bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interstitial Cystitis: a phenotype and rare variant exome sequencing study
Authors: Motelow Joshua E. , Malakar Ayan , Krishna Murthy Sarath Babu , Verbitsky Miguel , Kahn Atlas , Estrella Elicia , Kunkel Louis , Wiesenhahn Madelyn , Becket Jaimee , Harris Natasha , Lee Richard , Adam Rosalyn , Kiryluk Krzysztof , Gharavi Ali G. , Brownstein Catherine A. 
Published: February 2025

AbstractInterstitial cystitis/bladder pain syndrome (IC/BPS) is a poorly understood and underdiagnosed syndrome of chronic bladder/pelvic pain with urinary frequency and urgency. Though IC/BPS can be hereditary, little is known of its genetic etiology. Using the eMERGE data, we confirmed known phenotypic associations such as gastroesophageal reflux disease and irritable bowel syndrome and detected new associations, including osteoarthrosis/osteoarthritis and Barrett’s esophagus. An exome wide ultra-rare variants analysis in 348 IC/BPS and 11,981 controls extended the previously reported association withATP2C1andATP2A2,implicated in Mendelian desquamating skin disorders, but did not provide evidence for other previously proposed pathogenic pathways such as bladder development, nociception or inflammation. Pathway analysis detected new associations with “anaphase-promoting complex-dependent catabolic process”, the “regulation of MAPK cascade” and “integrin binding”. These findings suggest perturbations in biological networks for epithelial integrity and cell cycle progression in IC/BPS pathogenesis, and provide a roadmap for its future investigation.
Spatiotemporal Analysis of COVID-19 Risk in Malawi: The Impact of Age, Poverty, Population Density, and Environmental Factors
Authors: Afuleni Mwandida Kamba , Hall Ian , House Thomas , Johnson Olatunji 
Published: February 2025

AbstractBackgroundUnderstanding the spatiotemporal variation of COVID-19 transmission and its determinants is crucial for gaining deeper insights into the dynamics of disease spread. Regional and temporal differences in demographics, socioeconomic conditions, and environmental factors shaped the trajectory of the COVID-19 pandemic, underscoring the importance of advanced spatio-temporal modelling. This research aims to construct a spatiotemporal model to examine the relationship between age groups, poverty, population density, precipitation, and COVID-19 risk, as well as to pinpoint high-risk areas.MethodsHere we present a spatiotemporal statistical analysis using COVID-19 case data from Malawi recorded from 2 April 2020 to 27 March 2022. Bayesian spatiotemporal models were fitted, with weekly confirmed cases as the response variable and demographic, socioeconomic, and environmental factors as predictors.ResultsThe findings reveal that spatial and temporal factors, along with age, population density, and poverty, significantly affect observed COVID-19 incidence in Malawi, whereas precipitation does not. The greatest risk was observed during colder months (June–July), December’s festive season, and January. Urban centres and lake-shore districts were disproportionately impacted, with individuals aged 40 − 49 at particularly high risk.ConclusionsThese results emphasise the need to prioritise vaccinations for working-age populations in urban and tourist areas during high-risk periods. Moreover, ensuring adherence to public health guidelines and enhancing healthcare services in these districts is critical.Key MessagesThe age group 40–49 faced a significantly higher risk of COVID-19 compared to all other age groups.COVID-19 risk is generally low across Malawi during the study period, with Blantyre being a notable exception.Positive associations were identified between COVID-19 risk and factors such as age, poverty levels, and population density.Both spatial and temporal dynamics were found to have substantial impacts on COVID-19 transmission risk.
Cumulative remnant cholesterol and major adverse cardiovascular events among adults with type 2 diabetes
Authors: Qian Yu-Wen , Liu Zhong-Yue , Fang Fei , Wang Jia-Min , Shao Xiao-Ping , Jia Yi-Ping , Wu Xian-Bo , Li Fu-Rong , Zhang Wei , Yang Huan-Huan , Chen Guo-Chong , Wang Hai-Peng 
Published: February 2025

