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Nasal vaccination of triple-RBD scaffold protein with flagellin elicits long-term protection against SARS-CoV-2 variants including JN.1

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Signal Transduction and Targeted Therapy 2024年第5期9卷 2312-2323页

作者： Xian Li Mengxin Xu Jingyi yang Li Zhou Lin Liu Min Li Shasha Wang Mei-Qin Liu Zhixiang Huang Zhen Zhang Shuning Liu Yunqi Hu Haofeng Lin Bowen Liu Ying Sun Qingguo Wu Zheng-Li Shi Ke Lan Yu Chen huimin yan Yao-Qing Chen Wuhan Institute of Virology Chinese Academy of SciencesWuhanChina Vaccine and Immunology Research Center Translational Medical Research InstituteShanghai Public Health Clinical CenterFudan UniversityShanghaiChina University of Chinese Academy of Sciences BeijingChina School of Public Health(Shenzhen) Shenzhen Campus of Sun Yat-sen UniversityShenzhenGuangdongChina State Key Laboratory of Virology Modern Virology Research CenterCollege of Life SciencesWuhan UniversityWuhanChina Aerosol Bio-Tech(Suzhou)Co. LTDSuzhouJiangsuChina National Medical Products Administration Key Laboratory for Quality Monitoring and Evaluation of Vaccines and Biological Products Sun Yat-sen UniversityGuanzhouChina

Developing a mucosal vaccine against SARS-CoV-2 is critical for combatting the epidemic.Here,we investigated long-term immune responses and protection against SARS-CoV-2 for the intranasal vaccination of a triple receptor-binding domain(RBD)scaffold protein(3R-NC)adjuvanted with a flagellin protein(KFD)(3R-NC+KFDi.n).In mice,the vaccination elicited RBD-specific broad-neutralizing antibody responses in both serum and mucosal sites sustained at high level over a year.This long-lasting humoral immunity was correlated with the presence of long-lived RBD-specific IgG-and IgA-producing plasma cells,alongside the Th17 and Tfh17-biased T-cell responses driven by the KFD adjuvant.Based upon these preclinical findings,an open labeled clinical trial was conducted in individuals who had been primed with the inactivated SARS-CoV-2(IAV)vaccine.With a favorable safety profile,the 3R-NC+KFDi.n boost elicited enduring broad-neutralizing IgG in plasma and IgA in salivary secretions.To meet the challenge of frequently emerged variants,we further designed an updated triple-RBD scaffold protein with mutated RBD combinations,which can induce adaptable antibody responses to neutralize the newly emerging variants,including JN.1.Our findings highlight the potential of the KFD-adjuvanted triple-RBD scaffold protein is a promising prototype for the development of a mucosal vaccine against SARS-CoV-2 infection.

关键词： vaccination vaccine sustained

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Phosphatidic acid-enabled MKL1 contributes to liver regeneration:Translational implication in liver failure

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Acta Pharmaceutica Sinica B 2024年第1期14卷 256-272页

作者： Jiawen Zhou Xinyue Sun Xuelian Chen huimin Liu Xiulian Miao yan Guo Zhiwen Fan Jie Li Yong Xu Zilong Li State Key Laboratory of Natural Medicines Department of PharmacologyChina Pharmaceutical UniversityNanjing 211198China Institute of Biomedical Research Liaocheng UniversityLiaocheng 252200China Department of Pathology Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical SchoolNanjing 210008China Department of Infectious Diseases Nanjing Drum Tower Hospital Affiliated with Nanjing University Medical SchoolNanjing 210008China Institute of Viruses and Infectious Diseases Nanjing UniversityNanjing 210008China

Liver regeneration following injury aids the restoration of liver mass and the recovery of liver function.In the present study we investigated the contribution of megakaryocytic leukemia 1(MKL1),a transcriptional modulator,to liver regeneration.We report that both MKL1 expression and its nuclear translocation correlated with hepatocyte proliferation in cell and animal models of liver regeneration and in liver failure patients.Mice with MKL1 deletion exhibited defective regenerative response in the liver.Transcriptomic analysis revealed that MKL1 interacted with E2F1 to program pro-regenerative transcription.MAPKAPK2 mediated phosphorylation primed MKL1 for its interaction with E2F1.Of interest,phospholipase d2 promoted MKL1 nuclear accumulation and liver regeneration by catalyzing production of phosphatidic acid(PA).PA administration stimulated hepatocyte proliferation and enhanced survival in a MKL1-dependent manner in a pre-clinical model of liver failure.Finally,PA levels was detected to be positively correlated with expression of pro-regenerative genes and inversely correlated with liver injury in liver failure patients.In conclusion,our data reveal a novel mechanism whereby MKL1 contributes to liver regeneration.Screening for small-molecule compounds boosting MKL1 activity may be considered as a reasonable approach to treat acute liver failure.

