bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lipotoxic hepatocyte derived LIMA1 enriched small extracellular vesicles promote hepatic stellate cells activation via inhibiting mitophagy
Authors: Li Shihui , Yang Fuji , Cheng Fang , Zhu Ling , Yan Yongmin 
Published: May 2024

Abstract
Background
Hepatic stellate cells (HSCs) play a crucial role in the development of fibrosis in non-alcoholic fatty liver disease (NAFLD). Small extracellular vesicles (sEV) act as mediators for intercellular information transfer, delivering various fibrotic factors that impact the function of HSCs in liver fibrosis. In this study, we investigated the role of lipotoxic hepatocyte derived sEV (LTH-sEV) in HSCs activation and its intrinsic mechanisms.

Methods
High-fat diet (HFD) mice model was constructed to confirm the expression of LIMA1. The relationship between LIMA1-enriched LTH-sEV and LX2 activation was evaluated by measurement of fibrotic markers and related genes. Levels of mitophagy were detected using mt-keima lentivirus. The interaction between LIMA1 and PINK1 was discovered through database prediction and molecular docking. Finally, sEV was injected to investigate whether LIMA1 can accelerate HFD induced liver fibrosis in mice.

Results
LIMA1 expression was upregulated in lipotoxic hepatocytes and was found to be positively associated with the expression of the HSCs activation marker α-SMA. Lipotoxicity induced by OPA led to an increase in both the level of LIMA1 protein in LTH-sEV and the release of LTH-sEV. When HSCs were treated with LTH-sEV, LIMA1 was observed to hinder LX2 mitophagy while facilitating LX2 activation. Further investigation revealed that LIMA1 derived from LTH-sEV may inhibit PINK1-Parkin-mediated mitophagy, consequently promoting HSCs activation. Knocking down LIMA1 significantly attenuates the inhibitory effects of LTH-sEV on mitophagy and the promotion of HSCs activation.

Conclusions
Lipotoxic hepatocyte-derived LIMA1-enriched sEVs play a crucial role in promoting HSCs activation in NAFLD-related liver fibrosis by negatively regulating PINK1 mediated mitophagy. These findings provide new insights into the pathological mechanisms involved in the development of fibrosis in NAFLD.

Graphical Abstract
ZBP1 inhibits the replication of Senecavirus A by enhancing NF-κB signaling pathway mediated antiviral response in porcine alveolar macrophage 3D4/21 cells
Authors: Li Huizi , Zheng Tingting , Chen Ming , Lei Xiaoling , Li Shuo , Chen Xijiao , Wang Shishi , Ning Zhangyong 
Published: May 2024

Abstract
Background
Senecavirus A (SVA) caused porcine idiopathic vesicular disease (PIVD) showing worldwide spread with economic losses in swine industry. Although some progress has been made on host factors regulating the replication of SVA, the role of Z-DNA binding protein 1 (ZBP1) remains unclear.

Methods
The expression of ZBP1 in SVA-infected 3D/421 cells was analyzed by quantitative real-time PCR (qRT-PCR) and western blot. Western blot and qRT-PCR were used to detect the effects of over and interference expression of ZBP1 on SVA VP2 gene and protein. Viral growth curves were prepared to measure the viral proliferation. The effect on type I interferons (IFNs), interferon-stimulated genes (ISGs), and pro-inflammatory cytokines in SVA infection was analyzed by qRT-PCR. Western blot was used to analysis the effect of ZBP1 on NF-κB signaling pathway and inhibitor are used to confirm.

Results
ZBP1 is shown to inhibit the replication of SVA by enhancing NF-κB signaling pathway mediated antiviral response. SVA infection significantly up-regulated the expression of ZBP1 in 3D4/21 cells. Infection of cells with overexpression of ZBP1 showed that the replication of SVA was inhibited with the enhanced expression of IFNs (IFN-α, IFN-β), ISGs (ISG15, PKR, and IFIT1) and pro-inflammatory cytokines (IL-6, IL-8, and TNF-α), while, infected-cells with interference expression of ZBP1 showed opposite effects. Further results showed that antiviral effect of ZBP1 is achieved by activation the NF-κB signaling pathway and specific inhibitor of NF-κB also confirmed this.

Conclusions
ZBP1 is an important host antiviral factor in SVA infection and indicates that ZBP1 may be a novel target against SVA.

