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Background: Little is known about the heterogeneous etiology of suspected non-Alzheimer's pathophysiology (SNAP), a group of subjects with neurodegeneration in the absence of β-amyloid. Using antemortem MRI and pathological data, we investigated the etiology of SNAP and the association of neurodegenerative pathologies with structural medial temporal lobe (MTL) measures in β-amyloid-negative subjects. Methods: Subjects with antemortem MRI and autopsy data were selected from ADNI (n=63) and the University of Pennsylvania (n=156). Pathological diagnoses and semi-quantitative scores of MTL tau, neuritic plaques, α-synuclein, and TDP-43 pathology and MTL structural MRI measures from antemortem T1-weighted MRI scans were obtained. β-amyloid status (A+/A−) was determined by CERAD score and neurodegeneration status (N+/N−) by hippocampal volume. Results: SNAP reflects a heterogeneous group of pathological diagnoses. In ADNI, SNAP (A−N+) had significantly more neuropathological diagnoses than A+N+. In the A− group, tau pathology was associated with hippocampal, entorhinal cortex, and Brodmann area 35 volume/thickness and TDP-43 pathology with hippocampal volume. Conclusion: SNAP had a heterogeneous profile with more mixed pathologies than A+N+. Moreover, a role for TDP-43 and tau pathology in driving MTL neurodegeneration in the absence of β-amyloid was supported. [ABSTRACT FROM AUTHOR]

Background: To compare efficacy and toxicity of nimotuzumab versus cisplatin (CDDP) concurrent with intensity modulated radiation therapy (IMRT) in patients with nasopharyngeal carcinoma (NPC). Methods: We retrospectively reviewed patients with NPC from September 2008 to November 2013. The synchronous regimens included h-R3/RT (nimotuzumab and radiotherapy) one time per week for 6-8 weeks and CDDP/RT (cisplatin and radiotherapy) every three weeks for 2-3 cycles. All patients in our analysis completed the planned IMRT and received TPF (docetaxel + cisplatin + 5-fluorouracil) neoadjuvant chemotherapy for two cycles. Results: Among the 302 NPC patients who were treated definitively with TPF neoadjuvant chemotherapy followed by IMRT concurrent with nimotuzumab or cisplatin at West China Hospital Sichuan University, 52 patients received h-R3/RT with complete clinical and follow-up data. Based on age, sex and tumor stage, 104 eligible patients were propensity-matched, with 52 patients in each treatment group (h-R3/RT and CDDP/RT). With a median follow-up of 50 months, the 5-year overall survival (OS) and progression-free survival (PFS) rates for the h-R3/RT vs. CDDP/RT treatment groups were 63.9% vs. 81.4% (p = 0.024) and 58.0% vs. 80.6% (p = 0.028), respectively. The h-R3/RT patients experienced less leukopenia and milder nausea and vomiting. In our sub-analysis, for stage II patients, no significant differences were found in OS and PFS, whereas milder nausea and vomiting were found in the h-R3/RT group (p = 0.046). Moreover, for patients older than 60 years, there were no statistically significant differences in OS and PFS, whereas milder nausea and vomiting was observed in the h-R3/RT group (p = 0.020). Conclusions: Although CDDP/RT remains the preferred choice for most patients with NPC, h-R3/RT may be a treatment option for the patients with stage II, older than sixty years old, and who are intolerable to cisplatin. [ABSTRACT FROM AUTHOR]

Background: TGFβ has emerged as an attractive target for the therapeutic intervention of glioblastomas. Aberrant TGFβ overproduction in glioblastoma and other high-grade gliomas has been reported, however, to date, none of these reports has systematically examined the components of TGFβ signaling to gain a comprehensive view of TGFβ activation in large cohorts of human glioma patients. Methods: TGFβ activation in mammalian cells leads to a transcriptional program that typically affects 5-10% of the genes in the genome. To systematically examine the status of TGFβ activation in high-grade glial tumors, we compiled a gene set of transcriptional response to TGFβ stimulation from tissue culture and in vivo animal studies. These genes were used to examine the status of TGFβ activation in high-grade gliomas including a large cohort of glioblastomas. Unsupervised and supervised classification analysis was performed in two independent, publicly available glioma microarray datasets. Results: Unsupervised and supervised classification using the TGFβ-responsive gene list in two independent glial tumor gene expression data sets revealed various levels of TGFβ activation in these tumors. Among glioblastomas, one of the most devastating human cancers, two subgroups were identified that showed distinct TGFβ activation patterns as measured from transcriptional responses. Approximately 62% of glioblastoma samples analyzed showed strong TGFβ activation, while the rest showed a weak TGFβ transcriptional response. Conclusion: Our findings suggest heterogeneous TGFβ activation in glioblastomas, which may cause potential differences in responses to anti-TGFβ therapies in these two distinct subgroups of glioblastomas patients. [ABSTRACT FROM AUTHOR]

Low back pain caused by intervertebral disc degeneration (IDD) has emerged as a significant global public health concern, with far-reaching consequences for patients' quality of life and healthcare systems. Although previous research have revealed that the mechanisms of intervertebral disc cell apoptosis, pyroptosis and necroptosis can aggravate IDD damage by mediating inflammation and promoting extracellular matrix degradation, but they cannot explain the connection between different cell death mechanisms and ion metabolism disorders. The latest study shows that cell death mechanisms such as cellular senescence, ferroptosis, and cuproptosis, and PANopotosis have similar roles in the progression of intervertebral disc degeneration, but not exactly the same damage mechanism. This paper summarizes the effects of various cell death patterns on the disease progression of IDD, related molecular mechanisms and signaling pathways, providing new perspectives and potential clinical intervention strategies for the prevention and treatment of IDD., Competing Interests: Declarations. Ethical approval: Not applicable. Informed consent: Not applicable. Conflict of interest: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Autophagy is a conserved cellular process crucial for recycling cytoplasmic components and maintaining cellular homeostasis in eukaryotes. During autophagy, the formation of a protein complex involving AUTOPHAGY-RELATED PROTEIN 6 (ATG6) and phosphatidylinositol 3-kinase is pivotal for recruiting proteins involved in phagophore expansion. However, the intricate molecular mechanism regulating this protein complex in plants remains elusive., Results: Here, we aimed to unravel the molecular regulation of autophagy dynamics in Arabidopsis thaliana by investigating the involvement of the scaffold proteins 14-3-3λ and 14-3-3κ in regulating the proteolysis of ATG6. Phenotypic analyses revealed that 14-3-3λ and 14-3-3κ overexpression lines exhibited increased sensitivity to nutrient starvation, premature leaf senescence, and a decrease in starvation-induced autophagic vesicles, resembling the phenotypes of autophagy-defective mutants, suggesting the potential roles of 14-3-3 proteins in regulating autophagy in plants. Furthermore, our investigation unveiled the involvement of 14-3-3λ and 14-3-3κ in the RING finger E3 ligase SINAT1-mediated ubiquitination and destabilization of ATG6 in vivo. We also observed repressed turnover of ATG6 and translocation of GFP-ATG6 to mCherry-ATG8a-labelled punctate structures in the autophagy-defective mutant, which suggesting that ATG6 is probably a target of autophagy. Additionally, 14-3-3λ and 14-3-3κ interacted with Tumor necrosis factor Receptor Associated Factor 1a (TRAF1a) to promote the stability of TRAF1a in vivo under nutrient-rich conditions, suggesting a feedback regulation of autophagy. These findings demonstrate that 14-3-3λ and 14-3-3κ serve as scaffold proteins to regulate autophagy by facilitating the SINAT1-mediated proteolysis of ATG6, involving both direct and indirect mechanisms, in plants., Conclusions: 14-3-3 proteins regulate autophagy by directly or indirectly binding to ATG6 and SINAT1 to promote ubiquitination and degradation of ATG6. 14-3-3 proteins are involved in modulating autophagy dynamics by facilitating SINAT1-mediated ubiquitination and degradation of ATG6., Competing Interests: Declarations. Ethics approval and consent to participate: The experimental research and all plant materials (either cultivated or wild) were complied with relevant institutional, national, and international guidelines and legislation. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: The link between school bullying and eating disorders is a complex issue that is poorly understood globally, and is further complicated by the distinct cultural nuances within China. This study aims to fill this gap by investigating the association between different types of bullying and the risk of eating disorders among college students in Shantou City, China. Additionally, this study explores the mediating role of body dissatisfaction in the relationships between bullying roles and the risk of eating disorders., Methods: The present study employed a convenience sampling technique to recruit college students aged 16 years or older from a university in Shantou. The survey encompassed socio-demographic data, as well as measures of bullying and the risk of eating disorders. Kruskal-Wallis rank sum test, logistic regression, chi-square test, and mediation analysis were used to analyze the results., Results: A total of 1643 students were investigated in this study, revealing a prevalence of the risk of eating disorders at 29.21%. Additionally, the prevalence of bullying was found to be 5.78% for bullies, 24.83% for victims, and 28.36% for bully-victims. Furthermore, all types of bullying showed a significant positive correlation with the risk of eating disorders. Notably, gender differences were observed in the associations among social manipulation, cyber victimization, cyber perpetration, and the risk of eating disorders, with males exhibiting stronger correlations. Body dissatisfaction plays a mediating role between bullying-victims and the risk of eating disorders., Conclusions: A positive association has been observed between the type of school bullying and the risk of eating disorders among college students in Shantou. Additionally, gender and body dissatisfaction have been identified as significant factors that contribute to the relationship between school bullying and the risk of eating disorders., Competing Interests: Declarations. Ethics approval and consent to participate: Approval was granted by the Ethics Committee of Shantou University Medical College (SUMC-2023-001). All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional research committee. Informed consent was obtained from all individual participants and their guardians. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests. Conflict of interest: The authors declare no competing interests., (© 2024. The Author(s).)