关键词： Liver failure Liver regeneration Transcription regulation Transcription factor Hepatocytes Phosphatidic acid Phospholipase d2 Translational medicine

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RNA sequencing of exosomes secreted by fibroblast and Schwann cells elucidates mechanisms underlying peripheral nerve regeneration

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Neural Regeneration Research 2024年第8期19卷 1812-1821页

作者： Xinyang Zhou Yehua Lv huimin Xie yan Li Chang Liu Mengru Zheng Ronghua Wu Songlin Zhou Xiaosong Gu Jingjing Li Daguo Mi Suzhou Medical College of Soochow University SuzhouJiangsu ProvinceChina Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education Co-Innovation Center of NeuroregenerationNantong UniversityNantongJiangsu ProvinceChina Department of Orthopedic Nantong Traditional Chinese Medicine HospitalNantongJiangsu ProvinceChina Nantong Stomatological Hospital Affiliated to Nantong University NantongJiangsu ProvinceChina Department of General Practice Affiliated Hospital of Nantong UniversityNantongJiangsu ProvinceChina

Exosomes exhibit complex biological functions and mediate a variety of biological processes,such as promoting axonal regeneration and functional recove ry after injury.Long non-coding RNAs(IncRNAs)have been reported to play a crucial role in axonal regeneration.Howeve r,the role of the IncRNA-microRNAmessenger RNA(mRNA)-competitive endogenous RNA(ceRNA)network in exosome-mediated axonal regeneration remains unclear.In this study,we performed RNA transcriptome sequencing analysis to assess mRNA expression patterns in exosomes produced by cultured fibroblasts(FC-EXOs)and Schwann cells(SCEXOs).Diffe rential gene expression analysis,Gene Ontology analysis,Kyoto Encyclopedia of Genes and Genomes analysis,and protein-protein intera ction network analysis were used to explo re the functions and related pathways of RNAs isolated from FC-EXOs and SC-EXOs.We found that the ribosome-related central gene Rps5 was enriched in FC-EXOs and SC-EXOs,which suggests that it may promote axonal regeneration.In addition,using the miRWalk and Starbase prediction databases,we constructed a regulatory network of ceRNAs targeting Rps5,including 27 microRNAs and five IncRNAs.The ceRNA regulatory network,which included Ftx and Miat,revealed that exsosome-derived Rps5 inhibits scar formation and promotes axonal regeneration and functional recovery after nerve injury.Our findings suggest that exosomes derived from fibro blast and Schwann cells could be used to treat injuries of peripheral nervous system.

关键词： ceRNA network exosomes fibroblast cells Gene Ontology(GO) Kyoto Encyclopedia of Genes and Genomes(KEGG) protein-protein interaction(PPI)networks RNA-seq Schwann cells

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Trogocytosis of CAR molecule regulates CAR-T cell dysfunction and tumor antigen escape

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Signal Transduction and Targeted Therapy 2024年第1期9卷 326-337页

作者： You Zhai Yicong Du Guanzhang Li Mingchen Yu huimin Hu Changqing Pan Di Wang Zhongfang Shi Xu yan Xuesong Li Tao Jiang Wei Zhang Department of Molecular Neuropathology Beijing Neurosurgical InstituteCapital Medical UniversityBeijingPR China Department of Neurosurgery Beijing Tiantan HospitalCapital Medical UniversityBeijingPR China Department of Urology Peking University First HospitalInstitute of UrologyPeking UniversityNational Urological Cancer CenterBeijingPR China Department of Pathophysiology Beijing Neurosurgical InstituteCapital Medical UniversityBeijingPR China China National Clinical Research Center for Neurological Diseases BeijingPR China Center of Brain Tumor Beijing Institute for Brain DisordersBeijingPR China Research Unit of Accurate Diagnosis Treatmentand Translational Medicine of Brain TumorsChinese Academy of Medical SciencesBeijingPR China Chinese Glioma Genome Atlas Network(CGGA)and Asian Glioma Genome Atlas Network(AGGA) BeijingPR China

