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Ya Gao,1 Shuyue Li,1 Jian Zhang,1 Yidan Zhang,1 Yuan Zhao,1 Shuming Zhang,2 Lujie Zuo,3 Guofeng Yang1 1Department of Geriatrics, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050000, People’s Republic of China; 2Department of Internal Medicine, Fuping County Hospital, Baoding, Hebei, 073200, People’s Republic of China; 3Department of Otolaryngology, Head and Neck Surgery, Children’s Hospital of Hebei Province, Shijiazhuang, Hebei, 050000, People’s Republic of ChinaCorrespondence: Guofeng Yang, Department of Geriatrics, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050000, People’s Republic of China, Email yanggf@hebmu.edu.cnBackground: Parkinson’s disease (PD) is a neurodegenerative movement disorder that impacts various systems, including the substantia nigra (SN) par compacta (SNpc) and extranigral regions like the spinal cord. The presence of persistent inflammation in the SN and spinal cord is associated with movement difficulties in PD. Atractylenolide-I (ATR-I) is a natural sesquiterpene recognized for its anti-inflammatory and neuroprotective effects. This research aimed to assess the impact of ATR-I treatment on motor function and inflammation in MPTP-induced subacute PD mice, particularly focusing on the role of ATR-I in spinal cord inflammation.Methods: The motor functions of the mice were assessed using suspension and gait tests. Dopaminergic neuronal loss in the SNpc and microglial activation in both the SNpc and spinal cord were evaluated through immunofluorescence staining. The levels of inflammatory mediators in the spinal cord were measured using RT-qPCR analysis. The expressions of SIRT1 and PGC-1α in the spinal cord were analyzed through Western blotting and RT-qPCR.Results: ATR-I treatment improved motor deficits in MPTP-induced mice. Moreover, ATR-I reduced the loss of dopamine neurons and microglial activation in the SNpc of MPTP-induced mice. Additionally, ATR-I suppressed spinal cord inflammation by decreasing microglial activation and the mRNA expression of TNF-α, IL-1β, and iNOS in MPTP-induced mice. Interestingly, ATR-I also upregulated SIRT1 and PGC-1α levels in the spinal cord of MPTP-induced mice.Conclusion: These findings suggest that ATR-I exhibits anti-inflammatory and neuroprotective properties in PD. The attenuation of spinal cord inflammation via the SIRT1/PGC-1α pathway may contribute to enhancing motor function, highlighting ATR-I as a potential therapeutic avenue for PD.Keywords: Parkinson’s disease, atractylenolide-I, spinal cord, inflammation, SIRT1, PGC‑1&#x03B1

Li Zuo,1,* Wenhui Zhang,2,* Ying Wang,3 Xin Qi1 1Department of Pulmonary and Critical Care Medicine, China Aerospace Science & Industry Corporation 731 Hospital, Beijing, 100074, People’s Republic of China; 2General Practice Clinic, Sijiqing Town Community Health Service Center of Haidian District, Beijing, 100097, People’s Republic of China; 3Department of Pharmacy, Wangtai Branch of Jincheng General Hospital, Jincheng, 048006, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xin Qi, Department of pulmonary and critical care medicine, China Aerospace Science & Industry Corporation 731 Hospital, No. 3, Zhen Gang Nan Li, Feng Tai District, Beijing, 100074, People’s Republic of China, Email xinqixq015@163.comObjective: To explore serum KL-6 level and investigate its diagnostic value in interstitial lung diseases (ILDs).Methods: Serum KL-6 level was measured using the chemiluminescent enzyme immunoassay. Statistical analysis was performed for determining the KL-6 concentration of each group.Results: KL-6 level (U/mL) in the ILD group was 1388.321 ± 1943.116, which was higher than that in the control group, showing a significant statistical difference. ROC curve analysis based on the receiver operating characteristic curve showed the optimal cut-off value of 402.5U/mL, sensitivity of 77.4%, specificity of 93.4%, and accuracy of 89.4%; through Chi-square test with the two groups, the positive rate of KL-6 in patients with ILD was proved to be significantly higher than that in the control group. KL-6 level was 1063.00± 504.757 in the idiopathic pulmonary fibrosis (IPF) group, 1346.892 ± 1827.252 in the connective tissue disease-associated interstitial lung disease (CTD-ILD) group, 467.889± 288.859 in the organizing pneumonia (OP) group, 8252.333± 6050.625 in the pulmonary alveolar proteinosis (PAP) group, and 359.200± 392.707 in the sarcoidosis group. The rank sum test showed that the differences were statistically significant. KL-6 level was the lowest in the sarcoidosis group, followed by that in the OP group.Conclusion: Serum KL-6 level was confirmed to be highly sensitive, specific, and accurate in the diagnosis of ILD. Subgroup analysis showed that the KL-6 level was the lowest in the sarcoidosis group, followed by that in the OP group.Keywords: ILD, KL-6, diagnostic value, subgroup analysis

