bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multi-Omics Analysis for Identifying Cell-Type-Specific Druggable Targets in Alzheimer’s Disease
Authors: Liu Shiwei , Cho Min Young , Huang Yen-Ning , Park Tamina , Chaudhuri Soumilee , Rosewood Thea Jacobson , Bice Paula J , Chung Dongjun , Bennett David A. , Ertekin-Taner Nilüfer , Saykin Andrew J , Nho Kwangsik 
Published: January 2025

AbstractBackgroundAnalyzing disease-linked genetic variants via expression quantitative trait loci (eQTLs) is important for identifying potential disease-causing genes. Previous research prioritized genes by integrating Genome-Wide Association Study (GWAS) results with tissue- level eQTLs. Recent studies have explored brain cell type-specific eQTLs, but they lack a systematic analysis across various Alzheimer’s disease (AD) GWAS datasets, nor did they compare effects between tissue and cell type levels or across different cell type-specific eQTL datasets. In this study, we integrated brain cell type-specific eQTL datasets with AD GWAS datasets to identify potential causal genes at the cell type level.MethodsTo prioritize disease-causing genes, we used Summary Data-Based Mendelian Randomization (SMR) and Bayesian Colocalization (COLOC) to integrate AD GWAS summary statistics with cell-type-specific eQTLs. Combining data from five AD GWAS, three single-cell eQTL datasets, and one bulk tissue eQTL meta-analysis, we identified and confirmed both novel and known candidate causal genes. We investigated gene regulation through enhancer activity using H3K27ac and ATAC-seq data, performed protein-protein interaction and pathway enrichment analyses, and conducted a drug/compound enrichment analysis with the Drug Signatures Database (DSigDB) to support drug repurposing for AD.ResultsWe identified 27 candidate causal genes for AD using cell type-specific eQTL datasets, with the highest numbers in microglia, followed by excitatory neurons, astrocytes, inhibitory neurons, oligodendrocytes, and oligodendrocyte precursor cells (OPCs).PABPC1emerged as a novel astrocyte-specific gene. Our analysis revealed protein-protein interaction (PPI) networks for these causal genes in microglia and astrocytes. We found the “regulation of aspartic-type peptidase activity” pathway being the most enriched among all the causal genes. AD-risk variants associated with candidate causal genePABPC1is located near or within enhancers only active in astrocytes. We classified the genes into three drug tiers and identified druggable interactions, with imatinib mesylate emerging as a key candidate. A drug-target gene network was created to explore potential drug targets for AD.ConclusionsWe systematically prioritized AD candidate causal genes based on cell type- specific molecular evidence. The integrative approach enhances our understanding of molecular mechanisms of AD-related genetic variants and facilitates the interpretation of AD GWAS results.
A prospective cohort study to assess if alcohol intake measured by routine pregnancy self-report predicts developmental concerns uncovered by routine health visitor screening of children at 30 months of age
Authors: Tappin David , Mackay Daniel , Reynolds Lucy , Fitzgerald Niamh 
Published: January 2025

AbstractBackgroundStigmatized behaviours are often underreported, especially in pregnancy, making them challenging to address. The Alcohol and Child Development Study (ACDS) seeks to inform prevention of foetal alcohol harm, linking self-report as well as a maternal blood alcohol biomarker with child developmental outcomes.MethodsMaternity records from all pregnant women in the study city who presented for maternity care during the 12-month period June 2017 – June 2018 were transferred to the safe data facility creating the baseline cohort. Health Visitor routinely recorded child developmental screening data collected when the offspring were 30 months of age were transferred and linked to the cohort. Anonymous analysis was performed to assess associations between self-reported alcohol intake collected at maternity presentation with child development concerns and looked after by the local authority status of offspring at 30 months of age. Chi2 tests of association were used.Results14919 maternity records were transferred and 10876 could be linked to developmental screening data collected at 30 months of age. As expected self-reported current alcohol use after conception measured at presentation to maternity care was associated with offspring being looked after by the local authority (chi2=7.85, p=0.005) at age 30 months. 6.6% of children in care were attributable to self-report of current alcohol use during pregnancy. Developmental outcomes were generally inversely associated with self-report of current alcohol use notably concern regarding Social Development (chi2=4.08, p=0.043) and Speech, Language or Communication Development (chi2=4.37, p=0.037).ConclusionsExplanation for this unexpected inverse relationship may relate to known miss-representation of alcohol intake from maternal self-report (the risk) or inaccurate assessment of offspring development at 30 months (the outcome). However self-report of current intake at maternity presentation prompts an alcohol intervention which if effective might explain the anomalous findings.
Mendelian randomization studies: a metric for quality evaluation
Authors: Rosas-Chavez Fiorella , Merriman Tony R. 
Published: January 2025