Intervertebral disc degeneration (IVDD) is a common cause of low back pain. Procyanidin C1 (PCC1) has been demonstrated to exert a protective effect on nucleus pulposus (NP) cells, and therefore, plays a critical role in the prevention and therapy of IVDD. Clarifying the pathophysiological characteristics and molecular mechanisms of IVDD may be helpful in establishing novel preventive and therapeutic strategies. This study aimed to investigate the probable mechanisms underlying the protection against acidic pH stress induced human NP cell injury. In vitro, acidic pH stress induced degeneration, mitochondrial dynamics imbalance, mitophagy, and mitochondria-mediated apoptosis in NP cells, all of which were ameliorated by PCC1. Autophagy inhibition partially eliminated the protective effects of PCC1 on mitochondrial homeostasis in NP cells. Moreover, PCC1 activated the sirtuin 3 (SIRT3)/forkhead box O3 (FOXO3) signaling pathway, a pivotal signaling pathway involved in the regulation of mitochondrial homeostasis in NP cells. In vivo, PCC1 ameliorated IVDD in a rat model and preserved the extracellular matrix of NP cells. Consequently, the protective effects of PCC1 on NP cells may inhibit IVDD progression via regulation of the SIRT3/FOXO3 signaling pathway. Therefore, regulation of the SIRT3/FOXO3 signaling pathway may be a novel preventive and therapeutic strategy for IVDD., Competing Interests: Declarations. Conflict of interest: The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© 2024. The Author(s).)

Objectives: To explore whether monitored anesthesia care is more beneficial to the outcome of transcatheter aortic valve implantation., Methods: The research methodology involved comprehensive searches across major databases, including the Cochrane Library, PubMed, Scopus, and Web of Science, covering the period from January 1, 2010, to March 1, 2024. The aim was to identify trials comparing different anesthetic methods for transcatheter aortic valve implantation. The primary outcomes assessed were mortality and length of hospital stay, while secondary outcomes included common complications such as bleeding, stroke, paravalvular leakage, renal failure, and others. Data synthesis was conducted using risk ratios or standardized mean differences, along with 95% confidence intervals. The study protocol was prospectively registered with PROSPERO (CRD42024507749)., Results: A total of 35 trials and 45,616 patients were included in this study. The results showed that monitored anesthesia care significantly reduced the patient's risk of death, shortened the patient's length of hospital stay, and also reduced the risk of common complications such as paravalvular leakage (RR, 0.80; 95% CI: 0.72 to 0.88; p < 0.00001; I 2  = 0) and stroke (RR, 0.80; 95% CI: 0.65 to 0.99; p = 0.04; I 2  = 0)., Conclusion: Monitored anesthesia care has an absolute advantage in patient survival and effectively shortens the length of hospitalization. In addition, it also reduces the risk of complications such as paravalvular leakage and stroke. Monitoring care under anesthesia plays a vital role during TAVI surgery, not only helping to ensure the smooth progress of the surgery and patient safety, but also promoting the patient's recovery and recovery., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Chronic obstructive pulmonary disease (COPD) is characterized by lung remodeling induced by chronic inflammation, presenting challenges for effective treatment. Mesenchymal stem cells (MSCs) and their extracellular vesicles (EVs) have shown promise in mitigating inflammation and tissue repairing in various diseases, including COPD. However, the optimal therapeutic pathways for different stages of COPD remain unclear. Transfer RNA-derived small RNAs (tsRNAs) are emerging as key regulators of cellular processes. However, their role in COPD and MSC therapy remains poorly understood., Methods: This study explored the optimal administration routes and efficacy of bone marrow mesenchymal stem cells (BMSCs) and their extracellular vesicles (BMSC-EVs) in treating inflammatory or emphysematous COPD stages in mouse models. Male C57BL/6 mice were exposed to cigarette smoke daily for 6 or 16 weeks, with intraperitoneal CSE injections every 10 days, to model different stages of COPD. Mice were then treated with tracheal or intravenous injections of BMSCs or BMSC-EVs. PKH26 fluorescent dye labeled BMSCs and BMSC-EVs for pulmonary distribution observation. Lung tissue inflammation, apoptosis, EMT, and collagen deposition were assessed using HE staining, TUNEL assay, immunohistochemistry, and Sirius Red staining. Gene and tsRNA expression in lung tissues were analyzed by high-throughput sequencing. Differentially expressed tsRNAs (DE-tsRNAs) were validated by RT-qPCR. Statistical analysis was performed using GraphPad Prism 9.0. Data are presented as mean ± standard deviation (SD)., Results: In 16-week COPD mice characterized by emphysema, tracheal administration of BMSC-EVs showed more significant lung distribution and inhibition of emphysematous pathology. In 6-week COPD mice characterized by inflammation, intravenous injection of BMSCs led to significant pulmonary homing, significantly reduced lung inflammation, apoptosis, EMT, and collagen deposition (P < 0.05). High-throughput sequencing indicated BMSC treatment downregulated genes related to these processes while upregulating mitochondrial function genes. Co-expression networks of DE-tsRNAs and target genes suggested potential roles in COPD. RT-qPCR confirmed significant differential expression of two DE-tsRNAs during COPD progression and BMSC treatment (P < 0.05)., Conclusions: Our study provides insights into selecting MSC and MSC-EV administration routes for different COPD stages. High-throughput sequencing supports BMSCs' inhibitory effects on lung remodeling and identifies the first tsRNA expression profile in a COPD model, warranting further investigation., Competing Interests: Declarations. Ethics approval and consent to participate: All animal studies in this study were approved by the Animal Ethics Committee of Third Xiangya Hospital of Central South University. Approved Project Title: The Role and Mechanism of Mesenchymal Stem Cell Exosomes in Modulating the Epithelial-Mesenchymal Trophic Unit via miR-21/TGF-β/SMADs in COPD Airway Remodeling. Approval Number: 2020-s171, permitted on April 3, 2020. Consent for publication: Not applicable. Competing interests: The authors declared no competing interests., (© 2024. The Author(s).)

Alzheimer's disease (AD) is a highly heritable brain dementia, along with substantial failure of cognitive function. Large-scale genome-wide association studies (GWASs) have led to a set of SNPs significantly associated with AD and related traits. GWAS hits usually emerge as clusters where a lead SNP with the highest significance is surrounded by other less significant neighboring SNPs. Although functionality is not guaranteed even with the strongest associations in GWASs, lead SNPs have historically been the focus of the field, with the remaining associations inferred to be redundant. Recent deep genome annotation tools enable the prediction of function from a segment of a DNA sequence with significantly improved precision, which allows in-silico mutagenesis to interrogate the functional effect of SNP alleles. In this project, we explored the impact of top AD GWAS hits around APOE region on chromatin functions and whether it will be altered by the genetic context (i.e., alleles of neighboring SNPs). Our results showed that highly correlated SNPs in the same LD block could have distinct impacts on downstream functions. Although some GWAS lead SNPs showed dominant functional effects regardless of the neighborhood SNP alleles, several other SNPs did exhibit enhanced loss or gain of function under certain genetic contexts, suggesting potential additional information hidden in the LD blocks., Competing Interests: Declarations Competing interests Dr. Yan is a guest editor of this special collection. Dr. Saykin has received support from Avid Radiopharmaceuticals, a subsidiary of Eli Lilly (in kind contribution of PET tracer precursor) and holds advisory roles with Siemens Medical Solutions USA, Inc., NIH NHLBI, and Eisai. His editorial commitments include serving as Editor-in-Chief for the journal `Brain Imaging and Behavior’, and he participates in various NIH/NIA advisory committees., (© 2024. The Author(s).)

Background: Patients with BRAF 600E mutated mCRC are associated with specific clinicopathological features and poor prognosis. The relative efficacy of first-line FOLFOXIRI triplet chemotherapy or doublet chemotherapy combined with bevacizumab in patients with BRAF 600E mutated mCRC remains controversial., Methods: BRAF V600E-mutated mCRC patients from 3 institutions were included. The clinicopathological characteristics of the enrolled patients were analyzed. Overall survival (OS) of patients was divided into 4 fractions, including 0-25%, 25-50%, 50-75%,75-100% by quartile method. Patients with OS ranging from 0 to 25% were defined as the poor prognosis group, and patients with OS ranging from 75 to 100% were defined as the good prognosis group. A propensity score matching (PSM) analysis was performed to balance the baseline characteristics of patients treated with doublet chemotherapy and triplet chemotherapy combined with bevacizumab. Survival and tumor response of the two regimens were evaluated., Results: A total of 125 patients with BRAF V600E-mutated mCRC were enrolled. The median OS of BRAF V600E-mutated mCRC was 14.9 months and the median PFS of first-line therapy was 6.1 months. According to the multivariate analysis and the difference in baseline characteristics between the poor prognosis group and the good prognosis group, poor differentiation and liver metastasis were negative independent prognostic factors for OS in patientsx with BRAF V600E-mutated mCRC. Patients treated with first-line triplets had a longer OS than those treated with doublets both before PSM (17.4 months vs. 13.4 months, p = 0.022) and after PSM (17.4 months vs. 10.4 months, p = 0.004). There was no significant benefit between triplet-drug group and doublet-drug group for PFS, ORR and DCR. Subgroup analysis showed that patients in the triplet-drug group had a better prognosis with the following favorable factors: age ≤ 60 years old, PS score of 0-1, liver metastases and multiple organ metastases., Conclusion: The overall prognosis of BRAF V600E mutant mCRC patients is poor. Poor differentiation and liver metastases were negative independent prognostic factors for OS. First-line triplet-drug therapy was associated with better OS, especially in patients with good physical condition and high tumor burden., Competing Interests: Declarations Ethics approval and consent to participate The study was approved by the Institutional Review Board of West China Hospital, Sichuan University, Chengdu, China [Approval number: 2022 Review (NO.807)]. Consent to participate This is a retrospective observational study, so patients ' informed consent is not required. And this was approved by the Institutional Review Board of West China Hospital, Sichuan University. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Aim: To investigate the level of compassion fatigue among frontline nurses during the COVID-19 pandemic and to explore the relationship between occupational stressors and compassion fatigue among frontline nurses based on structural equation modelling., Background: Three years into the COVID-19 pandemic, nurses on the frontlines of the battle were overwhelmed by affective and emotional inputs while caring for patients, and they generally experienced varying degrees of psychological problems. High levels of compassion fatigue can affect nursing quality and patient safety and therefore should be taken seriously by nursing managers., Methods: A cross-sectional survey of 1432 frontline nurses in Sichuan Province, China, was conducted from January to March 2023 via convenience sampling methods. The General Information Questionnaire, the Nurses' Occupational Stressors Scale, the Ego-Resilience Scale, the Chinese version of the Compassion Fatigue Brief Scale, and the Perceived Organizational Support Scale were used to collect the data. Hypotheses were tested using structural equation models and bootstrapping methods., Results: Nurse occupational stressors had a significant direct effect on compassion fatigue (B = 2.429, p < 0.001). Perceived organizational support exerted a mediating effect of 11.36% between occupational stressors and compassion fatigue. In addition, ego-resilience had a moderating role in the relationship between nurses' occupational stressors and compassion fatigue, between nurses' occupational stressors and perceived organizational support, and between perceived organizational support and compassion fatigue. Multiple linear regression analysis revealed that the most influential dimension of occupational stressors on compassion fatigue was work-family conflict (β = 0.253, p < 0.001), followed by organizational issues (β = 0.153, p < 0.001), work demands (β = 0.103, p < 0.001) and difficulty taking leave (β = 0.102, p < 0.001)., Conclusion: Nurse occupational stressors are positively associated with compassion fatigue and influence nurse compassion fatigue through the mediating effect of perceived organizational support and the moderating mechanism of ego-resilience. Managers can reduce nurses' compassion fatigue levels by reducing occupational stressors, promoting nurses' perceived organizational support, and fostering ego-resilience., Implications for Nursing Management: This study further integrated the external and internal factors affecting compassion fatigue and constructed a structural equation model of the mechanism of compassion fatigue in frontline nurses, which has implications for the early identification and intervention of compassion fatigue in nurses., Competing Interests: Declarations Ethics approval and consent to participate This study was performed in line with the principles of the Declaration of Helsinki and was approved by the Ethics Board at Sichuan Provincial People ‘s Hospital (No.2023-012,issued on 6 January 2023) and followed informed consent and voluntary participation principles. Study participants were briefed in detail about the purpose and methodology of this study prior to being surveyed so that they could make their own choices about whether or not they wished to participate in the study. All study participants was anonymous can withdraw from the study at any time. Informed consent was obtained from all participants. Consent for publication Not applicable. Competing interests Sichuan Science and Technology Program surpports our study，but all authors declare we have no relevant interests to disclose, include financial and non-financial competing interests., (© 2024. The Author(s).)