Lijun Zuo,1,&ast; Yanhong Dong,2,&ast; Xiaoling Liao,1 Yang Hu,1 Yuesong Pan,3 Hongyi Yan,3 Xingao Wang,1 Xingquan Zhao,1 Yilong Wang,1 Raymond CS Seet,4,5 Yongjun Wang,1,3 Zixiao Li1,3,6– 8 1Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Alice Lee Centre for Nursing Studies, Yong Loo Lin School of Medicine, National University of Singapore, Clinical Research Centre, Singapore; 3China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, People’s Republic of China; 4Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; 5Division of Neurology, Department of Medicine, National University Hospital, Singapore; 6Beijing Tiantan Hospital, Capital Medical University, and the Research Unit of Artificial Intelligence in Cerebrovascular Disease, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China; 7National Center for Healthcare Quality Management in Neurological Diseases, Beijing, People’s Republic of China; 8Chinese Institute for Brain Research, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zixiao Li, Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, No. 119, South 4th Ring West Road, Fengtai District, Beijing, 100070, People’s Republic of China, Email lizixiao2008@hotmail.comObjective: The HALP (hemoglobin, albumin, lymphocyte, and platelet) score is a novel indicator that measures systemic inflammation and nutritional status that has not been correlated with the risk of post-stroke cognitive impairment in patients with acute ischemic stroke or transient ischemic attack (TIA).Methods: Study participants were recruited from 40 stroke centers in China. The HALP score was derived using a weighted sum of hemoglobin, albumin, lymphocytes and platelets, and study participants were categorized into 4 groups of equal sizes based on quartiles cutoffs of the HALP score. The Montreal Cognitive Assessment (MoCA)-Beijing Cognitive Assessment Scale (MoCA-Beijing) was performed at 2 weeks and 12 months following stroke onset. Post-stroke cognitive impairment was considered in patients with MoCA-Beijing≤ 22. Multiple logistic regression methods were employed to evaluate the relationship between the HALP score and the subsequent risk of developing post-stroke cognitive impairment.Results: The study population comprised 1022 patients (mean age 61.6± 11.0 years, 73% men). The proportion of individuals with MoCA-Beijing≤ 22 at 2 weeks was 49.2% and 32.4% at one year. Patients in the lowest quartile of HALP score (< 36.56) were observed to harbor the highest risk of post-stroke cognitive impairment at 12 months post-stroke/TIA compared to those in the highest quartile (odds ratio=1.59, 95% CI=1.07– 2.37, p=0.022), and lower domain scores for executive function, naming, and attention. There were no statistically significant differences between patients in the different quartiles of HALP score and HALP score at 2 weeks post-stroke/TIA.Conclusion: The HALP score is a simple score that could stratify the risk of post-stroke cognitive impairment in stroke/TIA patients to facilitate early diagnosis and interventions.Keywords: mild stroke, post stroke cognitive impairment, hemoglobin, albumin, lymphocyte, platelet

Lijun Zuo,1 Yanhong Dong,2 Yuesong Pan,3 Hongyi Yan,3 Xia Meng,3 Hao Li,3 Xingquan Zhao,1 Yilong Wang,1 Yongjun Wang,1 Xiaoling Liao1 1Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Alice Lee Centre for Nursing Studies, Yong Loo Lin School of Medicine, National University of Singapore, Clinical Research Centre, Singapore, 117597, Singapore; 3National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, People’s Republic of ChinaCorrespondence: Xiaoling Liao, Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, No. 119, South Fourth Ring West Road, Fengtai District, Beijing, 100070, People’s Republic of China, Tel +86-010-59978350, Fax +86-010-59973383, Email liao828@sina.comObjective: Cognitive impairment after stroke/transient ischemic attack (TIA) has a high prevalence. Cystatin C (CysC) has been found as a novel biomarker of neurodegenerative diseases, such as dementia and Alzheimer’s disease. We aimed to explore the possible correlations of serum CysC level with cognitive impairment in patients who had mild ischemic stroke and TIA after 1 year.Methods: We measured serum CysC level in 1025 participants with a minor ischemic stroke/TIA from enrolled from the Impairment of Cognition and Sleep (ICONS) study of the China National Stroke Registry-3 (CNSR-3). They were divided into four groups according to quartiles of baseline CysC levels. Patients’ cognitive functions were assessed by Montreal Cognitive Assessment (MoCA)-Beijing at day 14 and at 1 year. Multiple logistic regression models were performed to evaluate the relationship between CysC and post-stroke cognitive impairment (PSCI) at 1-year follow-up.Results: Cognitive impairment was defined as MoCA-Beijing ≤ 22. Most patients were in 60s (61.52± 10.97 years old) with a median (interquartile