bluuebunny/crossref_metadata_2025_split huggingface dataset:
Does combination treatment with progesterone and vaginal cervical cerclage improve pregnancy outcomes in women at high risk of preterm birth? A retrospective, secondary analysis of the C-STICH suture thread for cerclage trial data
Authors: Hodgetts Morton V , Morris RK , Toozs-Hobson P , Middleton L , Pilarski N , Bell L , Hogg M , Man R , Israfil-Bayli F , Shennan A , Simpson N , Lees C , Moakes CA 
Published: January 2025

AbstractBackgroundVaginal cervical cerclage and progesterone are established treatments for prevention of pregnancy loss and prematurity. There is limited data to assess the effect of these treatments in combination.ObjectiveTo investigate the association between progesterone and no progesterone treatment on pregnancy outcomes in women at high risk of preterm birth who have received a vaginal cervical cerclage.Study DesignThis is a secondary analysis of women recruited to the CSTICH trial, which recruited in 75 obstetric units in the UK. The primary outcome was pregnancy loss, defined as miscarriage and perinatal mortality, including any stillbirth or neonatal death in the first week of life. Secondary maternal outcomes included miscarriage and previable neonatal death; stillbirth; gestational age at delivery; preterm pre labour rupture of membranes and sepsis. Secondary neonatal outcomes included early/late neonatal death and sepsis. For each outcome, regression models were fitted adjusting for pre-specified prognostic variables.Results1943 women had a vaginal cerclage placed, with available progesterone data. From the 2048 women recruited to CSTICH; 843 (43%) women received progesterone and 1109 (57%) did not receive progesterone. Pregnancy loss occurred in 49 (5.9%) of 832 women who received progesterone and 91 (8.3%) of 1103 women who did not receive progesterone (adjusted risk ratio 0.70, 95% confidence interval (CI): 0.50 to 0.99; adjusted risk difference - 0.02, 95% CI: −0.04 to −0.001).ConclusionThere appears to be an association with progesterone use in women who receive a vaginal cervical cerclage and a reduction in pregnancy loss. This combination therapy may be an important opportunity to further reduce the risk of pregnancy loss in this high risk cohort.
A kinetic model for USP14 regulated substrate degradation in 26S proteasome
Authors: Wu Di , Ouyang Qi , Wang Hongli , Mao Youdong 
Published: January 2025

AbstractDespite high-resolution structural studies on the USP14-proteasome-substrate complexes, time-resolved cryo-electron microscopy (cryo-EM) results on USP14-regulated allostery of the 26S proteasome are still very limited and a quantitative understanding of substrate degradation dynamics remains elusive. In this study, we propose a mean field model of ordinary differential equations (ODEs) for USP14 regulated substrate degradation in 26S proteasome. The kinetic model incorporates recent cryo-EM findings on the allostery of 26S proteasome and generates results in good agreement with time-resolved experimental observations. The model elucidates that USP14 typically reduces the substrate degradation rate and reveals the functional dependence of this rate on the concentrations of substrate and adenosine triphosphate (ATP). The half-maximal effective concentration (EC50) of the substrate for different ATP concentrations is predicted. When multiple substrates are present, the model suggests that substrates that are easier to insert into the OB-ring and disengage from the proteasome, or less likely to undergo deubiquitination would be more favored to be degraded by the USP14-bound proteasome.Author SummaryThe proteasome is a crucial protein complex involved in the degradation of damaged or unnecessary proteins within cells, requiring ATP and ubiquitin for its functioning. It is regulated by cellular factors that transiently associate with it, often referred to as proteasome-associated proteins. USP14 is such a protein that activates its deubiquitination activity through reversible binding to the proteasome, thereby decreasing the substrate degradation activity of the proteasome. In this study, we developed a kinetic model to describe how USP14 regulates substrate degradation in proteasome based on recent experimental findings. The model yields result consistent with experimental observations, demonstrating that the mean-field description of mass action law for chemical reactions also applies to complex biomolecular machineries.
A20’s Linear Ubiquitin Binding Motif Restrains Pathogenic Activation of TH17/22 cells and IL-22 Driven Enteritis
Authors: Bowman Christopher John , Stibor Dorothea , Sun Xiaofei , Shimizu Hiromichi , Yamashita Emily , Lenci Nika , Advincula Rommel , Kim Min Cheol , Turnbaugh Jessie A. , Sun Yang , Razani Bahram , Turnbaugh Peter J. , Ye Chun Jimmie , Malynn Barbara A. , Ma Averil 
Published: January 2025

