bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tamoxifen exerts anti-peritoneal fibrosis effects by inhibiting H19-activated VEGFA transcription
Authors: Zhao Tingting , Sun Zhengyu , Lai Xueli , Lu Hongtao , Liu Lulu , Li Shuangxi , Yuan Ji-hang , Guo Zhiyong 
Published: September 2023

Abstract
Background
Peritoneal dialysis (PD) remains limited due to dialysis failure caused by peritoneal fibrosis. Tamoxifen (TAM), an inhibitor of estrogen receptor 1 (ESR1), has been reported to treat fibrosis, but the underlying mechanism remains unknown. In this study, we sought to explore whether tamoxifen played an anti-fibrotic role by affecting transcription factor ESR1.

Methods
ESR1 expression was detected in the human peritoneum. Mice were daily intraperitoneally injected with 4.25% glucose PD dialysate containing 40 mM methylglyoxal for 2 weeks to establish PD-induced peritoneal fibrosis. Tamoxifen was administrated by daily gavage, at the dose of 10 mg/kg. Chromatin immunoprecipitation (ChIP) and dual‐luciferase reporter assay were performed to validate ESR1 bound H19 promoter. Gain-of-function and loss-of-function experiments were performed to investigate the biological roles of H19 on the mesothelial-mesenchymal transition (MMT) of human peritoneal mesothelial cells (HPMCs). Intraperitoneal injection of nanomaterial-wrapped 2′-O-Me-modified small interfering RNA was applied to suppress H19 in the mouse peritoneum. RNA immunoprecipitation and RNA pull-down assays demonstrated binding between H19 and p300. Exfoliated peritoneal cells were obtained from peritoneal dialysis effluent to analyze the correlations between ESR1 (or H19) and peritoneal solute transfer rate (PSTR).

Results
ESR1 was increased significantly in the peritoneum after long-term exposure to PD dialysate. Tamoxifen treatment ameliorated high glucose-induced MMT of HPMCs, improved ultrafiltration rate, and decreased PSTR of mouse peritoneum. Tamoxifen reduced the H19 level by decreasing the ESR1 transcription of H19. Depletion of H19 reversed the pro-fibrotic effect of high glucose while ectopic expression of H19 exacerbated fibrotic pathological changes. Intraperitoneal injection of nanomaterial-wrapped 2′-O-Me-modified siRNAs targeting H19 mitigated PD-related fibrosis in mice. RNA immunoprecipitation (RIP) and RNA pull-down results delineated that H19 activated VEGFA expression by binding p300 to the VEGFA promoter and inducing histone acetylation of the VEGFA promoter. ESR1 and H19 were promising targets to predict peritoneal function.

Conclusions
High glucose-induced MMT of peritoneal mesothelial cells in peritoneal dialysis via activating ESR1. In peritoneal mesothelial cells, ESR1 transcribed the H19 and H19 binds to transcription cofactor p300 to activate the VEGFA. Targeting ESR1/H19/VEGFA pathway provided new hope for patients undergoing peritoneal dialysis.

Graphic Abstract
Identification of potential drug targets for rheumatoid arthritis from genetic insights: a Mendelian randomization study
Authors: Cao Yu , Yang Ying , Hu Qingfeng , Wei Guojun 
Published: September 2023

Abstract
Introduction
Rheumatoid arthritis (RA) is a chronic inflammatory illness that mostly affects the joints of the hands and feet and can reduce life expectancy by an average of 3 to 10 years. Although tremendous progress has been achieved in the treatment of RA, a large minority of patients continue to respond poorly to existing medications, owing in part to a lack of appropriate therapeutic targets.

Methods
To find therapeutic targets for RA, a Mendelian randomization (MR) was performed. Cis-expression quantitative trait loci (cis-eQTL, exposure) data were obtained from the eQTLGen Consortium (sample size 31,684). Summary statistics for RA (outcome) were obtained from two largest independent cohorts: sample sizes of 97,173 (22,350 cases and 74,823 controls) and 269,377 (8279 cases and 261,098), respectively. Colocalisation analysis was used to test whether RA risk and gene expression were driven by common SNPs. Drug prediction and molecular docking was further used to validate the medicinal value of drug targets.

Results
Seven drug targets were significant in both cohorts in MR analysis and supported by localization. PheWAS at the gene level showed only ATP2A1 associated with other traits. These genes are strongly associated with immune function in terms of biological significance. Molecular docking showed excellent binding for drugs and proteins with available structural data.