AbstractBackgroundMendelian randomization (MR) is a genetic epidemiological method used to infer causal relationships between exposures and outcomes. Its application in hyperuricemia and gout has grown exponentially owing to the ready availability of summary statistics from genome-wide association studies and the ease of applying the two-sample MR technique. However indications of poor study quality suggest the need for systematic evaluation.ObjectiveThis study evaluated the quality of two-sample MR studies on hyperuricemia and gout and developed a scoring system to help reviewers and readers assess their quality and validity.MethodsA systematic review was conducted on 86 two-sample MR studies published between 2016 and 2024. Studies were assessed using a scoring system encompassing study design, statistical methods, result interpretation, and adherence to STROBE-MR guidelines. Trends in quality over time were analyzed using regression models.ResultsStudy quality scores ranged from 0 to 19, with a mean of 9.1 and median of 11, demonstrating wide variability. High-quality studies adhered to MR assumptions, used independent datasets, and conducted replication analyses, while lower-quality studies often failed to correct the p-value when needed, test for confounders, address dataset overlap or report study power. Despite the increased publication of MR studies, overall quality not improved over time.ConclusionThere is variability in two-sample MR study quality. Our proposed scoring system offers a practical framework for evaluating MR studies, aiding researchers and clinicians in identifying robust findings while promoting higher methodological standards.
Development and evaluation of a behavioral intervention to reduce household plastic waste burning in rural Guatemala: Study protocol for Ecolectivos, a cluster-randomized community trial
Authors: Thompson Lisa M. , Raheel Hina , Lovvorn Amy E. , Hengstermann-Artiga Mayari , Lopez Maria Renee , Ramirez Alex , Barr Dana Boyd , Higgins Melinda , McCracken John P. , Saikawa Eri , Handley Margaret 
Published: January 2025

AbstractObjectiveHousehold waste burning, especially of plastics, is a major, but unaddressed environmental and health hazard in countries that lack infrastructure to properly manage waste. This study will implement village-level community working groups that aim to reduce household plastic waste burning and improve health-related quality of life in women of reproductive age in rural Guatemala.MethodsUsing a type 1 hybrid-effectiveness-implementation study design, we will randomize 16 rural villages in Jalapa, Guatemala and randomly select 400 women of reproductive age (25 in each village) who report burning plastic trash as a primary form of waste disposal to participate. In eight intervention villages, we will conduct 12-week community working groups to implement alternatives to burning plastic that are achievable over the subsequent 9 months. We will use the Behavior Change Wheel and RE-AIM, two implementation science frameworks, and a mixed-methods approach, to refine, implement, and evaluate community-initiated interventions that address plastic waste. At baseline, 4 and 12 months, we will measure personal exposures to fine particulate matter and black carbon, and urinary biomarkers of exposure (e.g., bisphenols, phthalates, polycyclic aromatic hydrocarbons, and volatile organic compounds). We will use filter-based 1,3,5-Triphenylbenzene, a known tracer of plastic incineration, to quantify emissions estimates of air pollutants due to plastic burning. Based on plastic waste reductions in intervention villages, we will assess regional impacts of pollutant emissions reduction, using a 3D chemical transport model. This study was registered atClinicalTrials.gov(NCT05130632) on November 23, 2021.SignificanceOur findings will be incorporated into community-driven public health actions to develop programs in other local contexts. This project has direct benefit not only to those residing in Guatemala, but potentially in other areas where open waste burning contributes to air pollutants both regionally and globally.Contributions to the literatureThe Ecolectivos project will engage communities to co-create sustainable alternatives to burning household plastic waste.Research will be refined during the formative phase, working groups will address behavior change during the main trial, and results will be disseminated using village-level fairs to introduce alternatives to burning plastic in control villages.This work will expand the evidence on barriers and enablers to implementing alternatives to burning plastic using the capability, opportunity, and motivation domains for key behaviors (guided by the Behavior Change Wheel framework) and focusing on reach and potential for scale-up (guided by RE-AIM framework).
Transcranial Magnetic Stimulation Measures of Corticospinal Excitability in Black and Hispanic/Latino People with Painful Peripheral Neuropathy
Authors: Wong Marlon L. , McTeague Lisa , Gonzalez Gabriel , Gonzalez Juan , Bolanos Jessica , Hosein Peter J. , Cabral Danylo F. , Fried Peter J. 
Published: January 2025

