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Hongxia Xin,1,2,* Shuoshuo Wei,1,3,* Hao Zheng,4,* Yanchao Qi,5,* Shuping Xu,6,* Bei Wang,2 Wangshu Jiang,7 Ning Deng,7,* Juan Chen1,2,* 1Department of Key Laboratory of Ningxia Stem Cell and Regenerative Medicine, Institute of Medical Sciences, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, People’s Republic of China; 2Department of Pulmonary and Critical Care Medicine, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, People’s Republic of China; 3Department of Pulmonary and Critical Care Medicine, Affiliated Yijishan Hospital, Wannan Medical College, Wuhu, Anhui, People’s Republic of China; 4Department of Pulmonary and Critical Care Medicine, Yanchi County People’s Hospital, Wuzhong, Ningxia, People’s Republic of China; 5Department of Pulmonary and Critical Care Medicine, Second People’s Hospital of Shizuishan, Shizuishan, Ningxia, People’s Republic of China; 6Department of Pulmonary and Critical Care Medicine II, Wuzhong People’s Hospital, WuZhong, Ningxia, People’s Republic of China; 7Ministry of Education Key Laboratory of Biomedical Engineering, College of Biomedical Engineering and Instrument Science, Zhejiang University, Hangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ning Deng, Ministry of Education Key Laboratory of Biomedical Engineering, College of Biomedical Engineering and Instrument Science, Zhejiang University, Hangzhou, 310058, People’s Republic of China, Email zju.dengning@gmail.com Juan Chen, Department of Pulmonary and Critical Care Medicine, General Hospital of Ningxia Medical University, Yongan Lane, Xingqing District, Yinchuan, Ningxia, 750004, People’s Republic of China, Email chenjuan7419@163.comBackground: Pulmonary rehabilitation (PR) is an effective intervention for people with chronic obstructive pulmonary disease (COPD). However, fewer than 5% of eligible individuals receive pulmonary rehabilitation, largely due to limited by the accessibility of rehabilitation and difficulties associated with travel and transport. Supervised home-based tele-rehabilitation (SHTR) is an alternative model to center-based pulmonary rehabilitation. We will determine whether supervised home-based tele-rehabilitation is non-inferior to center-based pulmonary rehabilitation.Methods: The participants will undergo an 8-week rehabilitation program. Pulmonary rehabilitation comprises four main modules: exercise training, education, nutritional support, and psychological and behavioral interventions. We mainly focus on the module of exercise training and education. The education module includes information on exercise training, nutrition, and psychology, which are presented in an educational booklet provided to each participant. Blinded assessors will evaluate the outcomes at baseline, post-intervention, and 6 months after the intervention. The primary outcome is the change in the 6-minute walking distance. Secondary outcomes will assess changes in the patients’ 1-minute sit-to-stand test, maximal inspiratory pressure (MIP), scales (CAT, mMRC, HAD), diaphragm ultrasound (TD, DE, DIF), changes in extrathoracic muscle volume and mass, completion rate of patient exercise prescriptions, occurrence of adverse events, as well as disease exacerbation and rehospitalization rates after rehabilitation and during the 6-month follow-up.Discussion: In order to improve the accessibility of pulmonary rehabilitation and patient-related outcomes, it is necessary to propose an alternative model of pulmonary rehabilitation. This trial will establish whether a supervised home-based tele-rehabilitation is not inferior to traditional center-based pulmonary rehabilitation.Trial Registration: Chinese Clinical Trial Registry ChiCTR2300076969. Registered on October 25, 2023. Keywords: COPD, tele-rehabilitation, protocol, randomized non-inferiority trial

Zhou Zhu,1– 3,* Huizi Gong,4,* Mingjuan Liu,1– 3 Hanlin Zhang,1,2 Leyan Yang,1,2 Xinyi Zhang,5 Heyi Zheng,1,2 Yanfeng Li,6 Mingli Li,7 Jun Li1,2 1Department of Dermatology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People’s Republic of China; 2State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People’s Republic of China; 3 4+4 Medical Doctor Program, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People’s Republic of China; 4Department of Dermatology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, People’s Republic of China; 5Departments of Internal Medicine and Cellular & Molecular Physiology, Yale School of Medicine, New Haven, CT, USA; 6Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People’s Republic of China; 7Department of Radiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Mingli Li, Department of Radiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan Wangfujing Dongcheng District, Beijing, 100730, People’s Republic of China, Email limingli@pumch.cn Jun Li, Department of Dermatology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan Wangfujing Dongcheng District, Beijing, 100730, People’s Republic of China, Email lijun35@hotmail.comBackground: Tabes dorsalis is a late manifestation of neurosyphilis, characterized by progressive ataxia, lightning pains, loss of proprioception, and urinary incontinence. The absence of a definitive diagnostic standard and the non-specific clinical manifestations have led to a significant rate of misdiagnoses.Methods: Hospitalized patients with tabes dorsalis at Peking Union Medical College Hospital between January 2010 and December 2023 were reviewed.Results: A total of 13 patients were included, with 10 males and 3 females. The median age was 50 years (range, 34– 64). The most frequent initial symptoms were limb numbness (30.8%) and lightning pains (30.8%). Eleven patients (84.6%) received misdiagnoses prior to the final diagnosis. The most frequently observed physical sign was positive Romberg’s sign (84.6%). Notably, Argyll Robertson pupil was presented in 7 subjects (53.8%). Serological tests revealed positive rapid plasma regain (RPR) and Treponema pallidum particle agglutination (TPPA) for all patients. All CSF samples were TPPA-reactive. Intramedullary hyperintensity on T2-weighted imaging of spinal MRI was found in 5 patients (38.5%). All patients received anti-syphilitic treatment, with effective treatment recorded in five cases.Conclusion: This study underscores the importance of neurological symptoms and signs in diagnosing tabes dorsalis. Individuals with progressive ataxia and positive Romberg’s sign should be closely monitored for potential neurosyphilis. Integrating clinical features, laboratory tests, and neuroimaging could reduce misdiagnosis and expedite the initiation of anti-syphilitic therapy.Keywords: tabes dorsalis, neurosyphilis, ataxia, cerebrospinal fluid

Jiping Zhang,* Xianan Sang,* Yichao Yuan, Jiawei Shen, Yuanyuan Fang, Minjing Qin, Hangsheng Zheng, Zhihong Zhu College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, 311402, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hangsheng Zheng; Zhihong Zhu, College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China, Email hs-zheng@163.com; zzhjanny@163.comBackground: Anthraquinone drugs are widely used in the treatment of tumors. However, multidrug resistance and severe cardiac toxicity limit its use, which have led to the discovery of new analogues. In this paper, 4-Deoxy-ϵ-pyrromycinone (4-Deo), belonging to anthraquinone compounds, was first been studied with the anti-tumor effects and the safety in vitro and in vivo as a new anti-tumor drug or lead compound.Methods: The quantitative analysis of 4-Deo was established by UV methodology. The anti-cancer effect of 4-Deo in vitro was evaluated by cytotoxicity experiments of H22, HepG2 and Caco2, and the anti-cancer mechanism was explored by cell apoptosis and cycle. The tumor-bearing mouse model was established by subcutaneous inoculation of H22 cells to evaluate the anti-tumor effect of 4-Deo in vivo. The safety of 4-Deo was verified by the in vitro safety experiments of healthy cells and the in vivo safety experiments of H22 tumor-bearing mice. Tumor tissue sections were labeled with CRT, HMGB1, IL-6 and CD115 to explore the preliminary anti-cancer mechanism by immunohistochemistry.Results: In vitro experiments demonstrated that 4-Deo could inhibit the growth of H22 by inducing cell necrosis and blocking cells in S phase, and 4-Deo has less damage to healthy cells. In vivo experiments showed that 4-Deo increased the positive area of CRT and HMGB1, which may inhibit tumor growth by triggering immunogenic cell death (ICD). In addition, 4-Deo reduced the positive area of CSF1R, and the anti-tumor effect may be achieved by blocking the transformation of tumor-associated macrophages (TAMs) to M2 phenotype.Conclusion: In summary, this paper demonstrated the promise of 4-Deo for cancer treatment in vitro and in vivo. This paper lays the foundation for the study of 4-Deo, which is beneficial for the further development anti-tumor drugs based on the lead compound of 4-Deo. Keywords: 4-deoxy-ϵ-pyrromycinone, lead compound, drug safety, drug efficacy, anti-tumor drug