range) National Institute of Health Stroke Scale(NIHSS) score of 3.00 (4.00) and greater than primary school level of education, and 743 participants (72.49%) were male. Among the 1025 participants, 331 participants (32.29%) patients suffered PSCI at 1-year follow-up. A U-shaped association was observed between CysC and 1-year PSCI [quartile (Q)1 vs Q3: adjusted odds ratio (aOR) 2.69, 95% CI 1.67– 4.34, p < 0.0001; Q2 vs Q3: aOR 1.63, 95% CI 1.03– 2.57, p = 0.0354; Q4 vs Q3: aOR 1.83, 95% CI 1.16– 2.87, p = 0.009]. Moreover, the U-shaped trends were also found between CysC level and the subscores of attention, recall, abstraction and language in MoCA.Conclusion: CysC showed a U-shaped correlation with 1-year overall cognitive function. It is probable that measurement of the serum CysC level would aid in the early diagnosis of PSCI.Keywords: mild stroke, post stroke cognitive impairment, cystatin C

Jiequn Huang,1 Changzhi Liu,1 Zhujiang Zhou,1 Han Xia,2 Zhensheng Zhu,2 Jianhai Lu,1 Jingcheng Lin,1 Zhen Chen,1 Qimei Ye,1 Liuer Zuo1 1Department of Intensive Care Unit, Shunde Hospital, Southern Medical University (The First People’s Hospital of Shunde Foshan), Foshan, Guangdong, People’s Republic of China; 2Department of Scientific Affairs, Hugobiotech Co, Ltd, Beijing, People’s Republic of ChinaCorrespondence: Liuer Zuo, Department of Intensive Care Unit, Shunde Hospital, Southern Medical University (The First People’s Hospital of Shunde, Foshan), Foshan, Guangdong, People’s Republic of China, Email 13500276597@163.comBackground: Pneumonia infected by Chlamydia abortus (C. abortus) is rare, especially complicated with severe acute respiratory distress syndrome (ARDS) and multiple organ dysfunction syndrome (MODS).Case Presentation: We presented the clinical details of a 44-year-old male who was diagnosed with C. abortus pneumonia, which rapidly progressed and ultimately led to ARDS, sepsis and MODS. Although he was initially diagnosed with pneumonia upon admission, no pathogenic bacteria were detected in sputum by conventional tests. Empirical intravenous infusion of meropenem and moxifloxacin was administered, but unfortunately, his condition deteriorated rapidly, especially respiratory status. On Day 2 after extracorporeal membrane oxygenation (ECMO) initiation, metagenomic next-generation sequencing (mNGS) was performed on the patient’s bronchoalveolar lavage fluid, which indicated an infection with C. abortus. The patient’s antimicrobial therapy was adjusted to oral doxycycline (0.1g every 12h), intravenous azithromycin (0.5g every day), and imipenem and cilastatin sodium (1g every 6h). The patient’s condition improved clinically and biologically. However, the patient was discharged due to financial reasons and unfortunately passed away eight hours later.Conclusion: Infections with C. abortus can result in severe ARDS and serious visceral complications which necessitate prompt diagnosis and active intervention by clinicians. The case highlights the significance of mNGS as an essential diagnostic tool for uncommon pathogens. Tetracyclines, macrolides or their combinations are effective choices for treatment of C. abortus pneumonia. Further study is needed to explore the transmission routes of C. abortus pneumonia and establish precise guidelines for antibiotic treatment.Keywords: Chlamydia abortus, ECMO, pneumonia, acute respiratory distress syndrome, metagenomic next-generation sequencing

Yue Xie,1,&ast; Yaning Jin,2,&ast; Shuyue Li,3 Baoxi Shen,4 Liping Ma,5 Lujie Zuo,6 Ya Gao,3 Guofeng Yang3 1Department of Neurology, the Second Medical Center and National Clinical Research Center for Geriatric Disease, Chinese PLA General Hospital, Beijing, 100853, People’s Republic of China; 2Chaoyang Second Retired Cadre Rest Center of Beijing Garrison, Beijing, 100853, People’s Republic of China; 3Department of Geriatrics, the Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050000, People’s Republic of China; 4Department of Neurosurgery, the First Medical Centre, Chinese PLA General Hospital, Medical School of Chinese PLA, Beijing, 100853, People’s Republic of China; 5Department of Neurology, Xinzhou People’s Hospital, Shanxi, 034000, People’s Republic of China; 6Department of Otolaryngology, Head and Neck Surgery, Children’s Hospital of Hebei Province, Shijiazhuang, Hebei, 050000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ya Gao; Guofeng Yang, Department of Geriatrics, the Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050000, People’s Republic of China, Email elegance86@163.com; gf_yanghb@126.comIntroduction: Alzheimer’s disease (AD) is the most common type of dementia, impacting approximately 50 million individuals globally. However, the current treatments available for AD are only symptomatic and have limited efficacy. This study aimed to investigate whether Leonurine could alleviate cognitive dysfunction in a mouse model of AD and explore its underlying