AbstractA20, encoded by theTNFAIP3gene, is a protein linked to Crohn’s disease and celiac disease in humans. We now find that mice expressing point mutations in A20’s M1 ubiquitin binding motif (ZF7) spontaneously develop proximate enteritis that requires both luminal microbes and T cells. Cellular and transcriptomic profiling reveal expansion of TH17/22 cells and aberrant expression of IL-17A and IL-22 in intestinal lamina propria of A20ZF7mice. While deletion of IL-17A from A20ZF7/ZF7mice exacerbates enteritis, deletion of IL-22 abrogates intestinal epithelial cell hyperproliferation, barrier dysfunction, and alarmin expression. A20ZF7/ZF7TH17/22 cells autonomously express more RORψt and IL-22 after differentiationin vitro. ATAC sequencing identified an enhancer region upstream of theIl22gene in A20ZF7/ZF7T cells, and this enhancer demonstrated increased activating histone acetylation coupled with exaggeratedIl22transcription. Finally, CRISPR/Cas9-mediated ablation of A20ZF7in human T cells increases RORψt expression andIL22transcription. These studies link A20’s M1 ubiquitin binding function with RORψt expression, epigenetic activation of TH17/22 cells, and IL-22 driven enteritis.
Autophagy-Mediated Downregulation of AXL and TIM-1 Promotes Sustained Zika Virus Infection
Authors: Yu Jingyou , Zheng Yi-Min , Sheridan Megan A. , Ezashi Toshihiko , Roberts R Michael , Liu Shan-Lu 
Published: January 2025

ABSTRACTZika virus (ZIKV) infection can lead to a variety of clinical outcomes, including severe congenital abnormalities. The phosphatidylserine (PS) receptors AXL and TIM-1 are recognized as critical entry factors for ZIKVin vitro. However, it remains unclear if and how ZIKV regulates these receptors during infection. In this study, we investigated AXL and TIM-1 expression in human alveolar basal epithelial A549 cells, glioblastoma U87 cells, and embryonic stem cells-derived trophoblast following ZIKV infection. We found that both the Asian strain FSS13025 and the African strain MR766 of ZIKV downregulate AXL, with a milder effect on TIM-1. We identified several ZIKV proteins, notably envelope (E), NS2A, NS3, and NS4B, that contribute to this downregulation. Notably, treatment with lysosomal inhibitor NH4Cl or the autophagy inhibitor 3-Methyladenine (3-MA) mitigated the AXL/TIM-1 downregulation, indicating autophagy’s involvement in the process. Importantly, this downregulation facilitates sustained viral replication and promotes viral spread by preventing superinfection and limiting cell death, which is also associated with impaired innate immune signaling. Our findings uncover a mechanism by which ZIKV downregulates entry factors to enhance prolonged viral replication and spread.AUTHOR SUMMARYZika virus (ZIKV) infection has been associated with severe birth defects, yet the mechanisms underlying its pathogenesis remain poorly understood. In this study, we investigated phosphatidylserine (PS) receptors AXL and TIM-1 and discovered that they promote ZIKV entry but are downregulated by the virus infection. We identified several ZIKV proteins involved in AXL and TIM-1 down-regulation through an autophagy-mediated process. Mechanistically, this loss of surface receptors protects host cells from superinfection and cell death, while dampening the innate immune response, ultimately promoting viral spread. Our results contribute to a better understanding of ZIKV’s interactions with host cells and offer insight into viral entry, innate signaling, and pathogenesis.
Neural circuits between nodose ganglion and pulmonary neuroendocrine cells regulate lung inflammatory responses
Authors: Chen Jie , Xie Shitao , Lin Zhekai , Zhao Caiqi , Tao Rujia , Ma Yingying , Chen Xiaoyan , Wu Renlan , Sui Pengfei , Wang Sheng , Ji Hongbin , Song Hai , Zhang Xiaoming , Sun Yangang , Song Yuanlin , Su Xiao 
Published: January 2025

