bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Brugada syndrome associated geneWT1impacts onSCN5Aexpression and cardiac conduction
Authors: Marsman E. Madelief J. , Offerhaus Joost A. , Mengarelli Isabella , Beekman Leander , Wilde Lisanne M.W. , Casini Simona , Goumans Marie-José , Verkerk Arie O. , Jurgens Sean J. , Wilde Arthur A.M. , Boukens Bastiaan J. , Remme Carol Ann , Bezzina Connie R. , Bosada Fernanda M. 
Published: January 2025

AbstractBrugada syndrome (BrS) is an inherited cardiac arrhythmic disorder caused by conduction slowing primarily affecting the right ventricular (RV) outflow tract (RVOT). A recent genome-wide association study (GWAS) implicated a genomic region in chromosome 11, overlapping the transcription factorWT1, in BrS susceptibility. Here, we investigated the role ofWT1on cardiac conduction using a heterozygous knockout mouse model (Wt1+/-). Transcriptomic analysis revealed increasedScn5aexpression predominantly inWt1+/-cardiomyocytes of the (sub)epicardium of the RV and RVOT without any changes in electrical properties. To unmask an effect on cardiac conduction, we performed optical mapping in a severely challenged setting offered byScn5ahaploinsufficiency, ageing, and exposure to the sodium channel blocker ajmaline and found that diminishedWt1improved the observed slowed conduction. Examination of human single-nuclei cardiac datasets indicated a strong negative correlation betweenWT1andSCN5Aexpression. In line with this observation, cardiac samples from patients with mutations inSCN5Ashowed increased WT1 protein abundance in histological sections, suggesting that increasedWT1, and not loss, is associated with BrS pathophysiology. By deleting the mouse orthologue of a BrS-associated noncoding region (RE) harboring a candidate regulatory element, we established that this RE controls expression ofWt1specifically in the (sub)epicardium of the RV. Lastly, transient overexpression ofWT1in hiPSC-derived cardiomyocytes resulted in reduced sodium current density. Our study therefore identifies the transcription factorWT1as a novel contributor to the pathophysiology of BrS, at least in part, throughSCN5A.
An adversarial scheme for integrating multi-modal data on protein function
Authors: Nasser Rami , Schaffer Leah V , Ideker Trey , Sharan Roded 
Published: January 2025

AbstractIn order to begin to decipher the structure of the cell, we need to integrate multiple types of data of different scales on subcellular organization. Such integration requires dealing with multiple data modalities and with missing data. To this end, we developed MIRAGE, a multi-modal generative model for integrating protein sequence, protein-protein interaction and protein localization data. Our approach successfully learns a joint embedding space that captures the complex relationships between these diverse modalities. We evaluate our model’s performance against existing methods, obtaining superior performance in several key tasks, including protein function prediction and module detection. MIRAGE source code is available athttps://github.com/raminass/MIRAGE.
Modular DNA Barcoding of Nanobodies Enables Multiplexedin situProtein Imaging and High-throughput Biomolecule Detection
Authors: Zhong Shilin , Wang Ruiyu , Gao Xinwei , Guo Qingchun , Lin Rui , Luo Minmin 
Published: January 2025

AbstractImmunodetection methods based on antibody-antigen interactions are routinely used in biological and clinical laboratories. DNA-labeled antibodies offer the advantage of simultaneous detection of multiple target molecules via orthogonal DNA barcode sequences. However, current methods for antibody-DNA conjugation typically involve non-site-specific modifications tailored for each specific application, a process that is labor-intensive and often compromises antibody affinity and specificity. To overcome these limitations, here we present a modular, site-specific, and cost-efficient DNA tagging strategy — multiplexed and modular barcoding of antibodies (MaMBA). Utilizing nanobodies as modular adaptors, MaMBA enables direct site-specific labeling of off-the-shelf IgG antibodies with a one-component design. We first applied MaMBA to develop themisHCR method for highly multiplexedin situprotein imaging via orthogonal hybridization chain reaction (HCR). We then introduced a cleavable version of MaMBA, which allows iterative use of the same HCR probes sets, thereby enhancing the multiplexity ofmisHCR (misHCRn).misHCRnachieves simultaneous labeling of 12 different target molecules within the same mouse brain sections. We further extended the cleavable MaMBA to develop the barcode-linked immunosorbent assay (BLISA) for multiplexed and high-throughput biomolecule detections. By combining BLISA with next-generation sequencing, we successfully measured SARS-CoV-2 IgG and HBV-associated antigens in a large number of human serum samples. Additionally, we demonstrated a small-scale drug screen by using BLISA to simultaneously detect eight protein targets. In conclusion, MaMBA offers a highly modular and easily adaptable approach for antibody DNA-barcoding, which can be broadly applied in basic research and clinical diagnostics.
Transcriptional Landscape of THAP9 across Oligodendrocyte Developmental Stages: Molecular Mechanisms and Network Analysis
Authors: Bhardwaj Tanuja , Patel Dhrumi , Majumdar Sharmistha 
Published: January 2025