molecular mechanisms.Methods: In this study, male APP/PS1 mice were orally administered Leonurine for two consecutive months. The cognitive functions of the mice were then evaluated using novel object recognition (NOR) and Morris water maze (MWM) tests. Hippocampal neuronal damage was observed through Nissl staining, Aβ levels were determined through ELISA, oxidative stress activity was detected through biochemical methods, and the nuclear factor erythroid-2-related factor 2 (Nrf-2) pathway was analyzed using western blot and real-time quantitative polymerase chain reaction analysis.Results: Our results demonstrated that Leonurine treatment markedly improved cognitive functions, as indicated by the improved performance in the model. Additionally, histopathology showed a reduction in hippocampal neuronal damage. This can be attributed to the potential of Leonurine to reduce Aβ 1-40 and Aβ 1-42 levels and alleviate oxidative stress. Its antioxidant effect is linked to the activation of the Nrf-2 signaling pathway in APP/PS1 mice, which promotes Nrf-2 nuclear translocation and expression of HO-1 and NQO-1.Conclusion: These findings suggest that Leonurine could be explored further as it could emerge as a promising drug for AD treatment.Keywords: Alzheimer’s disease, cognitive deficit, Leonurine, Nrf-2, oxidative stress

Lijun Zuo,1 YanHong Dong,2 Yang Hu,1 Xianglong Xiang,3 Tao Liu,4 Jianxin Zhou,5 Jiong Shi,1 Yongjun Wang1 1Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Alice Lee Centre for Nursing Studies, Yong Loo Lin School of Medicine, National University of Singapore, 117597 Singapore; 3China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, People’s Republic of China; 4Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing, People’s Republic of China; 5Department of Critical Care Medicine, Beijing Tiantan Hospital, Capital Medical University, Beijing, People’s Republic of ChinaCorrespondence: Yongjun Wang, Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, No. 119, South Fourth Ring West Road, Fengtai District, Beijing, 100070, People’s Republic of China, Tel +86-010-59978350, Fax +86-010-59973383, Email yongjunwang@ncrcnd.org.cnIntroduction: Stroke has been considered to raise the risk of dementia in several studies, but the relationship between brain structural changes and poststroke cognitive impairment (PSCI) is unclear.Methods: In this study, 23 PSCI patients with basal ganglia infarcts after 2 weeks and 29 age-matched controls underwent magnetic resonance imaging measuring cortical thickness and volume changes, as well as neuropsychological tests. CI was derived from a performance score < 1.5 standard deviations for normally distributed scores. We compared Z scores in different cognitive domains and cortical thickness and volumes in two groups. Multiple linear regressions were used to investigate the relationship between cortical thickness and volumes and neuropsychological tests.Results: A majority of PSCI patients were in their 50s (55.19± 8.52 years). PSCI patients exhibited significantly decreased Z scores in multiple domains, such as memory, language, visuomotor speed, and attention/executive function. The volumes of the middle posterior corpus callosum, middle anterior corpus callosum, and hippocampus in PSCI patients were markedly lower than controls. The thickness of the right inferior temporal cortex and insula were significantly smaller than controls. It found that the reduced right hippocampus was related to executive dysfunction. Hippocampus dysfunction may be involved in language impairment (p< 0.05) in PSCI patients with basal ganglia infarcts.Conclusion: These findings demonstrated that brain structure changed after ischemic stroke, and different gray-matter structural changes could lead to specific cognitive decline in PSCI patients with basal ganglia infarcts. Atrophy of the right hippocampus potentially serves as an imaging marker of early executive function of PSCI.Keywords: hippocampus volume, poststroke cognitive impairment, structural changes

Yiting Du,1,2 Limin Zuo,2 Ying Xiong,1 Xuedong Wang,3 Jun Zou,2 Hong Xu1 1Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children, West China Second University Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China; 2Chengdu Women’s and Children’s Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 611731, People’s Republic of China; 3Key Laboratory of Birth Defects and Related Diseases of Women and Children, West China Second University Hospital, Sichuan University, Chengdu, 610041, People’s Republic of ChinaCorrespondence: Ying Xiong, Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children, West China Second University Hospital, Sichuan University, Sec. 3 No. 17, South Renmin Road, Chengdu, 610041, People’s Republic of China, Email xiongying20006@163.comBackground: Bronchopulmonary dysplasia (BPD) refers to a chronic lung disease which is commonly observed