Background: Radiation-induced intestinal injury (RIII) interrupts the scheduled processes of abdominal and pelvic radiotherapy (RT) and compromises the quality of life of cancer survivors. However, the specific regulators and mechanisms underlying the effects of RIII remain unknown. The biological effects of RT are caused primarily by DNA damage, and ataxia telangiectasia mutated (ATM) is a core protein of the DNA damage response (DDR). However, whether ATM is regulated by deubiquitination signaling remains unclear., Methods: We established animal and cellular models of RIII. The effects of ubiquitin-specific protease 15 (USP15) on DNA damage and radion-induced intestinal injury were evaluated. Mass spectrometry analysis, truncation tests, and immunoprecipitation were used to identify USP15 as a binding partner of ATM and to investigate the ubiquitination of ATM. Finally, the relationship between the USP15/ATM axes was further determined via subsequent experiments., Results: In this study, we identified the deubiquitylating enzyme USP15 as a regulator of DNA damage and the pathological progression of RIII. Irradiation upregulates the expression of USP15, whereas pharmacological inhibition of USP15 exacerbates radiation-induced DNA damage and RIII both in vivo and in vitro. Mechanistically, USP15 interacts with, deubiquitinates, and stabilises ATM via K48-linked deubiquitination. Notably, ATM overexpression blocks the effect of USP15 genetic inhibition on DNA damage and RIII progression., Conclusions: These findings describe ATM as a novel deubiquitination target of USP15 upon radiation-induced DNA damage and intestinal injury, and provides experimental support for USP15/ATM axis as a potential target for developing strategies that mitigate RIII., (© 2024. The Author(s).)

Background: Type II diabetes mellitus (T2DM) is strongly linked with a heightened risk of coronary artery disease (CAD). Exploring biological targets common to T2DM and CAD is essential for CAD intervention strategies., Methods: RNA transcriptome data from CAD and T2DM patients and single-cell transcriptional data from myocardial tissue of CAD patients were used for bioinformatics analysis. Differential analysis and Weighted Gene Co-expression Network Analysis (WGCNA) were conducted to identify hub genes associated with the CAD Index (CADi) in these cells. We then intersected these genes with differentially expressed genes in the T2DM dataset to validate the key gene FGF7. Additional analyses included immune analysis, drug sensitivity, competing endogenous RNA (ceRNA) networks, and smooth muscle cell -related functional analysis., Results: An abnormally high proportion of smooth muscle cells was observed in CAD tissues compared to normal cardiomyocytes. The gene FGF7, which encodes the keratinocyte growth factor 7 protein, showed increased expression in both CAD and T2DM and was significantly positively correlated with the CADi (correlation = 0.24, p < 0.05). FGF7 expression was inversely correlated with CD4 + and CD8 + T-cell immune infiltration and correlated with the cardiovascular drugs. Overexpression of FGF7 in CAD samples enhanced interactions with mononuclear macrophages and influenced the metabolism of alanine, glutamate, nicotinamide, and retinol. We also identified that hsa-miR-15a-5p, hsa-miR-373-3p, hsa-miR-20a-5p, and hsa-miR-372-3p could regulate FGF7 expression., Conclusion: FGF7 serves as a critical shared biological target for T2DM and CAD, playing a significant role in CAD progression with potential therapeutic implications., (© 2024. The Author(s).)

Background: Resource-limited regions face a greater burden of infectious diseases due to limited access to molecular tests, complicating timely diagnosis and management. Current molecular point-of-care tests (POCTs) either come with high costs or lack adequate sensitivity and specificity. To facilitate better prevention and control of infectious diseases in underserved areas, we seek to address the need for molecular POCTs that better align with the World Health Organization (WHO)'s ASSURED criteria-Affordable, Sensitive, Specific, User-friendly, Rapid and robust, Equipment-free, and Deliverable to end users., Methods: A novel molecular POCT, Pasteur Pipette-assisted isothermal probe amplification (pp-IPA), was developed for malaria detection. Without any microfluidics, this method captures Plasmodium 18S rRNA in a modified Pasteur pipette using tailed genus-specific probes. After washing, the bound tailed probes are ligated to form a template for subsequent novel isothermal probe amplification using a pair of generic primers, bypassing nucleic acid extraction and reverse transcription. The method was assessed using cultured Plasmodium and compared with real-time quantitative reverse transcription PCR (RT-qPCR) or reverse transcription loop-mediated isothermal amplification (RT-LAMP) in clinical blood samples., Results: The entire assay is completed in 60-80 min with minimal hands-on time, using only a Pasteur pipette and a water bath. The pp-IPA's analytical sensitivity is 1.28 × 10 -4  parasites/μl, with 100% specificity against various blood-borne pathogens causing malaria-like symptoms. Additionally, pp-IPA needs only liquid-transfer skill for operation and the cost is around USD 0.25 per test, making it at least 300 times lower than mainstream POCT platforms., Conclusions: Designed to improve the accessibility of molecular detection in resource-limited settings, pp-IPA's simplicity, affordability, high sensitivity/specificity, and minimal equipment requirements make it a promising point-of-care pathogen identification tool in resource-constrained regions., (© 2024. The Author(s).)

Background: Exercise is effective in preventing frailty status in older adults, but the effect of an exercise program based on Wellness Motivation Theory (WMT) on the frailty status, self-efficacy for exercise, and quality of life for older adults with pre-frailty remains unclear. Our objective was to examine the efficacy of a multicomponent exercise program based on WMT on frailty status, self-efficacy, and quality of life among pre-frail older adults., Methods: This was a randomized controlled trial of pre-frail older adults aged from 60 years to 85 years. Participants in the intervention group performed exercise three times a week for 24 weeks, once at a community health service station instructed by two researchers and two times at home. Participants in the control group were given one-time advice on physical activity. The assessor was the only one blinded. The primary outcome was the reversal rate of pre-frailty. The secondary outcomes included self-efficacy and quality of life., Results: One hundred and forty-four participants were randomized into two groups (n = 72 in the intervention group and n = 72 in the control group) and analyzed. After 24 weeks, the proportion of pre-frailty was significantly lower in the intervention group than in control (31.8% versus 74.6%, P < 0.001). The absolute risk reduction was 42.8% [95% CI, 25.1-57.1]. In the 8th week and the 24th week, the frailty score of the intervention group was significantly lower than that of the control group. There were significant improvements in self-efficacy at week 2, week 8, and week 24. In weeks 8 and 24, participants in the intervention group reported a higher quality of life than the control group. There were no exercise-related injuries or falls among the participants., Conclusions: The exercise intervention based on WMT for pre-frail older adults could reverse pre-frailty, increase self-efficacy for exercise, and improve the quality of life in older Chinese., Study Registration Details: This study was registered in www., Clinicaltrials: gov on the 25th of July, 2024, with the identifier NCT06519695., Reporting Method: The Consolidated Standards of Reporting Trials (CONSORT) checklist was used in this study for properly reporting how the randomized trial was conducted., (© 2024. The Author(s).)