Yuelin Zhang, Xue Lin, Xinxin Chen, Weixiang Fang, Kailing Yu, Wenting Gu, Yinghui Wei, Hangsheng Zheng, Jigang Piao, Fanzhu Li School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, People’s Republic of ChinaCorrespondence: Fanzhu Li; Ji-Gang Piao, Email lifanzhu@zcmu.edu.cn; jgpiao@zcmu.edu.cnAbstract: Mesoporous silica nanoparticles (MSNs) have attracted extensive attention as drug delivery systems because of their unique meso-structural features (high specific surface area, large pore volume, and tunable pore structure), easily modified surface, high drug-loading capacity, and sustained-release profiles. However, the enduring and non-specific enrichment of MSNs in healthy tissues may lead to toxicity due to their slow degradability and hinder their clinical application. The emergence of degradable MSNs provided a solution to this problem. The understanding of strategies to regulate degradation and clearance of these MSNs for promoting clinical trials and expanding their biological applications is essential. Here, a diverse variety of degradable MSNs regarding considerations of physiochemical properties and doping strategies of degradation, the biodistribution of MSNs in vivo, internal clearance mechanism, and adjusting physical parameters of clearance are highlighted. Finally, an overview of these degradable and clearable MSNs strategies for biosafety is provided along with an outlook of the encountered challenges. Keywords: mesoporous silica nanoparticles, degradation, clearance, biodistribution, strategies

Yan Hu,1 Min Yu,1 Guoqing You,1 Jun Fan,1 Huiwen Zheng2 1Tuberculosis Reference Laboratory, Chongqing Tuberculosis Control Institute, Chongqing, People’s Republic of China; 2Laboratory of Respiratory Diseases, Beijing Key Laboratory of Pediatric Respiratory Infection Diseases, Beijing Pediatric Research Institute, Beijing Children’s Hospital, Capital Medical University, Key Laboratory of Major Diseases in Children, Ministry of Education, National Clinical Research Center for Respiratory Diseases, National Center for Children’s Health, Beijing, People’s Republic of ChinaCorrespondence: Jun Fan; Huiwen Zheng, Email zjwegg@163.com; hanhui820@126.comObjective: We compared the MeltPro assay to whole-genome sequencing (WGS) to investigate the molecular characterization of second-line injectable drug (SLID) resistance in multidrug-resistant tuberculosis (MDR-TB) isolates in Chongqing, China.Methods: A total of 122 MDR-TB patient isolates were collected between March 2019 and June 2020 from Chongqing Municipality, China. Conventional drug-susceptibility testing was performed using the proportion method, followed to generate minimum inhibitory concentrations (MICs) of SLIDs determined by microplate alamarblue assay. All strains were subjected to both MeltPro and WGS assays.Results: Among 122 MDR-TB isolates, 30 (24.6%), 22 (18.0%), and 14 (11.5%) were resistant to kanamycin (KM), amikacin (AM), and capreomycin (CM), respectively. Of the 31 SLID-resistant isolates, 24 (77.4%, 24/31) isolates harbored mutations in the rrs gene, with the most prevalent mutations in rrs A1401G (22/24, 91.7%). Mutation in rrs A1401G was associated with high levels of resistance to KM (MIC, ≥ 40 μg/mL) and AM (MIC, ≥ 64 μg/mL), but disparities in CM-resistance levels. Using phenotypic drug-susceptibility testing as gold standard, we found that the overall sensitivity of MeltPro and WGS was 87.1% and 90.32% and specificity 100% and 97.8%, respectively. Seven isolates had discordant results between phenotypic and genotypic resistance of SLIDs.Conclusion: MeltPro is a promising diagnostic tool for accurate identification of SLID-resistant MTB isolates with mutations in the rrs and eis genes. There was a disparity between MeltPro with WGS results in the proportion of heterogeneous drug-resistant bacteria with rrs mutation and limited probes. Resistance mechanisms other than genetic mutations will affect the consistency of MeltPro and WGS with phenotypic drug-susceptibility results.Keywords: MDR, MeltPro, resistance, genotype

Hua Zheng,1 Changqing Li,1 Lirong Zhang,2 Tailin Wang,3 Zengliang Cai,4 Mingxing Lei5,6 1College of Physical Education and Health Science, Chongqing Normal University, Chongqing, 401331, People’s Republic of China; 2Department of Physical Education, Xiamen University of Technology, Xiamen, Fujian, 361024, People’s Republic of China; 3School of Physical Education, North University of China, Taiyuan, Shanxi, 030051, People’s Republic of China; 4Department of Physical Education, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People’s Republic of China; 5Chinese PLA General School, Beijing, 100853, People’s Republic of China; 6Chinese PLA General Hospital, Beijing, 100853, People’s Republic of ChinaCorrespondence: Mingxing Lei, Department of Orthopedic Surgery, Chinese PLA General Hospital, 28 Fuxing Road, Haidian District, Beijing, 100039, People’s Republic of China, Tel +8618811772189, Email leimingxing@301hospital.com.cn Zengliang Cai, Department of Physical Education, Shanghai University of Traditional Chinese Medicine, No. 1200 Cailun Road, Shanghai, 201203, People’s Republic of China, Email caizengliang@shutcm.edu.cnBackground: University students are a vulnerable population prone to mental health challenges. This study aimed to investigate depression and its associated factors among university students in terms of demographics, eating habits, and exercises.Methods: A total of 2891 university students from three universities participated in this study between January 2024 and February 2024. An online survey questionnaire was distributed using a snow-ball strategy. The survey collected demographic, lifestyle, and psychological data, including depression and anxiety scores using the PHQ-9 and GAD-7 screening tools. Subgroup analysis was conducted according to sport frequency and sport type using Chi-square test for qualitative data and t-test for quantitative data. Multiple linear regression analysis was performed to identify risk factors for depression.Results: A total of 44.2% and 39.5% of the participants reported symptoms of depression and anxiety, respectively. Significant differences were observed in various characteristics across different sport frequency groups, with participants with higher sport frequency tending to have less depression (P< 0.001) and anxiety (P< 0.001) symptoms. As the frequency of weekly exercise increased, anxiety and depression scores gradually decreased. The mean PHQ-9 and GAD-7 scores were highest in the group with no sports and lowest in the group with a sport frequency of 3– 4 times per week (P< 0.001). Additionally, once exercise frequency reached 5 times per week or more, anxiety and depression scores no longer decreased. Subgroup analysis based on sport type revealed that participants engaging in specific sports, such as basketball, tennis, dance, and running, had lower depression (P< 0.001) and anxiety (P< 0.001) scores compared to the overall average. Based on multiple linear regression analysis, married status (P=0.036), enjoying barbecue food (P< 0.001), prolonged sedentary time (P=0.001), experiencing stress events (P< 0.001), and electronic device usage time (P< 0.001) were positively associated with depression scores, while loving eating vegetables (P=0.007), a relatively longer sport time (P=0.005), a higher exercise frequency (P=0.064), and no chronic disease (P< 0.001) were negatively associated with depression scores.Conclusion: This study highlights the importance of a healthy lifestyle, including regular exercise, limited exposure to electronic screens, and a balanced diet, in preventing and mitigating depression among university students. This study also suggests that exercising 3– 4 times a week is associated with the lowest levels of anxiety and depression. Activities such as basketball, tennis, dance, and running are effective in alleviating these mental health issues through regular exercise.Keywords: depression, eating habits, sports, university students, cross-sectional study

