bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mapping resources available for early identification and recovery-oriented intervention for people with psychosis in Addis Ababa, Ethiopia
Authors: Tsehay Mekonnen , Kelkile Teshome Shibre , Fekadu Wubalem , Cohen Alex , Misganaw Eleni , Hanlon Charlotte 
Published: January 2024

AbstractBackgroundThere is a pressing need to reduce the long duration of untreated illness and improve care and outcomes for people with psychosis in Ethiopia. This study aimed to map community resources that have the potential to be leveraged to achieve earlier and more recovery-oriented interventions for people with psychosis in Addis Ababa, Ethiopia.MethodA strength-based resource mapping exercise was undertaken in two sub-cities, covering an estimated population of half a million people. We identified the types of resources to be mapped, based on their importance for multi-sectoral care in mental health: healthcare facilities, religious organisations, traditional and faith healers, non-governmental organisations (NGOs), and social/community organisations. The lead investigator traversed the study sites to gather information on community resources, recorded the Global Positioning System (GPS) coordinates of the resources, and consulted with key informants. The information obtained was complemented by a participatory Theory of Change workshop attended by 30 stakeholders.ResultsWe identified 124 health facilities, of which only 16 health centres and nine hospitals currently provide mental health services. We identified three registered traditional healers, 38 religious organisations, 104 non-governmental organisations, and other charitable/community-based organisations. In addition, three health facilities, six holy water religious healing sites, and four traditional healers were identified as out-of-site resources that were popular and frequently visited by people living in the sub-cities. The two sub-cities also had six feeding centres each providing meals for 1000 people in need. There were extensive networks of social organisations and community-based associations. Existing care pathways are complex but commonly include traditional and religious healing sites as places of first contact.ConclusionsWe identified important available resources that provide a wealth of opportunities for improving the early identification and outcomes of people with psychosis.
Enolase inhibitors as therapeutic leads forNaegleria fowleriinfection
Authors: Milanes Jillian E. , Yan Victoria C. , Pham Cong-Dat , Muller Florian , Kwain Samuel , Rees Kerrick C. , Dominy Brian N. , Whitehead Daniel C. , Millward Steven W. , Bolejack Madison , Abendroth Jan , Phan Isabelle Q. , Staker Bart , Moseman E. Ashley , Zhang Xiang , Ma Xipeng , Jebet Audriy , Yin Xinmin , Morris James C. 
Published: January 2024

ABSTRACTInfections with the pathogenic free-living amoebaeNaegleria fowlerican lead to life-threatening illnesses including catastrophic primary amebic meningoencephalitis (PAM). Efficacious treatment options for these infections are lacking and the mortality rate remains >95% in the US. Glycolysis is very important for the infectious trophozoite lifecycle stage and inhibitors of glucose metabolism have been found to be toxic to the pathogen. Recently, human enolase 2 (ENO2) phosphonate inhibitors have been developed as lead agents to treat glioblastoma multiforme (GBM). These compounds, which cure GBM in a rodent model, are well-tolerated in mammals because enolase 1 (ENO1) is the predominant isoform used systemically. Here, we describe findings that demonstrate that these agents are potent inhibitors ofN. fowleriENO (NfENO) and are lethal to amoebae. In particular, (1-hydroxy-2-oxopiperidin-3-yl) phosphonic acid (HEX) was a potent enzyme inhibitor (IC50value of 0.14 ± 0.04 µM) that was toxic to trophozoites (EC50value of 0.21 ± 0.02 µM) while the reported CC50was >300 µM. Molecular docking simulation revealed that HEX binds strongly to the active site ofNfENO with a binding affinity of –8.6 kcal/mol. Metabolomic studies of parasites treated with HEX revealed a 4.5 to 78-fold accumulation of glycolytic intermediates upstream ofNfENO. Last, nasal instillation of HEX increased longevity of amoebae-infected rodents. Two days after infection, animals were treated for 10 days with 3 mg/kg HEX, followed by one week of observation. At the conclusion of the experiment, eight of 12 HEX-treated animals remained alive (resulting in an indeterminable median survival time) while one of 12 vehicle-treated rodents remained, yielding a median survival time of 10.9 days. Brains of six of the eight survivors were positive for amoebae, suggesting the agent at the tested dose suppressed, but did not eliminate, infection. These findings suggest that HEX is a promising lead for the treatment of PAM.
Evidence of interplays between the vascular and nociceptive systems revealed by changes in capsaicin pain caused by limb position change
Authors: Courtin Arthur S. , Knaepen Clara , Mouraux André , van Neerven Sabien Geraldine Antonia 
Published: January 2024