Background: Ureaplasma spp. can be classified into different serovars. It is unknown whether distinct serovars are associated with clinical signs and symptoms., Methods: We conducted a multicentre cross-sectional study. U. parvum serovars were identified on the basis of their multiple-banded antigen (MBA) genes. After adjusting for demographic variables and other reproductive tract infections, the odds ratio (OR) and 95% confidence interval (CI) were calculated to determine the impact of U. parvum serovars on clinical symptoms., Results: Among 5,277 individuals, U. parvum serovars 3 and 6 were the most prevalent serovars (17.9% and 16.0%, respectively). Potential confounders, such as age, body mass index (BMI), ethnicity, education level, contraceptive methods, number of sexual partners, gravidity, parity, and other sexually transmitted infections (STIs) that are associated with clinical symptoms (P < 0.1) were adjusted for in the univariate analysis. U. parvum serovar 14 was strongly positively associated with certain clinical symptoms, including redness and swelling of the vaginal wall (crude OR: 3.53, 95% CI: 1.92-6.49; adjusted OR: 5.21, 95% CI: 2.56-10.58), cervical bleeding and swelling (crude OR: 3.89, 95% CI: 2.38-6.36; adjusted OR: 7.37, 95% CI: 3.82-14.23), and cervical ectropion (crude OR: 2.08, 95% CI: 1.25-3.45; adjusted OR: 3.04, 95% CI: 1.60-5.74). In contrast, U. parvum serovar 3 was negatively associated with a variety of clinical symptoms, whereas no correlations were detected between U. parvum serovars 1and 6 with clinical symptoms., Conclusions: Different U. parvum serovars exhibit distinct correlations with clinical symptoms, suggesting that U. parvum serovars are pathogenically heterogeneous and that further differentiation of serovars may be necessary., Trial Registration: The study was registered with ClinicalTrials.gov ( https://www., Clinicaltrials: gov ; ID: NCT04694495; Registration Date: 2021-01-05)., (© 2024. The Author(s).)

Background: The estimated pulse wave velocity (ePWV) is a recently developed, simple and useful tool to measure arterial stiffness and to predict long-term cardiovascular mortality. However, the association of ePWV with mortality risk in patients with subarachnoid hemorrhage (SAH) is unclear. Herein, this study aims to assess the potential prediction value of ePWV on short- and long-term mortality of SAH patients., Methods: Data of adult patients with no traumatic SAH were extracted from the Medical Information Mart for Intensive Care (MIMIC) III and IV database in this retrospective cohort study. Weighted univariate and multivariable Cox regression analyses were used to explore the associations of ePWV levels with 30-day mortality and 1-year mortality in SAH patients. The evaluation indexes were hazard ratios (HRs) and 95% confidence intervals (CIs). In addition, subgroup analyses of age, the sequential organ failure assessment (SOFA) score, surgery, atrial fibrillation (AF), renal failure (RF), hepatic diseases, chronic obstructive pulmonary disease (COPD), sepsis, hypertension, and diabetes mellitus (DM) were also performed., Results: Among 1,481 eligible patients, 339 died within 30 days and 435 died within 1 year. After adjusting for covariates, ePWV ≥ 12.10 was associated with higher risk of both 30-day mortality (HR = 1.77, 95%CI: 1.17-2.67) and 1-year mortality (HR = 1.97, 95%CI: 1.36-2.85), compared to ePWV < 10.12. The receiver operator characteristic (ROC) curves showed that compared to single SOFA score, ePWV combined with SOFA score had a relative superior predictive performance on both 30-day mortality and 1-year mortality, with the area under the curves (AUCs) of 0.740 vs. 0.664 and 0.754 vs. 0.658. This positive relationship between ePWV and mortality risk was also found in age ≥ 65 years old, SOFA score < 2, non-surgery, non-hepatic diseases, non-COPD, non-hypertension, non-DM, and sepsis subgroups., Conclusion: Baseline ePWV level may have potential prediction value on short- and long-term mortality in SAH patients. However, the application of ePWV in SAH prognosis needs further clarification., (© 2024. The Author(s).)

Background: To assess the prevalence and epidemic pattern of multidrug-resistant tuberculosis in Hangzhou City, Zhejiang Province, China during 2012-2022., Methods: All the tuberculosis cases undergoing drug susceptibility testing during 2012-2022 were included in this study. De-identified information was extracted from the electronic database Tuberculosis Information Management System for analysis of drug resistance prevalence in Hangzhou and ecdemic multidrug-resistant tuberculosis which originated from other regions. Chi-square tests were used to compare drug resistance rates between different groups, while Chi-square tests for trend were used to evaluate the change of drug resistance rates over the years of 2012-2022. The sources and destinations of ecdemic multidrug-resistant tuberculosis were illustrated using a Sankey diagram., Results: Of 21,127 cases included in this study, 1119 (5.3%) were multidrug-resistant tuberculosis. A significant decline in multidrug-resistant tuberculosis rates was observed during 2012-2022. There was a significant difference in multidrug-resistant tuberculosis rates among immigrant population and local residents in Hangzhou City. Of 1119 multidrug-resistant tuberculosis cases, 515(46%) were ecdemic multidrug-resistant tuberculosis cases, of which 277(53.8%) were from other parts of Zhejiang Province and 238(46.2%) were from other provinces in China. Anhui, Jiangxi and Sichuan were among top three provinces which were the source of ecdemic multidrug-resistant tuberculosis cases. Three districts including Xiaoshan, Shangcheng and Linping districts had the most cases in Hangzhou. The proportion of ecdemic multidrug-resistant tuberculosis cases in Binjiang, Xiaoshan, Qiantang and Linping districtalso exceeded 30% of total cases., Conclusions: Multidrug-resistant tuberculosis prevalence has been declining in Hangzhou. Migrant population contributed to a significant potion of cases in Hangzhou. Interventions should be tailed to local and migrant residents., (© 2024. The Author(s).)

Background: MYB transcription factors regulate anthocyanin biosynthesis across numerous plant species. However, comprehensive genome-wide investigations regarding the R2R3-MYB gene family and its involvement in regulating anthocyanin biosynthesis in the red and white fruit color morphs of Fragaria pentaphylla remain scarce., Results: A total of 101 FpR2R3-MYB genes were identified from the F. pentaphylla genome and were divided into 34 subgroups based on phylogenetic analysis. Gene structure (exon/intron) and protein motifs were particularly conserved among the FpR2R3-MYB genes, especially members within the same subgroup. The FpR2R3-MYB genes were distributed over seven F. pentaphylla chromosomes. Analysis of gene duplication events revealed five pairs of tandem duplication genes and 16 pairs of segmental duplication genes, suggesting that segmental duplications are the major pattern for expansion of the FpR2R3-MYB gene family expansion in F. pentaphylla. Cis-regulatory elements of the FpR2R3-MYB promoters were involved in cellular development, phytohormones, environmental stress and photoresponse. Based on the analysis of the FpR2R3-MYB gene family and transcriptome sequencing (RNA-seq) data, FpMYB9 was identified as a key transcription factor involved in the regulation of anthocyanin synthesis in F. pentaphylla fruits. The expression of FpMYB9 increases significantly during the ripening stage of red fruits, as confirmed by reverse transcription quantitative real-time PCR. In addition, subcellular localization experiments further confirmed the nuclear presence of FpMYB9, supporting its role as a transcription factor involved in anthocyanin biosynthesis., Conclusion: Our results showed that the FpR2R3-MYB genes are highly conserved and play important roles in the anthocyanin biosynthesis in F. pentaphylla fruits. Our results also provide a compelling basis for further understanding of the regulatory mechanism underlying the role of FpMYB9 in anthocyanin formation in F. pentaphylla fruits., (© 2024. The Author(s).)

Objective: The Ureteral Access Sheath (UAS) has notable benefits but may fail to traverse the ureter in some cases. Our objective was to develop and validate a dynamic online nomogram for patients with ureteral stones who experienced UAS placement failure during retrograde intrarenal surgery (RIRS)., Methods: This study is a retrospective cohort analysis using medical records from the Second Hospital of Tianjin Medical University. We reviewed the records of patients with ureteral stones who underwent RIRS in 2022 to identify risk factors associated with UAS placement failure. Lasso combined logistic regression was utilized to identify independent risk factors associated with unsuccessful UAS placement in individuals with ureteral stones. Subsequently, a nomogram model was developed to predict the likelihood of failed UAS placement in this patient cohort. The model's performance was assessed through Receiver Operating Characteristic Curve (ROC) analysis, calibration curve assessment, and Decision Curve Analysis (DCA)., Results: Significant independent risk factors for unsuccessful UAS placement in patients with ureteral stones included age (OR = 0.95, P < 0.001), male gender (OR = 2.15, P = 0.017), body mass index (BMI) (OR = 1.12, P < 0.001), history of stone evacuation (OR = 0.35, P = 0.014), and ureteral stone diameter (OR = 0.23, P < 0.001). A nomogram was constructed based on these variables. Model validation demonstrated an area under the ROC curve of 0.789, indicating good discrimination. The calibration curve exhibited strong agreement, and the decision curve analysis revealed a favorable net clinical benefit for the model., Conclusions: Young age, male sex, high BMI, no history of stone evacuation, and small diameter of ureteral stones were independent risk factors for failure of UAS placement in patients with ureteral stones, and the dynamic nomogram established with these 5 factors was clinically effective in predicting the outcome of UAS placement., (© 2024. The Author(s).)

Background: Lung injury and pulmonary fibrosis (PF), frequently arising as sequelae of severe and acute lung disease, currently face a dearth of effective therapeutic potions. Mesenchymal stem cells (MSCs) with immunomodulatory and tissue repair functions have immense potential to treat lung injury and PF. However, the optimal route of administration, timing, and frequency of dosing remain elusive. Human embryonic stem cell-derived immunity-and-matrix-regulatory cells (IMRCs) have shown therapeutic potential for lung injury and PF., Methods: To ascertain the optimal therapeutic regimen for IMRCs in PF, we conducted an experimental study. Utilizing a mouse model of PF induced by bleomycin (BLM), IMRCs were administered via either a single or double intravenous (IV) or intratracheal (IT) injection on the first and seventh days post-BLM induction., Results: Our findings revealed that IV infusion of IMRCs surpassed IT infusion in enhancing survival rates, facilitating body weight recovery, and optimizing Ashcroft and Szapiel scores among the model mice. Notably, IV administration exhibited a more profound ability to mitigate lung inflammation and fibrosis. Moreover, earlier and more frequent administrations of IMRCs were found to be advantageous in enhancing their therapeutic effects. Specifically, early administration with two IV infusions significantly improved body weight, lung organ coefficient, pulmonary ventilation and diffusion functions, and PF. This was accompanied by an increase in alveolar type I and II epithelial cells and a suppression of macrophage infiltration via CD24., Conclusion: Collectively, these results suggested that IMRCs infusion ameliorated lung injury by promoting lung regeneration and inhibiting macrophage infiltration in a route, time, and frequency-dependent manner., (© 2024. The Author(s).)