Jian Zhou,1,2,&ast; Housheng Zheng,1,&ast; Huiru Zhang,1 Wenqiang Yu,1 Baoer Li,1 Liang Ye,1 Lu Wang1 1Hyperbaric Oxygen Department, International Cancer Center, Shenzhen University General Hospital, Shenzhen University Medical School, Shenzhen, 518055, People’s Republic of China; 2Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen, 518060, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Lu Wang, Hyperbaric oxygen department, Shenzhen University General Hospital, Shenzhen University Medical School, Shenzhen, 518055, People’s Republic of China, Tel +86-0755-21839715, Email luwangszu@163.com Liang Ye, International Cancer Center, Shenzhen University Medical School, Shenzhen, 518055, People’s Republic of China, Tel +86-0755-26631420, Fax +86-0755-86671943, Email liangyeszu@163.comObjective: MCM5 is a DNA licensing factor involved in cell proliferation and has been previously established as an excellent biomarker in a number of malignancies. Nevertheless, the role of MCM5 in GBM has not been fully clarified. The present study aimed to investigate the potential roles of MCM5 in the treatment of GBM and to elucidate its underlying mechanism, which is beneficial for developing new therapeutic strategies and predicting prognosis.Methods: Firstly, we obtained transcriptomic and proteomic data from the TCGA and CPTAC databases on glioma patients. Employing the DeSeq2 R package, we then identified genes with joint differential expression in GBM tissues subjected to chemotherapy. To develop a prognostic risk score model, we performed univariate and multivariate Cox regression analyses. In vitro knockdown and overexpression of MCM5 were used to further investigate the biological functions of GBM cells. Additionally, we also delved into the upstream regulation of MCM5, revealing associations with several transcription factors. Finally, we investigated differences in immune cell infiltration and drug sensitivity across diverse risk groups identified in the prognostic risk model.Results: In this study, the chemotherapy-treated GBM samples exhibited consistent alterations in 46 upregulated and 94 downregulated genes at both the mRNA and protein levels. Notably, MCM5 emerged as a gene with prognostic significance as well as potential therapeutic relevance. In vitro experiments subsequently validated the role of increased MCM5 expression in promoting GBM cell proliferation and resistance to TMZ. Correlations with transcription factors such as CREB1, CTCF, NFYB, NRF1, PBX1, TEAD1, and USF1 were discovered during upstream regulatory analysis, enriching our understanding of MCM5 regulatory mechanisms. The study additionally delves into immune cell infiltration and drug sensitivity, providing valuable insights for personalized treatment approaches.Conclusion: This study identifies MCM5 as a key player in GBM, demonstrating its prognostic significance and potential therapeutic relevance by elucidating its role in promoting cell proliferation and resistance to chemotherapy.Keywords: glioblastoma, minichromosome maintenance protein 5, chemotherapeutic drug resistance

Yiyang Gong,1,2,&ast; Minqin Zhou,2,&ast; Yanting Zhu,2,&ast; Jingying Pan,2 Xuanrui Zhou,2 Yike Jiang,2 Hong Zeng,2 Hao Zheng,2 Xitong Geng,2 Da Huang1 1Department of Thyroid Surgery; Second Affiliated Hospital of Nanchang University, Nanchang, People’s Republic of China; 2Second College of Clinical Medicine, Nanchang University, Nanchang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Da Huang, Department of Thyroid Surgery, Second Affiliated Hospital of Nanchang University, 1 Minde Road, Nanchang, Jiangxi Province, 330000, People’s Republic of China, Tel +13576113993, Email danmo0904@163.comPurpose: Hepatocellular carcinoma is the most common primary liver cancer, with poor prognosis. Complex immune microenvironment of the liver is linked to the development of HCC. PVALB is a calcium-binding protein which has been described as a cancer suppressor gene in thyroid cancer and glioma. Nevertheless, the role of PVALB in HCC is unknown.Materials and Methods: We obtained data from TCGA and GSE54236 datasets. MCP-counter, WGCNA and LASSO model were applied to identify PVALB. With UALCAN, MethSurv, and other websites, we probed the expression, methylation and survival of PVALB. LinkedOmics and GSEA were adopted for functional analysis, while TIMER, TISIDB, Kaplan-Meier plotter, TIDE databases were utilized to evaluate the relevance of PVALB to the tumor immune microenvironment and predict immunotherapy efficacy. TargetScan, DIANA, LncRNASNP2 databases and relevant experiments were employed to construct ceRNA network. Finally, molecular docking and drug sensitivity of PVALB were characterized by GeneMANIA, CTD, and so on.Results: PVALB was recognized as a gene associated with HCC and NK cell. Its expression was down-regulated in HCC tissue, which lead to adverse prognosis. Besides, the hypomethylation of PVALB was related to its reduced expression. Notably, PVALB was tightly linked to immune, and its reduced expression attenuated the anticancer effect of NK cells via the Fas/FasL pathway, leading to a adverse outcome. The lnc-YY1AP1-3/hsa-miR-6735-5p/PVALB axis may regulate the PVALB expression. Finally, we found immunotherapy might be a viable treatment option.Conclusion: In a word, PVALB is a prognostic indicator, whose low expression facilitates HCC progression by impacting NK cell infiltration.Keywords: PVALB, hepatocellular carcinoma, immune, ceRNA, bioinformatics, prognostic factor

Nan Jiang,1,&ast; Wei Jin,2,&ast; Zhenghui Fu,3,&ast; He Cao,1 Hong Zheng,3 Quqing Wang,1 Qiongting Zhang,3 Kang Ju,3 Jiwei Wang1 1Key Laboratory of Health Technology Assessment of Ministry of Health, School of Public Health, Fudan University, Shanghai, People’s Republic of China; 2Department of Patriotic Public Health and Health Promotion instruction, Shanghai Municipal Center for Health Promotion, Shanghai, People’s Republic of China; 3Shanghai Changning Mental Health Center (Affiliated to East China Normal University), Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jiwei Wang, Key Laboratory of Health Technology Assessment of Ministry of Health, School of Public Health, Fudan University, Shanghai, People’s Republic of China, Email jiweiwang@fudan.edu.cn Kang Ju, Shanghai Changning Mental Health Center (Affiliated to East China Normal University), Shanghai, People’s Republic of China, Email jukang2009@163.comPurpose: This study aims to explore the serial mediating effect of stigma and depression on the association between social support and medication adherence.Patients and Methods: A cross-sectional survey was undertaken in the Changning District of Shanghai using a five-part questionnaire from August to December 2023. A convenient sampling method was employed, and 35 patients with schizophrenia were invited from each of the 9 streets in Changning District to participate in the survey, resulting in a total of 305 valid questionnaires collected. The questionnaire measured social support, stigma, depression, medication adherence, and demographic characteristics. Data analysis involved descriptive statistics, independent samples t-tests, ANOVA, Pearson correlation analysis, and the bootstrap method.Results: There was a direct and significantly positive association between social support and medication adherence (β = 0.69, p < 0.001). Moreover, increased levels of stigma (β = - 0.45, p = 0.013) and depression (β = - 0.09, p = 0.017) were both associated with a decline in medication adherence. Bootstrapping analysis revealed that the association between social support and medication adherence operated indirectly through stigma (β = 0.11, 95% CI: 0.03, 0.18). Additionally, social support was indirectly associated with medication adherence through depression (β = 0.15, 95% CI: 0.04, 0.30). Further analysis indicated that social support had an indirect association with medication adherence through both stigma and depression (β = 0.04, 95% CI: 0.01, 0.07).Conclusion: Stigma and depression serially mediate the association between social support and medication adherence among patients with schizophrenia. This serial multiple mediation model underscores the importance of integrating social support interventions with psychological interventions aimed at reducing stigma and depression, thereby effectively enhancing medication adherence in patients with schizophrenia.Keywords: social support, stigma, depression, medication adherence, schizophrenia