Chimeric antigen receptor(CAR)T-cell therapy has demonstrated clinical response in treating both hematologic malignancies and solid tumors.Although instances of rapid tumor remissions have been observed in animal models and clinical trials,tumor relapses occur with multiple therapeutic resistance mechanisms.Furthermore,while the mechanisms underlying the long-term therapeutic resistance are well-known,short-term adaptation remains less understood.However,more views shed light on short-term adaptation and hold that it provides an opportunity window for long-term resistance.In this study,we explore a previously unreported mechanism in which tumor cells employ trogocytosis to acquire CAR molecules from CAR-T cells,a reversal of previously documented processes.This mechanism results in the depletion of CAR molecules and subsequent CAR-T cell dysfunction,also leading to short-term antigen loss and antigen masking.Such type of intercellular communication is independent of CAR downstream signaling,CAR-T cell condition,target antigen,and tumor cell type.However,it is mainly dependent on antigen density and CAR sensitivity,and is associated with tumor cell cholesterol metabolism.Partial mitigation of this trogocytosis-induced CAR molecule transfer can be achieved by adaptively administering CAR-T cells with antigen density-individualized CAR sensitivities.Together,our study reveals a dynamic process of CAR molecule transfer and refining the framework of clinical CAR-T therapy for solid tumors.

关键词： Together instance depletion

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Physical activity and exercise in liver cancer

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Liver Research 2024年第1期8卷 22-33页

作者： Haiyan Chen huimin Zhou Bo Wu Hanxiao Lu Jie Zhang yan Zhang Yuanlong Gu Guangwen Zhou Jie Xiang Jun yang Department of General Surgery Affiliated Hospital of Jiangnan UniversityJiangsuChina School of Medicine Jiangnan University WuxiJiangsuChina Department of General Surgery Shanghai Sixth People's HospitalShanghaiChina Department of Endocrinology Wuxi Mingci Cardiovascular HospitalWuxiJiangsuChina

Sarcopenia and physical deconditioning are common complications in patients with liver cancer,which are frequently caused by insufficient physical activity and poor nutritional status,resulting in physical frailty and a significant impact on the patient's physical fitness.Notably,sarcopenia,frailty,and poor cardiopulmonary endurance have all been linked to higher mortality rates among patients with liver cancer.Exercise intervention significantly improves various health parameters in liver cancer patients,including metabolic syndrome,muscle wasting,cardiorespiratory endurance,health-related quality of life,and reduction in hepatic venous pressure gradient.However,the link between physical exercise and liver cancer is commonly overlooked.In this article,we will examine the impact of exercise on liver cancer and present the most recent evidence on the best types of exercise for various stages of liver cancer.This article also summarizes and discusses the molecular mechanisms that control metabolism and systemic immune function in tumors.In brief,physical exercise should be considered an important intervention in the prevention and treatment of liver cancer and its complications.

关键词： Physical activity(PA) Exercise Liver cancer Sarcopenia Frailty Rehabilitation

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Polydopamine/polyethyleneimine co-crosslinked graphene oxide for the enhanced tribological performance of epoxy resin coatings

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Journal of Materials Science & Technology 2023年第5期136卷 13-20页

作者： Shaofeng Zhou Jin yan Jialin Chen huimin yan Yin Zhang Jin Huang Guizhe Zhao Qiaoxin Zhang Yaqing Liu Shanxi Province Key Laboratory of Functional Nanocomposites and School of Materials Science and EngineeringNorth University of ChinaTaiyuan 030051China School of Mechanical and Electronic Engineering Wuhan University of TechnologyWuhan 430070China Queen Marry University of London Engineering School Northwestern Polytechnical UniversityXi’an 710129China Southwest Technology and Engineering Research Institute Chongqing 400039China School of Chemistry and Chemical Engineering and Chongqing Key Laboratory of Soft-Matter Material Chemistry and Function ManufacturingSouthwest UniversityChongqing 400715China