AbstractBackgroundIndividuals with type 2 diabetes are prone to dyslipidemia. The relationship of cumulative exposure to elevated remnant cholesterol (RC) with major adverse cardiovascular events (MACEs) remains unclear for individuals with type 2 diabetes, especially for those with intensive lipid-lowering treatment.MethodsThis study included 5143 participants with type 2 diabetes from the Action to Control Cardiovascular Risk in Diabetes trial, who had at least four lipid measurements over the first three years of the trial and did not have MACEs across the measurements. Cumulative RC (cumRC) was calculated considering RC levels at each measurement and the between-measurement time interval. Cox proportional hazards regression models were used to estimate HRs and 95% CIs of MACEs associated with cumRC levels.ResultsDuring a median follow-up of 6.3 years, 472 participants developed MACEs, including 154 cardiovascular deaths, 211 with nonfatal myocardial infarction, and 148 with nonfatal stroke. After multivariable adjustment for conventional risk factors, higher levels of cumRC were associated with a higher risk of MACEs (HRQ4 vs. Q1= 1.71, 95% CI: 1.31-2.22; P-trend <0.001), with similar associations for cardiovascular death (P-trend = 0.009) and nonfatal myocardial infarction (P-trend <0.001), but no association for nonfatal stroke (P-trend = 0.099). The association of cumRC with the risk of MACEs was consistent across age, sex, and lipid trial assignment groups and remained after further adjusting for baseline RC.ConclusionAmong adults with type 2 diabetes, cumulative exposure to elevated RC is associated with a higher risk of MACEs, even in the context of intensive lipid management.
Causal relationship of polyunsaturated fatty acids with mental disorders: a systematic review and meta-analysis
Authors: Yao Yiying , Yang Xiaopeng , Yan Junwei , Lv Hongran , Yue Zihan , Yu Jiayao , Ye Mengfei , Lin Xiuqin , Qian Chao , Zhang Huafang , Liu Zheng 
Published: February 2025

AbstractMental disorders (MDs) are emerging as a significant threat to global health, with their intricate pathogenesis making the discovery of effective treatments a challenging endeavor. Currently, nutritional intervention, especially polyunsaturated fatty acids (PUFAs), has garnered widespread attention. This review aims to explore the potential causal relationship between PUFAs and MDs using Mendelian randomization (MR) meta-analysis. The study employed two-sample MR technology to analyze the association between PUFAs (including omega-3, omega-3%, omega-6, omega-6%, and the omega-6:omega-3 ratio) and MDs. It utilized data from genome-wide association studies to assess the role of PUFAs in 12 major MDs. The MR analysis revealed a causal link between genetically predicted omega-3 and MDs such as obsessive-compulsive disorder, bipolar disorder, schizophrenia, and major depressive disorder. Omega-3% showed protective effects against certain diseases, including emotional personality disorder. Meanwhile, the inverse correlation between genetically predicted omega-6 and the risk of attention deficit/hyperactivity disorder, as well as the association between a high omega-6:omega-3 ratio and increased risk of depression and other mood disorders, were also supported by meta-analyses. These findings suggest that high levels of omega-3 and omega-3% may reduce the risk of MDs, while a high omega-6:omega-3 ratio may increase the risk. The study highlights the potential of PUFAs, particularly omega-3, in the prevention and treatment of MDs, while also noting the complex interactions between omega-3 and omega-6 and their impact on MDs, which necessitates further research. These findings provide a scientific basis for future clinical trials and the development of dietary intervention measures.
Influence of gut microbiota on oral drug absorption and metabolism
Authors: Nelson Douglas , Veerareddy Vaishnavi , Kashyap Purna C , Tang Xiaojiao , Kalari Krishna R. , Kandimalla Karunya K. 
Published: February 2025

ABSTRACTGut bacteria influence host intestinal phenotype in ways that impact drug absorption and metabolism. By comparing colonic tissue from germ-free mice to that of mice colonized with human microbiota, this study evaluates microbiota-driven differences in gene expression, mucosal permeability, and P-gp efflux capacity. Transcriptomic analysis revealed upregulation of genes coding ATP-binding cassette drug transporters P-gp (Abcb1a, Abcb1b), BCRP (Abcg2), and MRP3 (Abcc3), along with increased expression of solute carriers MCT1 (Slc16a1) and OCTN2 (Slc22a5). Immunohistochemistry indicated greater P-gp expression and apical localization in humanized mice. No relevant gene expression changes were observed in human homologs of drug-metabolizing cytochrome P450 enzymes, though cytochrome P450 oxidoreductase (Por) upregulation suggests increased cytochrome activity. Other phase I drug-metabolizing enzymes, including multiple homologs of human carboxylesterase 2 (CES2) and several reductases, were upregulated with high significance. Regarding phase II metabolism, genes encoding most UDP-glucuronosyltransferases and glutathione S-transferases were upregulated, along with the enzymes responsible for synthesizing their corresponding co-substrates, UDP-glucuronic acid and glutathione. Small intestinal mucosal explants demonstrated higher permeability to14C-labeled polyethylene glycol 4000 (14C-PEG4000) in germ-free mice than in humanized mice. The14C-PEG4000 permeability differences are in agreement with changes in paracellular tight junctional proteins such as claudins, zonula occludens, and myosin II-related genes. These results demonstrate the broader impact of gut microbiome on oral drug absorption and metabolism and implicate the contributions of gut microbiome to individual variations in drug efficacy and toxicity.
EPICURUS: E-field-based spatial filtering procedure for an accurate estimation of local EEG activity evoked by Transcranial Magnetic Stimulation
Authors: Corominas-Teruel Xavier , Mutanen Tuomas P. , Leto Carlo , Colomina Maria Teresa , Gallea Cécile , Bracco Martina , Valero-Cabré Antoni 
Published: February 2025