Jiewei Huang,1,2 Jiajing Zhuang,2,3 Huaxian Zheng,4 Ling Yao,5,6 Qingquan Chen,7,8 Jiaqi Wang,1,2 Chunmei Fan1 1The Clinical Laboratory Center of the Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, 362018, People’s Republic of China; 2The Graduate School of Fujian Medical University, Fuzhou, Fujian Province, 350108, People’s Republic of China; 3Department of Ultrasound, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, 350001, People’s Republic of China; 4The School of Clinical Medicine, Fujian Medical University, Fuzhou, Fujian Province, 350108, People’s Republic of China; 5Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, 350000, People’s Republic of China; 6Department of Nephrology, Rheumatology and Immunology, Fujian Children’s Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, 350014, People’s Republic of China; 7The Sleep Disorder Medicine Center of the Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, 362018, People’s Republic of China; 8The School of Public Health, Fujian Medical University, Fuzhou, Fujian Province, 350108, People’s Republic of ChinaCorrespondence: Chunmei Fan, The Clinical Laboratory Center of the Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, 362018, People’s Republic of China, Tel +86 15906069575, Email fanchunmei9575@163.comObjective: Obstructive sleep apnea (OSA) is a common and potentially fatal sleep disorder. The purpose of this study was to construct an objective and easy-to-promote model based on common clinical biochemical indicators and demographic data for OSA screening.Methods: The study collected the clinical data of patients who were referred to the Sleep Medicine Center of the Second Affiliated Hospital of Fujian Medical University from December 1, 2020, to July 31, 2023, including data for demographics, polysomnography (PSG), and 30 biochemical indicators. Univariate and multivariate analyses were performed to compare the differences between groups, and the Boruta method was used to analyze the importance of the predictors. We selected and compared 10 predictors using 4 machine learning algorithms which were “Gaussian Naive Bayes (GNB)”, “Support Vector Machine (SVM)”, “K Neighbors Classifier (KNN)”, and “Logistic Regression (LR)”. Finally, the optimal algorithm was selected to construct the final prediction model.Results: Among all the predictors of OSA, body mass index (BMI) showed the best predictive efficacy with an area under the receiver operating characteristic curve (AUC) = 0.699; among the predictors of biochemical indicators, triglyceride-glucose (TyG) index represented the best predictive performance (AUC = 0.656). The LR algorithm outperformed the 4 established machine learning (ML) algorithms, with an AUC (F1 score) of 0.794 (0.841), 0.777 (0.827), and 0.732 (0.788) in the training, validation, and testing cohorts, respectively.Conclusion: We have constructed an efficient OSA screening tool. The introduction of biochemical indicators in ML-based prediction models can provide a reference for clinicians in determining whether patients with suspected OSA need PSG. Keywords: biochemical indicators, obstructive sleep apnea, machine learning, prediction model, triglyceride-glucose index

Jiaxin Zhao,1 Cheng Wang,1 Liang Zhao,1 Huiying Zhou,1 Rui Wu,1 Tao Zhang,1 Jiawei Ding,1 Junjie Zhou,2 Huilin Zheng,3 Lei Zhang,3 Tianci Kong,3 Jie Zhou,4 Zhenhua Hu1,4 1Department of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Fourth Affiliated Hospital, School of Medicine, Zhejiang University, Yiwu, Zhejiang Province, People’s Republic of China; 2Department of Radiology, Fourth Affiliated Hospital, School of Medicine, Zhejiang University, Yiwu, Zhejiang Province, People’s Republic of China; 3Zhejiang Provincial Collaborative Innovation Center of Agricultural Biological Resource Biochemical Manufacturing, School of Biological and Chemical Engineering, Zhejiang University of Science and Technology, Hangzhou, Zhejiang Province, People’s Republic of China; 4Department of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, People’s Republic of ChinaCorrespondence: Zhenhua Hu, Department of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Fourth Affiliated Hospital, School of Medicine, Zhejiang University, Yiwu, Zhejiang Province, People’s Republic of China, Tel/Fax +86-570-89935878, Email huzhenh@zju.edu.cn Jie Zhou, Department of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, People’s Republic of China, Tel +86-13429661721, Email jzhou329@zju.edu.cnPurpose: Nonsense-mediated RNA decay (NMD), a surveillance pathway for selective degradation of aberrant mRNAs, is associated with cancer progression. Its potential as a predictor for aggressive hepatocellular carcinoma (HCC) is unclear. Here, we present an innovative NMD risk model for predicting HCC prognosis.Methods: The Cancer Genome Atlas (TCGA) data of 374 liver HCC (LIHC) and 50 normal liver samples were extracted. A risk model based on NMD-related genes was developed through least absolute shrinkage and selection operator Cox (LASSO-Cox) regression of the LIHC-TCGA data. Prognostic validation was done using GSE54236, GSE116174, and GSE76427 data. Univariate and multivariate Cox regression analyses were conducted to assess the prognostic value of the model. We also constructed nomograms for survival prediction. Tumor immune infiltration was evaluated using the CIBERSORT algorithm, and the tumor cell phenotype was assessed. Finally, mouse experiments verified UPF3B knockdown effects on HCC tumor characteristics.Results: We developed a risk model based on four NMD-related genes (PABPC1, RPL8, SMG5, and UPF3B) and validated it using GSE54236, GSE116174, and GSE76427 data. The model effectively distinguished high- and low-risk groups corresponding to unfavorable and favorable HCC outcomes. Its prognostic prediction accuracy was confirmed through time-dependent ROC analysis, and clinical-use nomograms with calibration curves were developed. Single-cell RNA sequencing results indicated significantly higher expression of SMG5 and UPF3B in tumor cells. Knockdown of SMG5 and UPF3B inhibited HCC cell proliferation, invasion, and migration, while affecting cell-cycle progression and apoptosis. In vivo, UPF3B knockdown delayed tumor growth and increased immune cell infiltration.Conclusion: Our NMD-related gene-based risk model can help identify therapeutic targets and biomarkers for HCC. Additionally, it assists clinicians in predicting the prognosis of HCC patients.Keywords: nonsense-mediated RNA decay, hepatocellular carcinoma, biomarker, LASSO, survival, tumor immunity

Meihui Li,1,2 Haiyan Zheng,3 Jae Chul Koh,4 Ghee Young Choe,5,6 Eun Joo Choi,1,2 Francis Sahngun Nahm,1,2 Pyung Bok Lee1,2 1Department of Anesthesiology and Pain Medicine, Seoul National University College of Medicine, Seoul, Korea; 2Department of Anesthesiology and Pain Medicine, Seoul National University Bundang Hospital, Seongnam, Korea; 3Department of Anesthesiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 4Department of Anesthesiology and Pain Medicine, Korea University College of Medicine, Seoul, Korea; 5Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Korea; 6Department of Pathology, Seoul National University College of Medicine, Seoul, KoreaCorrespondence: Pyung Bok Lee, Email painfree@snu.ac.krObjective: To create a deep learning (DL) model that can accurately detect and classify three distinct types of rat dorsal root ganglion neurons: normal, segmental chromatolysis, and central chromatolysis. The DL model has the potential to improve the efficiency and precision of neuron classification in research related to spinal injuries and diseases.Methods: H&E slide images were divided into an internal training set (80%) and a test set (20%). The training dataset was labeled by two pathologists using pre-defined grades. Using this dataset, a two-component DL model was developed with the first component being a convolutional neural network (CNN) that was trained to detect the region of interest (ROI) and the second component being another CNN used for classification.Results: A total of 240 lumbar dorsal root ganglion (DRG) pathology slide images from rats were analyzed. The internal testing results showed an accuracy of 93.13%, and the external dataset testing demonstrated an accuracy of 93.44%.Conclusion: The DL model demonstrated a level of agreement comparable to that of pathologists in detecting and classifying normal and segmental chromatolysis neurons, although its agreement was slightly lower for central chromatolysis neurons. Significance: DL in improving the accuracy and efficiency of pathological analysis suggests that it may have a role in enhancing medical decision-making.Keywords: deep learning, dorsal root ganglion, chromatolysis, automated detection and spinal stenosis