AbstractThe lungs are organs exposed to the external environment, and the air we inhale contains various pathogens, such as endotoxins. The vagus nerve, which innervates the lungs, may play a role in detecting pathogens that invade the lungs. Through transcriptome analysis, tissue clearance imaging, electrical excitability recording, and gene- and cell-specific knockout experiments, we found that vagus nerve endings innervate pulmonary neuroendocrine cells (PNECs). These nerve endings sense bacterial endotoxins via pain receptors (TRPA1) rather than toll-like receptors (TLR4), eliciting electrical excitation and enhancing the production of neuropeptides (αCGRP) in the nodose ganglia. In turn, αCGRP released by sensory neurons from the nodose ganglia promotes both neuropeptide production and the proliferation of PNECs, thereby amplifying endotoxin-induced lung inflammatory responses. This reveals that the neural circuits between the nodose ganglion and PNECs play a critical role in regulating lung inflammatory responses.
Developmental synaptic pruning in the olivo-cerebellar circuit sculpts predictive processing
Authors: Verma Shivangi , Narayanan Sriram , Thirumalai Vatsala 
Published: January 2025

AbstractSynaptic pruning is a dominant process of circuit assembly, known to eliminate a large proportion of synapses formed during development. Yet, very little is understood about how the drastic elimination of a large number of synapses affects circuit computation and behavior. Here, using the olivocerebellar system of larval zebrafish, we first establish the timelines of olivary climbing fiber to Purkinje neuron synaptic pruning. We then show that during this window, encoding of sensory-motor mismatches is improved, sensory representations are fine-tuned, and predictive signals are more robust. All of these lead to faster and better behavioral responses which are adaptable to current sensory input. Thus, developmental synaptic pruning makes circuits fit for complex computations such as predictive processing.
Orally Delivered Milk-Derived Nanovesicles Loaded with Connexin 43 Peptides for Targeted Cardiac Ischemia-Reperfusion Therapy
Authors: Marsh Spencer R. , Amin Md Ruhul , Toldo Stefano , Beard Claire , Dogan Alan B. , Mezzaroma Eleonora , Andres Ethan , Stout Randy F. , Bannon Mark S. , Payne Laura Beth , Abbate Antonio , Sassi Yassine , Letteri Rachel A. , Gourdie Robert G. 
Published: January 2025

AbstractExtracellular vesicles have emerged as promising nanocarriers for targeted drug delivery, but their therapeutic potential is limited by challenges related to administration route, loading, targeted delivery and production at scale. Here, we report an innovative approach for targeted delivery of therapeutic peptides to injured tissues using milk-derived small extracellular vesicles (mEVs) as an abundant, safe, orally administrable nanoplatform. We demonstrate that a sub-population of mEVs naturally contain Connexin 43 (Cx43) and its Carboxyl-Terminal (CT) polypeptides, which have been shown to play crucial roles in wound healing and tissue repair. Leveraging this intrinsic property, we developed an esterification method to efficiently and uniformly load mEVs with enhanced levels of an exogenous Cx43 CT peptide (αCT11 - RPRPDDLEI), as assessed by flow cytometry-based vesicle quantification and mass spectrometry. These engineered mEVs exhibited remarkable injury targeting capabilities, with > 30-fold increases in uptake by injured cells compared to non-wounded cells in vitro and preferential accumulation in wounded tissues in vivo. Notably, αCT11-loaded mEVs orally administered after myocardial infarction reduced infarct size by >60% and preserved heart function in a mouse model of ischemia-reperfusion injury. This study represents a significant advance in nanomedicine, demonstrating the utilization of naturally occurring milk-derived extracellular vesicles as an oral delivery system for therapeutic peptides, achieving unprecedented targeting efficiency and efficacy in the treatment of myocardial ischemia-reperfusion injury.
Integrating GWAS and Transcriptome Data through PrediXcan and Multimodal Deep Learning to Reveal Genetic Basis and Novel Drug Repositioning Opportunities for Alzheimer’s Disease
Authors: Tian Xuecong , Su Ying , Zhang Sizhe , Sun Haiqing , Chen Chen , Chen Cheng , Zhou Luyu , Lv Xiaoyi , Roussos Panos , Zhang Wen 
Published: January 2025

AbstractAlzheimer’s Disease (AD) is the leading cause of dementia, imposing significant economic and social burdens. Although genome-wide association studies (GWAS) have identified approximately 70 risk loci, the functional mechanisms underlying AD remain unclear. In this study, we integrated the GWAS summary statistics from Jiang et al. with gene expression data from the GTEx project using S-PrediXcan method, encompassing 61 brain-related traits across 49 tissues. Comprehensive analysis identified five significant traits, including family history of AD, and highlighted key genes such as APOE, APOC1, and TOMM40, which play crucial roles in cholesterol metabolism, immune response, and neuroinflammation. Validation using the ROSMAP dataset confirmed the association of these genes with AD phenotypes. Furthermore, we developed AD-MIF, a novel deep multi-layer information fusion model that integrates multi-omics data, achieving a 10-20% improvement in AUC performance for predicting AD-related traits compared to traditional models. Gene enrichment analysis emphasized the importance of pathways such as cholesterol metabolism and immune response in the pathogenesis of AD. Additionally, drug repositioning analysis identified candidate drugs, including Dasatinib and Sirolimus, which may alleviate AD progression by reducing neuroinflammation and clearing senescent cells. Our findings advance the understanding of the genetic architecture of AD, improve predictive models, and propose potential therapeutic drugs.
Social Determinants of Healthy Aging: An Investigation using the All of Us Cohort
Authors: Chen Wei-Han , Lee Yao-An , Tang Huilin , Li Chenyu , Lu Ying , Huang Yu , Yin Rui , Armstrong Melissa J. , Yang Yang , Štiglic Gregor , Bian Jiang , Guo Jingchuan 
Published: January 2025

