bluuebunny/crossref_metadata_2025_split huggingface dataset:
Disproportionate High-Risk Nonsteroidal Anti-inflammatory Drug (NSAID) Prescribing in Rural Virginia
Authors: Rockwell Michelle S. , Grubb Christopher , Turner Jamie K. , Vinson Matthew , Yim Isaiah , Hanlon Alexandra L. , Epling John W. 
Published: January 2025

ABSTRACTIntroductionIndividuals living in rural areas experience limited access to safe and effective pain management. Using insurance claims for 1.3 million Virginians, we evaluated variation in high-risk nonsteroidal anti-inflammatory drug (NSAID) prescribing by rurality during 2019-2021.MethodsWe applied a difference-in-differences model to analyze the effect of the COVID-19 pandemic on high-risk NSAID prescribing rates, stratifying incidence rate ratios (IRR) by rurality.ResultsAlthough high-risk NSAID prescribing rates decreased modesty during 2020-2021, rural areas experienced significantly higher prescribing rates throughout the study period (IRR: 1.594 [95% CI: 1.408, 1.803], p<.001).ConclusionsContext-driven efforts to de-implement high-risk NSAID prescribing in rural Virginia are needed.
Socio-economic status and outcomes after transcatheter aortic valve implantation: a systematic review and meta-analysis
Authors: Verhemel Sarah , Protty Majd , Ruparelia Neil , Hailan Ahmed , Chase Alexander , Khawaja Saud , Hadjiloizou Nearchos , Malik Iqbal , Mikhail Ghada , Khamis Ramzi , Hartley Adam 
Published: January 2025

AbstractBackgroundTranscatheter aortic valve implantation (TAVI) procedures to treat severe aortic stenosis are rising, in line with aging populations and advancements in healthcare access. Economic development correlates with AS mortality rates. Socio-economic status (SES), defined by social and economic factors such as median household income, significantly influences cardiovascular outcomes. This study analyses the impact of SES on TAVI outcomes.MethodsFollowing PRISMA guidelines, a comprehensive search was conducted across PubMed, Medline, Embase, Cochrane,ClinicalTrials.govand Google Scholar, including literature up to August 1, 2024. The search employed keywords related to SES and TAVI. Of 393 identified studies, 127 were selected for full-text review, with ten addressing SES effects post-TAVI. Most studies had a retrospective design.ResultsThe patient cohort comprised 319,557 individuals, (144,583 from low SES backgrounds and 174,974 from high SES backgrounds). The analysis revealed a higher burden of comorbidities in low SES patients. Post-TAVI, lower SES related to increased 30-day mortality, major adverse cardiovascular events and the need for pacemaker implantation, although it did not affect in-hospital mortality or 30-day readmission rates.ConclusionThese findings underscore the substantial socio-economic disparities in TAVI outcomes and highlight the need for specific interventions to improve care for patients from less advantaged backgrounds.Key Learning PointsA.What is already knownLower SES negatively impacts cardiovascular outcomes due to disparities in healthcare access and comorbidities.TAVI is the standard treatment for severe aortic stenosis, especially in elderly patients.SES influences outcomes in cardiovascular procedures, but its impact on TAVI was unclear.B.What this study addsLow SES increases 30-day mortality, MACE, and pacemaker implantation rates after TAVI.SES does not affect in-hospital mortality or 30-day readmissions.Highlights the need for standardized SES metrics in TAVI research.
Multicancer analyses of short tandem repeat variations reveal shared gene regulatory mechanisms
Authors: Xia Feifei , Verbiest Max , Lundström Oxana , Sonay Tugce Bilgin , Baudis Michael , Anisimova Maria 
Published: January 2025