The meltwater streams of the McMurdo Dry Valleys are hot spots of biological diversity in the climate-sensitive polar desert landscape. Microbial mats, largely comprised of cyanobacteria, dominate the streams which flow for a brief window of time (~10 weeks) over the austral summer. These communities, critical to nutrient and carbon cycling, display previously uncharacterized patterns of rapid destabilization and recovery upon exposure to variable and physiologically detrimental conditions. Here, we characterize changes in biodiversity, transcriptional responses and activity of microbial mats in response to hydrological disturbance over spatiotemporal gradients. While diverse metabolic strategies persist between marginal mats and main channel mats, data collected from 4 time points during the austral summer revealed a homogenization of the mat communities during the mid-season peak meltwater flow, directly influencing the biogeochemical roles of this stream ecosystem. Gene expression pattern analyses identified strong functional sensitivities of nitrogen-fixing marginal mats to changes in hydrological activities. Stress response markers detailed the environmental challenges of each microhabitat and the molecular mechanisms underpinning survival in a polar desert ecosystem at the forefront of climate change. At mid and end points in the flow cycle, mobile genetic elements were upregulated across all mat types indicating high degrees of genome evolvability and transcriptional synchronies. Additionally, we identified novel antifreeze activity in the stream microbial mats indicating the presence of ice-binding proteins (IBPs). Cumulatively, these data provide a new view of active intra-stream diversity, biotic interactions and alterations in ecosystem function over a high-flow hydrological regime.

Lirong Zhang,1 Shaocong Zhao,1 Zhongbing Yang,2 Hua Zheng,3 Mingxing Lei4,5 1Department of Physical Education, Xiamen University of Technology, Xiamen, Fujian, 361024, People’s Republic of China; 2School of Physical Education, Guizhou Normal University, Guizhou, 550025, People’s Republic of China; 3College of Physical Education and Health Sciences, Chongqing Normal University, Chongqing, 401331, People’s Republic of China; 4National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation, Beijing, 100039, People’s Republic of China; 5Department of Orthopedic Surgery, Chinese PLA General Hospital, Beijing, 100039, People’s Republic of ChinaCorrespondence: Hua Zheng, College of Physical Education and Health Sciences, Chongqing Normal University, No. 37, Middle Road, University Town, Shapingba District, Chongqing, 401331, People’s Republic of China, Tel +86+15923028254, Email 20130296@cqnu.edu.cn Mingxing Lei, Department of Orthopedic Surgery, Chinese PLA General Hospital, Beijing, 100039, People’s Republic of China, Tel +86+18811772189, Email leimingxing@301hospital.com.cnBackground: Sleep problems are prevalent among university students, yet there is a lack of effective models to assess the risk of sleep disturbance. Artificial intelligence (AI) provides an opportunity to develop a platform for evaluating the risk. This study aims to develop and validate an AI platform to stratify the risk of experiencing sleep disturbance for university students.Methods: A total of 2243 university students were included, with 1882 students from five universities comprising the model derivation group and 361 students from two additional universities forming the external validation group. Six machine learning techniques, including extreme gradient boosting machine (eXGBM), decision tree (DT), k-nearest neighbor (KNN), random forest (RF), neural network (NN), and support vector machine (SVM), were employed to train models using the same set of features. The models’ prediction performance was assessed based on discrimination and calibration, and feature importance was determined using Shapley Additive exPlanations (SHAP) analysis.Results: The prevalence of sleep disturbance was 44.69% in the model derivation group and 49.58% in the external validation group. Among the developed models, eXGBM exhibited superior performance, surpassing other models in metrics such as area under the curve (0.779, 95% CI: 0.728– 0.830), accuracy (0.710), precision (0.737), F1 score (0.692), Brier score (0.193), and log loss (0.569). Calibration and decision curve analyses demonstrated favorable calibration ability and clinical net benefits, respectively. SHAP analysis identified five key features: stress score, severity of depression, vegetable consumption, age, and sedentary time. The AI platform was made available online at https://sleepdisturbancestudents-xakgzwectsw85cagdgkax9.streamlit.app/, enabling users to calculate individualized risk of sleep disturbance.Conclusion: Sleep disturbance is prevalent among university students. This study presents an AI model capable of identifying students at high risk for sleep disturbance. The AI platform offers a valuable resource to guide interventions and improve sleep outcomes for university students.Keywords: university students, sleep disturbance, machine learning, artificial intelligence, feature importance

Sheng Tian,1,2 Heqing Zheng,1,2 Wei Wu,1,2,&ast; Lanxiang Wu1,2,&ast; 1Department of Neurology, the Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, People’s Republic of China; 2Institute of Neuroscience, Nanchang University, Nanchang, 330006, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wei Wu; Lanxiang Wu, Email 13807038803@163.com; 1127370500@qq.comPurpose: Previous studies have shown that pyroptosis plays a vital role in the progress of neuropathic pain (NP), but the molecular mechanisms have not been fully elucidated. The aim of this study was to identify crucial pyroptosis-related genes (PRGs) in NP.Methods: We identified pyroptosis-related differentially expressed genes (PRDEGs) in NP by machine learning analysis of the GSE24982 and GSE60670 datasets. Furthermore, these PRDEGs were subjected to Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, Gene Set Enrichment Analysis (GSEA) and Friends analysis, respectively. Meanwhile, receiver operator characteristic (ROC) analysis was performed to assess the diagnostic value of PRDEGs in NP. Finally, we performed immune infiltration analysis of key PRDEGs using CIBERSORTR R package.Results: We found that 5 PRDEGs by least absolute shrinkage and selection operator (LASSO) regression and random forest and verified by RT-qPCR. GO, KEGG and GSEA revealed that these PRDEGs were mainly enriched in regulation of neuron death, IL-4 signaling, IL-23 pathway, and NF-κB pathway. ROC analysis revealed that most of the PRDEGs performed well in diagnosing NP. We also revealed transcription factors, miRNA regulatory networks and drug interaction networks of PRDEGs. For immune infiltration analysis, PRDEGs were mainly correlated with dendritic cells, monocytes and follicular T helper cells, suggested that it might be involved in the regulation of neuroimmune-related signaling.Conclusion: A total of five PRDEGs were can be employed as NP biomarkers, particularly Tlr4, Il1b and Casp8, and provide additional evidence for a vital role of pyroptosis in NP.Keywords: pyroptosis, machine learning, neuropathic pain, neuroinflammation, bioinformatic analysis