AbstractOligodendrocyte maturation and myelination are critical processes in human neurodevelopment, and their dysregulation is linked to numerous neurological disorders. While model organisms have provided insight into these processes, human-specific regulatory mechanisms remain poorly understood. This study investigated human THAP9, a protein homologous to theDrosophilaP-element transposase, whose function in oligodendrocytes remains unknown. An analysis of publicly available RNA-sequencing data and H3K27ac ChIP-sequencing data from oligodendrocyte progenitor cells (OPCs) and mature oligodendrocytes (MOs) revealed significant upregulation of THAP9 during oligodendrocyte maturation. Co-expression analysis demonstrated a strong correlation with established markers of oligodendrocyte development, including myelin-associated genes (MOG, MBP) and key transcriptional regulators (PDGFRA, SOX5, SOX6, SOX11). THAP9 lacks homologues in mice, highlighting potential human-specific mechanisms in oligodendrocyte development and emphasising the importance of studying species-specific factors in neurodevelopment.. Our findings suggest that THAP9 is a novel human-specific regulator of oligodendrocyte maturation and opens new avenues for studying myelination disorders.
A Randomized Double-Blind Phase 2 Clinical Trial Treating Cervical Intraepithelial Neoplasia 2/3 with PepCan orCandida
Authors: Nakagawa Mayumi , Evans Teresa , Bimali Milan , Coleman Hannah , Crane Jasmine , Darwish Nadia , Faulkner Jennifer L. , Jones Amy , Kelly Haley , Lieblong Benjamin J. , Lu Yong-Chen , Marsh Keanna , Nookaew Intawat , Quick Charles M. , Ussery David , Robeson Michael , Shah Sumit , Shibata Takeo , Williams Heather R. , Greenfield William 
Published: January 2025

ABSTRACTPURPOSEA non-surgical alternative for treating cervical intraepithelial neoplasia (CIN) 2/3 is an unmet need due to a risk of cervical incompetency.METHODSPepCan consists of four human papillomavirus (HPV) type 16 E6 peptides and aCandidaskin testing reagent (adjuvant). In this randomized, double-blind Phase 2 study, women with biopsy-confirmed CIN2/3 were treated with PepCan orCandidaat one to one ratio. Four intradermal injections were given every 3 weeks, with observation visits at 6 and 12 months post-vaccination. Quadrant biopsies were performed at the 12-month visit, and those whose lesions regressed to no CIN were considered to be complete responders. Regression rates of each treatment group were compared to that of a historical placebo group.RESULTSWith the intention-to-treat analysis, PepCan (n=39) showed 30.8% efficacy (95% confidence interval [CI], 17 to 47.6;p=0.25) whileCandida(n=42) demonstrated 47.6% efficacy (95% CI, 32 to 63.6;p<0.001). Likewise, with the per-protocol analysis, PepCan (n=24) showed 45.8% efficacy (95% CI, 25.6 to 67.2;p=0.08) andCandida(n=29) showed 62.1% efficacy (95% CI, 42.3 to 79.3;p<0.001). There was no difference between efficacy of PepCan andCandida. No dose-limiting toxicity was observed. HPV-specific T cell responses were elicited in both groups. Vaccine-induced HPV-specific CD4 and CD8 T cells were present in cervix regardless of histological response. Single-cell RNA-seq revealed increased expression of granzymes, CCR5, and EOMES in HPV-specific CD8-positive T cells of a histological responder, compared to non-responders. Six cytokines (CCL4, CCL5, interleukin-9, lymphotoxin-α, platelet-derived growth factor-ββ, tumor growth factor-β1) were significantly decreased in bothCandidarecipients and histological responders suggesting thatCandidamay possibly exert its anti-tumor effects through these systemic mediators.CONCLUSIONSCandidamay be effective in inducing histological regression. PepCan andCandidatreatments are safe.Candidashould be evaluated in a Phase 3 trial as a potential new treatment for CIN2/3.
Clinical aspects and serodiagnosis of myasthenia gravis in Algerian patients: a prospective study on a small group of patients
Authors: Bouchtout Mohamed Nadji , Phillips William D , Attal Elias , Daoudi Smail , Kechoud Sarah , Reddel Stephen W , Touil-Boukoffa Chafia , Attal Nabila , Raache Rachida 
Published: January 2025