AbstractBackgroundShort tandem repeats (STRs) have been reported to influence gene expression across various human tissues. While STR variations are enriched in colorectal (CRC), stomach (STAD) and endometrial (UCEC) cancers, particularly in microsatellite instable (MSI) tumors, their functional effects and regulatory mechanisms on gene expression remain poorly understood across these cancer types.ResultsHere, we leverage whole-exome sequencing and gene expression data to identify STRs for which repeat lengths are associated with the expression of nearby genes (eSTRs) in CRC, STAD and UCEC tumors. Our analyses reveal that tumor STR profiles effectively capture both MSI phenotype and population structure. While most eSTRs are cancer-specific, shared eSTRs across multiple cancers exhibit consistent effects on gene expression. Notably, coding-region eSTRs identified in all three cancer types show positive correlations with nearby gene expression. We further validate the functional effects of eSTRs by demonstrating associations between somatic eSTR mutations and gene expression changes during the transition from normal to tumor tissues, suggesting their potential roles in tumorigenesis. Combined with DNA methylation data, we perform the first quantitative analysis of the interplay between STR variations and DNA methylation in tumors. We identify eSTRs where repeat lengths are associated with methylation levels of nearby CpG sites (meSTRs) and show that over 70% of eSTRs are significantly linked to local DNA methylation. Importantly, the effects of meSTRs on DNA methylation remain consistent across cancer types.ConclusionsOverall, our findings enhance the understanding of how functional STR variations influence gene expression and DNA methylation. Our study highlights shared regulatory mechanisms of STRs across multiple cancers, offering a foundation for future research into their broader implications in tumor biology.
Wnt signaling drives stromal inflammation in inflammatory arthritis
Authors: Mueller Alisa A. , Zou Angela E. , Marsh Lucy-Jayne , Kemble Samuel , Nayar Saba , Watts Gerald F.M. , Murphy Cassandra L. , Taylor Emily , Major Triin , Gardner David , Buckley Christopher D. , Wei Kevin , Raychaudhuri Soumya , Korsunsky Ilya , Filer Andrew , Croft Adam P. , Brenner Michael B. 
Published: January 2025

AbstractThe concept that fibroblasts are critical mediators of inflammation is an emerging paradigm. In rheumatoid arthritis (RA), they are the main producers of IL-6 as well as a host of other cytokines and chemokines. Their pathologic activation also directly causes cartilage and bone degradation. Yet, therapeutic agents specifically targeting fibroblasts are not available. Here, we find that Wnt receptors and modulators are predominantly expressed in stromal populations in the synovium. Importantly, non-canonical Wnt activation induces robust inflammatory gene expression including an abundance of cytokines and chemokines in synovial fibroblastsin vitro. Strikingly, the addition of Wnt ligands or inhibition of Wnt secretion exacerbates or reduces arthritis severity, respectively,in vivoin a murine model of inflammatory arthritis. These observations are relevant in human disease, as Wnt activation signatures are enhanced in fibroblasts derived from inflamed RA synovial tissue as well as fibroblasts across other inflammatory diseases. Together, these findings implicate Wnt signaling as a major driver of fibroblast-mediated inflammation and joint pathology. They further suggest that targeting the Wnt pathway is a therapeutically relevant approach to rheumatoid arthritis, particularly in patients who do not respond to conventional treatments and who often express fibroblast-predominant synovial phenotypes.
Ramp sequence may explain synonymous variant association with Alzheimer’s disease in the Paired Immunoglobulin-like Type 2 Receptor Alpha (PILRA)
Authors: Miller Justin B. , Brandon J. Anthony , McKinnon Lauren M. , Sabra Hady W. , Lucido Chloe C. , Gonzalez Murcia Josue D. , Nations Kayla A. , Payne Samuel H. , Ebbert Mark T.W. , Kauwe John S.K. , Ridge Perry G. 
Published: January 2025