Objectives: To explore the role of nodule-pleural relationship, including nodule with pleural tail sign (PTS), nodule with pleural contact and nodule with pleural unrelated in CT-guided percutaneous transthoracic needle biopsy (PTNB)-induced pneumothorax, and whether employing different puncture routes has an impact on the incidence of pneumothorax in PTNB of nodules with PTS., Methods: Between April 1, 2019, to June 30, 2021, 775 consecutive PTNB procedures of pulmonary nodules in the Peking University Cancer Hospital were retrospectively reviewed. The univariate and multivariate regression analysis were used to identify the risk factors for pneumothorax in PTNB., Results: The nodule with pleural contact group has a lower incidence of pneumothorax than the nodule with PTS group (p = 0.001) and the nodule with pleural unrelated group (p = 0.002). It was observed that a higher incidence of pneumothorax caused by crossing PTS compared with no crossing PTS (p < 0.001). Independent risk factors for pneumothorax included crossing PTS (p < 0.001), perifocal emphysema (p < 0.001), biopsy side up (p < 0.001), longer puncture time (p < 0.001), deeper needle insertion depth (intrapulmonary) (p < 0.001) and nodules in the middle or lower lobe (p = 0.007)., Conclusion: Patients with crossing PTS, a nodule in the middle or lower lobe, longer puncture time, biopsy side up, deeper needle insertion depth (intrapulmonary), and perifocal emphysema were more likely to experience pneumothorax in PTNB. When performing the biopsy on a nodule with PTS, selecting a route that avoids crossing through the PTS may be advisable to reduce the risk of pneumothorax., (© 2024. The Author(s).)

Background: EYA4 variants are responsible for DFNA10 deafness. Due to its insidious onset and slow progression, hearing loss in autosomal dominant non-syndromic hearing loss (ADNSHL) is usually challenging to detect early in clinical settings, with limited intervention options. Genetic testing can aid in early detection of hearing loss, enabling timely intervention to reduce disability rates and improve the quality of life., Methods: In this study, we report the case of a Chinese family with postlingual and progressive hearing loss that was passed down for four generations. Whole-exome sequencing (WES) was performed on DNA samples from the proband. Candidate variants identified in the proband and family members were confirmed via Sanger sequencing. In silico prediction tools and co-segregation analyses were used to assess the pathogenicity of identified variants. A literature review of known EYA4 variants was performed, analysing variant frequency, distribution characteristics across different populations, and genotype-phenotype correlations., Results: We identified a novel EYA4 variant, c.1745&#95;1748del (p.Glu582ValfsTer6), in a Chinese family with ADNSHL, and co-segregation with the family's phenotype was confirmed. The audiometry showed mid-to-high frequency downsloping hearing loss. To date, 52 pathogenic variants of EYA4 have been reported, with majority identified in Asian populations. Most observed are the missense and frameshift variants., Conclusions: A novel variant of EYA4 was identified in a Chinese family with postlingual hearing loss, contributing to the expanding spectrum of EYA4 variants. The audiological features of EYA4 variants are highly heterogeneous and often challenging to detect early in clinical settings. Our findings highlight the significance of genetic testing in patients presenting with postlingual hearing loss., (© 2024. The Author(s).)

Background: Children with chronic kidney disease (CKD) are at high risk of cardiovascular disease. Cardiovascular magnetic resonance (CMR) is the reference method for assessing cardiac remodeling. To our knowledge, no study has reported a comprehensive analysis of left ventricular(LV) cardiac remodeling using CMR in different stages of pediatric CKD. This prospective case-control study aimed to investigate cardiac remodeling in pediatric CKD, using CMR, and determine its relationship with risk factors., Method: CMR was performed in 124 children with CKD and 50 controls. The cardiac remodeling parameters included left ventricular mass index (LVMI), LV remodeling index (LVRI), and LV wall thickness. Univariable and multivariable analyses were performed to assess the cardiac remodeling risk factors., Results: Cardiac remodeling was observed in 35.5% (44/124) of children with CKD. The LVMI, LVRI, and LV wall thickness were higher in advanced stages of CKD (P < 0.05). In the CKD stage 1-2 group, a lower in the estimated glomerular filtration rate was an independent determinant of impaired LVMI (β = -0.425, P = 0.019) and LVRI (β = -0.319, P = 0.044). A higher protein to creatinine ratio(PCR) was independently associated with impaired LVRI (β = 0.429, P = 0.022). In the CKD stage 3-5 group, higher in systolic blood pressure (SBP) (β = 0.464, P = 0.005) and PCR (β = 0.852, P = 0.031) were independent determinants of impaired LVMI. Additionally, higher SBP was positively correlated with impaired LVRI(r = 0.599, P < 0.001). There was a trend toward more abnormal cardiac remodeling in the CKD stage 3-5 group with hypertension than those without., Conclusion: Cardiac remodeling is prevalent in children with CKD, from an early stage. kidney markers are independently associated with cardiac remodeling. Hypertension increases the risk of cardiac remodeling in CKD stages 3-5. Strict BP control may help reverse or prevent remodeling., (© 2024. The Author(s).)

This study investigated the possible mechanisms of microRNA-124a on the differentiation of bone marrow mesenchymal stem cells (BMSCs) and its underlying mechanism. β-Thiol ethanol induced Notch1 mRNA expression, microRNA-124a inhibitor reduced the effects of β-thiol ethanol on Notch1 mRNA expression in BMSCs. Baicalin induced Hes1 mRNA expression, and microRNA-124a inhibitor reduced the effects of baicalin on Hes1 mRNA expression in BMSCs. Si-Notch1 suppressed Hes1 mRNA expression in BMSCs. Baicalin increased the effects of Notch1 on Hes1 mRNA expression in BMSCs. Si-Notch1 increased cell growth of BMSCs. Baicalin reduced the effects of si-Notch1 on cell growth and the differentiation of BMSCs. We demonstrated that microRNA-124a promoted the differentiation of BMSCs into neurons through Notch/Hes1 signal pathway., (© 2024. The Author(s).)

Purpose: Identifying primary hepatic angiosarcoma (PHA) preoperatively is challenging, often relying on postoperative pathology. Invasive biopsy increases bleeding risk, emphasizing the importance of early PHA diagnosis through imaging. However, comprehensive summaries of ultrasound, abdominal computed tomography (CT), magnetic resonance imaging (MRI), and whole- body positron emission tomography-CT (PET-CT) in this context are lacking. This study aimed to investigate the comprehensive imaging characteristics of PHA., Patients and Methods: Imaging data were collected from 7 patients diagnosed with PHA via pathology between January 2000 and December 2019 in two provincial grade III hospitals. All patients underwent routine color ultrasound examinations before surgery, with 3 patients receiving contrast-enhanced ultrasound (CEUS).CT scans, both plain and enhanced, were performed on 5 patients, and whole-body PET-CT examinations were conducted on 2 patients., Results: Among the 7 patients with PHA, 4 presented with a single solid intrahepatic mass (2 of which were large), 1 with a single exophytic macroblock type, 1 with a mixed type featuring multiple masses and nodules, and 1 with a multiple nodule type. Conventional ultrasound of PHA showed uneven echoes within the tumor, potentially accompanied by septal zone echoes, and a blood flow grade of 0-I. CEUS displayed early-stage circular high enhancement, a central non-enhancement area, and a "vascular sign" around the tumor. CT scans revealed low-density shadows in the plain scan stage, high peripheral ring enhancement, and punctate nodular enhancement in the arterial phase, with varying intensities and the presence of a "vascular sign." During the portal vein stage, the interior of the tumor was consistently unfilled and exhibited structural disorder. PET-CT showed low-density lesions in the liver and low fluorodeoxyglucose metabolism., Conclusions: Imaging diagnosis plays a crucial role in PHA diagnosis. When liver tumor imaging matches the above characteristics, consider PHA., (© 2024. The Author(s).)

Objectives: To identify independent predictors of late recurrence of atrial fibrillation (AF) after surgical ablation in patients undergoing rheumatic valve surgery., Methods: A total of 258 patients who underwent surgical ablation for AF with rheumatic heart disease at our hospital between January 2019 and June 2022 were retrospectively included. The patients were followed up for 12 months. Late recurrence was defined as any AF recurrence longer than 30 s between 3 and 12 months. Patients with or without late recurrence were divided into non-recurrence and recurrence groups. Univariate and multivariate analyses were performed to identify the predictors of late recurrence., Results: The in-hospital mortality rate was 0.8% (2/258), and the late recurrence rate of AF was 38.4%, including 152 and 95 cases in the non-recurrent and recurrent groups respectively, with a follow-up completion rate of 96.5% (247/256). There were no deaths during follow-up, two patients (0.8%) experienced a stroke, and one patient (0.4%) experienced gastrointestinal hemorrhage. The results of the univariate and multivariate analyses of the preoperative risk factors for late recurrence showed a left atrial (LA) anteroposterior diameter ≥ 52.9 mm (odds ratio [OR] = 2.366, 95% confidence interval [CI] = 1.089-5.138, P = 0.030], ratio of the superoinferior to the anteroposterior diameters of LA (S-AR) < 1.19 (OR = 4.639, 95% CI = 2.181-9.865, P < 0.001), and AF duration ≥ 39 months (OR = 6.152, 95% CI = 2.897-13.061, P < 0.001), and cardiothoracic ratio ≥ 0.63 (OR = 2.716, 95% CI = 1.314-5.612, P = 0.007) were the most significant independent risk factors., Conclusions: LA anteroposterior diameter ≥ 52.9 mm, S-AR < 1.19, and AF duration ≥ 36 months and cardiothoracic ratio ≥ 0.63 are independent predictors for late recurrence of AF after surgical ablation in patients undergoing rheumatic valve surgery., (© 2024. The Author(s).)

