bluuebunny/crossref_metadata_2025_split huggingface dataset:
Custom Biomedical FAIR Data Analysis in the Cloud Using CAVATICA
Authors: Berke Seth R , Kanchan Kanika , Marazita Mary L , Tobin Eric , Ruczinski Ingo 
Published: June 2024

AbstractThe historically fragmented biomedical data ecosystem has moved towards harmonization under the findable, accessible, interoperable, and reusable (FAIR) data principles, creating more opportunities for cloud-based research. This shift is especially opportune for scientists across diverse domains interested in implementing creative, nonstandard computational analytic pipelines on large and varied datasets. However, executing custom cloud analyses may present difficulties, particularly for investigators lacking advanced computational expertise. Here, we present an accessible, streamlined approach for the cloud compute platform CAVATICA that offers a solution. We outline how we developed a custom workflow in the cloud, for analyzing whole genome sequences of case-parent trios to detect sex-specific genetic effects on orofacial cleft risk, which required several programming languages and custom software packages. The approach involves just three components: Docker to containerize software environments, tool creation for each analysis step, and a visual workflow editor to weave the tools into a Common Workflow Language (CWL) pipeline. Our approach should be accessible to any investigator with basic computational skills, is readily extended to implement any scalable high-throughput biomedical data analysis in the cloud, and is applicable to other commonly used compute platforms such as BioData Catalyst. We believe our approach empowers versatile data reuse and promotes accelerated biomedical discovery in a time of substantial FAIR data.
Transcriptome- and proteome-wide Mendelian randomization to prioritize therapeutic targets for coronary heart disease
Authors: Gaziano Liam , Allara Elias , Giambartolomei Claudia , Stacey David , Zhao Jing Hua , Dashti Hesam , Jiang Tao , Ritchie Scott C. , Ferolito Brian R , Rasooly Danielle , Peloso Gina M. , Di Angelantonio Emanuele , Wheeler Eleanor , Pietzner Maik , Assimes Themistocles L , Wilson Peter WF , Cho Kelly , Aragam Krishna G , Burgess Stephen , Danesh John , Langenberg Claudia , Casas Juan Pablo , Michael Gaziano J , Pereira Alexandre C , Butterworth Adam S 
Published: June 2024

AbstractDespite widespread use of drugs targeting traditional cardiovascular risk factors such as lipids and blood pressure, a high burden of coronary heart disease (CHD) remains, hence novel therapeutics are needed for people who harbor residual risk. Using transcriptomic and proteomic data to instrument 15,527 genes or proteins, we conducted systematiccis-Mendelian randomization (MR) and conditional colocalization analyses with a genetic meta-analysis involving nearly 300,000 CHD cases. We identified 567 targets with putative causal relevance to CHD, of which 69 were not identified in previous genetic discovery or MR studies and were the sole causal signal in that genomic region. To aid translation of our findings, we annotated results with up-to-date information on drugs acting on these targets. Our results revealed opportunities for drug repurposing and development prioritization. For example, we provide evidence that cilostazol, a drug that targetsPDE3Aand is currently used for claudication, could be repurposed for prevention of CHD.
The impact of ethical implications intertwined with tuberculosis household contact investigation: a qualitative study
Authors: Mlambo LM , Milovanovic M , Hanrahan CF , Motsomi KW , Morolo MT , Mohlamonyane MP , Albaugh NW , Ahmed K , Martinson NA , Dowdy DW , West NS. 
Published: June 2024