AbstractBACKGROUNDSynonymous variantNC_000007.14:g.100373690T>C(rs2405442:T>C) in the Paired Immunoglobulin-like Type 2 Receptor Alpha (PILRA) gene was previously associated with decreased risk for Alzheimer’s disease (AD) in genome-wide association studies, but its biological impact is largely unknown.OBJECTIVEWe hypothesized thatrs2405442:T>Cdecreases mRNA and protein levels by destroying a ramp of slowly translated codons at the 5’ end ofPILRA.METHODSWe assessedrs2405442:T>Cpredicted effects onPILRAthrough quantitative polymerase chain reactions (qPCR) and enzyme-linked immunosorbent assays (ELISA) using Chinese hamster ovary (CHO) cells.RESULTSBoth mRNA (P=1.9184 × 10−13) and protein (P=0.01296) levels significantly decreased in the mutant versus the wildtype in the direction that we predicted based on destroying a ramp sequence.CONCLUSIONSWe show thatrs2405442:T>Calone directly impactsPILRAmRNA and protein expression, and ramp sequences may play a role in regulating AD-associated genes without modifying the protein product.Research in ContextSystematic review:Genetic variants identified through genome-wide association studies often lack biological support for their association with Alzheimer’s disease. Although synonymous variantrs2405442:T>CinPILRAwas previously reported as protective against Alzheimer’s disease, its effects have generally been attributed to linkage with missense variant,rs1859788:A>G.Interpretation:We show thatrs2405442:T>Calone decreases mRNA and protein levels by destroying a ramp of slowly translated codons at the beginning ofPILRA. We also show that a ramp sequence is present inPILRAand likely regulates mRNA and protein levels, thus offering a plausible biological mechanism explainingrs2405442:T>Cassociation with Alzheimer’s disease independent ofrs1859788:A>G.Future directions:We provide the first protocol to evaluate how disease-associated variants impact ramp sequences, which could explain why some genetic variants are reported by genome-wide association studies. Future studies might examine if the ramp sequence could be therapeutically targeted to regulatePILRAexpression without changing the protein product.
Maximizing Nature-based Solutions using Artificial Intelligence to align global biodiversity, climate, and water targets
Authors: Alejo Camilo , Luers Amy , Ventimiglia Andréa , Matthews H. Damon 
Published: January 2025

SummaryNature-based Solutions (NbS) can represent holistic pathways to reach sustainable biodiversity, climate, and water outcomes through conservation and restoration. Yet, existing prioritization frameworks rarely identify holistic NbS that maximize these outcomes. Here, we present an AI-driven framework that prioritizes NbS locations, maximizing biodiversity protection with ecological intactness, carbon storage, and water surface stability. We implement this framework through scenarios combining specific biodiversity and co-benefits outcomes to achieve Canada’s 30×30 conservation and restoration targets. Our results reveal inevitable environmental trade-offs and critical implications for equitable NbS and extractive activities. To achieve conservation targets, protecting threatened biodiversity and irrecoverable carbon storage in forests would effectively address trade-offs and enhance Protected Areas outcomes. However, minimizing trade-offs to achieve restoration targets will require targeted interventions in existing forested and agricultural lands. These findings demonstrate that frameworks integrating AI and biodiversity-co-benefit scenarios reveal strategic land use planning, policies, and investments for holistic NbS.
Off-target genomic effects in MRP8-Cre driver mice complicate its use in weight gain and metabolic studies
Authors: Soltani Fatemeh , Duval Cedric , Ariëns Robert A. S. , Kaartinen Mari T. 
Published: January 2025

AbstractBackgroundThromboinflammation of adipose tissue involves accumulation of pro-fibrinogenic factors to adipose tissue in obesity, which promotes immune cell infiltration, affects weight gain and can lead to metabolic dysfunction. The role of neutrophil genes in inflammation are frequently investigated using MRP8-Cre mice to generate neutrophil-specific knockouts. Recent study demonstrated that MRP8-Cre mice have off-target deletions inSerpine1andAp1s1genes.Serpine1, encoding plasminogen activator inhibitor-1, is a key anti-fibrinolytic factor linked to thromboinflammation and metabolic dysfunctions in obesity. In this study, we provide evidence suggesting a critical limitation in using MRP8-Cre model to study adipose tissue, weight-related dysfunctions and/or metabolic disorders.MethodsMRP8-Cre andF13a1-/-MRP8mice were placed on either control diet or high-fat diet for 16 weeks, with body weight monitored weekly. The expression ofSerpine 1, Ap1s1andAdgre1(macrophage marker) genes in inguinal and epididymal adipose tissues were analyzed using qRT-PCR and compared to the wild-type mice.ResultsMRP8-Cre shows noSerpine1orAp1s1expression in inguinal and epididymal adipose tissues. MRP8-Cre mouse is resistant to weight gain on obesogenic diet and does not show macrophage marker in adipose tissue compared to control obesity model. The resistance to weight gain translates to a neutrophil knockout model,F13a1-/-MRP8that was not expected to show resistance to weight gain as its global knockout does not exhibit this phenotype.ConclusionOur work suggests that MRP8-Cre model may not be suitable to investigate metabolic outcomes of neutrophil genes, or pathologies that have underlying etiology in thomboinflammation.
Clonality, specificity, and HLA restriction of human T cell receptors againstPlasmodium falciparumCSP
Authors: van Dijk Hannah , Wahl Ilka , Kraker Sara , Robben Paul M. , Dutta Sheetij , Wardemann Hedda 
Published: January 2025