Conclusion
This study identifies seven potential drug targets for RA. Drugs designed to target these genes have a higher chance of success in clinical trials and is expected to help prioritise RA drug development and save on drug development costs.
H3K18 lactylation of senescent microglia potentiates brain aging and Alzheimer's disease through the NFκB signaling pathway
Authors: Wei Lin , Yang Xiaowen , Wang Jie , Wang Zhixiao , Wang Qiguang , Ding Yan , Yu Aiqing 
Published: September 2023

AbstractCellular senescence serves as a fundamental and underlying activity that drives the aging process, and it is intricately associated with numerous age-related diseases, including Alzheimer's disease (AD), a neurodegenerative aging-related disorder characterized by progressive cognitive impairment. Although increasing evidence suggests that senescent microglia play a role in the pathogenesis of AD, their exact role remains unclear. In this study, we quantified the levels of lactic acid in senescent microglia, and hippocampus tissues of naturally aged mice and AD mice models (FAD4T and APP/PS1). We found lactic acid levels were significantly elevated in these cells and tissues compared to their corresponding counterparts, which increased the level of pan histone lysine lactylation (Kla). We aslo identified all histone Kla sites in senescent microglia, and found that both the H3K18 lactylation (H3K18la) and Pan-Kla were significantly up-regulated in senescent microglia and hippocampus tissues of naturally aged mice and AD modeling mice. We demonstrated that enhanced H3K18la directly stimulates the NFκB signaling pathway by increasing binding to the promoter of Rela (p65) and NFκB1(p50), thereby upregulating senescence-associated secretory phenotype (SASP) components IL-6 and IL-8. Our study provides novel insights into the physiological function of Kla and the epigenetic regulatory mechanism that regulates brain aging and AD. Specifically, we have identified the H3K18la/NFκB axis as a critical player in this process by modulating IL-6 and IL-8. Targeting this axis may be a potential therapeutic strategy for delaying aging and AD by blunting SASP.
Transcriptomics and translatomics identify a robust inflammatory gene signature in brain endothelial cells after ischemic stroke
Authors: Arbaizar-Rovirosa Maria , Gallizioli Mattia , Lozano Juan J. , Sidorova Julia , Pedragosa Jordi , Figuerola Sara , Chaparro-Cabanillas Nerea , Boya Patricia , Graupera Mariona , Claret Marc , Urra Xabier , Planas Anna M. 
Published: September 2023

AbstractVascular endothelial function is challenged during cerebral ischemia and reperfusion. The endothelial responses are involved in inflammatory leukocyte attraction, adhesion and infiltration, blood–brain barrier leakage, and angiogenesis. This study investigated gene expression changes in brain endothelial cells after acute ischemic stroke using transcriptomics and translatomics. We isolated brain endothelial mRNA by: (i) translating ribosome affinity purification, enabling immunoprecipitation of brain endothelial ribosome-attached mRNA for translatome sequencing and (ii) isolating CD31+ endothelial cells by fluorescence-activating cell sorting for classical transcriptomic analysis. Both techniques revealed similar pathways regulated by ischemia but they showed specific differences in some transcripts derived from non-endothelial cells. We defined a gene set characterizing the endothelial response to acute stroke (24h) by selecting the differentially expressed genes common to both techniques, thus corresponding with the translatome and minimizing non-endothelial mRNA contamination. Enriched pathways were related to inflammation and immunoregulation, angiogenesis, extracellular matrix, oxidative stress, and lipid trafficking and storage. We validated, by flow cytometry and immunofluorescence, the protein expression of several genes encoding cell surface proteins. The inflammatory response was associated with the endothelial upregulation of genes related to lipid storage functions and we identified lipid droplet biogenesis in the endothelial cells after ischemia. The study reports a robust translatomic signature of brain endothelial cells after acute stroke and identifies enrichment in novel pathways involved in membrane signaling and lipid storage. Altogether these results highlight the endothelial contribution to the inflammatory response, and identify novel molecules that could be targets to improve vascular function after ischemic stroke.
Making implementation science more efficient: capitalizing on opportunities beyond the field
Authors: Wensing Michel , Wilson Paul 
Published: September 2023