Graphical Abstract
Identification of Eleutherococcus senticosus NAC transcription factors and their mechanisms in mediating DNA methylation of EsFPS, EsSS, and EsSE promoters to regulate saponin synthesis
Authors: Dong Jing , Zhao Xuelei , Song Xin , Wang Shuo , Zhao Xueying , Liang Baoxiang , Long Yuehong , Xing Zhaobin 
Published: May 2024

Abstract
Background
The formation of pharmacologically active components in medicinal plants is significantly impacted by DNA methylation. However, the exact mechanisms through which DNA methylation regulates secondary metabolism remain incompletely understood. Research in model species has demonstrated that DNA methylation at the transcription factor binding site within functional gene promoters can impact the binding of transcription factors to target DNA, subsequently influencing gene expression. These findings suggest that the interaction between transcription factors and target DNA could be a significant mechanism through which DNA methylation regulates secondary metabolism in medicinal plants.

Results
This research conducted a comprehensive analysis of the NAC family in E. senticosus, encompassing genome-wide characterization and functional analysis. A total of 117 EsNAC genes were identified and phylogenetically divided into 15 subfamilies. Tandem duplications and chromosome segment duplications were found to be the primary replication modes of these genes. Motif 2 was identified as the core conserved motif of the genes, and the cis-acting elements, gene structures, and expression patterns of each EsNAC gene were different. EsJUB1, EsNAC047, EsNAC098, and EsNAC005 were significantly associated with the DNA methylation ratio in E. senticosus. These four genes were located in the nucleus or cytoplasm and exhibited transcriptional self-activation activity. DNA methylation in EsFPS, EsSS, and EsSE promoters significantly reduced their activity. The methyl groups added to cytosine directly hindered the binding of the promoters to EsJUB1, EsNAC047, EsNAC098, and EsNAC005 and altered the expression of EsFPS, EsSS, and EsSE genes, eventually leading to changes in saponin synthesis in E. senticosus.

Conclusions
NAC transcription factors that are hindered from binding by methylated DNA are found in E. senticosus. The incapacity of these NACs to bind to the promoter of the methylated saponin synthase gene leads to subsequent alterations in gene expression and saponin synthesis. This research is the initial evidence showcasing the involvement of EsNAC in governing the impact of DNA methylation on saponin production in E. senticosus.
Genome-wide identification of heavy-metal ATPases genes in Areca catechu: investigating their functionality under heavy metal exposure
Authors: Khan Noor Muhammad , Ali Akhtar , Wan Yinglang , Zhou Guangzhen 
Published: May 2024

AbstractHeavy-metal ATPases (HMAs) play a vital role in plants, helping to transport heavy metal ions across cell membranes.However, insufficient data exists concerning HMAs genes within the Arecaceae family.In this study, 12 AcHMA genes were identified within the genome of Areca catechu, grouped into two main clusters based on their phylogenetic relationships.Genomic distribution analysis reveals that the AcHMA genes were unevenly distributed across six chromosomes. We further analyzed their physicochemical properties, collinearity, and gene structure.Furthermore, RNA-seq data analysis exhibited varied expressions in different tissues of A. catechu and found that AcHMA1, AcHMA2, and AcHMA7 were highly expressed in roots, leaves, pericarp, and male/female flowers. A total of six AcHMA candidate genes were selected based on gene expression patterns, and their expression in the roots and leaves was determined using RT-qPCR under heavy metal stress. Results showed that the expression levels of AcHMA1 and AcHMA3 genes were significantly up-regulated under Cd2 + and Zn2 + stress. Similarly, in response to Cu2+, the AcHMA5 and AcHMA8 revealed the highest expression in roots and leaves, respectively. In conclusion, this study will offer a foundation for exploring the role of the HMAs gene family in dealing with heavy metal stress conditions in A. catechu.
Ambulance service satisfaction level and associated factors among service users in Addis Ababa, Ethiopia
Authors: Asfaw Fisseha Zeleke , Yalew Ayalnesh Zemene , Godie Mezgebu , Fikadu Ayele , Workina Abdata 
Published: May 2024

Abstract
Introduction
Pre-hospital ambulance service is the most important part of healthcare service. Client satisfaction with the service indicates the degree of adaptation to the appropriate quality and quantity of services. Patients’ dissatisfaction with the service can affect their expectations of the overall services that they will receive later in the definitive care facility. However, it is not a well-addressed area in developing countries, including Ethiopia.

Objective
This study aimed to identify the ambulance service satisfaction level and associated factors among service users in Addis Ababa, Ethiopia.