in preterm infants. It can usually be caused by several pathological processes that endanger the long-term lung development, such as inflammation and immune dysfunction.Methods: In this study, a bioinformatics approach was applied to identify the differentially expressed immune-related genes (DEIRGs). We downloaded the transcriptional profiles (GSE32472 dataset) from the Gene Expression Omnibus (GEO) database and performed gene set enrichment analysis (GSEA). Cell type Identification By Estimating Relative Subsets of RNA Transcripts (CIBERSORT), microenvironment cell populations counter (MCPcounter), and Estimation of STromal and Immune cells in Malignant Tumor tissues using Expression data (ESTIMATE) were used for the analysis of the immune cell infiltration landscape of BPD. A weighted co-expression network was subsequently constructed using weighted gene co-expression network analysis (WGCNA) to screen candidate differentially expressed immune related genes (DEIRGs).Results: GSEA results indicated that immune-related pathways were mainly involved in BPD. Ten significantly different immune cell types were observed between BPD and normal groups. A total of 228 DEGs in the turquoise module were identified, and 31 DEIRGs were further identified. Cluster of the differentiation 8 alpha (CD8A) expression was down-regulated in BPD, and its expression was validated by the GSE25286, GSE25293, GSE99633 datasets and qRT-PCR. In addition, CD8A expression was closely associated with immune cells infiltration, especially T cells CD8 and neutrophil.Conclusion: A distinct immune cell infiltration landscape was found between BPD and normal group. CD8A can be a novel candidate biomarker for BPD, which plays an essential role in the onset and progress of hyperoxia-related BPD via the disruption of immune cell functions.Keywords: bronchopulmonary dysplasia, CD8A, preterm infants, immunocytes infiltrate, hyperoxia

Zhen Chen1 &ast;, Liming Zeng2 &ast;, Genglong Liu,3,4 Yangpeng Ou,5 Chuangang Lu,6 Ben Yang,7 Liuer Zuo1 &#x002A1Department of Intensive Care Unit, Shunde Hospital, Southern Medical University (The First People’s Hospital of Shunde), Foshan, Guangdong Province, 528308, People’s Republic of China; 2Medical Research Center, Shunde Hospital, Southern Medical University (The First People’s Hospital of Shunde), Foshan, Guangdong Province, 528308, People’s Republic of China; 3Department of Pathology, Guangzhou Medical University, Guangzhou, Guangdong Province, 511495, People’s Republic of China; 4Baishideng Publishing Group Inc, Pleasanton, CA, 94566, USA; 5Department of Oncology, Huizhou Third People’s Hospital, Guangzhou Medical University, Huizhou, Guangdong Province, 516000, People’s Republic of China; 6Department of Thoracic Surgery, Sanya Central Hospital, Sanya, Hainan Province, 572000, People’s Republic of China; 7Department of Burn Surgery, Huizhou Municipal Central Hospital, Huizhou, Guangdong Province, 516000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhen Chen; Liuer Zuo, Department of Intensive care Unit, Shunde Hospital, Southern Medical University (The First People’s Hospital of Shunde), Foshan, Guangdong Province, 528308, People’s Republic of China, Email jeanyz@foxmail.com; 13500276597@163.comBackground: The immune system plays a fundamental role in the pathophysiology of sepsis, and autophagy and autophagy-related molecules are crucial in innate and adaptive immune responses; however, the potential roles of autophagy-related genes (ARGs) in sepsis are not comprehensively understood.Methods: A systematic search was conducted in ArrayExpress and Gene Expression Omnibus (GEO) cohorts from July 2005 to May 2022. Machine learning approaches, including modified Lasso penalized regression, support vector machine, and artificial neural network, were applied to identify hub ARGs, thereby developing a prediction model termed ARG classifier. Diagnostic and prognostic performance of the model was comprehensively analyzed using multi-transcriptome data. Subsequently, we systematically correlated the ARG classifier/hub ARGs with immunological characteristics of multiple aspects, including immune cell infiltration, immune and molecular pathways, cytokine levels, and immune-related genes. Further, we collected clinical specimens to preliminarily investigate ARG expression levels and to assess the diagnostic performance of ARG classifier.Results: A total of ten GEO and three ArrayExpress datasets were included in this study. Based on machine learning algorithms, eight key ARGs (ATG4C, BAX, BIRC5, ERBB2, FKBP1B, HIF1A, NCKAP1, and NFKB1) were integrated to establish ARG classifier. The model exhibited excellent diagnostic values (AUC > 0.85) in multiple datasets and multiple points in time and superiorly distinguished sepsis from other critical illnesses. ARG classifier showed significant correlations with clinical characteristics or endotypes and performed