A new integrative analysis of histopathology and single cell RNA-seq reveals the CCL5 mediated T and NK cell interaction with vascular cells in idiopathic pulmonary arterial hypertension.

BACKGROUND: Inflammation and dysregulated immunity play vital roles in idiopathic pulmonary arterial hypertension (IPAH), while the mechanisms that initiate and promote these processes are unclear. METHODS: Transcriptomic data of lung tissues from IPAH patients and controls were obtained from the Gene Expression Omnibus database. Weighted gene co-expression network analysis (WGCNA), differential expression analysis, protein-protein interaction (PPI) and functional enrichment analysis were combined with a hemodynamically-related histopathological score to identify inflammation-associated hub genes in IPAH. The monocrotaline-induced rat model of pulmonary hypertension was utilized to confirm the expression pattern of these hub genes. Single-cell RNA-sequencing (scRNA-seq) data were used to identify the hub gene-expressing cell types and their intercellular interactions. RESULTS: Through an extensive bioinformatics analysis, CXCL9, CCL5, GZMA and GZMK were identified as hub genes that distinguished IPAH patients from controls. Among these genes, pulmonary expression levels of Cxcl9, Ccl5 and Gzma were elevated in monocrotaline-exposed rats. Further investigation revealed that only CCL5 and GZMA were highly expressed in T and NK cells, where CCL5 mediated T and NK cell interaction with endothelial cells, smooth muscle cells, and fibroblasts through multiple receptors. CONCLUSIONS: Our study identified a new inflammatory pathway in IPAH, where T and NK cells drove heightened inflammation predominantly via the upregulation of CCL5, providing groundwork for the development of targeted therapeutics.

Il34 rescues metronidazole-induced impairment of spinal cord regeneration in zebrafish central nervous system.

Metronidazole (MTZ), a commonly used anti-infective drug in clinical practice, has also been employed as a prodrug in cell-targeted ablation systems in scientific research, exhibiting significant application value. However, it has been demonstrated that MTZ can induce neurotoxic symptoms to some extent during its use, and there is currently a lack of effective means to circumvent its toxicity in both clinical and research settings, which limits its application. Therefore, exploring the specific mechanisms underlying MTZ-induced neurotoxic symptoms and elucidating countermeasures will enhance the practical value of MTZ. In this study, using a zebrafish spinal cord injury regeneration model, we confirmed that MTZ neurotoxicity leads to impaired axon regeneration in the central nervous system. By overexpressing il34 in the central nervous system of zebrafish, we eliminated the inhibitory effect of MTZ on axonal regeneration and demonstrated that the pro-regenerative effect against MTZ neurotoxicity is not caused by excessive macrophages/microglia chemoattracted by interleukin 34(Il34). Transcriptome sequencing analysis and GO enrichment analysis of differentially expressed genes between groups revealed that Il34 may counteract MTZ neurotoxicity and promote spinal cord injury repair through biological processes that enhance cellular adhesion and cell location. In summary, our work uncovers a possible cause of MTZ neurotoxicity and provides a new perspective for eliminating MTZ toxicity.

Hyperuricemia as an independent risk factor for metabolic dysfunction-associated fatty liver disease in nonobese patients without type 2 diabetes mellitus.

According to the latest consensus statement, fatty liver complicated by specific metabolic abnormalities can be diagnosed as metabolic dysfunction-associated fatty liver disease (MAFLD) in nonobese patients without type 2 diabetes mellitus (T2DM). However, hyperuricemia (HUA), a manifestation of metabolic disorders, is excluded from diagnostic criteria. This study explored the association between HUA and MAFLD in nonobese patients without T2DM. A total of 28,187 participants were recruited from the Examination Center of the China-Japan Friendship Hospital from 2018 to 2022 and divided into four subgroups: nonobese patients without T2DM, obese patients without T2DM, nonobese patients with T2DM, and obese patients with T2DM. MAFLD was diagnosed by ultrasound combined with laboratory examinations. The association of HUA with MAFLD subgroups was performed by logistical regression analysis. The predictive ability of UA for MAFLD subgroups was assessed by receiver operating characteristics (ROC). HUA was positively associated with MAFLD in nonobese patients without T2DM in both males and females, even after adjusting for sex, BMI, dyslipidemia, and abnormal liver function. The association increased gradually with aging, especially in those over 40 yr old. HUA was an independent risk factor for MAFLD in nonobese patients without T2DM. We suggest that UA abnormalities might be considered in the diagnosis of MAFLD in nonobese patients without T2DM.NEW & NOTEWORTHY HUA is an independent risk factor for MAFLD in nonobese patients without T2DM. The association of HUA with MAFLD in nonobese patients without T2DM increased gradually with aging, especially in those over 40 yr old. In nonobese patients without T2DM, univariate analysis showed that females with HUA had a higher risk of MAFLD than males. However, the difference was narrowed after adjustment for confounders.