ABSTRACTBackgroundThe concurrent use of Transcranial magnetic stimulation (TMS) with electroencephalography (EEG) is increasingly integrated in research and clinical protocols to provide proof of effect by magnetic pulses. However, a reliable identification of evoked local EEG activity over TMS targeted cortical sites remains still challenging.MethodsHere we present EPICURUS, a novel EEG spatial filtering approach, by which, individual MRI based simulations of TMS- electrical fields (E-fields) guide the reconstruction of TMS evoked o EEG signals originated in the primary motor cortex, minimizing crosstalk from non relevant more distant sources.ResultsA reduction of late Transcranial Evoked-Potentials (TEPs) components (>100 ms post pulse onset) suggest our E-field-based spatial filter approach efficiently reduced intrusion of non-locally relevant distant sources engaged by TMS, particularly when combined with a suppression of auditory entries.ConclusionThe individually customized E-field-based spatial filtering procedure here developed for TMS- EEG datasets shows promise improving the spatio-temporal mapping of primary sources activated by magnetic pulses.HIGHLIGHTSConcurrent TMS-EEG recordings are a well-established tool to monitor brain state of activity and provide proof of effect and target engagement.The lack of spatial specificity of EEG prevents an accurate estimation of the locally activated EEG sources, hindering the interpretation of TMS effects.We here developed a spatial filtering approach for TMS-EEG based on individual estimation of E- field spread following stimulation.Our E-field spatial filter combined with auditory constraints reduced non-relevant distant signal components and improved the reliability of local EEG estimates.
IFIT3 RNA-binding activity promotes influenza A virus infection and translation efficiency
Authors: Sullivan Owen M. , Nesbitt Daniel J. , Schaack Grace A. , Feltman Elizabeth , Nipper Thomas , Kongsomros Supasek , Reed Sevilla G. , Nelson Sarah L. , King Cason R. , Shishkova Evgenia , Coon Joshua J. , Mehle Andrew 
Published: February 2025

AbstractHost cells produce a vast network of antiviral factors in response to viral infection. The interferon-induced proteins with tetratricopeptide repeats (IFITs) are important effectors of a broad-spectrum antiviral response. In contrast to their canonical roles, we previously identified IFIT2 and IFIT3 as pro-viral host factors during influenza A virus (IAV) infection. During IAV infection, IFIT2 binds and enhances translation of AU-rich cellular mRNAs, including many IFN-simulated gene products, establishing a model for its broad antiviral activity. But, IFIT2 also bound viral mRNAs and enhanced their translation resulting in increased viral replication. The ability of IFIT3 to bind RNA and whether this is important for its function was not known. Here we validate direct interactions between IFIT3 and RNA using electromobility shift assays (EMSAs). RNA-binding site identification (RBS-ID) experiments then identified an RNA-binding surface composed of residues conserved in IFIT3 orthologs and IFIT2 paralogs. Mutation of the RNA-binding site reduced the ability IFIT3 to promote IAV gene expression and translation efficiency when compared to wild type IFIT3. The functional units of IFIT2 and IFIT3 are homo- and heterodimers, however the RNA-binding surfaces are located near the dimerization interface. Using co-immunoprecipitation, we showed that mutations to these sites do not affect dimerization. Together, these data establish the link between IFIT3 RNA-binding and its ability to modulate translation of host and viral mRNAs during IAV infection.ImportanceInfluenza A viruses (IAV) cause considerable morbidity and mortality through sporadic pandemics as well as annual epidemics. Zoonotic IAV strains pose an additional risk of spillover into a naive human population where prior immunity can have minimal effect. In this case, the first line of defense in the host is the innate immune response. Interferon stimulated genes (ISGs) produce a suite of proteins that are front-line effectors of innate immune responses. While ISGs are typically considered antiviral, new work has revealed an emerging trend where viruses co-opt ISGs for pro-viral function. Here, we determine how the ISG IFIT3 is used by IAV as a pro-viral factor, advancing our understanding of IFIT3 function generally as well as specifically in the context of IAV infection.
Study on community knowledge and awareness of invasive species
Authors: Stazione Leonel 
Published: February 2025