Methods
A cross-sectional study was conducted in five governmental hospitals in Addis Ababa city. A face-to-face exit interview technique was employed on a total of 410 consecutively selected participants using a pretested tool developed from similar sources. The cleaned data was entered into the Epi-Data Manager 4.6 version and then exported to SPSS version 26 for analysis. The dependent variable was dichotomized into satisfied and unsatisfied to compute bivariate logistic regression. In the multivariate logistic regression model, predictors with a p-value < 0.05 at the 95% CI were considered to have a significant association.

Result
A total of 410 respondents were included in the study. The mean of participants’ responses regarding ambulance personnel, call operator, treatment on the scene, and ambulance subscale was 3.64, 3.48, 3.40, and 3.43, respectively. The study found that only 21.5% of participants were satisfied by the ambulance service they received. There was a statistically significant association between ambulance service satisfaction and age (AOR = 3.52, 95% CI: 1.01–12.36), monthly income (AOR = 3.13, 95% CI: 1.41–6.94), ambulance response time (AOR = 10.33, 95% CI: 2.09–51.06), type of ambulance used (AOR = 4.55, 95% CI: 2.19–9.43), and previous ambulance usage (AOR = 2.33, 95% CI: 1.34–4.05).

Conclusion
The study found a low level of satisfaction among ambulance users. The findings suggest that ambulance personnel performance is a key determinant of user satisfaction, while treatment at the scene and in the ambulances, and call operator areas require improvement. Age, monthly income, ambulance response time, type of ambulance, and previous ambulance use also influenced satisfaction. Improving the quality of services, reducing response time, and ensuring call operators are trained are vital steps to enhance satisfaction.
Modifications of the readiness assessment for pragmatic trials tool for appropriate use with Indigenous populations
Authors: Hikaka Joanna , McCreedy Ellen M. , Jutkowitz Eric , McCarthy Ellen P. , Baier Rosa R. 
Published: May 2024

Abstract
Background
Inequities in health access and outcomes exist between Indigenous and non-Indigenous populations. Embedded pragmatic randomized, controlled trials (ePCTs) can test the real-world effectiveness of health care interventions. Assessing readiness for ePCT, with tools such as the Readiness Assessment for Pragmatic Trials (RAPT) model, is an important component. Although equity must be explicitly incorporated in the design, testing, and widespread implementation of any health care intervention to achieve equity, RAPT does not explicitly consider equity. This study aimed to identify adaptions necessary for the application of the ‘Readiness Assessment for Pragmatic Trials’ (RAPT) tool in embedded pragmatic randomized, controlled trials (ePCTs) with Indigenous communities.

Methods
We surveyed and interviewed participants (researchers with experience in research involving Indigenous communities) over three phases (July-December 2022) in this mixed-methods study to explore the appropriateness and recommended adaptions of current RAPT domains and to identify new domains that would be appropriate to include. We thematically analyzed responses and used an iterative process to modify RAPT.

Results
The 21 participants identified that RAPT needed to be modified to strengthen readiness assessment in Indigenous research. In addition, five new domains were proposed to support Indigenous communities’ power within the research processes: Indigenous Data Sovereignty; Acceptability – Indigenous Communities; Risk of Research; Research Team Experience; Established Partnership). We propose a modified tool, RAPT-Indigenous (RAPT-I) for use in research with Indigenous communities to increase the robustness and cultural appropriateness of readiness assessment for ePCT. In addition to producing a tool for use, it outlines a methodological approach to adopting research tools for use in and with Indigenous communities by drawing on the experience of researchers who are part of, and/or working with, Indigenous communities to undertake interventional research, as well as those with expertise in health equity, implementation science, and public health.

Conclusion
RAPT-I has the potential to provide a useful framework for readiness assessment prior to ePCT in Indigenous communities. RAPT-I also has potential use by bodies charged with critically reviewing proposed pragmatic research including funding and ethics review boards.
The prognostic value of combined uric acid and neutrophil-to-lymphocyte ratio in acute ischemic stroke patients treated with intravenous thrombolysis
Authors: Wang Chentao , Zhou Meili , Kang Tingting , You Shoujiang , Cao Yongjun , Kong Weina , Shi Jijun 
Published: May 2024

Abstract
Background
Serum uric acid (UA) and the neutrophil-to-lymphocyte ratio (NLR) have been reported to be associated with outcomes in acute ischemic stroke (AIS). However, whether UA is related to the prognosis of AIS patients undergoing intravenous thrombolysis (IVT) remains inconclusive. We sought to explore the combined effect of UA and NLR on the prognosis of AIS treated with IVT.