Background: School bullying, a serious problem for the physical and mental health of adolescents, is presently a significant issue in China. It is essential to recognize and comprehend potential risk factors and establish efficient preventive strategies. The purpose of this study was to examine the association between childhood maltreatment and school bullying in adolescents and to assess the mediating role of peer relationships., Methods: Between March and April 2024, a cross-sectional survey was conducted among 2119 adolescents aged between 12 and 18 years in Guangdong Province, China. Self-report questionnaires were employed to collect data on childhood maltreatment, school bullying, and peer relationships. Subgroup analyses and mediating effects modeling were employed to analyze the data., Results: The results indicated that adolescents who had experienced maltreatment were more at risk of bullying victimization (OR: 2.92, 95% CI: 2.34-3.64, P < 0.001), bullying perpetration (OR: 2.84, 95% CI: 1.99-4.05, P < 0.001), and bully-victimization (OR: 2.93, 95% CI: 1.95-4.41, P < 0.001), compared to adolescents who have not. Sexual abuse showed the most significant connection with all forms of bullying. The mediating effect of peer relationships was found to mediate the association between child maltreatment and bullying behaviour. The results indicated that worse peer relationships may exacerbate the adverse effects of maltreatment experiences and increase the risk of adolescents becoming bullies, either perpetrators or victims of bullying., Conclusions: Child maltreatment has been identified as one of the most significant influences on bullying behaviour in adolescents. The quality of peer relationships has been demonstrated to play an important role in preventing and reducing the occurrence of bullying. The results underscore the crucial role of early intervention in cases of child maltreatment and the fostering of positive peer relationships in schools., (© 2024. The Author(s).)

Background: We concurrently developed a prospective study to assess clinical outcomes among patients receiving 9-month bedaquiline (BDQ)-containing regimens, aiming to provide valuable data on the use of this short-course regimen in China., Methods: This open-label, randomized, controlled, multicenter, non-inferiority trial was conducted at sixteen hospitals, and enrolled participants aged 18 years and older with pulmonary rifampicin/multidrug tuberculosis. Participants were randomly assigned, in a 1:1 ratio. Individuals within the standard-regimen group received 6 months of BDQ, linezolid, levofloxacin, clofazimine, and cycloserine plus 12 months of levofloxacin, and any three potentially effective drugs from clofazimine, cycloserine pyrazinamide, ethambutol and protionamide, whereas individuals within shorter-regimen group received 9 months of BDQ, linezolid, levofloxacin, clofazimine and cycloserine. The primary outcome was the percentage of participants with a composite unfavorable outcome (treatment failure, death, treatment discontinuation, or loss to follow-up) by the end of the treatment course after randomization in the modified intention-to-treat population. The noninferiority margin was 10%. This trial was registered with www.chictr.org.cn , ChiCTR2000029012., Results: Between Jan 1, 2020, and Dec 31, 2023, 264 were screened and randomly assigned, 132 of 264 participants were assigned to the standard-regimen group and 132 were assigned to the shorter-regimen. Thirty-three (12.55%) of 264 participants were excluded from the modified intention-to-treat analysis. As a result, 231 participants were included in the modified intention-to-treat analysis (116 in the standard-regimen group and 115 in the shorter-regimen group).In the modified intention-to-treat population, unfavorable outcomes were reported in 19 (16.5%) of 115 participants for whom the outcome was assessable in the shorter-regimen group and 26 (22.4%) of 116 participants in the standard care group (risk difference 5.9 percentage points (97.5% CI - 5.8 to 17.5)). One death was reported in the standard-regimen group. The incidence of QTcF prolongation in the shorter-regimen group (22.6%, 26/115) was similar to the standard-regimen group (24.1%, 28/116)., Conclusions: The 9-month, all-oral regimen is safe and efficacious for the treatment of pulmonary rifampicin/multidrug-resistant tuberculosis. The high incidence of QTc prolongation associated with the use of BDQ highlights the urgent need of routine electrocardiogram monitoring under treatment with BDQ-containing regimens in the Chinese population., (© 2024. The Author(s).)

Background: Umbilical cord blood (UCB) is a rich source of multifunctional stem cells characterized by low immunogenicity. Recent research in the fields of aging and regenerative medicine has revealed the potential of human umbilical cord blood-derived exosomes (UCB-Exos) in promoting wound healing, anti-aging, and regeneration. However, their role in neurodegenerative diseases, specifically Parkinson's disease (PD), remains unexplored. This study investigates the potential therapeutic effects and underlying mechanisms of UCB-Exos on PD., Methods: Large extracellular vesicles (LEv), Exos, and soluble fractions (SF) of human UCB plasma were extracted to investigate their effects on motor dysfunction of the MPTP-induced PD mouse model and identify the key components that improve PD symptoms. UCB-Exos were administered by the caudal vein to prevent or treat the PD mouse model. The motor function and pathological markers were detected. Differentially expressed gene and KEGG enrichment pathways were screened by transcriptome sequence. MN9D and SH-SY5Y cells were cultured and evaluated for cell viability, oxidative stress, cell cycle, and aging-related indexes by qRT-PCR, western blot, immunofluorescence, and flow cytometry. The protein expression level of the MAPK p38 and ERK1/2 signaling pathway was detected by western blot., Results: We observed that LEv, Exos, and SF all exhibited potential in ameliorating motor dysfunction in MPTP-induced PD model mice, with UCB-Exos demonstrating the most significant effect. UCB-Exos showed comparable efficacy in preventing and treating motor dysfunction, cognitive decline, and substantia nigra pathological damage in PD mice. Further investigations revealed that UCB-Exos could potentially alleviate oxidative damage, aging and degeneration, and energy metabolism disorders in neurons. Transcriptome sequencing results corroborated that genes differentially expressed due to UCB-Exos were primarily enriched in the neuroactive ligand-receptor interaction, Dopaminergic synapse, and MAPK signaling pathway. We also observed that UCB-Exos significantly inhibited the hyperphosphorylation of the MAPK p38 and ERK1/2 signaling pathways both in vitro and in vivo., Conclusions: Our study provides a comprehensive evaluation of UCB-Exos on the neuroprotective effects and suggests that inhibition of hyperphosphorylation of MAPK p38 and ERK 1/2 signaling pathways by regulating transcription levels of HspB1 and Ppef2 may be the key mechanism for UCB-Exos to improve PD-related pathological features., (© 2024. The Author(s).)

Objective: Obesity is a common feature in women with polycystic ovary syndrome (PCOS) and potentially significantly influences reproductive function. However, opinions are divided as to which factor is a more appropriate obesity predictor of reproductive outcomes. The aim of this study was to investigate the discriminatory capability of anthropometric measures in predicting reproductive outcomes in Chinese women with PCOS., Methods: A total of 998 women with PCOS from PCOSAct were included. Logistic regression models were used to compute the odds ratios (ORs) and 95% confidence interval (95% CIs) to assess the effect of anthropometric measures, including body mass index (BMI), waist circumference (WC), hip circumference (HC), the waist‒hip ratio (WHR) and the waist‒height ratio (WHtR), on reproductive outcomes. The discrimination abilities of the models were assessed and compared based on the area under the receiver operating characteristic curve (AUC), Akaike's information criterion (AIC) and integrated discrimination improvement (IDI)., Results: Among PCOS women, there was a graded association between anthropometric measures and predicted reproductive outcomes across quintiles of anthropometric measures, including a linear association among WHR, BMI and reproductive outcomes and among waist circumference, WHtR and live birth, pregnancy, and ovulation. However, only a linear association was noted between the hip and ovulation. C-statistic comparisons and IDI analyses revealed a trend towards a significant superiority of BMI for ovulation and WHR for live birth, pregnancy and conception in the models. Combining obesity variables improved discrimination in the multivariable models for reproductive outcomes., Conclusions: Our findings support that BMI is a better predictor of ovulation and that the WHR is a better predictor of live birth, pregnancy and conception, whereas the combination of obesity variables contributes to the discrimination of reproduction., (© 2024. The Author(s).)

Background: The development of the human vermiform appendix at the cellular level, as well as its function, is not well understood. Appendicitis in preschool children, although uncommon, is associated with a high perforation rate and increased morbidity., Methods: We performed single-cell RNA sequencing (scRNA-seq) on the human appendix during fetal and pediatric stages as well as preschool-age inflammatory appendices. Transcriptional features of each cell compartment were discussed in the developing appendix. Cellular interactions and differentiation trajectories were also investigated. We compared scRNA-seq profiles from preschool appendicitis to those of matched healthy controls to reveal disease-associated changes. Bulk transcriptomic data, immunohistochemistry, and real-time quantitative PCR were used to validate the findings., Results: Our analysis identified 76 cell types in total and described the cellular atlas of the developing appendix. We discovered the potential role of the BMP signaling pathway in appendiceal epithelium development and identified HOXC8 and PITX2 as the specific regulons of appendix goblet cells. Higher pericyte coverage, endothelial angiogenesis, and goblet mucus scores together with lower epithelial and endothelial tight junction scores were found in the preschool appendix, which possibly contribute to the clinical features of preschool appendicitis. Preschool appendicitis scRNA-seq profiles revealed that the interleukin-17 signaling pathway may participate in the inflammation process., Conclusions: Our study provides new insights into the development of the appendix and deepens the understanding of appendicitis in preschool children., (© 2024. The Author(s).)

Introduction: Acute myocardial infarction (AMI) is a serious, deadly disease with a high incidence. However, it remains unclear how necroptosis affects the pathophysiology of AMI. Using bioinformatic analyses, this study investigated necroptosis in AMI., Methods: We obtained the GSE66360 dataset related to AMI by the GEO database. Venn diagrams were used to identify necroptosis-related differential genes (NRDEGs). The genes with differential expression in AMI were analyzed using gene set enrichment analysis, and a PPI network was established. A transcription factor prediction and enrichment analysis were conducted for the NRDEGs, and the relationships between AMI, NRDEGs, and immune cells were determined. Finally, in the additional dataset, NRDEG expression levels, immune infiltration, and ROC curve analysis were confirmed, and gene expression levels were further verified experimentally., Results: GSEA revealed that necroptosis pathways were significantly enriched in AMI. We identified 10 NRDEGs, including TNF, TLR4, FTH1 and so on. Enrichment analysis indicated that the NOD-like receptor and NF-kappa B signaling pathways were significantly enriched. Four NRDEGs, FTH1, IFNGR1, STAT3, and TLR4, were identified; however, additional datasets and further experimental validation are required to confirm their roles. In addition, we determined that a high abundance of macrophages and neutrophils prompted AMI development., Conclusions: In this study, four potential genes that affect the development of AMI through necroptosis (FTH1, IFNGR1, STAT3, and TLR4) were identified. In addition, we found that a high abundance of macrophages and neutrophils affected AMI. This helps determine the pathological mechanism of necroptosis and immune cells that influence AMI and provides a novel strategy for targeted therapy., (© 2024. The Author(s).)