Xiaotian Ji,1 Shuhui Wu,1 Dan Zhao,1 Qi Bai,1 Yun Wang,1 Ke Gong,2 Huie Zheng,1 Mingfang Zhu1 1Department of Dermatology, the Second Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, People’s Republic of China; 2Department of Traditional Chinese Medicine, Cangzhou Central Hospital, Cangzhou, People’s Republic of ChinaCorrespondence: Mingfang Zhu, Department of Dermatology, the Second Affiliated Hospital of Hunan University of Chinese Medicine, 233 Cai E North Road, Kaifu District, Changsha, People’s Republic of China, Tel +86-13907317358, Fax +86-731-84917727, Email 320492@hnucm.edu.cnBackground: The association between acne and gut microbiota has garnered considerable attention; nevertheless, given the substantial diversity within gut microbiota, the precise cause-and-effect relationship linking specific microbial species to acne remains elusive. To address this gap in knowledge, our study utilized Mendelian randomization analysis to elucidate a potential causal link between gut microbiota composition and acne development while also investigating underlying mechanisms involving microbial factors associated with metabolic disorders.Materials and Methods: The independent single nucleotide polymorphisms (SNPs) closely associated with 196 gut microbiota samples (N=18340) were selected as variable tools. The relationship between gut microbiota and acne (N=212438) was analyzed using the Twosample package in R4.3.1, employing various methods including inverse variance weighting (IVW), weighted median, MR-Egger, Simple-mode, and Weighted-mode. To ensure the stability of the estimates, a series of sensitivity analyses were conducted, such as Cochran’s Q-test, MR-Egger intercept analysis, leave-one-out analysis, and funnel plots. Additionally, the impact of each instrumental variable was calculated.Results: In the Mendelian randomization analysis, we identified twelve microbial taxa potentially associated with acne: family.Bacteroidaceae, family.Clostridiaceae1, genus.Allisonella, genus.Bacteroides, genus.Butyricimonas, genus.Clostridiumsensustricto1, and genus.Coprococcus3. These seven bacterial groups were found to be potential risk factors for acne. Conversely, family.Lactobacillaceae and genus.Ruminococcustorquesgroup along with genus.CandidatusSoleaferrea, genus.Fusicatenibacter, family.Lactobacillaceae, and genus.Lactobacillus exhibited a protective effect against acne. Furthermore, our investigation revealed that some of these microbial taxa have been implicated in metabolic diseases through previous studies. Importantly though, no causal relationship was observed in the reverse Mendelian randomization analysis.Keywords: acne, gut microbiota, Mendelian randomization, metabolic disease

Yunzhi Xiang,&ast; Guanghui Wang,&ast; Baoliang Liu, Haotian Zheng, Qiang Liu, Guoyuan Ma, Jiajun Du Institute of Oncology, Shandong Provincial Hospital, Shandong University, Jinan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jiajun Du, Shandong Provincial Hospital, No. 324 Jingwu Road, Huaiyin District, Jinan, 250000, People’s Republic of China, Email dujiajun@sdu.edu.cnBackground: In recent years, the immunotherapy of lung adenocarcinoma has developed rapidly, but the good therapeutic effect only exists in some patients, and most of the current predictors cannot predict it very well. Tumor-infiltrating macrophages have been reported to play a crucial role in lung adenocarcinoma (LUAD). Thus, we want to build novel molecular markers based on macrophages.Methods: By non-negative matrix factorization (NMF) algorithm and Cox regression analysis, we constructed macrophage-related subtypes of LUAD patients and built a novel gene signature consisting of 12 differentially expressed genes between two subtypes. The gene signature was further validated in Gene-Expression Omnibus (GEO) datasets. Its predictive effect on prognosis and immunotherapy outcome was further evaluated with rounded analyses. We finally explore the role of TRIM28 in LUAD with a series of in vitro experiments.Results: Our research indicated that a higher LMS score was significantly correlated with tumor staging, pathological grade, tumor node metastasis stage, and survival. LMS was identified as an independent risk factor for OS in LUAD patients and verified in GEO datasets. Clinical response to immunotherapy was better in patients with low LMS score compared to those with high LMS score. TRIM28, a key gene in the gene signature, was shown to promote the proliferation, invasion and migration of LUAD cell.Conclusion: Our study highlights the significant role of gene signature in predicting the prognosis and immunotherapy efficacy of LUAD patients, and identifies TRIM28 as a potential biomarker for the treatment of LUAD.Keywords: lung adenocarcinoma, macrophage, TRIM28, prognosis, immunotherapy

Han Zheng, Ai-E Xu, Gang Qiao, Xiao-Yu Sun, Jia Deng, Yong Zhang Laser Center, Hangzhou Third People’s Hospital, Zhejiang, 310009, People’s Republic of ChinaCorrespondence: Han Zheng, Laser Center, Hangzhou Third People’s Hospital, No. 38 West Lake Avenue, Hangzhou, 310009, People’s Republic of China, Tel +86-13958159341, Email zhenghanzz98@outlook.comBackground and Aim: There is a dearth of scholarly investigation pertaining to the effectiveness and safety of laser therapy for nevus of Ota manifestation in infants. The objective of this study is to examine the efficacy and safety of administering laser therapy at an early stage to treat nevus of Ota in infants.Methods: A total of 102 infants below the age of one who had nevus of Ota were treated at the Laser Center at Hangzhou Third People’s Hospital. The treatment approach involved a combination of the Q-switched laser (with a wavelength of 755 nm) and the Q-switched laser (with a wavelength of 1064 nm). The treatment sessions were conducted at six-month intervals. Prior to and after each session, photographs and relevant parameters were documented, including any skin reactions. Subsequent follow-up was conducted through phone calls, WeChat, and text messages, and the parents/guardians of the infants completed a general questionnaire as well as Conner’s Abbreviated Symptom Questionnaire.Results: Laser therapy exhibited significant efficacy in the treatment of nevus of Ota in infants. Success rates reached 88.7% after four sessions and 99.3% after seven sessions. No instances of serious adverse reactions, except for pain, were reported. Among the 47 infants subject to follow-up, 14 experienced a recurrence, resulting in a recurrence rate of 29.8%. Factors contributing to these recurrences included lesion size, subtypes, exposure to the sun, and location. Subsequent laser treatments, typically involving two to three additional sessions, proved effective in mitigating recurrences. Notably, none of the infants exhibited any signs of fear, anxiety, or other psychological abnormalities following laser therapy, and the overall satisfaction rate was markedly high.Conclusion: Commencing laser therapy promptly for nevus of Ota in infants is recommended. This early intervention significantly contributes to the overall well-being of infants, addressing both physical and psychological aspects.Keywords: infants, laser, nevus of Ota, psychology, Q755, Q1064

Zhiyun Zhang, Hao Zheng, Qingquan Yu, Xianghong Jing Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing, People’s Republic of ChinaCorrespondence: Xianghong Jing, Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing, People’s Republic of China, Email jxhtjb@263.netAbstract: The spinal dorsal horn (SDH) transmits sensory information from the periphery to the brain. Wide dynamic range (WDR) neurons within this relay site play a critical role in modulating and integrating peripheral sensory inputs, as well as the process of central sensitization during pathological pain. This group of spinal multi-receptive neurons has attracted considerable attention in pain research due to their capabilities for encoding the location and intensity of nociception. Meanwhile, transmission, processing, and modulation of incoming afferent information in WDR neurons also establish the underlying basis for investigating the integration of acupuncture and pain signals. This review aims to provide a comprehensive examination of the distinctive features of WDR neurons and their involvement in pain. Specifically, we will examine the regulation of diverse supraspinal nuclei on these neurons and analyze their potential in elucidating the mechanisms of acupuncture analgesia.Keywords: WDR neurons, spinal dorsal horn, pain, central sensitization, receptive fields, DNIC, acupuncture analgesia