Methods
A total of 555 AIS patients receiving IVT treatment were enrolled. Patients were categorized into four groups according to the levels of UA and NLR: LNNU (low NLR and normal UA), LNHU (low NLR and high UA), HNNU (high NLR and normal UA), and HNHU (high NLR and high UA). Multivariable logistic regression analysis was used to evaluate the value of serum UA level and NLR in predicting prognosis. The primary outcomes were major disability (modified Rankin scale (mRS) score 3–5) and death within 3 months.

Results
After multivariate adjustment, a high NLR (≥ 3.94) increased the risk of 3-month death or major disability (OR, 2.23; 95% CI, 1.42 to 3.55, p < 0.001). However, there was no statistically significant association between a high UA level (≥ 313.00 µmol/L) and clinical outcome. HNHU was associated with a 5.09-fold increase in the risk of death (OR, 5.09; 95% CI, 1.31–19.83; P value = 0.019) and a 1.98-fold increase in the risk of major disability (OR, 1.98; 95% CI 1.07–3.68; P value = 0.030) in comparison to LNNU.

Conclusions
High serum UA levels combined with high NLR were independently associated with 3-month death and major disability in AIS patients after IVT.
Combined image-guided radiofrequency and iodine-125 seeds implantation in the treatment of recurrent hepatocellular carcinoma after hepatectomy
Authors: Cao Fei , Zheng Jiaping , Hao Weiyuan 
Published: May 2024

Abstract
Background
Currently, there is no consensus on the treatment of recurrent hepatocellular carcinoma (HCC) after hepatectomy. It is necessary to assess the efficacy and safety of radiofrequency ablation (RFA) combined with iodine-125 seeds implantation (RFA-125I) in the treatment of recurrent HCC.

Methods
This study retrospectively analyzed the clinical data of patients with postoperative recurrence of HCC receiving RFA-125I or RFA treatment from January 2013 to January 2023. Both RFA and 125I seeds implantation were performed under dual guidance of ultrasound and CT. Overall survival (OS), progression-free survival (PFS), recurrence, and complications were compared between the two groups.

Results
A total of 210 patients with recurrent HCC were enrolled in this study, including 125 patients in the RFA-125I group and 85 patients in the RFA group. The RFA-125I group showed a significantly better survival benefit than RFA group (median OS: 37 months vs. 16 months, P < 0.001; median PFS: 15 months vs. 10 months, P = 0.001). The uni- and multivariate analysis showed that RFA-125I was a protective factor for OS and PFS. There were no procedure-related deaths and no grade 3 or higher adverse events in both groups.

Conclusions
RFA combined with 125I seeds implantation under dual guidance of ultrasound and CT is effective and safe for the treatment of HCC patients with recurrence after hepatectomy.
Causal relationship between lipid-lowering drugs and ovarian cancer, cervical cancer: a drug target mendelian randomization study
Authors: Li Jinshuai , Yang Zixian , Wang Tao , Li Mengqi , Wu Xiangjian , Fu Xiaoyan , Yang Chunfeng , Li Yangpu , Wang Ximing , Lan Zhiming , Li Minfang , Chen Sheng 
Published: May 2024

Abstract
Background
The causal impact of lipid-lowering drugs on ovarian cancer (OC) and cervical cancer (CC) has received considerable attention, but its causal relationship is still a subject of debate. Hence, the objective of this study is to evaluate the impact of lipid-lowering medications on the occurrence risk of OC and CC through Mendelian randomization (MR) analysis of drug targets.

Methods
This investigation concentrated on the primary targets of lipid-lowering medications, specifically, 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) and proprotein convertase kexin 9 (PCSK9). Genetic variations associated with HMGCR and PCSK9 were derived from published genome-wide association study (GWAS) findings to serve as substitutes for HMGCR and PCSK9 inhibitors. Employing a MR approach, an analysis was conducted to scrutinize the impact of inhibitors targeting HMGCR and PCSK9 on the occurrence of OC and CC. Coronary heart disease (CHD) risk was utilized as a positive control, and the primary outcomes encompassed OC and CC.