AbstractIn a globalized world, invasive species (IS) have significant ecological and socio-economic impacts, emphasizing the need for public awareness and effective management. This work presents a study about environmental perceptions and biological invasion knowledge on both teacher and non-teacher communities, using a semi-structured, online questionnaire. Data on demographic profiles, perceptions of environmental impact and knowledge of biological invasions were compiled. Results revealed that teachers perceived higher environmental and biological invasion impacts than non-teachers. While most respondents acknowledged the high impact of IS, teachers exhibited higher levels of awareness and concern. The unintentional transport of IS was identified as the main threat, and human health concerns were the primary reason for species removal. This study highlights the importance of enhancing environmental education in both formal and non-formal settings to address the impacts of IS. A multidisciplinary approach is recommended to raise public awareness and ensure sustainable management across diverse community sectors.
Structural and Functional Insights into GGCX-FIX Interaction: Implications for Vitamin K-Dependent Bleeding Disorders
Authors: Liu Kang , Li Shixin , Tong Jiangbo , Jiang Nan , Hong Minwen , Gu Yi , Chen Luju , Liang Dan , Jin Yongchao , Zhao Yuan , Hou Dongmei , Huang Jinlin , Tie Jian-Ke , Hao Zhenyu 
Published: February 2025

AbstractGamma-carboxylation, catalyzed by γ-glutamyl carboxylase (GGCX), is a critical post-translational modification essential for the biological activity of vitamin K-dependent proteins (VKDPs). Mutations in GGCX, depending on their specific location, result in vitamin K-dependent coagulation factor deficiency type 1 (VKCFD1), which encompasses a broad spectrum of clinical manifestations ranging from mild to severe, including bleeding disorders, osteoporosis, and vascular calcification. The limited knowledge of GGCX’s structure and functional regions hinders our understanding of the consequences of GGCX mutations and the treatment for VKCFD1. This study aimed to identify key functional regions of GGCX and their interactions with VKDPs to better elucidate the molecular mechanisms underlying these diverse clinical symptoms. Using AlphaFold 3 and molecular dynamics simulations, we developed a complex binding model of GGCX, FIX, and reduced vitamin K, which revealed critical regions and residues involved in their interaction. Site-directed mutagenesis and cell-based assays further validated the model, confirming that multisite and regional cooperative binding of FIX to GGCX plays a key role in modulating γ-carboxylation efficiency. Additionally, novel residues (I296, M303, M401, M402) were identified as essential for GGCX’s dual enzymatic activities: carboxylation and vitamin K epoxidation. We further demonstrated that the spatial proximity of these active sites supports the hypothesis that GGCX’s carboxylation and vitamin K epoxidation centers are interconnected, ensuring the efficient coupling of these processes. Our GGCX-FIX binding and carboxylation model aligns with known pathogenic GGCX mutations, providing valuable insights into the molecular basis of coagulation disorders caused by GGCX mutants.
Subtype-specific enhancer RNAs define transcriptional regulators and prognosis in breast cancers
Authors: Patel Aamena Y , Zarrineh Peyman , Sheth Jigar H , Mohan Sumitra , Iqbal Mudassar , Nagarajan Sankari 
Published: February 2025