Xu Zuo,1 Yinuo Gu,1 Xiaoping Guo,1 Wenxue Zheng,1 Haoyu Zheng,1 Yiming An,1 Caina Xu,2,3 Fang Wang1,3 1Department of Pathogeny Biology, College of Basic Medical Sciences, Jilin University, Changchun, 130021, People’s Republic of China; 2Department of Biochemistry, College of Basic Medical Sciences, Jilin University, Changchun, 130021, People’s Republic of China; 3Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, 130021, People’s Republic of ChinaCorrespondence: Caina Xu; Fang Wang, Email xucaina@jlu.edu.cn; wf@jlu.edu.cnPurpose: Inhaled corticosteroids, including budesonide (BUD), are widely employed for the treatment of asthma. However, the frequent use of corticosteroids is associated with numerous adverse effects and poses challenges to ongoing drug therapy and patient adherence. Budesonide liposomal nanoparticles (BUD-LNPs) were developed to improve the bioavailability of the drug and thereby improve the effectiveness of asthma treatment.Methods: BUD-LNPs were prepared via thin-film hydration, and the characterizations, stability, and in vitro release of BUD-LNPs were studied. In vitro cellular uptake was observed by laser-scanning confocal microscope (LSCM) and flow cytometry. And the in vitro anti-inflammatory activity of BUD-LNPs was evaluated by measuring the expression of pro-inflammatory cytokines in activated macrophages. Besides, the accumulation time in the lung of drugs delivered via liposomal carriers and free drugs was compared in vivo. And the in vivo therapeutic efficacy of BUD-LNPs was assessed in OVA-induced asthmatic mice. Finally, in vivo biosafety assessment was performed.Results: The particle size, PDI, and zeta potential of BUD-LNPs were 127.63± 1.33 nm, 0.27± 0.02, and 3.33± 0.13 mV, respectively. BUD-LNPs exhibited excellent biosafety and anti-inflammatory activity in vitro. Furthermore, compared with the free drugs, the utilization of liposomal nano-vehicles for drugs delivery could effectively extend the duration of drugs accumulation in the pulmonary system. Additionally, treatment with BUD-LNPs alleviated airway hyperresponsiveness, reduced airway mucus secretion, and mitigated pulmonary inflammation in OVA-induced asthmatic mice. And the BUD-LNPs demonstrated superior therapeutic efficacy compared to free BUD.Conclusion: BUD-LNPs was successfully prepared with excellent stability and sustained release for 24 h in vitro. The data of anti-inflammatory activity, asthma therapeutic effects and safety studies indicated that drug delivery mediated by liposomal nano-vehicles was a feasible and desirable strategy for medical strategy and showed great promise in the clinical therapy of asthma.Keywords: liposomal nanoparticles, asthma, budesonide, pulmonary delivery, nano-vehicles

This study introduces a novel approach for the path planning of a 6-degree-of-freedom free-floating space robotic manipulator, focusing on collision and obstacle avoidance through reinforcement learning. It addresses the challenges of dynamic coupling between the spacecraft and the robotic manipulator, which significantly affects control and precision in the space environment. An innovative reward function is introduced in the reinforcement learning framework to ensure accurate alignment of the manipulator’s end effector with its target, despite disturbances from the spacecraft and the need for obstacle and collision avoidance. A key feature of this study is the use of quaternions for orientation representation to avoid the singularities associated with conventional Euler angles and enhance the training process’ efficiency. Furthermore, the reward function incorporates joint velocity constraints to refine the path planning for the manipulator joints, enabling efficient obstacle and collision avoidance. Another key feature of this study is the inclusion of observation noise in the training process to enhance the robustness of the agent. Results demonstrate that the proposed reward function enables effective exploration of the action space, leading to high precision in achieving the desired objectives. The study provides a solid theoretical foundation for the application of reinforcement learning in complex free-floating space robotic operations and offers insights for future space missions.

Yinlin Wang,1 Xinyue Zhang,2 Haiyan Zheng,1 Zihuai Zhou,1 Si Li,1 Jimin Jiang,1 Mingxing Li,1 Baiping Fu1 1Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Clinical Research Center for Oral Diseases of Zhejiang Province, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou, People’s Republic of China; 2School of Health Policy and Management, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People’s Republic of ChinaCorrespondence: Baiping Fu; Mingxing Li, Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Clinical Research Center for Oral Diseases of Zhejiang Province, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou, People’s Republic of China, Email fbp@zju.edu.cn; 7315019@zju.edu.cnObjective: This study was to investigate a novel antibacterial biomimetic mineralization strategy for exploring its potential application for root canal disinfection when stabilized cerium oxide was used.Material and Methods: A biomimetic mineralization solution (BMS) consisting of cerium nitrate and dextran was prepared. Single-layer collagen fibrils, collagen membranes, demineralized dentin, and root canal system were treated with the BMS for mineralization. The mineralized samples underwent comprehensive characterization using various techniques, including transmission electron microscopy (TEM), high-resolution TEM (HRTEM), Fourier transform infrared spectroscopy (FTIR), scanning transmission electron microscopy (STEM), selected-area electron diffraction (SAED), energy-dispersive X-ray spectroscopy (EDX), X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM), and micro-CT. Additionally, the antimicrobial properties of the BMS and the remineralized dentin were also analyzed with broth microdilution method, live/dead staining, and SEM.Results: Cerium ions in the BMS underwent a transformation into cerium oxide nanoparticles, which were deposited in the inter- and intra-fibrillar collagen spaces through a meticulous bottom-up process. XPS analysis disclosed the presence of both Ce (III) and Ce (IV) of the generated cerium oxides. A comprehensive examination utilizing SEM and micro-CT identified the presence of cerium oxide nanoparticles deposited within the dentinal tubules and lateral canals of the root canal system. The BMS and remineralized dentin exhibited substantial antibacterial efficacy against E. faecalis, as substantiated by assessments involving the broth dilution method and live/dead staining technique. The SEM findings revealed the cell morphological changes of deceased E. faecalis.Conclusion: This study successfully demonstrated antibacterial biomimetic mineralization as well as sealing dentinal tubules and lateral branches of root canals using cerium nitrate and dextran. This novel biomimetic mineralization could be used as an alternative strategy for root canal disinfection.Keywords: cerium oxide, dextran, biomimetic mineralization, root canal disinfection

Cong Xia,1 Ting Wei,2,3 Qi Tang,2,3 Hongying Zheng,2,3 Mei Sun,2,3 Gang Chen,2,3 Jun Lv2,3 1School of Health Management Anhui Medical University, Hefei, People’s Republic of China; 2School of Public Health, Fudan University, Shanghai, People’s Republic of China; 3China Research Center on Disability, Fudan University, Shanghai, People’s Republic of ChinaCorrespondence: Gang Chen; Jun Lv, School of Public Health, Fudan University, 130 Dong’an Road, Xuhui District, Shanghai, 200032, People’s Republic of China, Tel +86-13661432703 ; +86-13671684324, Email gchen@shmu.edu.cn; lujun@shmu.edu.cnPurpose: To investigate the family support, anxiety, depression, health-related quality of life (HRQoL), and their associations among parents and grandparents of children with disabilities.Methods: This is a cross-sectional study and a total of 327 family caregivers were included. Chi-square test, Mann–Whitney U-test, and two independent t-test were used to identify the intergenerational differences in sociodemographic characteristics, received family support, anxiety, depression, and HRQoL. Eight generalized linear models were developed to examine the associations in both generations.Results: Parents and grandparents were most in need of rehabilitation and financial support, but both populations received the least amount of financial support. 33.6% and 36.1% of family caregivers had the risk of anxiety and depression and found no significant intergenerational differences. As for HRQoL, intergenerational differences were found in the physical component score, but not found in the mental component score. Among parents, childcare support of respite care and household tasks assistance was negatively associated with their depression (p< 0.05), professional support of appropriate surgery for children (p< 0.05) and psychological support from professional psychologists (p< 0.01) were negatively associated with their anxiety and depression, psychological support from relatives and friends was negatively associated with their depression (p< 0.05) whereas was positively associated with their mental HRQoL (p< 0.01). As for grandparents, financial support for daily living expenses was negatively associated with depression (p< 0.05), and psychological support from families was negatively associated with depression (p< 0.05) whereas was positively associated with mental HRQoL (p< 0.05). However, no relationship was found between family support and anxiety among grandparents. Notably, no association was found between family support and physical HRQoL among both populations.Conclusion: Both parents and grandparents had high risks of anxiety, depression and low levels of mental HRQoL. To efficiently improve psychological health, care providers and policymakers may consider intergenerational differences and provide targeted family support.Keywords: mental health, health-related quality of life, family support, children with disabilities, intergenerational differences