Results
The findings of the study suggest a notable elevation in the risk of OC among patients treated with HMGCR inhibitors (OR [95%CI] = 1.815 [1.316, 2.315], p = 0.019). In contrast, no significant correlation was observed between PCSK9 inhibitors and the occurrence of OC. Additionally, the analysis did not reveal any noteworthy connection between HMGCR inhibitors, PCSK9 inhibitors, and CC.

Conclusion
HMGCR inhibitors significantly elevate the risk of OC in patients, but their mechanism needs further investigation, and no influence of PCSK9 inhibitors on OC has been observed. There is no significant relationship between HMGCR inhibitors, PCSK9 inhibitors, and CC.
The impact of an innovative community-based peer-led intervention on uptake and coverage of sexual and reproductive health services among adolescents and young people 15–24 years old: results from the Yathu Yathu cluster randomised trial
Authors: Phiri Mwelwa Muleba , Schaap Albertus , Hensen Bernadette , Sigande Lucheka , Simuyaba Melvin , Mwenge Lawrence , Zulu-Phiri Rosemary , Mwape Louis , Floyd Sian , Fidler Sarah , Hayes Richard , Simwinga Musonda , Ayles Helen 
Published: May 2024

Abstract
Background
The Yathu Yathu (“For Us, By Us”) cluster-randomized trial (CRT) evaluated a peer-led community-based sexual and reproductive health(SRH) intervention implemented to address persistent barriers to SRH service use among adolescents and young people (AYP). We report the impact of the intervention on coverage of key SRH services among AYP.

Methods
The trial was conducted from Jul 2019-Oct 2021 in two urban communities in Lusaka, Zambia, divided into 20 zones (~ 2350 AYP/zone). Zones were randomly allocated to intervention (N = 10) or control (N = 10) arm. In all zones, a census was conducted and all AYP aged 15-24-years offered participation. The intervention consisted of peer-led community-based hubs providing SRH services; a prevention points card (PPC) system to incentivize and track SRH service use and community engagement. This paper reports on the outcome of coverage (accessing at least one key SRH service), comparing intervention and control arms using PPC data and standard methods of analysis for CRTs.

Results
Among enumerated AYP, 93.6% (14,872/15,894) consented to participate from intervention zones and 95.1% (14,500/15,255) from control zones. Among those who accepted a PPC, 63.8% (9,493/14,872) accessed at least one key SRH service during the study period in the intervention arm, compared to 5.4% (776/14,500) in the control arm (adjPR 12.3 95%CI 9.3–16.2, p < 0.001).

Conclusions
The Yathu Yathu intervention increased coverage of key SRH services among AYP and reached two-thirds of AYP. These findings demonstrate the potential of providing peer-led community-based SRH services.

Trial registration
ISRCTN75609016 (11/10/2021), clinicaltrials.gov number NCT04060420 (19/08/2019); retrospectively registered.
An exploratory cross-sectional study on Mental health literacy of Spanish adolescents
Authors: González-Sanguino Clara , Rodríguez-Medina Jairo , Redondo-Pacheco Jesús , Betegón Elena , Valdivieso-León Lorena , Irurtia María Jesús 
Published: May 2024

Abstract
Background
Mental health literacy (MHL) is especially important for young people, but comprehensive studies on MHL in adolescents are limited, with no nationwide studies in Spain. This research aims to study MHL among Spanish adolescents and its relationship with sociodemographic factors.

Methods
An exploratory study is carried out using stratified random sampling in Spanish adolescents (N = 1000), aged 12–16 years and balanced in terms of gender, age and territorial distribution. Data collection took place in October and November 2023 through online surveys using the CAWI methodology. Sociodemographic variables, contact with mental health and the Spanish version of the Mental Health Literacy Questionnaire (MHLq-E), a self-administered instrument of 32 Likert-type items (1–5) that assesses the dimensions of help-seeking skills, knowledge about causes and symptoms, and stigma, were evaluated. Descriptive and multivariate analyses of variance (MANOVA) were conducted.

Results
In general, adequate levels of literacy were observed, although some aspects related to help-seeking towards teachers, stigmatising attitudes towards people of low economic status and knowledge of severe mental health problems could be improved. The results show contact with previous mental health problems as a key variable for stigma and knowledge about symptomatology together with age. Likewise, gender and family educational level were found to be related to the ability to seek professional help.

Conclusion
This study provides information on levels of MHL among Spanish adolescents and highlights significant socio-demographic variables. These findings pave the way for interventions aimed at improving adolescents' understanding, attitudes and skills to manage mental health problems, making possible to adapt content and focus on specific groups, thus increasing its effectiveness.