Discovery of potential RIPK1 inhibitors by machine learning and molecular dynamics simulations.

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) plays a crucial role in inflammation and cell death, so it is a promising candidate for the treatment of autoimmune, inflammatory, neurodegenerative, and ischemic diseases. So far, there are no approved RIPK1 inhibitors available. In this study, four machine learning algorithms were employed (random forest, extra trees, extreme gradient boosting and light gradient boosting machine) to predict small molecule inhibitors of RIPK1. The statistical metrics revealed similar performance and demonstrated outstanding predictive capabilities in all four models. Molecular docking and clustering analysis were employed to confirm six compounds that are structurally distinct from existing RIPK1 inhibitors. Subsequent molecular dynamics simulations were performed to evaluate the binding ability of these compounds. Utilizing the Shapley additive explanation (SHAP) method, the 1855 bit has been identified as the most significant molecular fingerprint fragment. The findings propose that these six small molecules exhibit promising potential for targeting RIPK1 in associated diseases. Notably, the identification of Cpd-1 small molecule (ZINC000085897746) from the Musa acuminate highlights its natural product origin, warranting further attention and investigation.

DrugRep: an automatic virtual screening server for drug repurposing.

Computationally identifying new targets for existing drugs has drawn much attention in drug repurposing due to its advantages over de novo drugs, including low risk, low costs, and rapid pace. To facilitate the drug repurposing computation, we constructed an automated and parameter-free virtual screening server, namely DrugRep, which performed molecular 3D structure construction, binding pocket prediction, docking, similarity comparison and binding affinity screening in a fully automatic manner. DrugRep repurposed drugs not only by receptor-based screening but also by ligand-based screening. The former automatically detected possible binding pockets of the receptor with our cavity detection approach, and then performed batch docking over drugs with a widespread docking program, AutoDock Vina. The latter explored drugs using seven well-established similarity measuring tools, including our recently developed ligand-similarity-based methods LigMate and FitDock. DrugRep utilized easy-to-use graphic interfaces for the user operation, and offered interactive predictions with state-of-the-art accuracy. We expect that this freely available online drug repurposing tool could be beneficial to the drug discovery community. The web site is http://cao.labshare.cn/drugrep/ .

A Workflow Combining Machine Learning with Molecular Simulations Uncovers Potential Dual-Target Inhibitors against BTK and JAK3.

The drug development process suffers from low success rates and requires expensive and time-consuming procedures. The traditional one drug-one target paradigm is often inadequate to treat multifactorial diseases. Multitarget drugs may potentially address problems such as adverse reactions to drugs. With the aim to discover a multitarget potential inhibitor for B-cell lymphoma treatment, herein, we developed a general pipeline combining machine learning, the interpretable model SHapley Additive exPlanation (SHAP), and molecular dynamics simulations to predict active compounds and fragments. Bruton's tyrosine kinase (BTK) and Janus kinase 3 (JAK3) are popular synergistic targets for B-cell lymphoma. We used this pipeline approach to identify prospective potential dual inhibitors from a natural product database and screened three candidate inhibitors with acceptable drug absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties. Ultimately, the compound CNP0266747 with specialized binding conformations that exhibited potential binding free energy against BTK and JAK3 was selected as the optimum choice. Furthermore, we also identified key residues and fingerprint features of this dual-target inhibitor of BTK and JAK3.