AbstractImplementation researchers often find themselves as research partners in practice improvement projects, clinical trials or other applied health studies. The implementation science component in these projects can be described as supportive, descriptive or explanatory. This commentary reflects on the potential contributions of such projects to implementation science. They may provide evidence on implementation strategies, so it is essential to identify and evaluate these separately from the clinical and preventive interventions of interest. The use of theory on implementation processes and associated factors can contribute to knowledge accumulation, particularly if the focus is on what actually gets implemented when, why and how. The development and validation of relevant measures is a third potential contribution to implementation science. Although not all issues in implementation science can be addressed in this way, capitalization on the opportunities beyond the field can contribute to implementation science.
Impaction bone grafting for contained acetabular defects in total hip arthroplasty
Authors: Abu-Zeid Mohamed Yousry , Habib Mohamed El-Sawy , Marei Sameh Mohamed , Elbarbary Ahmed Nasr-Eldin , Ebied Ahmed Ali , Mesregah Mohamed Kamal 
Published: September 2023

Abstract
Background
Acetabular bone loss is a technical challenge in total hip arthroplasty (THA). This study sought to report the functional and radiological results of acetabular reconstruction using impaction bone grafting (IBG) in patients with acetabular bone deficiency undergoing primary or revision THA.

Methods
In this prospective study, full history taking, preoperative clinical and radiological evaluation, and preoperative planning and templating were performed. The Paprosky classification and the American Academy of Orthopaedic Surgeons classification were used to assess the acetabular deficiencies. Clinical outcomes were assessed utilizing the Harris hip score (HHS) and a 4-question satisfaction questionnaire. Graft incorporation was evaluated in the last follow-up X-rays.

Results
This study included 50 patients with a mean age of 46.7 ± 15.3 years. The THA was primary in 14 (28%) patients and revision in 36 (72%) patients. The mean HHS improved significantly from 28.8 ± 24.1 preoperatively to 76.6 ± 6.1, with a mean follow-up period of 23 months. Overall, 88% of patients were very satisfied. Complete radiological graft incorporation to host bone was achieved in 35 (70%) patients, and the remaining patients had partial incorporation. Complete graft incorporation was associated more frequently with primary THA, autografts, cementless cups, decreased defect size, and decreased graft layer thickness.

Conclusions
IBG for acetabular reconstruction in THA can achieve excellent clinical and radiological outcomes with a low complication rate.

Level of evidence
Level IV.
Arabic version of the Extended Nordic Musculoskeletal Questionnaire, cross-cultural adaptation and psychometric testing
Authors: Al Amer Hamad S. , Alharbi Ahmad A. 
Published: September 2023

Abstract
Background
The Extended Nordic Musculoskeletal Questionnaire (NMQ-E) had never been adapted into Arabic. We culturally adapted the NMQ-E to Arabic in five stages and investigated its psychometric properties.

Methods
After translating and cross-culturally adapting the NMQ-E into Arabic, through forward translation, translation synthesis, backward translation, expert committee review, and pilot testing, the psychometric properties were investigated. The construct validity was assessed by having the participants completing the Arabic version of the NMQ-E with four Arabic scales that measured musculoskeletal pain in all regions covered in the NMQ-E. Participants’ baseline records were also used to evaluate internal consistency (Cronbach’s α). Seven days later, participants completed the Arabic NMQ-E again to evaluate its test–retest reliability employing intraclass correlation coefficient (ICC) and standard error of measurement (SEM) for the age questions, and Cohen’s kappa coefficient (κ), the proportion of observed agreement (Po), the proportion of positive agreement (Ppos), and the proportion of negative agreement (Pneg) for the dichotomous items.

Results
A total of 127 participants, 70 males and 57 females with mean age 32.5 ± 12.2 years, were included. Significant differences were found between participants with and without musculoskeletal pain in the corresponding scales, signifying the content validity of the questionnaire. Cronbach’s α for both the prevalence and consequences pain sections combined ranged from 0.30 to 1.00. The test–retest reliability of the age questions was excellent, with ICC values ranging between 0.995 and 1.00. The SEM was 0.77 for the neck region and 0 for the rest of the regions. The prevalence questions demonstrated almost perfect agreement, with κ values ranging between 0.82 and 1.00, the Po between 0.94 and 1.00, the Ppos between 0.80 and 1.00, and the Pneg between 0.93 and 1.00. The consequences of pain questions showed moderate-to-perfect agreement, with κ values ranging between 0.57 and 1.00, between 0.83 and 1.00 for the Po, between 0.50 and 1.00 for the Ppos, and between 0.86 and 1.00 for the Pneg.