AbstractPlasmodium falciparummalaria remains a significant global health challenge. Current vaccines elicit antibody responses against circumsporozoite protein (PfCSP) that prevent the infection of hepatocytes but offer only moderate protection. Cellular immunity has emerged as a critical component of pre-erythrocytic protection that might be leveraged to develop improved PfCSP vaccines. Here, we characterized the clonality, molecular features, epitope specificity, and HLA-restrictions of the human PfCSP-specific CD4+and CD8+T cell response to vaccination with an adjuvanted PfCSP vaccine, FMP013/ALFQ. Using TCR expression cloning, we identified novel conserved CD4+T cell epitopes in the PfCSP N terminus and show that the C-terminal CS.T3 epitope was targeted by CD4+and rare CD8+T cells, which recognized this epitope co-receptor-independently presented on a class II HLA. Our findings provide insights into the utility of these epitopes as targets for strain-transcending immunity compared to the immunodominant but highly polymorphic epitopes in the PfCSP C terminus, offering guidance for the design of improved malaria vaccines.
Single-molecule analysis of PARP1-G-quadruplex interaction
Authors: Gaur Paras , Bain Fletcher E. , Meah Riaz , Spies Maria 
Published: January 2025

ABSTRACTThe human genome contains numerous repetitive nucleotide sequences that display a propensity to fold into non-canonical DNA structures including G-quadruplexes (G4s). G4s have both positive and negative impacts on various aspects of nucleic acid metabolism including DNA replication, DNA repair and RNA transcription. Poly (ADP-ribose) polymerase (PARP1), an important anticancer drug target, has been recently shown to bind a subset of G4s, and to undergo auto-PARylation. The mechanism of this interaction, however, is poorly understood. Utilizing Mass Photometry (MP) and single-molecule total internal reflection fluorescence microscopy (smTIRFM), we demonstrate that PARP1 dynamically interacts with G4s with a 1:1 stoichiometry. Interaction of a single PARP1 molecule with nicked DNA or DNA containing G4 and a primer-template junction is sufficient to activate robust auto-PARylation resulting in the addition of poly (ADP-ribose) chains with molecular weight of several hundred kDa. Pharmacological PARP inhibitors EB-47, Olaparib and Veliparib differently affect PARP1 retention on G4-containing DNA compared to nicked DNA.
Polygenic transcriptome risk scores enhance predictive accuracy in atopic dermatitis
Authors: Antonatos Charalabos , Budu-Aggrey Ashley , Pontikas Alexandros , Akritidis Adam , Pasmatzi Efstathia , Tsiogka Aikaterini , Gregoriou Stamatis , Grafanaki Katerina , Paternoster Lavinia , Vasilopoulos Yiannis 
Published: January 2025

AbstractBackgroundIncorporation of gene expression when estimating polygenic risk scores (PRS) in atopic dermatitis (AD) may provide additional insights in disease pathogenesis and enhance predictive accuracy.ObjectiveIn this study, we developed polygenic transcriptome risk scores (PTRSs) derived from AD-enriched tissues and evaluated their performance against traditional PRS models and a baseline risk model incorporating eosinophil and lymphocyte counts in the prediction of AD.MethodsWe conducted transcriptome-wide association studies (TWAS) using the PrediXcan framework to construct tissue-specific PTRSs. Risk score performance was assessed in 256888 Europeans (10,816 cases) and validated in an independent cohort of 64152 Europeans (2669 cases) from the UK Biobank.ResultsWe observed a modest correlation between PRS and PTRS, exerting independent effects on AD risk. While PRS demonstrated superior predictive performance compared to single-tissue PTRSs, combining both models significantly enhanced prediction accuracy, yielding a c-statistic of 0.646 (95% confidence intervals: 0.634–0.656). Notably, tissue-specific PTRSs revealed stronger associations with baseline risk factors, where Eppstein-Bar virus (EBV)-transformed lymphocytes and unexposed skin PTRSs tissues reported positive associations with lymphocyte counts.ConclusionOur findings highlight the value of integrating transcriptome-based risk models to incorporating additional omics layer to refine risk prediction and enhance our understanding of genetic architecture of complex traits.
Maternal thyroid hormone imbalance and risk of autism spectrum disorder
Authors: Elbedour Leena , Weinberg May , Meiri Gal , Michaelovski Analya , Menashe Idan 
Published: January 2025