better in predicting mortality (AUC = 0.70) than other clinical characteristics. Additionally, the identified hub ARGs were significantly associated with immune cell infiltration (B, T, NK, dendritic, T regulatory, and myeloid-derived suppressor cells), immune and molecular pathways (inflammation-promoting pathways, HLA, cytolytic activity, apoptosis, type-II IFN response, complement and coagulation cascades), levels of several cytokines (PDGFRB, IL-10, IFNG, and TNF), which indicated that ARG classifier/hub ARGs adequately reflected the immune microenvironment during sepsis. Finally, using clinical specimens, the expression levels of key ARGs in patients with sepsis were found to differ significantly from those of control patients, and ARG classifier exhibited superior diagnostic performance, compared to procalcitonin and C-reactive protein.Conclusion: Collectively, a diagnostic and prognostic model (ARG classifier) based on eight ARGs was developed which may assist clinicians in diagnosis of sepsis and recognizing patient at high risk to guide personalized treatment. Additionally, the ARG classifier effectively reflected the immune microenvironment diversity of sepsis and may facilitate personalized counseling for specific therapy.Keywords: sepsis, autophagy-related genes, machine learning, model, multi-transcriptome, immune microenvironment

Huijing Tan,1 Lijie Zuo,1,2 Shutao Ma,1 Dingyuan Wang,3 Rui Li,1,2 Yiqi Yang,1,2 Weili Liu,1,2 Yihebali Chi1 1Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People’s Republic of China; 2Beijing Chaoyang Sanhuan Cancer Hospital, Beijing, 100021, People’s Republic of China; 3Department of Breast Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People’s Republic of ChinaCorrespondence: Yihebali ChiDepartment of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 17 South Panjiayuan Lane, Chaoyang District, Beijing, 100021, People’s Republic of ChinaTel +8613911075626Email yihebalichi@hotmail.comBackground: Leiomyosarcoma (LMS) accounts for 24% of all soft tissue sarcomas (STSs) and this STS subtype has high metastatic potential. Previous studies indicated the best median progression-free survival (mPFS) time was 9.2 months and the best overall response rate (ORR) was 30.9%. We evaluated the efficacy and safety of epirubicin combined with temozolomide (EPI-TMZ) for treatment of advanced LMS.Methods: This was a retrospective review of the records of patients with advanced LMS at the National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College. All patients initiated EPI-TMZ treatment between January 2018 and December 2020.Results: We examined 15 patients who received EPI-TMZ for LMS. This was a first-line treatment in 6 patients, a second- or third-line treatment in 7 patients, and a fourth-line treatment in 2 patients. At the time of data cutoff (April 25, 2021), the median PFS was 10 months, 1 patient had clinical complete response (cCR), 7 had partial response (PR), and 7 had stable disease (SD). The overall response rate (ORR) was 53.3% (8/15) and the disease control rate (DCR) was 100.0% (15/15). The most common treatment-related adverse effects were leukopenia, neutropenia, thrombocytopenia, anemia, nausea, vomiting, fatigue, and oral mucositis. One patient had severe adverse effect (febrile neutropenia), but there were no treatment-related deaths.Conclusion: EPI-TMZ is potentially effective for treatment of advanced LMS, and the adverse effects appear tolerable. EPI-TMZ provided better outcomes than reported in previous studies of other treatments for advanced LMS.Keywords: epirubicin, temozolomide, advanced leiomyosarcoma, chemotherapy

This study utilizes synchrotron X-ray micro-tomography and pore scale modeling to investigate the process of gas exsolution and how it affects non-wetting phase relative permeability. Exsolved gas distributions are measured on Domengine and Boise sandstone samples using synchrotron X-ray micro-tomography. Observed gas phase distributions are compared to a new model that simulates the growth and distribution of exsolved gas phase at the pore-scale. Water relative permeability curves are calculated using a Stokes flow simulator with modeled and observed gas distributions, under various conditions, such as rock geometry, and pressure depletion rates. By comparing the actual bubble distributions with modeled distributions, we conclude that exsolved gas is more likely to form and accumulate at locations with higher water velocities. This suggests that convective delivery of CO2 to the gas bubble is a primary mechanism for bubble growth, as compared to diffusive transport through the aqueous phase. For carbonated brine flowing up a fault at half a meter per day, with 5% exsolved gas, the water relative permeability is estimated to be 0.6∼0.8 for various sandstones. The reduction of water mobility reduces upward brine migration when even a small amount of exsolution occurs.