Conclusions
The results suggest that the Arabic NMQ-E is a valid and reliable tool that can be used to screen Arab adults for the prevalence and consequences of musculoskeletal pain.
Molecular and phenotypic spectrum of cardio-facio-cutaneous syndrome in Chinese patients
Authors: Feng Biyun , Li Xin , Zhang Qianwen , Wang Yirou , Gu Shili , Yao Ru-en , Li Zhiying , Gao Shiyang , Chang Guoying , Li Qun , Li Niu , Fu Lijun , Wang Jian , Wang Xiumin 
Published: September 2023

Abstract
Background
Cardio-facio-cutaneous (CFC) syndrome is a RASopathy subtype that presents with unique craniofacial dysmorphology, congenital heart disease, dermatologic abnormalities, growth retardation, and intellectual disability. This study describes the phenotypic spectrum of CFC in China and its association with CFC syndrome gene variants.

Results
Twenty Chinese CFC patients, aged 0.6–9.5 years old, were included in this study and their clinical phenotypic spectrum was compared with that of 186 patients with CFC from non-Chinese ethnicities. All 20 Chinese patients with CFC carried de novo heterozygous BRAF, MAP2K1, and MAP2K2 variants. Two novel variants were detected and consistently predicted to be deleterious using bioinformatic tools. The clinical features of CFC in the Chinese patients included hypertrophic cardiomyopathy (2/20, 10%), pulmonary valve stenosis (2/20, 10%), curly or sparse hair (7/20, 35%), epilepsy (1/20, 5%), and hypotonia (10/20, 50%); these features were less frequently observed in Chinese patients than non-Chinese patients (p < 0.05). In contrast, feeding difficulties (19/20, 95%) were more frequently observed in the Chinese patients. Absent eyebrows and severe short stature were more common in patients with BRAF variants than in those with MAP2K1/2 variants. Facial recognition software was used to recognize most CFC patients using artificial intelligence.

Conclusion
This study identified novel and common variants in our cohort of 20 Chinese patients with CFC. We uncovered differences in clinical features between Chinese and non-Chinese patients and detected genotype–phenotype correlations among the BRAF and MAP2K1/2 variant subgroups. This is the largest cohort of Chinese CFC patients to our knowledge, providing new insights into a subtype of RASopathy.
Metabolomic profiling of Wilson disease, an inherited disorder of copper metabolism, and diseases with similar symptoms but normal copper metabolism
Authors: Qiu Yijie , Su Mingchuan , Xiao Xina , Zhou Dingzi , Xie Linshen 
Published: September 2023

Abstract
Background
Wilson’s disease (WD) is a hereditary disorder that results in the accumulation of copper. The pathogenic mechanism is not well understood, and diagnosing the disease can be challenging, as it shares similarities with more prevalent conditions. To explore the metabolomic features of WD and differentiate it from other diseases related to copper metabolism, we conducted targeted and untargeted metabolomic profiling using ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and liquid chromatography-tandem mass spectrometry (LC-MS). We compared the metabolomic profiles of two subgroups of WD patients, namely hepatic WD (H-WD) and neurological WD (N-WD), H-WD patients and liver cirrhosis patients (who exhibit similar symptoms but have normal copper levels), and N-WD patients and Parkinson’s disease patients (who exhibit similar symptoms but have normal copper levels).

Results
Our pairwise comparisons revealed distinct metabolomic profiles for male and female WD patients, H-WD and N-WD patients, N-WD and Parkinson’s disease patients, and H-WD and liver cirrhosis patients. We then employed logistic regression analysis, receiver operating characteristic (ROC) analysis, and model construction to identify candidate diagnostic biomarkers that differentiate H-WD from liver cirrhosis and N-WD from Parkinson’s disease. Based on the spatial distribution of data obtained via PLS-DA analysis, we discovered variations in hydrophilic metabolites (aminoacyl-tRNA biosynthesis; alanine, aspartate, and glutamate metabolism; phenylalanine metabolism; arginine biosynthesis; and nicotinate and nicotinamide) and lipophilic metabolites (TG(triglyceride) (16:0_16:1_22:6), TG (16:0_16:0_22:6), and TG (16:0_16:1_22:5)) between H-WD and N-WD. Moreover, WD patients display metabolic traits that distinguish it from comparable conditions (liver cirrhosis and Parkinson’s disease).