Haishi Zheng,1,2 Yirixiati Aihaiti,2 Yongsong Cai,2 Qiling Yuan,2 Mingyi Yang,2 Zheng Li,2 Ke Xu,2 Peng Xu1,2 1Department of Orthopedics, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, People’s Republic of China; 2Department of Joint Surgery, HongHui Hospital, Xi’an Jiaotong University, Xi’an, People’s Republic of ChinaCorrespondence: Peng Xu, Department of Orthopedics, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, People’s Republic of China, Tel +86 13772090019, Email xupeng369@mail.xjtu.edu.cnPurpose: The goal of this study was to explore the expression characteristics of RNA modification-related genes, reveal immune landscapes and identify novel potential diagnostic biomarkers in osteoarthritis (OA) and rheumatoid arthritis (RA) patients.Patients and Methods: RNA microarray and single-cell sequencing (scRNA-seq) data were downloaded from gene expression omnibus (GEO) database. Differentially expressed RNA modification-related genes were identified and then functionally annotated. Univariate logistic regression and lasso regression analysis were used to identify primary disease genes for OA and RA. Validation was done using scRNA-seq analysis and immunohistochemistry (IHC) in human knee synovial tissues and a murine destabilization of the medial meniscus (DMM) model. Through WGCNA analysis, genes associated with cell pyroptosis or autophagy in OA and RA were identified, which were then combined with differentially expressed RNA modification-related genes to construct a PPI interaction network. Furthermore, hub genes were selected for ceRNA interaction network analysis, correlation analysis with OA and RA molecular subtypes, as well as correlation analysis with 22 immune cells.Results: Six RNA modification-related genes (ADAMDEC1, IGHM, OGN, TNFRSF11B, SCARA3 and PTN) were identified as potential OA and RA pathogenesis biomarkers. Their expression was validated in human knee synovial tissues and a murine DMM model. Functional enrichment of differentially expressed RNA modification-related genes between RA and OA was analyzed using GO, KEGG, GSEA, and GSVA. Based on WGCNA and PPI analysis, the six hub genes related to pyroptosis and RNA modification (CXCL10, CXCL9, CCR7, CCL5, CXCL1, and CCR2) were identified as central nodes for ceRNA interaction, correlation with OA and RA molecular subtypes, and association with 22 immune cells.Conclusion: Our research revealed the significance of RNA modification-related genes in the development of OA and RA pathogenesis, thereby providing a novel research direction for understanding the mechanisms, diagnosis, and treatment of OA and RA.Keywords: m6A, m5C, m1A, osteoarthritis, rheumatoid arthritis, single-cell sequencing

Mingjuan Liu,1– 3 Meiyi Tong,1,2 Jia Zhou,1,2 Yining Lan,1,2 Mengyin Wu,1,2 Hanlin Zhang,1,2 Ling Leng,2 Heyi Zheng,1,2 Yanfeng Li,4 Mingli Li,5 Jun Li1,2 1Department of Dermatology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, People’s Republic of China; 2State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, People’s Republic of China; 3 4+4 M.D. Program, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100005, People’s Republic of China; 4Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, People’s Republic of China; 5Department of Radiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, People’s Republic of ChinaCorrespondence: Mingli Li; Jun Li, Email limingli@pumch.cn; lijun35@hotmail.comPurpose: General paresis is a common type of neurosyphilis featuring progressive cognitive deterioration. The lack of a golden standard of diagnosis and its nonspecific clinical manifestations resulted in a high rate of misdiagnoses. This study aims to investigate the clinical, laboratory and radiological presentations of general paresis and enrich its knowledge for timely diagnoses.Patients and methods: The study collected hospitalized patients admitted for general paresis from September 2002 to November 2022. Their socio-demographical and medical status, clinical presentations, cognitive assessments, laboratory and radiographical manifestations and treatment information were collected retrospectively.Results: A total of 20 males and 5 females were included. Patients’ ages ranged from 30 to 66 years (average 50.3 years). The average and median time for diagnosing general paresis was 14.1 months and 10.0 months respectively. The most frequent initial symptom is memory deterioration (68.0%). Impaired calculative ability and memory deterioration were the most frequent cognitive anomalies, as found in 50% and 45.4% of subjects during examination. The mean and median scores of MoCA was 16.7 and 17 respectively. Serological tests revealed positive TPPA for all patients and a median RPR titer at 1:64 positive. All CSF samples with TPPA and FTA-ABS results reported positivity. The MRI manifestations of general paresis include patchy or speckled hyperintensities (70.8%) and cerebral atrophy (45.8%). The most common lesioned sites in MRI were the ventricular and paraventricular area (50.0%) and temporal lobes (45.8%). For treatment, penicillin-based anti-syphilitic plans were adopted in 17 patients (68.0%).Conclusion: The clinical features and radiological alternations of general paresis patients often exhibited diverse and nonspecific alternations. However, some specific clinical manifestations and auxiliary examinations can provide meaningful clues for the identification and differential diagnosis of this disease.Keywords: neurosyphilis, general paresis, syphilis, neuropsychiatric symptoms

Dandan Wu,1,&ast; Junxiao Cong,1,&ast; Jiali Wei,1 Jing Hu,1 Wenhao Sun,1 Wei Ran,2 Chenghui Liao,1 Housheng Zheng,1 Liang Ye1 1Department of Immunology, International Cancer Center, Shenzhen University Health Science Center, Shenzhen, People’s Republic of China; 2State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Liang Ye, Department of Immunology, International Cancer Center, Shenzhen University Health Science Center, Shenzhen, 518055, People’s Republic of China, Tel +86-0755-26631420, Fax +86-0755-86671943, Email liangyeszu@163.comBackground: The emergence of the coronavirus disease 2019 (COVID-19) pandemic and the new severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) variants of concern (VOCs) requires the continuous development of safe, effective, and affordable prevention and therapeutics. Nanobodies have demonstrated antiviral activity against a variety of viruses, providing a new candidate for the prevention and treatment of SARS-CoV-2 and its variants.Methods: SARS-CoV-2 glycoprotein spike 1 subunit (S1) was selected as the target antigen for nanobody screening of a naïve phage display library. We obtained a nanobody, named Nb-H6, and then determined its affinity, inhibition, and stability by ELISA, Competitive ELISA, and Biolayer Interferometry (BLI). Infection assays of authentic and pseudotyped SARS-CoV-2 were performed to evaluate the neutralization of Nb-H6. The structure and mechanism of action were investigated by AlphaFold, docking, and residue mutation assays.Results: We isolated and characterized a nanobody, Nb-H6, which exhibits a broad affinity for S1 and the receptor binding domain (RBD) of SARS-CoV-2, or Alpha (B.1.1.7), Delta (B.1.617.2), Lambda (C.37), and Omicron (BA.2 and BA.5), and blocks receptor angiotensin-converting enzyme 2 (ACE2) binding. Moreover, Nb-H6 can retain its binding capability after pH or thermal treatment and effectively neutralize both pseudotyped and authentic SARS-CoV-2, as well as VOC Alpha (B.1.1.7), Delta (B.1.617.2), and Omicron (BA.2 and BA.5) pseudoviruses. We also confirmed that Nb-H6 binds two distinct amino acid residues of the RBD, preventing SARS-CoV-2 from interacting with the host receptor.Conclusion: Our study highlights a novel nanobody, Nb-H6, that may be useful therapeutically in SARS-CoV-2 and VOC outbreaks and pandemics. These findings also provide a molecular foundation for further studies into how nanobodies neutralize SARS-CoV-2 and variants and imply potential therapeutic targets for the treatment of COVID-19.Keywords: COVID-19, antiviral medication, single-domain antibody, neutralizing antibody, bio-screening