AbstractMyasthenia gravis (MG) is a clinically heterogeneous disease, and its diagnosis relies primarily on serological tests such as ELISA and RIPA. This study reports the clinical characteristics of a cohort of Algerian patients with MG and evaluates the diagnostic accuracy of ELISA and RIPA for detecting anti-AChR and anti-MuSK autoantibodies. Serological analyses were performed using ELISA, RIPA, and cell-based assays (CBA) in a subset of 23 patients. Algerian MG patients did not exhibit any specific clinical features compared to other populations. The results demonstrated a good correlation between ELISA and RIPA for anti-AChR and anti-MuSK autoantibodies. However, 100% of patients with generalized MG and none of those with ocular MG were positive for anti-AChR by ELISA, compared to 83.3% and 40% by RIPA, respectively. None of the 23 patients were positive for anti-MuSK by RIPA or an in-house CBA. These findings suggest that anti-AChR ELISA may serve as a reliable diagnostic tool for MG in settings where RIPA is unavailable. Combining clinical and electrophysiological findings with serological testing may enhance the accuracy of MG diagnosis.
Synergistic impact of CAG intermediate alleles in theHTTgene and microRNA dysregulation exacerbates spliceosome impairment and accelerates Tau pathology in the caudate nucleus of late-onset Alzheimer’s disease
Authors: Castilla-Silgado Juan , Perez-Oliveira Sergio , Pinto-Hernandez Paola , Fernandez-Sanjurjo Manuel , Corte-Torres Maria Daniela , Iglesias-Gutierrez Eduardo , Menendez-Gonzalez Manuel , Alvarez Victoria , Tomas-Zapico Cristina 
Published: January 2025

AbstractBackgroundLate-onset Alzheimer’s disease (LOAD) accounts for more than 95% of AD cases. Previously, we have described that 6% of AD patients present CAG intermediate alleles in the huntingtin gene (HTT IAs). The caudate nucleus, the most affected region in Huntington’s disease, is highly sensitive to theseHTTCAG expansions, as they can induce epigenetic changes, including altered microRNA profiles. All this implies a potential source of gene expression deregulation, affecting disease onset and/or progression in LOAD patients withHTT IAs.MethodsWe genotypedHTTCAG repeats and Apolipoprotein E (APOE) inpostmortembrain frozen samples from 323 LOAD patients and 335 healthy controls. From them, we selected caudate samples ofHTT IAcarrier and non-carrier LOAD patients and controls, with neuropathological study, and performed next-generation microRNA sequencing,in silicotarget prediction and pathway analysis, followed by molecular and histopathological studies.ResultsOur study revealed that the presence ofHTT IAsdecreases survival in LOAD patients after disease onset. MicroRNA profiles in the caudate nucleus are altered in all LOAD compared to the control cases but are more pronounced inHTT IAscarriers.In silicoanalysis suggests that the microRNAs expressed differentially inHTT IAscarriers regulate key components of the spliceosome, affecting splicing factors of the SRSF family or the nuclear FUS-SFPQ complex, which was confirmed by different techniques. This leads to an increase in Tau 3R protein, conducting to a higher presence of ghost tangles, the last state of neurofibrillary tangles, in LOAD patients withHTT IAs. In addition, they also present a higher number of HTT-positive neurons in a CAG repeat expansion-dependent manner.ConclusionsOur findings demonstrate a synergistic effect ofHTT IAsand miRNAs deregulation in the evolution of tau pathology, which could be related to an accelerated misprocessing and subsequent aggregation of the Tau 3R isoform, favoring a subsequent faster disease progression. The incorporation of genetic screening forHTTalleles into clinical practice would allow a more accurate classification of LOAD patients, facilitating the design of personalized therapeutic interventions and improving the prospects for the management of this debilitating disease.
Generalized Linear Mixed Model Approach for Analyzing Water, Sanitation, and Hygiene Facilities in Bangladesh: Insights from BDHS 2022 Data
Authors: Mim Mahmila Sanjana , Rahaman Lutfor , Sajib Anamul Haque 
Published: January 2025