AbstractBackgroundHousehold contact investigation (HCI) is an effective and widely used approach to identify persons with tuberculosis (TB) disease and infection, globally. Despite widespread recommendations for the use of HCI, there remains poor understanding of the impact on and value of contact investigation for participants. Further, how HCI as a practice impacts psychosocial factors, including stigma and possible unintended disclosure of illness among persons with TB, their families, and communities, is largely unknown.MethodsThis exploratory qualitative study nested within a randomized trial (ClinicalTrials.gov:NCT04520113, 17 August 2020) was conducted in South Africa to understand the impacts of HCI on index patients living with TB and their household contact persons in two rural districts in the Limpopo province (Vhembe and Capricorn) and Soshanguve, a peri-urban township in Gauteng province. People with TB and household members of people with TB were recruited to participate in in-depth interviews and focus group discussions using semi-structured guides. We explored individual, interpersonal, and community-level perceptions of potential impacts of household contact investigation to elucidate their perceptions of HCI. Thematic analysis identified key themes.ResultsTwenty-four individual interviews and six focus group discussions (n=39 participants) were conducted. Participants viewed HCI as an effective approach to finding TB cases, helpful in educating households about TB symptoms and reducing barriers to health-related services. At the interpersonal level, HCI aided people with TB in safely disclosing their TB status to family members and facilitated family and social support for accountability. The introduction of HIV testing during HCI was reported by some participants as making household members slightly uncomfortable, decreasing interest in household members being tested for TB. HCI negatively impacted community-level TB and HIV-related stigma due to healthcare worker visibility at home.ConclusionOur data suggests varying impacts of HCI on people with TB, their families and interpersonal relationships, and communities, highlighting the importance of considering approaches that address concerns about community stigma and HIV testing to enhance acceptance of HCI.
Estimating the lives that could be saved by expanded access to weight-loss drugs
Authors: Pandey Abhishek , Ye Yang , Wells Chad R. , Singer Burton H. , Galvani Alison P. 
Published: June 2024

AbstractObesity is a major public health crisis in the United States (US) affecting 42% of the population, exacerbating a spectrum of other diseases and contributing significantly to morbidity and mortality overall. Recent advances in pharmaceutical interventions, particularly glucagon-like peptide-1 (GLP-1) receptor agonists (e.g., semaglutide, liraglutide) and dual gastric inhibitory polypeptide and glucagon-like peptide-1 (GIP/GLP-1) receptor agonists (e.g., tirzepatide), have shown remarkable efficacy in weight loss. However, limited access to these medications due to high costs and insurance coverage issues restricts their utility in mitigating the obesity epidemic. We quantify the annual mortality burden directly attributable to limited access to these medications in the US. By integrating hazard ratios of mortality across body mass index categories with current obesity prevalence data, combined with willingness to take the medication, observed adherence to and efficacy of the medications, we estimate the impact of making these medications accessible to all those eligible. Specifically, we project that with expanded access, over 43,000 deaths could be averted annually, including more than 12,000 deaths among people with type 2 diabetes. These findings underscore the urgent need to address barriers to access and highlight the transformative public health impact that could be achieved by expanding access to these novel treatments.
Mapping Of The Sino-European Science And Technology Collaborations On Personalized Medicine: An Updated Overview
Authors: Pontoriero Letizia , Mazzoni Andrea , de Santis Giovanni , Gentili Matteo , Moltzen Ejner , Puch Sabine , Lange Carolin , Frosini Andrea , D’Errico Gianni 
Published: June 2024

AbstractAimPersonalized medicine is part of the future frontier of public health and precision healthcare systems have been implemented for years, both within Europe and beyond. To establish the state of the art of Sino-EU science and innovation in Personalized medicine, we have mined the major dedicated databases globally. Here we present the updated mapping on the Sino-EU collaborations. Patents, scientific publications and preprints related to Personalized medicine have been mapped and analyzed after being extracted through databases mining. The integration of the previous mapping provides a more complete overview, which does not show relevant variations, confirming previous trends. In this work we complete the mapping by providing a digital tool for consulting the various data collected.
Integration of clinical, pathological, radiological, and transcriptomic data improves the prediction of first-line immunotherapy outcome in metastatic non-small cell lung cancer
Authors: Captier Nicolas , Lerousseau Marvin , Orlhac Fanny , Hovhannisyan-Baghdasarian Narinée , Luporsi Marie , Woff Erwin , Lagha Sarah , Salamoun Feghali Paulette , Lonjou Christine , Beaulaton Clément , Salmon Hélène , Walter Thomas , Buvat Irène , Girard Nicolas , Barillot Emmanuel 
Published: June 2024