AbstractThis experiment aimed at confirming our incidental observation that, when capsaicin is applied on the volar forearm, raising the arm to a vertical position leads to a dramatic increase in capsaicin-evoked pain and to explore possible underlying mechanisms.Twenty healthy volunteers received a 2% capsaicin patch on one forearm and a vehicle patch on the other. Patches were kept in place for 60 minutes. The sensation caused by the patch was assessed repeatedly -in resting position and when the arm was raised vertically-before, during and after patch application. In addition, capsaicin-induced secondary hyperalgesia was assessed using mechanical pinprick stimuli. Half of the participants were seated upright while the other half were lying supine, to assess whether the effect of limb position was due to gravity.After a few minutes of patch application, raising the capsaicin treated arm (but not the vehicle treated arm) led to a strong increase of the pain experienced at the patch. This effect of raising the arm did not differ between participants in the supine and seated groups and is therefore likely related to the position of the arm relative to the ground (gravity) rather than to the body. Mechanical secondary hyperalgesia and the arm raising effect were strongly decorrelated at the last time point after patch removal, indicating different underlying mechanisms.Our results indicate that capsaicin-evoked pain can be strongly modulated by limb posture and that this effect may be caused by an interplay between vascular and nociceptive systems.
Exploring human rare disease variants from a multidimensional perspective illuminates receptor – G protein coupling diversity
Authors: Redfern-Nichols Theo , O’Brien Shannon L , Huang Xianglin , Medel-Lacruz Brian , Calebiro Davide , Selent Jana , Ladds Graham , Marti-Solano Maria 
Published: January 2024

ABSTRACTG protein-coupled receptors (GPCRs) are transmembrane proteins capable of detecting signals as diverse as odours, neurotransmitters, and hormones. Upon activation, receptor signalling converges onto four Gα protein subtypes to regulate intracellular responses. Therefore, variation in a single Gα protein gene can potentially impact the function of numerous receptors. In this work, we have performed a multidimensional study of rare disease mutations in Gαs, a prototypical Gα protein. By integrating data from 3D structures, GPCR / G protein functional pairings, transcriptomics, biophysics, and molecular dynamics with systems pharmacology modelling, our results reveal why mutations impairing receptor / Gαs coupling result in highly specific context-based signalling defects. Furthermore, we show that mutations leading to the same rare disease can alter different signal transduction steps, highlighting the importance of patient-specific treatment strategies. By closely dissecting G protein coupling, our study provides a blueprint to interrogate GPCR pathway signalling diversity in different (patho)physiological contexts.
RareACTN2Frameshift Variants Resulting in Protein Extension Cause Distal Myopathy and Hypertrophic Cardiomyopathy through Protein Aggregation
Authors: Ranta-aho Johanna , Felice Kevin J. , Jonson Per Harald , Sarparanta Jaakko , Palmio Johanna , Tasca Giorgio , Sabatelli Mario , Yvorel Cédric , Harzallah Ines , Touraine Renaud , Pais Lynn , Austin-Tse Christina A. , Ganesh Vijay , O’Leary Melanie C. , Rehm Heidi L. , Hehir Michael K. , Subramony Sub , Wu Qian , Udd Bjarne , Savarese Marco 
Published: January 2024