AbstractThis study aims to provide preliminary descriptive data on transcranial magnetic stimulation (TMS) measures obtained in Black and Hispanic/Latino individuals with chronic painful peripheral neuropathy (PN), including those with chemotherapy-induced peripheral neuropathy (CIPN) and diabetic neuropathy (DN). CIPN and DN share similar neuropathic symptoms and underlying physiological mechanisms, in particular altered central nervous system processing. TMS is a non-invasive technique that can assess corticospinal excitability and the function of GABAergic and glutamatergic pathways, potentially serving as a diagnostic tool for PN. This secondary analysis utilized data from a pilot randomized sham-controlled trial of transcutaneous auricular vagus nerve stimulation (taVNS) in people with PN. TMS measures, including resting motor threshold (RMT), unconditioned MEP amplitude (spTMS), short interval intracortical inhibition (SICI), and intracortical facilitation (ICF), were assessed at baseline over 2 separate visits. Test-retest reliability was evaluated, and changes in TMS measures following transcutaneous auricular vagus nerve stimulation were analyzed. Baseline TMS measures showed no significant differences between CIPN and DN groups. The study found good test-retest reliability for TMS measures, with ICC values between 0.73 and 0.87 for all TMS measures. Post taVNS, neuropathic pain symptoms improved, with a slight decrease in ICF. Overall, TMS measures demonstrated good reliability in this sample of Black and Hispanic/Latino individuals with PN, and these findings provide valuable preliminary data for future studies aimed at establishing the psychometric properties and diagnostic utility of TMS measures in PN.
A priority not guided by policy? A scooping review of policy and strategic framework on Maternal Waiting Homes
Authors: Mwansa Melvin Kunda , Chimpinde Kafiswe , Naidoo Mergan 
Published: January 2025

AbstractIntroductionMaternal Waiting Homes (MWHs) are lodgings located near health facilities where women await their delivery date and be transferred to a health facility shortly before delivery or earlier should complications arise. They are a critical strategy to improve maternal health outcomes, as they been identified as a tool for reducing maternal and perinatal mortality, especially in low-resourced countries. However, they are limited countries with deliberate policies to promote their implementation. This study aimed to review the policy and strategic framework of modern maternal waiting homes in Africa and Zambia.MethodsWe searched published, unpublished, and grey literature from the following sources: Google Scholar, CINAHL, PubMed, Scopus, Medline, and ResearchGate. Initial search between the 25thand 27thMarch 2024 and the final search was re-run on December 18, 2024. We used relevant synonyms and keywords (such as policy on MWHs, strategies on MWHs, National Development Plans, strategic plans, Health policies, and initiatives on MWHs in developing countries or middle- and low-income countries in the English language. The study further reviewed policies, strategies, development plans, and health strategic plans that facilitated the promotion of maternal health in Zambia.ResultsDatabase search yielded a total of ninety-four (94) items. Eighteen (18) additional items were located through hand-searching reference at the Zambia National Archives Centre. Ten (10) articles described MWH policies, strategies, and implementation guidelines from the seven (7) countries. From the Zambia National Archives Centre, nine (9) documents comprised policies, national development plans and strategic plans obtained through the national archives centre. Only one country (Timor-Leste) had a deliberate policy on maternal waiting homes. Zambia does not have a policy or strategy in place that promotes maternal waiting homes.ConclusionLike in many other African countries, In Zambia, no strategic policy has been implemented to promote maternal waiting homes. While MWHs are acknowledged in various strategic health plans and some policies, they are not consistently prioritised or adequately funded. countries, including Zambia must have MWHs policy that should employ deliberate strategies to reduce maternal and newborn morbidities and mortalities.
Spherical Code of Retinal Orientation-Selectivity Enables Decoding in Ensembled and Retinotopic Operation
Authors: Laniado Dimitrios D. , Maron Yariv , Gemmer John A. , Sabbah Shai 
Published: January 2025