ABSTRACTIntroductionThe increasing aging population raises significant concerns about the ability of individuals to age healthily, avoiding chronic diseases and maintaining cognitive and physical functions. However, the pathways through which SDOH factors are associated with healthy aging remain unclear.MethodsThis retrospective cohort study used the registered tier data from theAll of UsResearch Program (AoURP) registered tier dataset v7. Eligible study participants are those aged 50 and older who have responded to any of the SDOH survey questions with available EHR data. Three different algorithms were trained (logistic regression [LR], multi-layer perceptron [MLP], and extreme gradient boosting [XGBoost]). The outcome is healthy aging, which is measured by a composite score of the status for 1) comorbidities, 2) cognitive conditions, and 3) mobility function. We evaluate the model performance by area under the receiver operating characteristic curve (AUROC) and assess the fairness of best-performed model through predictive parity. Feature importance is analyzed using SHapley Additive exPlanations (SHAP) values.ResultsOur study included 99,935 participants aged 50 and above, and the mean (SD) age was 74 (9.3), with 55,294 (55.3%) females, 67,457 (67.5%) Whites, 11,109 (11.1%) Hispanic ethnicity, and 44,109 (44.1%) are classified as healthy aging. Most of the individuals lived in their own house (64%), were married (51%), obtained college or advanced degrees (74%), and had Medicare (56.2%). The best predictive model was XGBoost with random oversampler, with a performance of AUROC [95% CI]: 0.793 [0.788-0.796], F1 score: 0.697 [0.692-0.701], recall: 0.739 [0.732-0.748], precision: 0.659 [0.655-0.663], and accuracy: 0.716 [0.712-0.720], and the XGBoost model achieved predictive parity by similar positive and negative predictive values across race and sex groups (0.86-1.06). In feature importance analysis, health insurance type is ranked as the most predictive feature, followed by employment status, substance use, and health insurance coverage (yes/no).ConclusionIn this cohort study, XGBoost model accurately predicted individuals achieving healthy aging, outperforming LR and MLP. Our findings underscore the significant role of health insurance in contributing to healthy aging.
Dopaminergic network connectivity alterations are associated with postoperative cognitive dysfunction
Authors: Lammers-Lietz Florian , Borchers Friedrich , Feinkohl Insa , Kanar Cicek , Krampe Henning , Lichtner Gregor , Sreekanth Jayanth , Wiebach Janine , Weygandt Martin , Spies Claudia , Winterer Georg , Paul Friedemann ,   the BioCog consortium
Published: January 2025

ABSTRACTPostoperative cognitive dysfunction (POCD) is a detrimental complication after surgery with a lasting impact on the patients’ daily life. It is most common after postoperative delirium. Dopaminergic dysfunction has been suggested to play a role in delirium, but little knowledge exists regarding its relevance for POCD. We hypothesized that POCD is associated with altered resting-state functional connectivity of the ventral tegmental area (VTA) and the substantia nigra pars compacta (SNc) in functional magnetic resonance imaging (fMRI) before surgery and at postoperative follow-up after three months.Patients ≥65 years old underwent resting-state fMRI and neuropsychological assessment before major elective surgery and at follow-up three months later. POCD was determined as the reliable change index. Connectivity between VTA or SNc and 132 regions were calculated. Principal component analysis (PCA) was used for dimensionality reduction in preoperative connectivity, and components explaining >5% of variance were retained for analysis. To study postoperative changes in patients with POCD, we applied the same transformation to postoperative connectivity, and multi-factor analysis. Regression analyses were used to describe connectivity alterations while adjusting for age, sex, MMSE, surgery and anaesthesia.Of 214 patients, 26 (12%) developed POCD. Among 132 principal components, four components for VTA- and SNc-FC were selected for further analysis. For both VTA and SNc connectivity, one component was significantly associated with POCD. No postoperative alterations of dopaminergic networks were associated with POCD.Altered preoperative functional connectivity of the dopaminergic system predisposes to POCD. Particularly relevant regions are associated with sensory, especially spatial perception and higher cognitive functions.HIGHLIGHTSDopaminergic dysfunction is a hallmark ofdeliriumNo evidence for postoperative cognitive dysfunction (POCD)Methods: resting-state functional connectivity of the VTA and SNcConnectivity alterations of the VTA and SNc predispose for POCDAffected areas involed in perception, spatial processing and cognition
Halting predicted vertebrate declines requires tackling multiple drivers of biodiversity loss
Authors: Capdevila Pol , O’Brien Duncan , Marconi Valentina , Johnson Thomas F. , Freeman Robin , McRae Louise , Clements Christopher F. 
Published: January 2025

