commonly involves alleles of large effect, which experience fitness advantages when in positive linkage disequilibrium (LD). Because segregating inversions suppress recombination and facilitate the maintenance of LD between locally adapted loci, they are also commonly found to be associated with adaptive divergence. However, it is unclear what fraction of an adaptive response can be attributed to inversions and alleles of large effect, and whether the loci within an inversion could still drive adaptation in the absence of its recombination-suppressing effect. Here, we use genome-wide association studies to explore patterns of local adaptation in three species of sunflower:Helianthus annuus,H. argophyllus, andH. petiolaris, which each harbour a large number of species-specific inversions. We find evidence of significant genome-wide repeatability in signatures of association to phenotypes and environments, which are particularly enriched within regions of the genome harbouring an inversion in one species. This shows that while inversions may facilitate local adaptation, at least some of the loci can still harbour mutations that make substantial contributions without the benefit of recombination suppression in species lacking a segregating inversion. While a large number of genomic regions show evidence of repeated adaptation, most of the strongest signatures of association still tend to be species-specific, indicating substantial genotypic redundancy for local adaptation in these species.
Pulmonary osteoclast-like cells in silica induced pulmonary fibrosis
Authors: Hasegawa Yoshihiro , Franks Jennifer M. , Tanaka Yusuke , Uehara Yasuaki , Read David F. , Williams Claire , Srivatsan Sanjay , Pitstick Lori B. , Nikolaidis Nikolaos M. , Shaver Ciara M. , Wu Huixing , Gardner Jason C. , Osterburg Andrew R. , Yu Jane J. , Kopras Elizabeth J. , Teitelbaum Steven L. , Wikenheiser-Brokamp Kathryn A. , Trapnell Cole , McCormack Francis X. 
Published: February 2023

AbstractThe pathophysiology of silicosis is poorly understood, limiting development of therapies for those who have been exposed to the respirable particle. We explored the mechanisms of silica-induced pulmonary fibrosis in a mouse model using multiple modalities including wholelung single-nucleus RNA sequencing. These analyses revealed that in addition to pulmonary inflammation and fibrosis, intratracheal silica challenge induced osteoclast-like differentiation of alveolar macrophages and recruited monocytes, driven by induction of the osteoclastogenic cytokine, receptor activator of nuclear factor-κB ligand (RANKL) in pulmonary lymphocytes and alveolar type II cells. Furthermore, anti-RANKL monoclonal antibody treatment suppressed silica-induced osteoclast-like differentiation in the lung and attenuated silica-induced pulmonary fibrosis. We conclude that silica induces osteoclast-like differentiation of distinct recruited and tissue resident monocyte populations, leading to progressive lung injury, likely due to sustained elaboration of bone resorbing proteases and hydrochloric acid. Interrupting osteoclast-like differentiation may therefore constitute a promising avenue for moderating lung damage in silicosis.One Sentence SummarySilica induces the alveolar epithelium to reprogram recruited and resident pulmonary myeloid cells to become osteoclasts that contribute to pulmonary fibrosis.