AbstractDistal myopathies are a group of rare, inherited muscular disorders characterized by progressive loss of muscle fibers that begins in the distal parts of arms and legs. Recently, variants in a new disease gene,ACTN2, have been shown to cause distal myopathy.ACTN2, a gene previously only associated with cardiomyopathies, encodes alpha-actinin-2, a protein expressed in both cardiac and skeletal sarcomeres. The primary function of alpha-actinin-2 is to link actin and titin to the sarcomere Z-disk. NewACTN2variants are continuously discovered, however, the clinical significance of many variants remains unknown. Thus, lack of clear genotype-phenotype correlations inACTN2-related diseases, actininopathies, persists.ObjectiveThe objective of the study is to characterize the pathomechanisms underlying actininopathies.MethodsFunctional characterization in C2C12 cell models of severalACTN2variants is conducted, including frameshift and missense variants associated with dominant actininopathies. We assess the genotype-phenotype correlations of actininopathies using clinical data from several patients carrying these variants.ResultsThe results show that the missense variants associated with a recessive form of actininopathy do not cause detectable alpha-actinin-2 aggregates in the cell model. Conversely, dominant frameshift variants causing a protein extension do produce alpha-actinin-2 aggregates.InterpretationThe results suggest that alpha-actinin-2 aggregation is the disease mechanism underlying some dominant actininopathies, and thus we recommend that protein-extending frameshift variants inACTN2should be classified as pathogenic. However, this mechanism is likely elicited by only a limited number of variants. Alternative functional characterization methods should be explored to further investigate other molecular mechanisms underlying actininopathies.
Identifying compounds to treat opiate use disorder by leveraging multi-omic data integration and multiple drug repurposing databases
Authors: Stratford Jeran K. , Carnes Megan Ulmer , Willis Caryn , Minto Melyssa S. , Elnimeiry Logain , Mathur Ravi , Schu Matthew , Quach Bryan C. , Carter Javan , Nolen Tracy , Vandergrift Nathan , Kosten Thomas , Johnson Eric Otto , Webb Bradley T. 
Published: January 2024

ABSTRACTGenes influencing opioid use disorder (OUD) biology have been identified via genome-wide association studies (GWAS), gene expression, and network analyses. These discoveries provide opportunities to identifying existing compounds targeting these genes for drug repurposing studies. However, systematically integrating discovery results and identifying relevant available pharmacotherapies for OUD repurposing studies is challenging. To address this, we’ve constructed a framework that leverages existing results and drug databases to identify candidate pharmacotherapies.For this study, two independent OUD related meta-analyses were used including a GWAS and a differential gene expression (DGE) study of post-mortem human brain. Protein-Protein Interaction (PPI) sub-networks enriched for GWAS risk loci were identified via network analyses. Drug databases Pharos, Open Targets, Therapeutic Target Database (TTD), and DrugBank were queried for clinical status and target selectivity. Cross-omic and drug query results were then integrated to identify candidate compounds.GWAS and DGE analyses revealed 3 and 335 target genes (FDR q<0.05), respectively, while network analysis detected 70 genes in 22 enriched PPI networks. Four selection strategies were implemented, which yielded between 72 and 676 genes with statistically significant support and 110 to 683 drugs targeting these genes, respectively. After filtering out less specific compounds or those targeting well-established psychiatric-related receptors (OPRM1andDRD2), between 2 and 329 approved drugs remained across the four strategies.By leveraging multiple lines of biological evidence and resources, we identified many FDA approved drugs that target genes associated with OUD. This approach a) allows high-throughput querying of OUD-related genes, b) detects OUD-related genes and compounds not identified using a single domain or resource, and c) produces a succinct summary of FDA approved compounds eligible for efficient expert review. Identifying larger pools of candidate pharmacotherapies and summarizing the supporting evidence bridges the gap between discovery and drug repurposing studies.
Genetic Association and Transferability for Urinary Albumin-Creatinine Ratio as a Marker of Kidney Disease in four Sub-Saharan African Populations and non-continental Individuals of African Ancestry
Authors: Brandenburg Jean-Tristan , Chen Wenlong Carl , Boua Palwende Romuald , Govender Melanie Ann , Agongo Godfred , Micklesfield Lisa K. , Sorgho Hermann , Tollman Stephen , Asiki Gershim , Mashinya Felistas , Hazelhurst Scott , Morris Andrew P , Fabian June , Ramsay Michèle ,   as members of AWI-Gen and the H3Africa Consortium
Published: January 2024