To enhance the wear resistance of graphene oxide(GO)nano-filled epoxy resin(EP)coatings with ex-cellent dispersion,GO were modified using a co-crosslinking strategy between polydopamine(PDA)and polyethyleneimine(PEI)through an environmentally friendly,simple and low-cost process.High-density amino-branched PEI and highly adhesive PDA formed covalent bond cross-links with GO(PDA/PEI-GO)through the Michael addition and Schiffbase reactions.With the introduction of amino active sites,the PDA self-polymerization reaction time was significantly shorted from 24 to 6 h.The covalently cross-linked network increased the lamellar spacing of GO and enhanced the interfacial bonds between the PDA/PEI-GO lamellae and EP matrix.Due to the improved dispersion and surface activity of GO,the PDA/PEI-GO nano-filled EP coating exhibited excellent wear resistance.Reciprocating friction with GCr15 stainless steel ball,the average friction coefficient and wear rate of the coating were reduced by 31.9%and 62.7%,respectively,compared to the pure EP coating.In addition,the wear mechanism of the PDA/PEI-GO/EP coating changed from adhesive and fatigue wear to abrasive wear,and it maintained good wear resistance by forming a GO lubrication transfer film on the counterpart surface.Therefore,this study may provide a new strategy for improving the dispersion of graphene in wear-resistant polymer materials for practical applications.

关键词： Graphene oxide Co-crosslinking Epoxy coatings Tribological properties

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Effect on serum metabolomics of rats with premature ovarian insufficiency by Zhibian(BL54) through Shuidao(ST28) acupuncture

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Journal of Traditional Chinese Medicine 2024年第4期 722-733页

作者： yan Jing FENG huimin QIU Fang WANG Haijun YIN Luyun JIN Xiaofei ZHAO Jiyu WANG Hongyang yan Xiaoqin Second Clinical College of Shanxi University of Traditional Chinese Medicine Research Center of Experimental Acupuncture Science Tianjin University of Traditional Chinese Medicine Department of Cervical and Lumbar Vertebral Diseases Jinzhong Hospital Affiliated to Shanxi University of Traditional Chinese Medicine

OBJECTIVE: To analyze the serum metabolic targets of the "Zhibian(BL54) through Shuidao(ST28)" acupuncture technique in cyclophosphamide(CTX)-induced premature ovarian insufficiency(POI) model rats and to elucidate the potential molecular mechanism of acupuncture in improving POI. METHODS: We used an intraperitoneal injection of CTX to establish the POI rat model(POI group) and compared serum hormone levels and ovarian histopathological changes to evaluate the effect of the Zhibian(BL54) through Shuidao(ST28) technique(ZS + POI group) on ovarian function. Then, nontargeted metabolomics was performed using rat serum by ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry(UPLC-Q-TOF/MS). RESULTS: After acupuncture intervention, the serum hormone levels and ovarian pathological morphology of POI rats were effectively improved. Moreover, UPLC-Q-TOF/MS results showed that the ZS+POI group showed a significant reversal of the levels of 6 differential metabolites. Among them, the levels of four serum metabolic markers, divanillyltetrahydrofuran ferulate, trans-ferulic acid, tryptamine, and neuraminic acid, increased significantly. Further analysis of biological effects showed that all metabolites were involved in the regulation of reproductive hormone levels and antioxidant and antiapoptotic effects. CONCLUSIONS: The "Zhibian(BL54) through Shuidao(ST28)" acupuncture method may improve the ovarian function of POI rats by regulating serum metabolite markers to exert antioxidant and antiapoptotic effects, which provides a theoretical basis for the clinical application of acupuncture in the treatment of POI.

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An mRNA vaccine encoding Chikungunya virus E2-E1 protein elicits robust neutralizing antibody responses and CTL immune responses

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Virologica Sinica 2022年第2期37卷 266-276页

作者： Ningning Ge Jin Sun Zhihua Liu Jiayi Shu huimin yan Zhihua Kou Yu Wei Xia Jin CAS Key Laboratory of Molecular Virology and Immunology Institut Pasteur of ShanghaiChinese Academy of SciencesShanghai 200031China University of Chinese Academy of Sciences Beijing 100049China Shanghai Public Health Clinical Center Fudan UniversityShanghai 200540China Wuhan Institute of Virology Chinese Academy of SciencesWuhan 430071China