Background: For localized prostate cancer, a comprehensive treatment approach centered around radical prostatectomy (RP) is often their optimal choice. Successful RP can typically reduce prostate-specific antigen (PSA) levels to below 0.1 ng/mL within 6 to 8 weeks postoperatively. However, in clinical practice, 5 to 24% of patients may have a PSA ≥ 0.1 ng/mL at 6 to 8 weeks after surgery, a phenomenon known as PSA persistence. Many studies based on data from Europe and United States have shown an association between PSA persistence and poor postoperative outcomes, further analyzing the risk factors for PSA persistence. However, relevant research based on data from China remains scarce., Methods: Retrospective study of 1,347 prostate cancer patients who underwent RP at the First Affiliated Hospital of Zhejiang University School of Medicine from July 15, 2016, to August 31, 2022. Based on inclusion criteria, univariate and multivariate logistic regression analyses were conducted to explore the independent risk factors for persistent PSA., Results: Among the 826 prostate cancer patients after RP, 124 patients experienced persistent PSA. In univariate logistic regression analysis, robot-assisted laparoscopic radical prostatectomy (RARP), preoperative PSA, high-risk group, preoperative International Society of Urological Pathology (ISUP) grades 2-5, postoperative ISUP grades 3-5, percentage of positive cores, cT3, ≥pT3b, extracapsular extension (EPE), seminal vesicle invasion (SVI), positive surgical margins (PSM) and Prostate Specific Antigen Density (PSAD) were all significantly associated with PSA persistence after RP (P < 0.05). In terms of surgical approach, RARP was considered a protective factor against postoperative PSA persistence (OR:0.53, p < 0.05). In multivariate logistic regression analysis, preoperative ISUP grade 4, percentage of positive cores and PSM were independent risk factors of PSA persistence after RP (P < 0.05)., Conclusion: Preoperative PSA, high-risk group, preoperative ISUP grades 2-5, postoperative ISUP grades 3-5, percentage of positive cores, cT3, ≥pT3b, EPE, SVI, PSM and PSAD were independent risk factors for PSA persistence in prostate cancer patients after RP. This provides assistance for early monitoring and treatment of patients at high risk of persistent PSA in clinical practice., (© 2024. The Author(s).)

Background: Glucagon-like peptide-1 receptor (GLP1R) agonists have been shown to reduce major cardiovascular events in diabetic patients, but their role in heart failure (HF) remains controversial. Recent evidence implies their potential benefits on cardiometabolism such as lipid metabolism, which may contribute to lowering the risk of HF. Consequently, we designed a Mendelian randomization (MR) study to investigate the causal relationships of circulating lipids mediating GLP1R agonists in HF., Methods: The available cis-eQTLs for GLP1R target gene were selected as instrumental variables (IVs) of GLP1R agonism. Positive control analyses of type 2 diabetes mellitus (T2DM) and body mass index (BMI) were conducted to validate the enrolled IVs. Two-sample MR was performed to evaluate the associations between GLP1R agonism and HF as well as left ventricular ejection fraction (LVEF). Summary data for HF and LVEF were obtained from two genome-wide association studies (GWASs), which included 977,323 and 40,000 individuals of European ancestry, respectively. The primary method employed was the random-effects inverse variance weighted, with several other methods used for sensitivity analyses, including MR-Egger, MR PRESSO, and weighted median. Additionally, multivariable MR and mediation MR were applied to identify potentially causal lipid as mediator., Results: A total of 18 independent IVs were included. The positive control analyses showed that GLP1R agonism significantly reduced the risk of T2DM (OR = 0.79, 95% CI = 0.75-0.85, p < 0.0001) and decreased BMI (OR = 0.95, 95% CI = 0.93-0.96, p < 0.0001), ensuring the effectiveness of selected IVs. We found favorable evidence to support the protective effect of GLP1R agonism on HF (OR = 0.75, 95% CI = 0.71-0.79, p < 0.0001), but there was no obvious correlation with increased LVEF (OR = 1.01, 95% CI = 0.95-1.06, p = 0.8332). Among the six blood lipids, only low-density lipoprotein cholesterol (LDL-C) was both associated with GLP1R agonism and HF. The causal effect of GLP1R agonism on HF was partially mediated through LDL-C by 4.23% of the total effect (95% CI = 1.04-7.42%, p = 0.0093)., Conclusions: This study supported the causal relationships of GLP1R agonists with a reduced risk of HF. LDL-C might be the mediator in this association, highlighting the cardiometabolic benefit of GLP1R agonists on HF., (© 2024. The Author(s).)

Background: Osteosarcoma (OS) is a malignant bone tumor that commonly occurs in children and adolescents under the age of 20. Dysregulation of microRNAs (miRNAs) is an important factor in the occurrence and progression of OS. MicroRNA miR-744-5p is aberrantly expressed in various tumors. However, its roles and molecular targets in OS remain unclear., Methods: Differentially expressed miRNAs in OS were analyzed using the Gene Expression Omnibus dataset GSE65071, and the potential hub miRNA was identified through weighted gene co-expression network analysis. Quantitative real-time PCR (qRT-PCR) was used to detect the expression of miR-744-5p in OS cell lines. In vitro experiments, including CCK-8 assays, colony formation assays, flow cytometry apoptosis assays, and tube formation assays, were performed to explore the effects of miR-744-5p on OS cell biological behaviors. The downstream target genes of miR-744-5p were predicted through bioinformatics, and the binding sites were validated by a dual-luciferase reporter assay., Results: The lowly expressed miRNA, miR-744-5p, was identified as a hub miRNA involved in OS progression through bioinformatic analysis. Nuclear factor I X (NFIX) was confirmed as a direct target for miR-744-5p in OS. In vitro studies revealed that overexpression of miR-744-5p could restrain the growth of OS cells, whereas miR-744-5p inhibition showed the opposite effect. It was also observed that treatment with the conditioned medium from miR-744-5p-overexpressed OS cells led to poorer proliferation and angiogenesis in human umbilical vein endothelial cells (HUVECs). Furthermore, NFIX overexpression restored the suppression effects of miR-744-5p overexpression on OS cell growth and HUVECs angiogenesis., Conclusion: Our results indicated that miR-744-5p is a potential tumor-suppressive miRNA in OS progression by targeting NFIX to restrain the growth of OS cells and angiogenesis in HUVECs., (© 2024. The Author(s).)

Background: Type 2 diabetes mellitus (T2D) is associated with an increased risk of cognitive dysfunction. Angiopoietin-like protein 8 (ANGPTL8) is an important regulator in T2D, but the role of ANGPTL8 in diabetes-associated cognitive dysfunction remains unknown. Here, we explored the role of ANGPTL8 in diabetes-associated cognitive dysfunction through its interaction with paired immunoglobulin-like receptor B (PirB) in the central nervous system., Methods: The levels of ANGPTL8 in type 2 diabetic patients with cognitive dysfunction and control individuals were measured. Mouse models of diabetes-associated cognitive dysfunction were constructed to investigate the role of ANGPTL8 in cognitive function. The cognitive function of the mice was assessed by the Barnes Maze test and the novel object recognition test, and levels of ANGPTL8, synaptic and axonal markers, and pro-inflammatory cytokines were measured. Primary neurons and microglia were treated with recombinant ANGPTL8 protein (rA8), and subsequent changes were examined. In addition, the changes induced by ANGPTL8 were validated after blocking PirB and its downstream pathways. Finally, mice with central nervous system-specific knockout of Angptl8 and PirB -/- mice were generated, and relevant in vivo experiments were performed., Results: Here, we demonstrated that in the diabetic brain, ANGPTL8 was secreted by neurons into the hippocampus, resulting in neuroinflammation and impairment of synaptic plasticity. Moreover, neuron-specific Angptl8 knockout prevented diabetes-associated cognitive dysfunction and neuroinflammation. Mechanistically, ANGPTL8 acted in parallel to neurons and microglia via its receptor PirB, manifesting as downregulation of synaptic and axonal markers in neurons and upregulation of proinflammatory cytokine expression in microglia. In vivo, PirB -/- mice exhibited resistance to ANGPTL8-induced neuroinflammation and synaptic damage., Conclusion: Taken together, our findings reveal the role of ANGPTL8 in the pathogenesis of diabetes-associated cognitive dysfunction and identify the ANGPTL8-PirB signaling pathway as a potential target for the management of this condition., (© 2024. The Author(s).)