AbstractBackgroundGenome-wide association studies (GWAS) have predominantly focused on populations of European and Asian ancestry, limiting our understanding of genetic factors influencing kidney disease in Sub-Saharan African (SSA) populations. This study presents the largest GWAS for urinary albumin-to-creatinine ratio (UACR) in SSA individuals, including 8,970 participants living in different African regions and an additional 9,705 non-resident individuals of African ancestry from the UK Biobank and African American cohorts.MethodsUrine biomarkers and genotype data were obtained from two SSA cohorts (AWI-Gen and ARK), and two non-resident African-ancestry studies (UK Biobank and CKD-Gen Consortium). Association testing and meta-analyses were conducted, with subsequent fine-mapping, conditional analyses, and replication studies. Polygenic scores (PGS) were assessed for transferability across populations.ResultsTwo genome-wide significant (P<5×10−8) UACR-associated loci were identified, one in theBMP6 regionon chromosome 6, in the meta-analysis of resident African individuals, and another in theHBBregion on chromosome 11 in the meta-analysis of non-resident SSA individuals, as well as the combined meta-analysis of all studies. Replication of previous significant results confirmed associations in known UACR-associated regions, includingTHB53,GATM,andARL15. PGS estimated using previous studies from European ancestry, African ancestry, and multi-ancestry cohorts exhibited limited transferability of PGS across populations, with less than 1% of observed variance explained.ConclusionThis study contributes novel insights into the genetic architecture of kidney disease in SSA populations, emphasizing the need for conducting genetic research in diverse cohorts. The identified loci provide a foundation for future investigations into the genetic susceptibility to chronic kidney disease in underrepresented African populations Additionally, there is a need to develop integrated scores using multi-omics data and risk factors specific to the African context to improve the accuracy of predicting disease outcomes.
Titin-Truncating variants Predispose to Dilated Cardiomyopathy in Diverse Populations
Authors: DePaolo John , Bornstein Marc , Judy Renae , Abramowitz Sarah , Verma Shefali S. , Levin Michael G. , Arany Zoltan , Damrauer Scott M. 
Published: January 2024

AbstractImportanceThe effect of high percentage spliced in (hiPSI)TTNtruncating variants (TTNtvs) on risk of dilated cardiomyopathy (DCM) has historically been studied among population subgroups defined by genetic similarity to European reference populations. This has raised questions about the effect of TTNtvs in diverse populations, especially among individuals genetically similar to African reference populations.ObjectiveTo determine the effect of TTNtvs on risk of DCM in diverse population as measured by genetic distance (GD) in principal component (PC) space.DesignCohort studySettingPenn Medicine Biobank (PMBB) is a large, diverse biobank.ParticipantsParticipants were recruited from across the Penn Medicine healthcare system and volunteered to have their electronic health records linked to biospecimen data including DNA which has undergone whole exome sequencing.Main Outcomes and MeasuresRisk of DCM among individuals carrying a hiPSI TTNtv.ResultsCarrying a hiPSI TTNtv was associated with DCM among PMBB participants across a range of GD deciles from the 1000G European centroid; the effect estimates ranged from odds ratio (OR) = 3.29 (95% confidence interval [CI] 1.26 to 8.56) to OR = 9.39 (95% CI 3.82 to 23.13). When individuals were assigned to population subgroups based on genetic similarity to the 1000G reference populations, hiPSI TTNtvs conferred significant risk of DCM among those genetically similar to the 1000G European reference population (OR = 7.55, 95% CI 4.99 to 11.42,P<0.001) and individuals genetically similar to the 1000G African reference population (OR 3.50, 95% CI 1.48 to 8.24,P=0.004).Conclusions and RelevanceTTNtvs are associated with increased risk of DCM among a diverse cohort. There is no significant difference in effect of TTNtvs on DCM risk across deciles of GD from the 1000G European centroid, suggesting genetic background should not be considered when screening individuals for titin-related DCM.Key PointsQuestionDo high percentage spliced in (hiPSI) titin truncating variants (TTNtvs) confer similar levels of risk for dilated cardiomyopathy (DCM) across diverse populations?FindingsIn a cohort study that comprised 43,731 individuals of diverse genetic background with electronic health records linked to whole exome sequencing data, hiPSI TTNtvs conferred increased risk of DCM across all individuals irrespective of genetic background as measured by genetic distance from the 1000 Genomes Project European centroid.MeaningThe findings of this study suggest that TTNtvs increase risk of DCM among individuals independent of genetic background and that genetic similarity to a reference population should not play a role in screening for genetic causes of dilated cardiomyopathy.
Label-free virtual peritoneal lavage cytology via deep-learning-assisted single-color stimulated Raman scattering microscopy
Authors: Fang Tinghe , Wu Zhouqiao , Chen Xun , Tan Luxin , Li Zhongwu , Ji Jiafu , Fan Yubo , Li Ziyu , Yue Shuhua 
Published: January 2024