SummarySelectivity to orientations of edges is seen at the earliest stages of visual processing, in retinal orientation-selective ganglion cells (OSGCs), thought to prefer vertical or horizontal orientation. However, as stationary edges are projected on the hemispherical retina as lines of longitude or latitude, how edge orientation is encoded, and decoded by the brain, is unknown. Here, by mapping the OS of thousands of OSGCs at known retinal locations in mice, we identified three OSGC types whose preferences match two longitudinal fields, and a fourth type matching two latitudinal fields, the members of each field-pair being non-orthogonal. A geometric decoder revealed that two OS sensors yield optimal orientation decoding when approaching the deviation from orthogonality we observed for OSGC field-pairs. Retinotopically-organized decoding generated type-specific variation in decoding efficiency across the visual field. OS tuning was greater in the dorsal retina, possibly reflecting an evolutionary adaptation to an environmental gradient of edges.
Identification of an ambisense kolmiovirus from birds
Authors: Kishimoto Mai , Imai Sakiho , Igarashi Manabu , Horie Masayuki 
Published: January 2025

AbstractViruses in the familyKolmioviridae(KoVs) are unique among RNA viruses in that they have small, highly self-complementary, circular, negative-sense genomes and are satellite viruses requiring the envelope protein of co-infected helper viruses to form infectious virions. For approximately 40 years, only hepatitis D virus (HDV) had been identified, but recent studies have uncovered novel KoVs in diverse animal species. Serinus canaria-associated deltavirus (scKoV) was recently identified form a single RNA-seq data from canary skin. However, only the partial genome sequence corresponding to the transcript encoding DAg has been identified, leaving questions regarding its full genetic composition and origins. In this study, we examined publicly available RNA-seq data and identified multiple complete genome sequences of scKoV. Our results demonstrated that genetically diverse scKoVs infect multiple bird species with recent inter-order transmission. Additionally, scKoV was detected in various tissues including parenchymal organs, suggesting that scKoV is a genuine avian KoV. Notably, analysis of the genome structure and transcriptional pattern clearly revealed that scKoV transcribes a genomic-sense mRNA encoding a novel gene, in addition to the previously known antigenomic-sense DAg transcript. Furthermore, this newly identified gene appears to express two protein isoforms via alternative splicing. These findings mark the first KoV with an ambisense genome that utilizes alternative splicing, which may represent a strategy to increase gene-coding capacity despite the constraints imposed by its small and self-complementarity genome. Moreover, co-infection with avian bornaviruses was detected in most scKoV-positive RNA-seq datasets, suggesting that avian bornaviruses are candidate helper viruses for scKoV. In conclusion, our study on scKoV provides novel insights into the evolution and diversity of KoVs.
Dmrt2Orchestrates Neuronal Development in the Embryonic Cingulate Cortex: Unveiling Sex-Biased Vulnerabilities
Authors: Bermejo-Santos Ana , Torrillas-de la Cal Rodrigo , Rubio-García Miguel , Serrano-Saiz Esther 
Published: January 2025

ABSTRACTSexual differences are prevalent in the brain. DMRT family of transcription factors (TF) has been postulated as an important determinant of sex differences. Up to now, the role of DMRTs in the brain has been focused on the DMA subfamily. Here, we show an unprecedented role forDmrt2in regulating the proliferation and neuronal development of cortical neurons in mice.Dmrt2expression is observed in deep-layer neurons of the cingulate cortex (CgCx) throughout development. Downregulation ofDmrt2mRNA in the CgCx primordium results in premature cell cycle exit of embryonic progenitors and subsequent reduction in cortical plate cellular density at later developmental stages.Dmrt2is expressed at higher levels in male embryos during early development, potentially explaining their increased vulnerability toDmrt2depletion. As development progresses,Dmrt2expression is maintained in deeper-layer neurons, where this TF controls distinct terminal processes, including migration, axonal targeting, and neuronal-specific gene expression.Our findings suggest a potential mechanistic link between the function of aDmrtfamily member and sex-specific susceptibility to neurological disorders. This study expands our understanding ofDmrtgene function in the brain and provides insights into the molecular basis of sexual differences in neurodevelopmental processes.
Human cytomegalovirus gH/gL/gO binding to PDGFRα provides a regulatory signal activating the fusion protein gB that can be blocked by neutralizing antibodies
Authors: Schultz Eric P. , Ponsness Lars , Lanchy Jean-Marc , Zehner Matthias , Klein Florian , Ryckman Brent J. 
Published: January 2025