AbstractGene expression is tightly controlled by DNA elements called enhancers by associating with lineage-specific transcription factors. These enhancers transcribe non-coding RNAs (called enhancer RNAs or eRNAs). eRNA expression is an early indicator of transcription factor activity and is associated with treatment response and survival in cancer patients. However, the attempts to identify prognostic eRNAs in breast cancers were inadequate, as these studies ignored the heterogenous nature of breast cancers with distinct molecular subtypes. By analysing ∼300,000 eRNA loci profiled using RNA-sequencing datasets from 1,095 breast cancer patients using machine learning approaches, we categorised eRNAs which are specific to breast cancer molecular subtypes and survival. The classified eRNAs were associated with gene pathways related to relevant subtypes. Interestingly, transcription factor analyses highlighted involvement of nuclear receptors other than the estrogen receptor with luminal-specific eRNAs. Basal eRNAs showed association with the transcriptional corepressor TRIM28 and androgen receptor. Luminal eRNAs were associated with better outcomes and Her2 eRNAs with worse outcome in patients. Overall, we demonstrate that machine learning approaches performed on RNA-seq datasets can classify subtype-specific and prognostic eRNAs which can be used to identify critical gene pathways and transcription factor networks in breast cancer.
Single-nuclear transcriptomics of lymphedema-associated adipose reveals a pro-lymphangiogenic stromal cell population
Authors: Westcott Gregory P. , Emont Margo P. , Gulko Anton , Zhou Zhibo , Kim Charissa , Varma Gopal , Tsai Leo L. , O’Donnell Eliza , Loureiro Zinger Yang , Liang Wenle , Jacobs Christopher , Tsai Linus T. , Padera Timothy P. , Singhal Dhruv , Rosen Evan D. 
Published: February 2025

AbstractChronic lymphedema is a progressive, disfiguring disease that results from dysfunction of the lymphatic vasculature, causing distal accumulation of interstitial fluid, localized development of tissue edema, and expansion of subcutaneous adipose tissue (SAT). As the molecular mechanisms governing SAT remodeling in this disease are unclear, we performed single-nucleus RNA sequencing on paired control and affected SAT biopsies from patients with unilateral lymphedema. Lymphedema samples were characterized by expansion of SAA+adipocytes, pro-adipogenic stem cells, and proliferation of lymphatic capillaries. AGRIA1+lymphedema-enriched stromal cell population expressingVEGFC,ADAMTS3, andCCBE1was identified, suggesting an enhanced axis of communication between adipose stem and progenitor cells (ASPCs) and lymphatic endothelial cells. Furthermore, lymphedema ASPC-conditioned media promoted lymphatic endothelial tube elongationin vitro. These findings indicate a critical role for ASPCs in regulating adipocyte differentiation and lymphatic vascular remodeling in lymphedema, and provide a valuable resource for better understanding this disease.
Regulation of lipid dysmetabolism and neuroinflammation linked with Alzheimer’s disease through modulation of Dgat2
Authors: Yadav Archana , Ouyang Xiaosen , Barkley Morgan , Watson John C , Madamanchi Kishore , Kramer Josh , Zhang Jianhua , Melkani Girish 
Published: February 2025

AbstractAlzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) plaque accumulation, cognitive decline, lipid dysregulation, and neuroinflammation. Mutations in the Amyloid Precursor Protein (APP), and accumulation of Aβ42contribute to AD, however, underlying mechanisms linking beta amyloid to lipid metabolism and neuroinflammation remain unclear. UsingDrosophilamodels, we demonstrate thatAppNLGandAβ42lead to progressive locomotor impairments, disrupted sleep activity, memory deficits, lipid dysregulation, loss of synaptic integrity, and neuroinflammation. Lipid accumulation and neuroinflammation have also been observed in theAppNLG-Fknockin mouse model, supporting their involvement in AD pathogenesis. Furthermore, we demonstrate a role of Diacylglycerol O-acyltransferase 2 (Dgat2), a key enzyme in lipid regulation, in modulating AD phenotypes, as Dgat2 and the levels of its potential transcription factors were altered in AD Drosophila and mouse models. InAppNLGandAβ42 DrosophilaAD models,Dgat2knockdown reduced lipid accumulation, restored synaptic integrity, improved locomotor and cognitive function, and attenuated neuroinflammation. Additionally, Dgat2 modulation improved sleep quality and circadian rhythms, further implicating lipid metabolism in AD progression. InAppNLG-Fmice, Dgat2 inhibition mitigated lipid dysmetabolism decreased neuroinflammatory responses, and reduced expression of AD risk genes. These findings underscore the intricate interplay between amyloid pathology, lipid dysregulation, and neuroinflammation, and suggest that targeting Dgat2 may provide a novel therapeutic strategy for mitigating AD-associated dysfunction. Understanding the conserved impact of lipid homeostasis across species offers valuable insights into potential translational interventions for AD.