The association between adverse ergonomic factors and work-related musculoskeletal symptoms among medical staff in China: a cross-sectional study.

We investigated the prevalence of work-related musculoskeletal symptoms (WMSs) among medical staff and evaluated the associations of different levels of adverse ergonomic factors with WMSs. A total of 6099 Chinese medical staff were asked to complete a self-reported questionnaire to assess the prevalence and risk factors of WMSs from June 2018 to December 2020. A prevalence rate of 57.5% was observed for WMSs among overall medical staffs, which mainly affected the neck (41.7%) and shoulder (33.5%). 'Keeping sitting for long hours very frequently' (OR = 1.26, 95% CI: 1.04, 1.53) was positively associated with WMSs in doctors, while 'keeping sitting for long hours occasionally' (OR = 0.91, 95% CI: 0.85, 0.97) was identified as a protective factor of WMSs in nurses. The associations of adverse ergonomic factors, organisational factors, and environmental factors with WMSs were different among medical staff in different positions.Practitioner summary: We conducted a multi-city study concerning the risk factors of WMSs by carrying out a face-to-face one-to-multiple questionnaire survey among medical staff in China. As a risk factor of WMSs in medical staff, adverse ergonomic factors should be paid more attention by the standard setting department and policy makers.Abbreviations: WMSDs: work-related musculoskeletal disorders; WMSs: work-related musculoskeletal symptoms; MSDs: musculoskeletal disorders; NMQ: Nordic Musculoskeletal Questionnaires; DMQ: Dutch Musculoskeletal Questionnaires; NIOSH: National Institute for Occupational Safety and Health; ORs: odds ratios.

Exploring non-linear built environment effects on urban vibrancy under COVID-19: The case of Hong Kong.

The coronavirus disease (COVID-19) pandemic has enormously changed the way people perceive and use urban spaces, exacerbating some pre-existing issues including urban vibrancy decline. This study aims to explore built environment effects on urban vibrancy under COVID-19, which will help recalibrate planning models and design principles. Based on multi-source geo-tagged big data of Hong Kong, this study reveals variations in urban vibrancy and employs machine learning modeling and interpretation methods to examine built environment effects on urban vibrancy before, during, and after the outbreak of COVID-19, with review volume of restaurants & food retailers as the indicator for urban vibrancy and built environment depicted from five dimensions (i.e., building form, street accessibility, public transport accessibility, functional density, and functional mixture). We found that (1) urban vibrancy concussively decreased during the outbreak and slowly recovered afterwards; (2) built environment's capability to stimulate urban vibrancy was weakened during the outbreak and restored afterwards; (3) the relationships between built environment and urban vibrancy were non-linear and moderated by the pandemic. This research enriches our understandings of the role of the pandemic in influencing urban vibrancy and its correlation with built environment, enlightening decision makers with nuanced criteria for pandemic-adaptive urban planning and design.

DysRegSig: an R package for identifying gene dysregulations and building mechanistic signatures in cancer.

SUMMARY: Dysfunctional regulations of gene expression programs relevant to fundamental cell processes can drive carcinogenesis. Therefore, systematically identifying dysregulation events is an effective path for understanding carcinogenesis and provides insightful clues to build predictive signatures with mechanistic interpretability for cancer precision medicine. Here, we implemented a machine learning-based gene dysregulation analysis framework in an R package, DysRegSig, which is capable of exploring gene dysregulations from high-dimensional data and building mechanistic signature based on gene dysregulations. DysRegSig can serve as an easy-to-use tool to facilitate gene dysregulation analysis and follow-up analysis. AVAILABILITY AND IMPLEMENTATION: The source code and user's guide of DysRegSig are freely available at Github: https://github.com/SCBIT-YYLab/DysRegSig. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Prevalence and risk factors analysis for low back pain among occupational groups in key industries of China.