Many next-generation e-science applications require fast and reliable transfer of large volumes of data with guaranteed performance, which is typically enabled by the bandwidth reservation service in high-performance networks. One prominent issue in such network environments with large footprints is that node and link failures are inevitable, hence potentially degrading the quality of data transfer. We consider two generic types of bandwidth reservation requests (BRRs) concerning data transfer reliability: (i) to achieve the highest data transfer reliability under a given data transfer deadline, and (ii) to achieve the earliest data transfer completion time while satisfying a given data transfer reliability requirement. We propose two periodic bandwidth reservation algorithms with rigorous optimality proofs to optimize the scheduling of individual BRRs within BRR batches. The efficacy of the proposed algorithms is illustrated through extensive simulations in comparison with scheduling algorithms widely adopted in production networks in terms of various performance metrics.

Ling Zuo,1 Hongyu Tao,2 Huanli Xu,2 Cong Li,2 Gan Qiao,1,3 Mingyue Guo,1 Shousong Cao,1 Minghua Liu,1 Xiukun Lin1 1Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan 646000, People’s Republic of China; 2Department of Pharmacology, School of Basic Medicine, Capital Medical University, Beijing 100069, People’s Republic of China; 3Central Nervous System Drug Key Laboratory of Sichuan Province, Luzhou, Sichuan 646000, People’s Republic of ChinaCorrespondence: Xiukun Lin; Minghua Liu Tel +86 830 316 2291; +86 830 319 3872Email xiukunLin@126.com; liumhvip@163.comPurpose: MiR-34a, which acts as an important tumor suppressor gene, plays an important role in pancreatic cancer. However, the therapeutic application of miR-34a is limited by the lack of an effective delivery system. In the present study, we synthesize exosomes-coated miR-34a (exomiR-34a), and the anticancer effect of exomiR-34a was evaluated in pancreatic cancer.Materials and Methods: An ultrasound approach was used to synthesize exomiR-34a, and its transfection efficiency was examined by confocal microscopy and flow cytometry. The level of miR-34a and its targeted gene Bcl-2 was detected by real-time quantitative PCR (qRT-PCR). MTT analysis was performed to determine the effect of exomiR-34a on the growth of pancreatic cancer cells. Annexin-V/PI double staining and Western blot analysis were carried out to determine the apoptosis of the pancreatic cancer cells. The xenograft nude mice model bearing human pancreatic cancer Panc28 cells was used to determine the antitumor effect of exomiR-34a in vivo.Results: The exomiR-34a could cross the cell membrane efficiently, and downregulated the expression of the targeted gene Bcl-2. Treatment with exomiR-34a inhibited the growth of the pancreatic cancer cells significantly and the nanoparticles also induced apoptosis in cancer cells via affecting the expression of apoptotic-related genes. In vivo study using xenograft nude mice bearing Panc28 cancer cells revealed that exomiR-34a suppressed the growth of tumors significantly.Conclusion: ExomiR-34a can inhibit the growth of pancreatic cancer both in vitro and in vivo. Targeting miR-34a is a promising strategy for the treatment of pancreatic cancer. ExomiR-34a has the potential to be developed as a novel anticancer agent for the treatment of human pancreatic malignancy.Keywords: pancreatic cancer, miR-34a, exosomes, Bcl-2, anticancer

Xiaofang Jiang,1,* Lin Zhou,2,3,* Lihua Zuo,2,3 Xiaohui Wang,4 Yingying Shi,2,3 Xiangyu Du,5 Jun Zhang,2,3 Liwei Liu,2,3 Zhuolun Li,2,3 Lianping Xue,2,3 Xin Liu,1 Zhi Sun2,3 1Department of Traditional Chinese Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province 450052, People’s Republic of China; 2Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province 450052, People’s Republic of China; 3Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou, Henan Province 450052, People’s Republic of China; 4Department of Ultrasonography, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province 450052, People’s Republic of China; 5School of Basic Medical Science, Henan University, Kaifeng, Henan Province 475001, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhi Sun; Lin ZhouDepartment of Pharmacy, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Erqi District, Zhengzhou 450052, Henan Province, People’s Republic of ChinaTel/Fax +86 371 66862570Email sunzhi2013@163.com; fcczhoul@zzu.edu.cnPurpose: Shenkang injection, a traditional