AbstractThe survival of patients with metastatic non-small cell lung cancer (NSCLC) has been increasing with immunotherapy, yet efficient biomarkers are still needed to optimize patient care. In this study, we explored the benefits of multimodal approaches to predict immunotherapy outcome using multiple machine learning algorithms and integration strategies. We leveraged a novel multimodal cohort of 317 metastatic NSCLC patients treated with first-line immunotherapy, collecting at baseline positron emission tomography images, digitized pathological slides, bulk transcriptomic profiles, and clinical information. Most integration strategies investigated yielded multimodal models surpassing both the best unimodal models and established univariate biomarkers, such as PD-L1 expression. Additionally, several multimodal combinations demonstrated improved patient risk stratification compared to models built with routine clinical features only. Our study thus provided new evidence of the superiority of multimodal over unimodal approaches, advocating for the collection of large multimodal NSCLC cohorts to develop and validate robust and powerful immunotherapy biomarkers.
Deep learning of protein energy landscape and conformational dynamics from experimental structures in PDB
Authors: Tang Yike , Yu Mendi , Bai Ganggang , Li Xinjun , Xu Yanyan , Ma Buyong 
Published: June 2024

AbstractProtein structure prediction has reached revolutionary levels of accuracy on single structures, implying biophysical energy function can be learned from known protein structures. However apart from single static structure, conformational distributions and dynamics often control protein biological functions. In this work, we tested a hypothesis that protein energy landscape and conformational dynamics can be learned from experimental structures in PDB and coevolution data. Towards this goal, we develop DeepConformer, a diffusion generative model for sampling protein conformation distributions from a given amino acid sequence. Despite the lack of molecular dynamics (MD) simulation data in training process, DeepConformer captured conformational flexibility and dynamics (RMSF and covariance matrix correlation) similar to MD simulation and reproduced experimentally observed conformational variations. Our study demonstrated that DeepConformer learned energy landscape can be used to efficiently explore protein conformational distribution and dynamics.
Sex-specific effects of gut microbiome on shaping bile acid metabolism
Authors: Yang Yifei , Chi Liang , Hsiao Yun-Chung , Lu Kun 
Published: June 2024

AbstractGut microbiome is a group of microorganisms that plays important roles in contributing to health and diseases. These bacterial compositions have been demonstrated to impact bile acids (BAs) profiles, either by directly metabolizing primary BAs to secondary BAs or indirect ways through host metabolism by influencing BAs synthesis, transportation and conjugation in liver. It has been observed sexually dimorphic gut microbiome and bile acids composition, with variations in expression levels of bile acid metabolizing genes in the liver. However, associations betweensex-specific differences in gut microbiome and BAs profiles are not well understood. This study aimed to investigate whether gut microbiome could influence BAs profiles in host in a sex-specific manner. We transplanted cecum feces of male and female C57BL/6 mice to male mice and measured BAs concentrations in feces, serum and liver samples 7 days after fecal transplantation. We found different BAs profiles between mice with male and female gut microbiome, including altering levels and proportions of secondary BAs. We also observed varied expression levels of genes related to bile acid metabolism in the liver and distal ileum.Our results highlight sex-specific effects of gut microbiome on shaping bile acid metabolism through gut bacteria and regulation of host genes.
Yersiniaactively downregulates type III secretion and adhesion at higher cell densities
Authors: Ermoli Francesca , Spahn Christoph , Glatter Timo , Diepold Andreas 
Published: June 2024