BACKGROUND: With the acceleration of industrialization and population aging, low back pain (LBP) has become the leading cause of life loss years caused by disability. Thus, it places a huge economic burden on society and is a global public health problem that needs urgent solution. This study aimed to conduct an epidemiological investigation and research on a large sample of workers in key industries in different regions of China, determine the incidence and distribution characteristics of LBP, explore the epidemic law, and provide a reference basis for alleviating global public health problems caused by LBP. METHODS: We adopted a modified epidemiological cross-sectional survey method and a stratified cluster sampling method. All on-duty workers who fulfill the inclusion criteria are taken as the research participants from the representative enterprises in key industries across seven regions: north, east, central, south, southwest, northwest, and northeast China. The Chinese version of the musculoskeletal disease questionnaire, modified by a standardized Nordic questionnaire, was used to collect information, and 57,501 valid questionnaires were received. Descriptive statistics were used, and multivariate logistic regression analysis (p < 0.05) was performed to explore the association between musculoskeletal disorders and potential risk factors. RESULTS: LBP annual incidence among workers in China's key industries is 16.4%. There was a significant difference in LBP incidence among occupational groups across different industries (p < 0.05). The multivariate regression model showed the following as risk factors for LBP: frequent repetitive movements with the trunk, working in the same positions at a high pace, trunk position, frequently turning around with your trunk, often working overtime, lifting heavy loads (i.e., more than 20 kg), education level, staff shortage, working age (years), cigarette smoking, use of vibration tools at work, body mass index, lifting heavy loads (i.e., more than 5 kg), and age (years). Physical exercise, often standing at work, and absolute resting time were protective factors. CONCLUSION: LBP incidence among key industries and workers in China is high. Thus, it is urgent to take relevant measures according to the individual, occupational, and psychosocial factors of LBP to reduce the adverse impact of LBP on workers' health.

Shoulder work-related musculoskeletal disorders and related factors of workers in 15 industries of China: a cross-sectional study.

BACKGROUND: Changes in modern industrial production practices can easily lead to shoulder work-related musculoskeletal disorders (WMSD). The current reports on shoulder WMSD are limited to some industries are less well studied, and the sample size is usually small. This study aimed to describe the prevalence and severity of shoulder WMSD in a large sample of Chinese workers from 15 industries, analyze the possible correlations with sociodemographic and work-related variables, and compare the differences between industries. METHODS: A cross-sectional study was conducted among a sample of 55,749 participants from 252 enterprises in 15 industries throughout China. A Chinese version of the musculoskeletal disease questionnaire was used to collect the demographic factors, shoulder symptoms in past 12 months, and work-related factors including posture-related factors, repetition, vibration, work organization, job control, and environmental factors as independent variables. Descriptive statistics were used, and the binary logistic regression analysis was performed to explore the association between shoulder WMSD and potential demographic and work-related factors. RESULTS: Nearly 35.5% of participants reported shoulder pain and discomfort in the previous 12 months. Biopharmaceutical manufacturing (56.2%), medical services (54.4%), and aviation services (50.1%) were the three industries with the highest prevalence of shoulder WMSD. The pain score of aviation services workers was the highest. The related factors for shoulder WMSD varied among the different industries. CONCLUSION: Our study found a relatively high prevalence of shoulder WMSD in China. There were large differences in the prevalence of shoulder WMSD among industries, and the related factors were particular to each industry. Such information is useful to help occupational health practitioners and policymakers conduct preventive programs to reduce shoulder disorders in these working populations.

Single-Cell Infrared Microspectroscopy Quantifies Dynamic Heterogeneity of Mesenchymal Stem Cells during Adipogenic Differentiation.

The central relevance of cellular heterogeneity to biological phenomena raises the rational needs for analytical techniques with single-cell resolution. Here, we developed a single-cell FTIR microspectroscopy-based method for the quantitative evaluation of cellular heterogeneity by calculating the cell-to-cell similarity distance of the infrared spectral data. Based on this method, we revealed the infrared phenotypes might reflect the dynamic heterogeneity changes in the cell population during the adipogenic differentiation of the human mesenchymal stem cells. These findings provide an alternative label-free optical approach for quantifying the cellular heterogeneity, and the combination with other single-cell analysis tools will be very helpful for understanding the genotype-to-phenotype relationship in cellular populations.

Hierarchical two-step floating catchment area (2SFCA) method: measuring the spatial accessibility to hierarchical healthcare facilities in Shenzhen, China.