Conclusions
Our analysis reveals significant variations in the levels of metabolites in critical metabolic pathways and numerous lipids in WD.ROC analysis indicates that three metabolites may be considered as candidate biomarkers for diagnosing WD.
COLLAGENE enables privacy-aware federated and collaborative genomic data analysis
Authors: Li Wentao , Kim Miran , Zhang Kai , Chen Han , Jiang Xiaoqian , Harmanci Arif 
Published: September 2023

AbstractGrowing regulatory requirements set barriers around genetic data sharing and collaborations. Moreover, existing privacy-aware paradigms are challenging to deploy in collaborative settings. We present COLLAGENE, a tool base for building secure collaborative genomic data analysis methods. COLLAGENE protects data using shared-key homomorphic encryption and combines encryption with multiparty strategies for efficient privacy-aware collaborative method development. COLLAGENE provides ready-to-run tools for encryption/decryption, matrix processing, and network transfers, which can be immediately integrated into existing pipelines. We demonstrate the usage of COLLAGENE by building a practical federated GWAS protocol for binary phenotypes and a secure meta-analysis protocol. COLLAGENE is available athttps://zenodo.org/record/8125935.
Coupling of co-transcriptional splicing and 3’ end Pol II pausing during termination in Arabidopsis
Authors: Zhou Sixian , Zhao Fengli , Zhu Danling , Zhang Qiqi , Dai Ziwei , Wu Zhe 
Published: September 2023

AbstractBackgroundIn Arabidopsis, RNA Polymerase II (Pol II) often pauses within a few hundred base pairs downstream of the polyadenylation site, reflecting efficient transcriptional termination, but how such pausing is regulated remains largely elusive.ResultHere, we analyze Pol II dynamics at 3’ ends by combining comprehensive experiments with mathematical modelling. We generate high-resolution serine 2 phosphorylated (Ser2P) Pol II positioning data specifically enriched at 3’ ends and define a 3’ end pause index (3’PI). The position but not the extent of the 3’ end pause correlates with the termination window size. The 3’PI is not decreased but even mildly increased in the termination deficient mutant xrn3, indicating 3’ end pause is a regulatory step early during the termination and before XRN3-mediated RNA decay that releases Pol II. Unexpectedly, 3’PI is closely associated with gene exon numbers and co-transcriptional splicing efficiency. Multiple exons genes often display stronger 3’ end pauses and more efficient on-chromatin splicing than genes with fewer exons. Chemical inhibition of splicing strongly reduces the 3’PI and disrupts its correlation with exon numbers but does not globally impact 3’ end readthrough levels. These results are further confirmed by fitting Pol II positioning data with a mathematical model, which enables the estimation of parameters that define Pol II dynamics.ConclusionOur work highlights that the number of exons via co-transcriptional splicing is a major determinant of Pol II pausing levels at the 3’ end of genes in plants.
Evaluation of the socioprofessional consequences of thoracic outlet syndrome
Authors: Logiou Charlotte , Demondion Xavier , Tiffreau Vincent , Wieczorek Valérie , Thevenon André 
Published: September 2023

Summary
Purpose
Thoracic outlet syndrome (TOS) is a ductal syndrome that can have a significant functional impact. Various studies have highlighted positional factors and repetitive movements as risk factors for the development of TOS. However, there are few literature data on the socioprofessional consequences of TOS.

Methods
We performed a prospective, cross-sectional, descriptive, multicentre study of workers having received a Doppler ultrasound diagnosis of TOS between December 17th, 2018, and March 16th, 2021. Immediately after their diagnosis, patients completed a self-questionnaire on the impact of TOS on their work activities. We assessed the frequency of TOS-related difficulties at work and the associated socioprofessional consequences. Trial Registration Number (TRN) is NCT03780647 and date of registration December 18, 2018.

Results
Eighty-two participants (95.3%) reported difficulties at work. Seventy-seven of the participants with difficulties (94%) worked in the tertiary sector; these difficulties were due to prolonged maintenance of a posture, carrying loads, and repetitive movements. Although the majority of participants experienced organizational problems and lacked support at work, few of them had approached support organizations, expert and/or healthcare professionals.

Conclusions
TOS was almost always associated with difficulties at work (95.3%). However, poor awareness of sources of help or a perceived lack of need may discourage people with TOS from taking steps to resolve these difficulties. It is clear that the socioprofessional management of TOS requires significant improvements.