Background: The fruit ripening period is an important target trait in fruit tree crop breeding programs. Thus, citrus tree breeders seek to develop extreme early ripening cultivars that allow optimization of citrus maturation periods. In this study, we explored the regulatory network involved in fruit ripening in Citrus sinensis using the 'Newhall' navel orange variety and its early-ripening mutant, 'Gannanzao'. This research will provide a basis for further research on important signaling pathways, gene functions and variety breeding of Citrus sinensis related to fruit ripening period., Results: Physiological analyses suggested that early fruit ripening in 'Gannanzao' is regulated by early accumulation of abscisic acid (ABA), persistently high levels of jasmonic acid (JA), and higher sucrose content in the pericarp. Pericarp samples from 'Gannanzao' and 'Newhall' navel oranges were sampled for RNA sequencing analysis at 180, 200, and 220 days after flowering; 1430 differentially expressed genes (DEGs) were identified. Functional enrichment analysis indicated that these DEGs were mainly enriched in the plant hormone signal transduction and sugar metabolism pathways, as well as other pathways related to fruit ripening. Important DEGs associated with fruit ripening in 'Gannanzao' included genes involved in ABA and JA metabolism and signal transduction, as well as sugar metabolism. Weighted gene co-expression network analysis showed that the deep pink module had the strongest correlations with ABA content, JA content, and early ripening. Based on gene functionality and gene expression analyses of 37 genes in this module, two candidate hub genes and two ethylene response factor 13 (ERF13) genes (Cs&#95;ont&#95;5g000690 and Cs&#95;ont&#95;5g000700) were identified as key genes regulated by ABA and JA signaling. These findings will help to clarify the mechanisms that underlie early citrus fruit ripening and will lead to the development of excellent genetic resources for further breeding of extreme early-ripening varieties., Conclusions: Through analyses of the 'Newhall' navel orange cultivar and its early-ripening mutant 'Gannanzao', we identified genes involved in ABA and JA metabolism, signal transduction, and sugar metabolism that were related to fruit ripening. Among these, two ERF13 genes were inferred to be key genes in the regulation of fruit ripening. These findings provide insights into the genetic architecture related to early fruit ripening in C. sinensis., (© 2024. The Author(s).)

Background: Elevated blood glucose at hospital admission is frequently observed and has been associated with adverse outcomes in various patient populations. This meta-analysis sought to consolidate existing evidence to assess the association between elevated blood glucose at admission and clinical outcomes amongst pneumonia patients., Methods: We searched PubMed, Medline, Cochrane library, Web of Science (WoS), and Scopus databases for studies, published up to 31 August 2023, and reporting on the clinical outcomes and the blood glucose levels at admission. Data were extracted by two independent reviewers. Random-effects meta-analyses were used to pool odds ratios (ORs) with 95% confidence intervals (CI) for dichotomous outcomes and weighted mean differences (WMDs) for continuous outcomes., Results: A total of 23 studies with 34,000 participants were included. Elevated blood glucose at admission was significantly associated with increased short-term (pooled OR: 2.67; 95%CI: 1.73-4.12) and long-term mortality (pooled OR: 1.70; 95%CI: 1.20-2.42). Patients with raised glucose levels were more likely to require ICU admission (pooled OR: 1.86; 95%CI: 1.31-2.64). Trends also suggested increased risks for hospital readmission and mechanical ventilation, though these were not statistically significant. Elevated blood glucose was linked with approximately 0.72 days longer duration of hospital stay., Conclusion: Elevated blood glucose level at the time of hospital admission is associated with several adverse clinical outcomes, especially mortality, in patients with pneumonia. These findings underscore the importance of recognizing hyperglycemia as significant prognostic marker in pneumonia patients. Further research is needed to determine whether targeted interventions to control glucose levels can improve these outcomes., (© 2024. The Author(s).)

Background: N6-methyladenosine (m6A) regulates the progression of breast cancer (BC). We aimed to investigate the action and mechanism involved of methyltransferase-like protein 16 (METTL16) in BC growth and metastasis., Methods: RT-qPCR, immunoblotting, and IHC were performed to test the levels of gene expression. CCK-8, clone formation, wound healing, and transwell assays were applied to measure the cell proliferation, migration, and invasion. m6A RNA methylation and MeRIP assay were utilized to confirm the m6A level of total RNA and FBXO5 mRNA. RIP was utilized to ascertain the interaction between METTL16 and FBXO5 mRNA. The in vivo murine subcutaneous tumor and metastasis model were constructed to further confirm the action of METTL16., Results: METTL16 was overexpression in BC cells and tissues. Inhibition of METTL16 restrained the growth and metastasis of BC. Furthermore, the METTL16 level and FBXO5 level was positively correlated in BC tissues, and METTL16 aggrandized the stability of FBXO5 mRNA depending on the m6A modification. Overexpression of FBXO5 antagonized the restrained function of METTL16 knockdown on BC cells' proliferation, migration, invasion, and EMT., Conclusion: METTL16 boosts the mRNA stability of FBXO5 via m6A modification to facilitate the malignant action of BC in vitro and in vivo, offering new latent targets for cure of BC., (© 2024. The Author(s).)

Background: N 1 -Methyladenosine (m 1 A) is an abundant modification of transcripts regulating mRNA structure and translation efficiency. However, the characteristics and biological functions of mRNA m 1 A modification in adult hippocampal neurogenesis remain enigmatic., Results: We found that m 1 A demethylase Alkbh3 was dramatically enriched in neurons and neuronal genesis. Functionally, depletion of Alkbh3 in neural stem cells (NSCs) significantly decreased m 1 A modification, neuronal differentiation and proliferation coupling with increasing gliogenesis, whereas overexpressing Alkbh3 facilitated neuronal differentiation and proliferation. Mechanistically, the m 1 A demethylation of Mmp15 mRNA by Alkbh3 improved its RNA stability and translational efficacy, which promoted neurogenesis. Therapeutically, the silencing of Alkbh3 reduced hippocampal neurogenesis and impaired spatial memory in the adult mice., Conclusions: We reveal a novel function of m 1 A demethylation on Mmp15 mRNA in Alkbh3-mediated neurogenesis, which shed light on advancing Alkbh3 regulation of neurogenesis as a novel neurotherapeutic strategy., (© 2024. The Author(s).)

The fracture healing outcome is largely dependent on the quantities as well as osteogenic differentiation capacities of mesenchymal stem cells (MSCs) at the lesion site. Herein, macrophage membrane (MM)-reversibly cloaked nanocomplexes (NCs) are engineered for the lesion-targeted and hierarchical co-delivery of short stromal derived factor-1α peptide (sSDF-1α) and Ckip-1 small interfering RNA (Ckip-1 siRNA, siCkip-1) to promote bone repair by concurrently fostering recruitment and osteogenic differentiation of endogenous MSCs. To construct the NCs, a membrane-penetrating α-helical polypeptide first assembles with siCkip-1, and the cationic NCs are sequentially coated with catalase and an outer shell of sSDF-1α-anchored MM. Due to MM-assisted inflammation homing, intravenously injected NCs could efficiently accumulate at the fractured femur, where catalase decomposes the local hydrogen peroxide to generate oxygen bubbles that drives the shedding of sSDF-1α-anchored MM in the extracellular compartment. The exposed, cationic inner core thus enables robust trans-membrane delivery into MSCs to induce Ckip-1 silencing. Consequently, sSDF-1α-guided MSCs recruitment cooperates with siCkip-1-mediated osteogenic differentiation to facilitate bone formation and accelerate bone fracture healing. This study provides an enlightened strategy for the hierarchical co-delivery of macromolecular drugs into different cellular compartments, and it also renders a promising modality for the management of fracture healing., (© 2024. The Author(s).)

Background: To evaluate the incidence of metabolic syndrome (MetS) in patients with unilateral and bilateral staghorn calculi (SC) and evaluate the impact on the outcome of percutaneous nephrolithotomy (PCNL)., Methods: The clinical data of patients who underwent PCNL for the treatment of SC between 2019 and 2022 were retrospectively reviewed. SC was divided into unilateral and bilateral. The incidence of MetS was compared between the patients with unilateral SC and the patients with bilateral SC, and the impact on the outcome of PCNL was assessed., Results: A total of 1778 patients underwent PCNL between 2019 and 2022. After screening computed tomography, 379 patients were confirmed to have SC, finally, leaving 310 patients with follow-up and complete data to be included in the study. Eighty-four had bilateral SC and 226 had unilateral SC. The patients with bilateral SC had a significantly higher body mass index and higher rates of complete staghorn stones and metabolic syndrome. Higher body mass index, hypertension, diabetes mellitus, hyperlipidaemia, and MetS were present in 62.58%, 44.84%, 21.94%, 60.65% and 27.42% of all patients, respectively. The number of MetS components remained significantly associated with bilateral SC. Specifically, when the number of MetS components increases from 0 to 3-4, the likelihood of developing bilateral staghorn calculi increases by 21.967 times. Eighty-five patients with MetS( +) had a higher rate of overall complications (number (N)(%), 29 (34.12) vs.33 (14.46), P < 0.001) and a comparable stone-free rate to 225 MetS(-) patients. Multivariable analysis confirmed that hyperlipidaemia (P = 0.044, odds ratio [OR] = 1.991, 95% confidence interval [CI] 1.020-3.888) and MetS (P = 0.005, OR = 2.427, 95% CI 1.316-4.477) were independent risk factors for overall complications., Conclusions: MetS is correlated with the formation of bilateral SC and is the main predictor for complications of PCNL especially for low-grade complications (I-II)., (© 2024. The Author(s).)

Background: Dysfunction or deficiency of corneal epithelium results in vision impairment or blindness in severe cases. The rapid and effective regeneration of corneal epithelial cells relies on the limbal stem cells (LSCs). However, the molecular and functional responses of LSCs and their niche cells to injury remain elusive., Methods: Single-cell RNA sequencing was performed on corneal tissues from normal mice and corneal epithelium defect models. Bioinformatics analysis was performed to confirm the distinct characteristics and cell fates of LSCs. Knockdown of Creb5 and OSM treatment experiment were performed to determine their roles of in corneal epithelial wound healing., Results: Our data defined the molecular signatures of LSCs and reconstructed the pseudotime trajectory of corneal epithelial cells. Gene network analyses characterized transcriptional landmarks that potentially regulate LSC dynamics, and identified a transcription factor Creb5, that was expressed in LSCs and significantly upregulated after injury. Loss-of-function experiments revealed that silencing Creb5 delayed the corneal epithelial healing and LSC mobilization. Through cell-cell communication analysis, we identified 609 candidate regeneration-associated ligand-receptor interaction pairs between LSCs and distinct niche cells, and discovered a unique subset of Arg1 + macrophages infiltrated after injury, which were present as the source of Oncostatin M (OSM), an IL-6 family cytokine, that were demonstrated to effectively accelerate the corneal epithelial wound healing., Conclusions: This research provides a valuable single-cell resource and reference for the discovery of mechanisms and potential clinical interventions aimed at ocular surface reconstruction., (© 2024. The Author(s).)