BACKGROUND: Spatial accessibility to healthcare facilities has drawn much attention in health geography. In China, central and local governments have aimed to develop a well-organized hierarchical system of healthcare facilities in recent years. However, few studies have focused on the measurement of healthcare accessibility in a hierarchical service delivery system, which is crucial for the assessment and implementation of such strategies. METHODS: Based on recent improvements in 2SFCA (two-step floating catchment area) method, this study aims to propose a Hierarchical 2SFCA (H2SFCA) method for measuring spatial accessibility to hierarchical facilities. The method considers the varied catchment area sizes, distance decay effects, and transport modes for facilities at various levels. Moreover, both the relative and absolute distance effects are incorporated into the accessibility measurement. RESULTS: The method is applied and tested in a case study of hierarchical healthcare facilities in Shenzhen, China. The results reveal that the general spatial accessibility to hierarchical healthcare facilities in Shenzhen is unevenly distributed and concentrated. The disparity of general accessibility is largely caused by the concentrated distribution of tertiary hospitals. For facilities at higher levels, average accessibility of demanders is higher, but there are also larger disparities in spatial accessibility. The comparison between H2SFCA and traditional methods reveals that traditional methods underestimate the spatial disparity of accessibility, which may lead to biased suggestions for policy making. CONCLUSIONS: The results suggest that the supply of healthcare resources at primary facilities is far from sufficient. To improve the spatial equity in spatial accessibility to hierarchical healthcare facilities, various actions are needed at different levels. The proposed H2SFCA method contributes to the modelling of spatial accessibility to hierarchical healthcare facilities in China and similar environments where the referral system has not been well designed. It can also act as the foundation for developing more comprehensive measures in future studies.

DRAP: a toolbox for drug response analysis and visualization tailored for preclinical drug testing on patient-derived xenograft models.

BACKGROUND: One of the key reasons for the high failure rate of new agents and low therapeutic benefit of approved treatments is the lack of preclinical models that mirror the biology of human tumors. At present, the optimal cancer model for drug response study to date is patient-derived xenograft (PDX) models. PDX recaptures both inter- and intra-tumor heterogeneity inherent in human cancer, which represent a valuable platform for preclinical drug testing and personalized medicine applications. Building efficient drug response analysis tools is critical but far from adequate for the PDX platform. RESULTS: In this work, we first classified the emerging PDX preclinical trial designs into four patterns based on the number of tumors, arms, and animal repeats in every arm. Then we developed an R package, DRAP, which implements Drug Response Analyses on PDX platform separately for the four patterns, involving data visualization, data analysis and conclusion presentation. The data analysis module offers statistical analysis methods to assess difference of tumor volume between arms, tumor growth inhibition (TGI) rate calculation to quantify drug response, and drug response level analysis to label the drug response at animal level. In the end, we applied DRAP in two case studies through which the functions and usage of DRAP were illustrated. CONCLUSION: DRAP is the first integrated toolbox for drug response analysis and visualization tailored for PDX platform. It would greatly promote the application of PDXs in drug development and personalized cancer treatments.

Differential network analysis depicts regulatory mechanisms for hepatocellular carcinoma from diverse backgrounds.

Aim: To elucidate the integrative combinational gene regulatory network landscape of hepatocellular carcinoma (HCC) molecular carcinogenesis from diverse background. Materials & methods: Modified gene regulatory network analysis was used to prioritize differentially regulated genes and links. Integrative comparisons using bioinformatics methods were applied to identify potential critical molecules and pathways in HCC with different backgrounds. Results: E2F1 with its surrounding regulatory links were identified to play different key roles in the HCC risk factor dysregulation mechanisms. Hsa-mir-19a was identified as showed different effects in the three HCC differential regulation networks, and showed vital regulatory role in HBV-related HCC. Conclusion: We describe in detail the regulatory networks involved in HCC with different backgrounds. E2F1 may serve as a universal target for HCC treatment.

Interleukin-18 Expression Increases in the Aorta and Plasma of Patients with Acute Aortic Dissection.