AbstractThe T3SS injectisome is used by Gram-negative bacteria, including important pathogens, to manipulate eukaryotic target cells by injecting effector proteins. Some bacterial species display bimodal expression of the T3SS, allowing the T3SS-negative population to benefit from the activity of their T3SS-positive siblings without investing in the assembly and production of injectisomes. In contrast,Yersinia enterocolitica, a main T3SS model organism that uses the system to evade the host immune response, was thought to uniformly express and assemble injectisomes, which are then activated by target cell contact. In this study, we found that at higher local bacterial concentrations,Yersiniaactively downregulates T3SS expression, assembly and activity. This effect is reversible, highly specific, and distinct from stationary phase adaptation. A key player is the main T3SS transcription factor VirF, which is downregulated at the higher cell densities suppressing T3SS activity and whosein transexpression restores T3SS expression and assembly. Transcript analysis showed that this effect is mediated by increased levels of the regulatory RNAscsrBC, which sequester the regulatory protein CsrA and destabilize thevirFtranscript. Downregulation of the VirF-dependent adhesin YadA led to a drastic reduction in bacterial cell adhesion. We propose that the phenotype described in this study, active downregulation of cell attachment and T3SS secretion at higher local bacterial densities, is a strategy implemented to promote bacterial replication and dissemination at later stages of infection.
Functional protein mining with conformal guarantees
Authors: Boger Ron S. , Chithrananda Seyone , Angelopoulos Anastasios N. , Yoon Peter H. , Jordan Michael I. , Doudna Jennifer A. 
Published: June 2024

1AbstractMolecular structure prediction and homology detection provide a promising path to discovering new protein function and evolutionary relationships. However, current approaches lack statistical reliability assurances, limiting their practical utility for selecting proteins for further experimental and in-silico characterization. To address this challenge, we introduce a novel approach to protein search leveraging principles from conformal prediction, offering a framework that ensures statistical guarantees with user-specified risk and provides calibrated probabilities (rather than raw ML scores) for any protein search model. Our method (1) lets users select many biologically-relevant loss metrics (i.e. false discovery rate) and assigns reliable functional probabilities for annotating genes of unknown function; (2) achieves state-of-the-art performance in enzyme classification without training new models; and (3) robustly and rapidly pre-filters proteins for computationally intensive structural alignment algorithms. Our framework enhances the reliability of protein homology detection and enables the discovery of new proteins with likely desirable functional properties.
Acceptability and feasibility of maternal screening for Group B Streptococcus: a rapid review
Authors: Constantinou Georgina , Webb Rebecca , Ayers Susan , Mitchell Eleanor J , Daniels Jane 
Published: June 2024

AbstractBackgroundThe risks and benefits of maternal screening for GBS during pregnancy or the intrapartum period are widely debated, since screen positive results trigger prophylactic antibiotic use. There is little known about women’s and health professional’s views regarding GBS screening.ObjectivesTo conduct a rapid review to synthesise evidence on women and health professionals’: (1) knowledge and awareness of; (2) preferences for; and (3) acceptability of GBS screening programmes, and (4) how feasible they are to implement.MethodLiterature searches were conducted using online databases from their inception to 2023. Papers were included if they reported primary research from the perspectives of health professionals and women, about their knowledge and awareness, preferences, acceptability and feasibility of different types of GBS screening programmes. Data were assessed for confidence using GRADE- CERQual and analysed using a convergent synthesis approach.Findings42 papers were eligible for inclusion. A total of 16,306 women and professionals were included. Women generally did not have extensive knowledge about GBS. Health professionals had a higher level of knowledge than women. Women were generally (but not universally) positive about GBS testing procedures. Some women were concerned about the impact on their place of birth.Discussion and ConclusionWhere GBS screening programmes are available, parents must be provided with high quality information about them. Health professionals and service managers need to weigh up the benefits and risks of screening for GBS with local feasibility and treatment options, and with women’s individual values and birth plans.Statement of significanceProblem:Maternal GBS colonisation at birth can lead to invasive GBS disease. The risks and benefits of screening for GBS during pregnancy is widely debated.What is already known:Different countries use different GBS screening strategies, such as the universal screening strategy vs risk based.What this paper adds:The World Health Organization reviewed their GBS policy guidelines in 2024.Resultsfrom this paper were used to ensure women and health professional’s views were considered. This paper found that women are generally (but not universally) positive about GBS testing procedures with some concerned about the impact on their birth choices.
Maternal Colonization, Perinatal Exposure, and Neonatal Acquisition of Resistant Enterobacterales
Authors: Mithal Leena B. , Sajwani Alima , Aron Abigail , Kremer Aspen , Sumner Jack T. , Castro Manzano Valeria C. , Donnelly Grayson , Watson Andrew D. , Shuai Weitao , Miller Emily S. , Fisher Joel B. , Hartmann Erica M. , Arshad Mehreen 
Published: June 2024