AbstractMaternal thyroid hormones play crucial roles in fetal neurodevelopment, with hypothyroidism and hyperthyroidism consistently being reported as potential risk factors for autism spectrum disorder (ASD) in offspring. Nevertheless, the mechanism underlying this association remains vague. In this retrospective cohort study of 51,296 singleton births in a single hospital, we examined the impact of different maternal thyroid conditions on the risk of ASD in the offspring. Chronic and gestational hyper-and hypothyroidism were determined based on ICD-9 criteria and maternal thyroid hormone levels, respectively. ASD diagnosis was determined based on DSM-5 criteria. Kaplan-Meier plots and Cox regression models were used to assess ASD risk in the offspring of women with and without thyroid conditions. A total of 4,306 (8.4%) of the mothers showed abnormal thyroid function. ASD cumulative incidence was similar in the offspring of women with normal and abnormal thyroid function (log-rank p=0.28). However, further classification of the study groups revealed an increased ASD risk in the offspring of women with both chronic and gestational thyroid dysfunction (aHR= 2.68, 95%CI=1.52-4.72). In addition, trimester-specific analysis revealed a dose effect in that the longer the period of thyroid imbalance, the higher the ASD risk, namely, for one, two or three trimesters of hypo- or hyperthyroidism, aHR= 1.69 (95%CI=1.19-2.83), aHR=2.39 (95%CI=1.24-5.78), aHR=3.25 (95%CI=1.07-7.21), respectively. Thus, the findings suggest that uncontrolled gestational thyroid dysfunction is associated with an elevated risk of ASD in offspring, underscoring the importance of routine thyroid function screening and treatment throughout pregnancy in mitigating ASD risk in offspring.
Pregnenolone Reduces Provoked Craving and Cocaine Use in Men and Women with Cocaine Use Disorder: A Pilot Trial
Authors: Sakmar Elcin , Wemm Stephanie , Fogelman Nia , Hermes Gretchen , Sinha Rajita , Milivojevic Verica 
Published: January 2025

AbstractAimChronic cocaine use is associated with decreases in neuroactive steroid levels. These adaptations may contribute to continued cocaine use and high relapse risk in individuals with cocaine use disorder (CUD). Thus, this pilot study assessed chronic treatment with 2 supraphysiologic doses of the neuroactive steroid precursor pregnenolone (PREG, 300 mg/day; 500 mg/day) to boost endogenous neuroactive steroid levels and assess its impact on provoked craving and cocaine use outcomes in an 8-week trial in men and women with CUD.MethodsFifty-five treatment-seeking individuals with CUD were randomly assigned to receive either placebo (PLA; n=18; 12M/6F), 300mg PREG/day (n=20; 15M/5F) or 500mg PREG/day (n=17; 12M/5F) for 8 weeks, along with outpatient weekly relapse prevention treatment. Plasma was collected at weeks 2, 5 and 7 to assess circulating pregnenolone levels. A subset of subjects participated in a 3-day experimental component of guided imagery exposure to stress, cocaine cue and neutral conditions in about week 2 of the trial to assess craving response. Cocaine use outcomes was also assessed over the 8-week treatment period. Intent-to-treat analyses were conducted using linear mixed effects models.ResultsThere were no differences between treatment groups on demographic variables and baseline cocaine use. Plasma pregnenolone levels were higher in the 300mg and 500mg PREG groups compared to PLA (p’s< 0.032). Participant trial completion rates were 100% for PLA, 90% for 300mg and 94% for 500mg PREG groups. Placebo group had increased craving in response to stress (p< .001) and cocaine cue (p< .001) provocation, whereas the PREG groups showed no increased in provoked cocaine craving. For cocaine use outcomes during the 8-week trial, a significant main effect of treatment group (p= .005) on the weekly amounts of cocaine use showed e significantly lower amounts used in the 300mg PREG compared to the 500mg PREG group (p= 0.01) and to PLA (p= .047). There was also a trend for a treatment group main effect for days of cocaine used (p<.12)ConclusionsThese pilot findings suggest that supraphysiologic neuroactive steroid PREG doses reduces cocaine craving and may also improve cocaine use outcomes in treatment seeking individuals with CUD. Findings support further assessment and development of PREG in the treatment of CUD.