BACKGROUND: Interleukin- (IL-) 18 is a proinflammatory cytokine related to cardiovascular diseases, including hypertension and atherosclerosis. This study is aimed at determining whether IL-18 is related to aortic dissection (AD) and identifying the underlying mechanisms. METHODS: IL-18 expression in human aorta samples from AD (n = 8) and non-AD (NAD, n = 7) patients was measured. In addition, the IL-18, IL-6, interferon- (IFN-) γ, and IL-18-binding protein (IL-18BP) concentrations in plasma samples collected from the NAD and AD patients were detected. The effects of IL-18 on macrophage differentiation and smooth muscle cell (SMC) apoptosis were investigated in vitro. RESULTS: IL-18 expression was significantly increased in the aorta samples from the AD patients compared with those from the NAD patients, especially in the torn section. Aortic IL-18 was mainly derived from macrophages and also partly derived from CD4+ T lymphocytes and vascular SMCs. Plasma IL-18, IFN-γ, and IL-6 levels were significantly higher in the AD group than in the NAD group, and the IL-18 levels were positively correlated with the IFN-γ and IL-6 levels. In addition, plasma IL-18BP and free IL-18 levels were also elevated in the AD group. Linear regression analysis showed that the IL-18 level was independently associated with the presence of AD. In addition, anti-mouse IL-18-neutralizing monoclonal antibodies (anti-IL-18 nAb) inhibited angiotensin II-induced M1 macrophage differentiation and SMC apoptosis in vitro. CONCLUSION: IL-18 may participate in AD by regulating macrophage differentiation and macrophage-induced SMC apoptosis.

Clinical features of laryngeal myasthenia gravis: A case series.

BACKGROUND: Myasthenia gravis (MG) is an autoimmune disease. Dysarthria, dysphagia, and difficulty swallowing as exclusive initial and primary complaints in MG (laryngeal MG) are rare and seldom reported. METHODS: Here we review and analyze the largest series of laryngeal MG patients. RESULTS: A total of 30 patients with laryngeal MG as primary manifestation were found in 20 case reports/series. Dysarthria was the most frequent primary symptom (14/30), followed by dysphagia (11/30), slurred speech (4/30) and dysphonia (1/30). Sixty-three percent visited the otolaryngology department first. Only 23.33% of patients were diagnosed with MG at the first clinic visit. Forty-five percent laryngeal MG patients were acetylcholine receptor (AChR) antibody positive, 52.9% showed decremental response in the repetitive nerve stimulation (RNS) test, and 92.6% were positive in the neostigmine/edrophonium test. Fluctuating weakness was examined in 16 of 30 patients and observed in 14/16 patients. CONCLUSION: Laryngeal MG is a rare and possibly under-diagnosed condition. The patients can present with dysarthria, dysphagia, or difficulty swallowing. Fluctuation in severity of disease by neostigmine/edrophonium test is a typical feature for MG patients. AChR antibody and RNS tests should be included to evaluate the pathologic changes in the neuromuscular junction.

CTLPScanner: a web server for chromothripsis-like pattern detection.

Chromothripsis is a recently observed phenomenon in cancer cells in which one or several chromosomes shatter into pieces with subsequent inaccurate reassembly and clonal propagation. This type of event generates a potentially vast number of mutations within a relatively short-time period, and has been considered as a new paradigm in cancer development. Despite recent advances, much work is still required to better understand the molecular mechanisms of this phenomenon, and thus an easy-to-use tool is in urgent need for automatically detecting and annotating chromothripsis. Here we present CTLPScanner, a web server for detection of chromothripsis-like pattern (CTLP) in genomic array data. The output interface presents intuitive graphical representations of detected chromosome pulverization region, as well as detailed results in table format. CTLPScanner also provides additional information for associated genes in chromothripsis region to help identify the potential candidates involved in tumorigenesis. To assist in performing meta-data analysis, we integrated over 50 000 pre-processed genomic arrays from The Cancer Genome Atlas and Gene Expression Omnibus into CTLPScanner. The server allows users to explore the presence of chromothripsis signatures from public data resources, without carrying out any local data processing. CTLPScanner is freely available at http://cgma.scu.edu.cn/CTLPScanner/.