Chinese herbal prescription, had been widely used in renal disease due to its perfect curative effect. In this research, a novel, sensitive, accurate and rapid liquid chromatography-tandem mass spectrometric method was developed to simultaneously detect the seven active ingredients in rat plasma of Shenkang injection and investigate its pharmacokinetic behaviors with metabolism profiling meanwhile.Methods: For accurate pharmacokinetic quantitation, a WATERS ACQUITY UPLC® BEH C18 column was used to perform a separation and acetonitrile-water (0.1% formic acid) was selected as mobile phase for gradient elution with a flow rate of 0.20 mL/min. A heated electrospray ionization with selective reaction monitoring mode was used to monitor the precursor-product ion transitions for all the analytes and IS.Results: They all showed good linearity over a wide concentration range (r> 0.996 3) and the lower limit of quantification (LLOQ) was 0.1– 1.0 ng/mL for analytes. The validation parameters were all within the acceptable limits. Furthermore, for metabolism profiling study, metabolites of the seven ingredients were identified from the rat plasma based on the accurate mass and fragment ions. The metabolic pathways mainly focus on reduction, dehydration and conjugation.Conclusion: This study provided an overview of disposition of Shenkang injection, which is highly instructive for better understanding the effectiveness and toxicity of this drug.Keywords: Shenkang injection, pharmacokinetics, metabolism profiling, UHPLC-MS/MS, UHPLC-Q-orbitrap HRMS

Xiao-ling Liao,1 Li-jun Zuo,1 Ning Zhang,2 Yang Yang,2 Yue-song Pan,3 Xiang-long Xiang,3 Ling-yun Chen,4 Xia Meng,3 Hao Li,3 Xing-quan Zhao,1 Yi-long Wang,1 Chun-xue Wang,2 Jiong Shi,3 Yong-jun Wang1 On behalf of the Impairment of CognitiON and Sleep quality for patients after acute ischemic stroke or transient ischemic attack (ICONS) Investigators1Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Department of Neuropsychology, Beijing Tiantan Hospital, Capital Medical University, Beijing, People’s Republic of China; 3National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, People’s Republic of China; 4Department of Medicine, Eisai China INC, Shanghai, People’s Republic of ChinaCorrespondence: Yong-jun WangDepartment of Neurology, Beijing Tiantan Hospital, Capital Medical University, No. 119, South Fourth Ring West Road, Fengtai District, Beijing 100070, People’s Republic of ChinaTel +86-10-59978350Fax +86-10-59973383Email yongjunwang@ncrcnd.org.cnBackground and Purpose: More and more evidence suggests that cognitive impairment (CI) after stroke is closely related to the quality of life of stroke patients. The primary aim of this study is to investigate the occurrence and longitudinal changes of CI at different stages after acute ischemic stroke (AIS) in Chinese patients.Methods: The data of this study come from the impairment of cognition and Sleep after acute ischemic stroke or transient ischemic attack in Chinese patients study (ICONS), a nationwide multicenter prospective registry that recruited consecutive AIS or transient ischemic attack in-hospital patients within 7 days after onset. Patients were followed for Montreal Cognitive Assessment (MoCA) scale at 2-week (2w), 3 months (3m) and 12 months (12m). CI was defined as MoCA score≦22. No cognitive impairment (NCI) was defined as MoCA score> 22.Results: A total of 2432 AIS patients were enrolled in this study. Overall, 72.94% of patients were male and the average age was 60.95 years. Median National Institutes of Health Stroke Scale score was 3. The occurrence rate of CI was 52.38%, 35.55% and 34.16% at 2w, 3m and 12m. Among patients with CI at 2w and 3m, 39.9% and 27.9% of patients returned to NCI at next follow-up point. At 3m and 12m follow-up, there were also 9.6% and 12.7% new CI patients. The two cognitive items with the highest abnormal rate were “Delayed recall” (89.35%, 83.33% and 82.80%) and “Visuospatial/executive” (78.91%, 73.42% and 70.08%). The cognitive item with the highest percentage of improved patients was “Orientation” (60.91– 76.68%), and the cognitive item with the lowest percentage of improved patients was “Language” (35.85– 44.50%).Conclusion: CI had a relatively high occurrence at 2w to 12m after AIS. CI at 3m and 12m was significantly lower than that at 2w after stroke. The occurrence of abnormalities and recovery probability for different cognitive items also differed greatly.Keywords: cognitive impairment, ischemic stroke, longitudinal cohort study, occurrence