AbstractThis study aims to identify key determinants and barriers to effective WASH facilities in Bangladesh, crucial for preventing health issues and ensuring fair access. For identifying the vital factors associated with access to WASH facilities, data obtained from Bangladesh Demographic and Health Survey (BDHS) 2022 have been analyzed. Since the survey employed a two-stage stratified clustered sampling approach, the responses from each cluster are likely to be correlated and exhibit variation between clusters, reflecting the inherent heterogeneity. To overcome this problem and incorporate cluster effect along with fixed effects, Generalized Linear Mixed Model (GLMM) for binary response has been employed rather than the conventional fixed effect logistic regression model for analyzing individual and combined basic WASH facilities in Bangladesh. The superiority of GLMM over fixed effect logistic regression model for binary response have been observed based on Akaike Information Criterion (AIC) and likelihood ratio test (LRT). The study shows that, age of household head, partner’s education level, media exposure, women empowerment, wealth index, mother’s age and mother’s education of children under 5 had significant association with basic handwashing facility. Basic sanitation facility was associated with division, place of residence, sex and age of the household head, household size, partner’s education level, working status, wealth index, mother’s age, and mother’s education of children under 5. Wealth index significantly affected the access to basic drinking water facility. Moreover, combined WASH facilities were influenced by the sex and age of the household head, household size, partner’s education level, working status, media exposure, wealth index, mother’s age, and mother’s education of children under 5. Findings of this study can be used to enhance accessibility to basic WASH facilities, contributing to the achievement of 6thSustainable Development Goal (SDG).
Optimizing Transfection Efficiency in Primary Human Splenic Fibroblast Cells
Authors: Kaur Ashpreet , Assogba Victoria A. , Assogba Jovy M. G. , Assogba Barnabe D. 
Published: January 2025

AbstractTransfection, a fundamental molecular biology technique, is crucial in introducing foreign DNA into cells. Despite its pivotal importance, mastering this technique remains a formidable challenge. In this study, we employed the calcium phosphate reagent and conducted a systematic exploration through time-dependent experiments to assess its impact on human primary splenic fibroblast cells (HSFC). The results precisely delineate optimal time frames for achieving enhanced transfection efficiency, offering conclusive evidence for the efficacy of calcium phosphate in transient transfection within the cells. The data significantly advances our comprehension of HSFC reactions, contributing to refining transfection methodologies with broader implications for biomedical applications.
Comparative analysis of cerebrospinal fluid neurofilament medium, light and heavy chain in neurodegenerative diseases using a novel assay for the detection of neurofilament medium chain
Authors: Fazeli Badrieh , Botzenhardt Sara , Bachhuber Franziska , Klassen Paula , Klose Veronika , Dorst Johannes , Wiesenfarth Maximilian , Uzelac Zeljko , Jesse Sarah , Brenner David , Anderl-Straub Sarah , Ludolph Albert C. , Otto Markus , Weishaupt Jochen , Tumani Hayrettin , Halbgebauer Steffen 
Published: January 2025