AbstractAnthropogenic threats are reshaping Earth’s biodiversity at an unprecedented rate and scale1–3. Conservation policies often prioritise threats like habitat loss and exploitation based on their global prevalence. However, these assessments rarely quantify the impacts of individual or interacting threats, potential masking the true effects of the Anthropocene4–6. Here, we quantitatively analyse the trends of 3,129 vertebrate populations worldwide with documented exposure to specific and multiple threats. Populations impacted solely by habitat loss or exploitation, the most prevalent threats, do not show the fastest declines. Rather, populations exposed to disease, invasive species, pollution, and climate change decline more rapidly. However, habitat loss and exploitation – along with climate change – do act as additive interactive threats, amplifying population declines. Notably, these interactive threats contribute to population declines, more than temporal or spatial sources of variation. Finally, counterfactual scenarios show that to achieve global non-negative vertebrate population trends, we need to mitigate the effects of multiple threats. These findings underscore the urgency of addressing the compounding effects of multiple threats to halt biodiversity loss and suggest that the local-scale impacts of climate change may be more severe than previously recognized.
Safety Monitoring of Health Outcomes following Influenza Vaccination during the 2023-2024 Season among U.S. Medicare Beneficiaries Aged 65 Years and Older
Authors: Lloyd Patricia C. , Acharya Gyanada , Zhao Henu , Shah Nimesh , Anguzu Godwin , Ambarsoomzadeh Derick , Clarke Tainya C. , Ng Xinyi , Hu Mao , Chillarige Yoganand , Forshee Richard A. , Anderson Steven A. 
Published: January 2025

ABSTRACTBackgroundInfluenza vaccination is widely recommended for individuals aged 6 months and older in the United States (U.S.). While the safety of annual influenza vaccines is well established, FDA conducts routine monitoring and evaluation of safety. This study assessed the safety of 2023-2024 influenza vaccines among elderly U.S. Medicare beneficiaries.MethodsA self-controlled case series (SCCS) analysis compared incidence rate ratios (IRR) of anaphylaxis, encephalitis/encephalomyelitis/acute disseminated encephalomyelitis, Guillain-Barré syndrome (GBS), transverse myelitis, hemorrhagic stroke (HS), non-hemorrhagic stroke (NHS), transient ischemic attack (TIA), and NHS or TIA, following 2023-2024 seasonal influenza vaccinations in risk and control intervals among Medicare beneficiaries aged 65 years and older. We used conditional Poisson regression to estimate IRRs and 95% confidence intervals (CIs) adjusted for event-dependent observation time for certain outcomes, seasonality, and uncertainty from outcome misclassification where feasible. For health outcomes with statistically significant associations, we stratified results by concomitant vaccination status.ResultsWe observed a total of 20,258,006 influenza vaccinees among the Medicare population, and no statistically significant elevations of risk for anaphylaxis, encephalitis/encephalomyelitis (with ADEM), GBS, HS, or TM. For the combined NHS/TIA outcome (22-42-day risk window), we observed a small elevation in risk that was statistically significant in both the Fee-For-Service (FFS) and Medicare Advantage (MA) populations that received a high-dose vaccine. This risk was also statistically significant among MA beneficiaries that received any influenza vaccine. Additionally, we observed a small statistically significant risk for the individual TIA outcome (22-42-day risk window) among the MA population that received any influenza vaccine.ConclusionResults from this study indicate that the benefits of seasonal influenza vaccines continue to outweigh the risks. The small statistically significant increased risk of stroke outcomes observed in the study must be carefully considered in light of the known benefits of influenza vaccination.