AbstractClinical guidelines for gastric cancer treatment recommend intraoperative peritoneal lavage cytology to detect free cancer cells. Patients with positive cytology require neoadjuvant chemotherapy instead of instant resection and conversion to negative cytology results in improved survival. However, the accuracy of cytological diagnosis by pathologists or artificial intelligence is disturbed by manually-produced, unstandardized slides. In addition, the elaborate infrastructure makes cytology accessible to a limited number of medical institutes. Here, we developed CellGAN, a deep learning method that enables label-free virtual peritoneal lavage cytology by producing virtual hematoxylin-eosin-stained images with single-color stimulated Raman scattering microscopy. A structural similarity loss was introduced to overcome the challenge of existing unsupervised virtual pathology techniques unable to present cellular structures accurately. This method achieved a structural similarity of 0.820±0.041 and a nucleus area consistency of 0.698±0.102, indicating the staining fidelity outperforming the state-of-the-art method. Diagnosis using virtually stained cells reached 93.8% accuracy and substantial consistency with conventional staining. Single-cell detection and classification on virtual slides achieved a mean average precision of 0.924 and an area under the receiver operating characteristic curve of 0.906, respectively. Collectively, this method achieves standardized and accurate virtual peritoneal lavage cytology and holds great potential for clinical translation.
Short-term outcomes of the digital combined lifestyle intervention CooL-MiGuide: a descriptive case series study
Authors: Philippens Nicole , Janssen Ester , Kremers Stef , Crutzen Rik 
Published: January 2024

Introduction: The objective of this study is to investigate the changes over time in anthropometrics, behaviours and health perceptions after eight months of participation in the Combined Lifestyle Intervention (CLI) CooL-MiGuide, a digital version of the Coaching on Lifestyle (CooL) intervention with the add-on of a digital platform and an app. Method: Longitudinal data were collected between January 2022 and December 2023 from adults, mainly in the South-Western area of the Netherlands, that meet the inclusion criteria for the CLI (i.e. being obese (Body Mass Index (BMI)>30) or being overweight (25<BMI<30) combined with comorbidity; and being sufficiently motivated). We collected a broad set of data at baseline (T0) and after eight months of participation (T1) on anthropometrics (self-reported weight, length, waist circumference), control and support (self-mastery, social support), physical activity (sedentary time on least/most active days, physical active minutes), diet attentiveness (attentiveness to meal composition, amounts of food and consuming), alcohol consumption, smoking, perceived fitness (perceived health, fitness when waking, fitness during daytime, impact daily stress), sleep and stress. Changes over time were analyzed using paired t-tests comparing T1 to baseline. Effect sizes were calculated using Cohen’s d. Results: The results show positive changes after eight months in anthropometrics, sedentary time, diet attentiveness, sleep, stress, fitness, and perceived health of the participants. Largest effect sizes were found for weight (Cohen’s d=0.62, average weight loss of 3.82kg), perceived health (Cohen’s d=0.58) and perceived fitness of the participants when waking and during daytime (Cohen’s d=0.41 and 0.52 respectively). Conclusion: CooL-MiGuide participants show relevant changes in the essential constructs perceived health and weight. The digital version of CooL can be a valuable alternative for people who prefer participation from a location of their choice.