Arthropod-borne chikungunya virus(CHIKV)infection can cause a debilitating arthritic disease in human.However,there are no specific antiviral drugs and effective licensed vaccines against CHIKV available for clinical use.Here,we developed an m RNA-lipid nanoparticle(m RNA-LNP)vaccine expressing CHIKV E2-E1 antigen,and compared its immunogenicity with soluble recombinant protein s E2-E1 antigen expressed in S2 cells.For comparison,we first showed that recombinant protein antigens mixed with aluminum adjuvant elicit strong antigenspecific humoral immune response and a moderate cellular immune response in C57BL/6 mice.Moreover,s E2-E1vaccine stimulated 12-23 folds more neutralizing antibodies than s E1 vaccine and s E2 vaccine.Significantly,when E2-E1 gene was delivered by an m RNA-LNP vaccine,not only the better magnitude of neutralizing antibody responses was induced,but also greater cellular immune responses were generated,especially for CD8+T cell responses.Moreover,E2-E1-LNP induced CD8~+T cells can perform cytotoxic effect in vivo.Considering its better immunogenicity and convenience of preparation,we suggest that more attention should be placed to develop CHIKV E2-E1-LNP m RNA vaccine.

关键词： Chikungunya virus(CHIKV) mRNA vaccine Neutralizing antibody Cytotoxic T-lymphocytes(CTL)

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Mucosal epithelial cells: the initial sentinels and responders controlling and regulating immune responses to viral infections

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Cellular & Molecular Immunology 2021年第7期18卷 1628-1630页

作者： Jingyi yang huimin yan Vaccine and Immunology Research Center Translational Medical Research InstituteShanghai Public Health Clinical CenterFudan UniversityShanghaiChina

In the context of host defense,immune protection is mostly provided by hematopoietic immune cells,including neutrophils,macrophages,T cells,B cells,etc.However,in recent decades,emerging evidence has identified many additional diverse roles of nonhematopoietic cells in mammalian immunity,although most of these studied focused on a single-cell type.In July 2020,Krausgruber et al.in the laboratory of Christoph Bock published the paper“Structural cells are key regulators of organ-specific immune responses”in Nature.The authors used multiomics and systematically investigated the regulation of immune-associated genes in three major types of structural cells(epithelial cells,endothelial cells,and fibroblasts)in 12 different organs in mice.

关键词： immunity organs mostly

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Effects of Chinese herbs in children with Henoch-Schonlein purpura nephritis:a randomized controlled trial

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Journal of Traditional Chinese Medicine 2014年第1期34卷 15-22页

作者： Dandan Ding huimin yan Xiaofang Zhen Traditional Chinese Medicine Department Beijing Children's Hospital Affiliated to Capital Medical University

OBJECTIVE:To research the curative effect of Chinese herbs for clearing away heat,promoting diuresis,nourishing the kidney,and consolidating essence in children with Henoch-Schonlein purpura nephritis(HSPN)with internal accumulation of damp-toxin using randomized controlled observations on large samples.To seek the mechanism of the therapy and its scope of indications.METHODS:Overall,186 children with HSPN were randomly divided into two groups:treatment group(n=126)treated with Chinese herbs for clearing heat and promoting diuresis and a control group(n=60)treated with Western Medicine.The treatment was carried out for three courses of 4weeks each.We recorded changes in patient urine routines,24 h urinary protein,blood-coagulating series,immunoglobulin and T-cell subgroups,and improvements in main symptoms.We evaluated the alleviation of clinical symptoms and the improvement of proteinuria,hematuria,and other lab-oratory test results.Finally,we analyzed the patient population suitable for this therapy according to the relationship between the grouping of patient body weight and curative effect.RESULTS:Damp-heat syndrome improved in the treatment group,with a significant difference in total effective rate after a 4-week treatment(χ2=13.5220,P=0.0002)and in curative rate after a12-week treatment(χ2=6.3410,P=0.0118),compared to those in the control group.The curative effect in the treatment group was greater than that in the control group but there was no statistical difference between the two groups.The curative effect after a 4-week treatment of patients in the treatment group weighing 30 kg or less based on Traditional Chinese Medicine(TCM)signs and urinary protein was significantly greater than that in the control group.However,there was no statistical difference in the curative effect on urinary red cells and various indexes after a 12-week treatment between the two groups.CONCLUSION:Therapy for clearing away heat,promoting diuresis,nourishing the kidney,and consolidating essence using TCM is effective in child

关键词：随机对照试验中国传统医学过敏性肾炎紫癜儿童药材西药治疗

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