ABSTRACTHerpesviruses require membrane fusion for entry and spread, a process facilitated by the fusion glycoprotein B (gB) and the regulatory factor gH/gL. The human cytomegalovirus (HCMV) gH/gL can be modified by the accessory protein gO, or the set of proteins UL128, UL130 and UL131. While the binding of the gH/gL/gO and gH/gL/UL128-131 complexes to cellular receptors including PDFGRα and NRP2 has been well-characterized structurally, the specific role of receptor engagements by the gH/gL/gO and gH/gL/UL128-131 in regulation of fusion has remained unclear. We describe a cell-cell fusion assay that can quantitatively measure fusion on a timescale of minutes and demonstrate that binding of gH/gL/gO to PDGFRα dramatically enhances gB-mediated cell-cell fusion. In contrast, gH/gL/pUL128-131-regulated fusion is significantly slower and gH/gL alone cannot promote gB fusion activity within this timescale. The genetic diversity of gO influenced the observed cell-cell fusion rates, correlating with previously reported effects on HCMV infectivity. Mutations in gL that had no effect on formation of gH/gL/gO or binding to PDGFRα dramatically reduced the cell-cell fusion rate, suggesting that gL plays a critical role in linking the gH/gL/gO-PDGFRα receptor-binding to activation of gB. Several neutralizing human monoclonal antibodies were found to potently block gH/gL/gO-PDGFRα regulated cell-cell fusion, suggesting this mechanism as a therapeutic target.SIGNIFICANCEDevelopment of vaccines and therapeutics targeting the fusion apparatus of HCMV has been limited by the lack anin vitrocell-cell fusion assay that faithfully models the receptor-dependent fusion characteristic of HCMV entry. The cell-cell fusion assay described here demonstrated that the binding of gH/gL/gO to its receptor, PDGFRα serves to regulate the activity of the fusion protein gB. Moreover, this regulatory mechanism is specifically vulnerable to inhibition by neutralizing antibodies. The cell-cell fusion assay described here provides a new tool to characterize neutralizing mAbs as therapeutic agents.
Niemann-Pick C-like endo-lysosomal dysfunction in DHDDS patient cells, a congenital disorder of glycosylation, can be treated with miglustat
Authors: Best Hannah L. , Cook Sophie R. , Waller-Evans Helen , Lloyd-Evans Emyr 
Published: January 2025

AbstractDHDDS (dehydrodolichol diphosphate synthetase) and NgBR (Nogo-B Receptor) collectively form an enzymatic complex important for the synthesis of dolichol – a key component of protein N-glycosylation. Mutations inDHDDSand the gene encoding NgBR (NUS1)are associated with neurodevelopmental disorders that clinically present with epilepsy, motor impairments, and developmental delay. Previous work has demonstrated both DHDDS and NgBR can also interact with NPC2 (Niemann-Pick C (NPC) type 2) – a protein which functions to traffic cholesterol out of the lysosome and, when mutated, can cause a lysosomal storage disorder (NPC disease) characterised by an accumulation of cholesterol and glycosphingolipids. Abnormal cholesterol accumulation has also been reported in cells from individuals and animal models with mutations in NUS1, and suspected lipid storage has been shown in biopsies from individuals with mutations in DHDDS. Our findings provide further evidence for overlap between NPC2 and DHDDS disorders, showing that DHDDS patient fibroblasts have increased lysosomal volume, store cholesterol and ganglioside GM1, and have altered lysosomal Ca2+homeostasis. Treatment of DHDDS cells - with the approved NPC small molecule therapy miglustat - improves these disease-associated phenotypes, identifying a possible therapeutic option for DHDDS patients. These data suggest that treatment options currently approved for NPC disease may be translatable to DHDDS/NUS1 patients.