AbstractObjectiveNeurofilaments are key axonal proteins, with neurofilament light (NfL) and heavy (NfH) chain recognized as promising biomarkers for neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). However, neurofilament medium chain (NfM) remained previously underexplored due to a lack of quantitative assays. In this study, we developed a sensitive immunoassay to measure NfM in cerebrospinal fluid (CSF) and analyzed its levels in ALS, Alzheimer’s disease (AD), frontotemporal dementia (FTD), and Lewy body dementia (LBD). Correlations among neurofilaments and their diagnostic performance were also evaluated.MethodsIn this study CSF levels of three neurofilament proteins were measured in 271 participants, including patients with ALS (n=91), AD (n=25), FTD (n=38), LBD (n=18), non-neurodegenerative controls (CTRL, n=51), and 48 individuals initially evaluated for ALS but ultimately diagnosed with other conditions (CTRL.DD).ResultsAll three neurofilaments were significantly elevated in ALS compared to CTRL and CTRL.DD groups (p<0.0001 for both), with NfM and NfL also increased in FTD (p<0.0001 for both) and AD (NfM, p=0.0017; NfL, p=0.0135 ) compared to CTRL. NfH demonstrated the greatest distinction between ALS and FTD (p<0.0001). Strong correlations were observed among neurofilament subunits, particularly between NfM and NfL (r=0.94, 95% CI: 0.93-0.96, p<0.0001). All neurofilaments effectively distinguished ALS from CTRL and CTRL.DD, with AUC values ranging from 0.92 to 0.99. NfM and NfL showed high accuracy in differentiating AD (NfM, AUC: 0.89; NfL, AUC: 0.90) and FTD (NfM, AUC: 0.91; NfL, AUC: 0.92) from CTRL, while NfH best separated ALS from FTD (AUC: 0.96).ConclusionThis study provides the first quantitative comparison of NfM with NfL and NfH in a neurodegenerative cohort, highlighting its potential diagnostic value. Further research with larger cohorts, longitudinal studies, and investigations into neurofilament distribution in different compartments is needed to clarify the distinct roles of NfM, NfL, and NfH in the diagnosis and treatment of neurological diseases.
Harnessing Artificial Intelligence for Accurate Diagnosis and Radiomics Analysis of Combined Pulmonary Fibrosis and Emphysema: Insights from a Multicenter Cohort Study
Authors: Zhang Shichen , Wang Hongqiu , Tang Haiyun , Li Xiaoqin , Wu Nian-Wei , Li Bo , Chen Xin , Chen Kaishi , Xie Baosong , Zhou Aiyuan , Mo Chunheng 
Published: January 2025

AbstractCombined Pulmonary Fibrosis and Emphysema (CPFE), recognized as a distinct pulmonary syndrome in 2022, is characterized by unique clinical features and pathogenesis that can lead to respiratory failure and death. However, the diagnosis of CPFE presents significant challenges that impede effective treatment. Here, we assembled a multicenter dataset of three-dimensional (3D) computed tomography (CT) images of patients lungs from multiple hospitals across different provinces in China, including Xiangya Hospital, West China Hospital, and Fujian Provincial Hospital. Utilizing this dataset, we developed CPFENet, a deep learning-assisted diagnostic model specifically designed for CPFE patients. This model accurately classifies patients into CPFE, chronic obstructive pulmonary disease (COPD), and pulmonary fibrosis based on 3D CT data, demonstrating diagnostic performance comparable to that of professional radiologists. Furthermore, we extracted radiomic features from the 3D CT images to generate a CPFE score, a robust and efficient metric for characterizing the presence of CPFE. Using this score, we identified significant differences in CPFE scores between genders. To validate our findings, we retrospectively analyzed the gender distribution of patients across the participating hospitals, corroborating the accuracy of our results. Overall, our study represents the first multicenter systematic investigation of CPFE, providing a diagnostic model and clinical indicators that enable accurate classification and characterization of the syndrome. This research offers a valuable direction and benchmark for future studies on CPFE, potentially facilitating the development of targeted therapeutic strategies and improving patient outcomes.
Genetic prediction and adverse selection
Authors: Azevedo Eduardo , Beauchamp Jonathan , Karlsson Linnér Richard 
Published: January 2025

AbstractThe predictive power of genetic data has been increasing rapidly and is reaching levels of clinical utility for many diseases. Meanwhile, many jurisdictions have banned insurers from utilizing genetic information. This has led to concerns that further improvements in genetic prediction will lead to adverse selection. We make three contributions to this debate. First, we develop a method to measure the amount of selection in an insurance market where consumers have access to current genetic prediction technology. Second, we extend the method to estimate the amount of selection given expected improvements in genetic prediction technology. Third, using the UK Biobank dataset with nearly 500,000 genotyped individuals, we apply the method to the critical illness insurance market. We find that expected improvements in genetic prediction are likely to lead to unsustainably high levels of selection and thus threaten the viability of the market. We discuss policy implications.