AbstractBackgroundMulti-drug resistant Enterobacterales, in particular with ceftriaxone resistance (CefR-E), are globally prevalent. Pregnant people colonized with resistant Enterobacterales are at risk of perinatally transmitting to neonates; infections with CefR-E strains are associated with higher mortality, morbidity and health care costs. This study aimed to estimate the rate of gut colonization of AmpR-E (ampicillin resistant Enterobacterales) and CefR-E in a population of healthy mother-infant dyads in the Chicago area and investigate the genetic characteristics of CefR-E.MethodsPregnant persons anticipating vaginal birth at two Chicago area hospitals were enrolled. Patients with preterm delivery (<35 weeks), fever during labor, cesarean delivery, exposure to antibiotics in 3rd trimester, and neonatal intensive care were excluded. Pregnancy and birth history were obtained from parent and medical record. Maternal vaginal and rectal swabs, and infant stool samples were collected and screened for resistance by plating on MacConkey with ceftriaxone. Whole genome sequencing (WGS) and analysis was conducted on the CefR-E isolates.ResultsBetween July 2020 and April 2022, 261 mother-infant dyads were enrolled with 184 maternal samples and 157 infant stool samples analyzed. Rate of maternal AmpR-E gut colonization was 97% (179/184). Rate of maternal and infant CefR-E gut colonization was 14% (26/184) and 7% (11/157) respectively. Perinatal transmission of CefR-E was 50% (11 of 22) positive mothers with available infant sample). No clinical variables were significantly associated with maternal CefR-E colonization or perinatal transmission. Type of infant nutrition (breastmilk) was significantly associated with decreased perinatal transmission of AmpR-E to infant (p=0.015). WGS of the CefR-E showed that 19/42 isolates wereE. coli, and transmission primarily occurred from mothers colonized withE. coli.ConclusionsThis study demonstrates that a sizable minority of pregnant persons are colonized with CefR-E in the U.S., a higher burden than previously reported for developed countries. Enterobacterales appear adept in perinatal transmission, with half of infants born to colonized pregnant persons harboring CefR-E in first week of life.
Genetic analysis implicatesERAP1and HLA as risk factors for severe Puumala virus infection
Authors: Haapaniemi Hele , Strausz Satu , Tervi Anniina ,   FinnGen, Jones Samuel E. , Kanerva Mari , Fors-Connolly Anne-Marie , Ollila Hanna M. 
Published: June 2024

AbstractPuumala virus (PUUV) infections can cause severe illnesses such as Hemorrhagic Fever with Renal Syndrome in humans. However, human genetic risk factors contributing to disease severity are still poorly understood. Our goal was to elucidate genetic factors contributing to PUUV infections and understand the biological mechanisms underlying individual vulnerability to the disease. Leveraging data from the FinnGen study, we conducted a genome-wide association study on severe Hemorrhagic Fever with Renal Syndrome caused by PUUV with 2,227 cases. We identified associations at the Human Leukocyte Antigen (HLA) locus andERAP1with severe PUUV infection. HLA molecules are canonical mediators for immune recognition and response.ERAP1facilitates immune system recognition and activation by cleaving viral proteins into smaller peptides which are presented to the immune system via HLA class I molecules. Notably, we identified that the lead variant (rs26653, OR = 0.84, p = 2.93×10-8) in theERAP1gene was a missense variant changing amino acid arginine to proline. From the HLA region, we showed independent and significant associations with both HLA class I and II genes. Furthermore, we showed independent associations with nine HLA alleles and severe PUUV infection using conditional HLA fine-mapping. The strongest association was found with theHLA-C*07:01allele (OR = 1.5, p = 4.0×10−24) followed by signals atHLA-B*13:02, HLA-DRB1*01:01, andHLA-DRB1*11:01alleles (p<5×10−8). Our findings suggest that viral peptide processing withERAP1and antigen presentation through HLA alleles contribute to the development of severe PUUV disease.