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Gut microbial metabolite targets HDAC3-FOXK1-interferon axis in fibroblast-like synoviocytes to ameliorate rheumatoid arthritis

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Bone Research 2024年第2期12卷 421-437页

作者： Hongzhen Chen xuekun fu Xiaohao Wu Junyi Zhao Fang Qiu Zhenghong Wang Zhuqian Wang Xinxin Chen Duoli Xie Jie Huang Junyu Fan Xu Yang Yi Song Jie Li Dongyi He Guozhi Xiao Aiping Lu Chao Liang Department of Systems Biology School of Life SciencesSouthern University of Science and TechnologyGuangdong Provincial Key Laboratory of Cell Microenvironment and Disease ResearchShenzhen Key Laboratory of Cell MicroenvironmentShenzhen 518055China Institute of Integrated Bioinfomedicine and Translational Science(IBTS) School of Chinese MedicineHong Kong Baptist UniversityHong Kong SAR 999077China Department of Biochemistry School of MedicineSouthern University of Science and TechnologyGuangdong Provincial Key Laboratory of Cell Microenvironment and Disease ResearchShenzhen Key Laboratory of Cell MicroenvironmentShenzhen 518055China Division of Immunology and Rheumatology Stanford UniversityStanfordCA 94305USA VA Palo Alto Health Care System Palo AltoCA 94304USA Institute of Plant and Food Science Department of BiologySouthern University of Science and TechnologyShenzhen 518055China Department of Rheumatology Guanghua Hospital Affiliated to Shanghai University of Traditional Chinese MedicineShanghai University of Traditional Chinese MedicineShanghaiChina Department of Computational Biology St.Jude Children’s Research HospitalMemphisTNUSA Department of Laboratory Medicine Peking University Shenzhen HospitalShenzhenChina Guangdong-Hong Kong-Macao Joint Lab on Chinese Medicine and Immune Disease Research Guangzhou 510006China Shanghai University of Traditional Chinese Medicine Shanghai 200032China State Key Laboratory of Proteomics National Center for Protein Sciences(Beijing)Beijing Institute of Lifeomics100850 BeijingChina

Rheumatoid arthritis(RA)is an autoimmune *** studies hold an opinion that gut microbiota is environmentally acquired and associated with RA ***,accumulating evidence demonstrates that genetics also shape the gut *** is known that some strains of inbred laboratory mice are highly susceptible to collagen-induced arthritis(CIA),while the others are resistant to ***,we show that transplantation of fecal microbiota of CIA-resistant C57BL/6J mice to CIA-susceptible DBA/1J mice confer CIA resistance in DBA/1J mice.C57BL/6J mice and healthy human individuals have enriched *** than DBA/1J mice and RA *** of *** prevents CIA in DBA/1J *** identify that *** mainly produces propionate and C57BL/6J mice and healthy human individuals have higher level of ***-like synoviocytes(FLSs)in RA are activated to undergo tumor-like *** disrupts HDAC3-FOXK1 interaction to increase acetylation of FOXK1,resulting in reduced FOXK1 stability,blocked interferon signaling and deactivation of *** treat CIA mice with propionate and show that propionate attenuates ***,a combination of propionate with anti-TNF etanercept synergistically relieves *** results suggest that *** or propionate could be an alternative or complementary approach to the current therapies.

关键词： HDAC3 cytes interferon

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LIM domain proteins Pinch1/2 regulate chondrogenesis and bone mass in mice

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Bone Research 2020年第4期8卷 416-428页

作者： Yiming Lei xuekun fu Pengyu Li Sixiong Lin Qinnan Yan Yumei Lai Xin Liu Yishu Wang Xiaochun Bai Chuanju Liu Di Chen Xuenong Zou Xu Cao Huiling Cao Guozhi Xiao Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research Shenzhen Key Laboratory of Cell Microenvironmentand School of MedicineSouthern University of Science and TechnologyShenzhen 518055China Department of Spine Surgery Orthopedic Research InstituteThe First Affiliated Hospital of Sun Yat-sen UniversityGuangdong Provincial Key Laboratory of Orthopedics and TraumatologyGuangzhou 510080China Department of Orthopedic Surgery Rush University Medical CenterChicagoIL 60612USA Department of Cell Biology School of Basic Medical SciencesSouthern Medical UniversityGuangzhou 510515China Department of Orthopedic Surgery New York University School of MedicineNew YorkNY 10003USA Department of Cell Biology New York University School of MedicineNew YorkNY 10016USA Research Center for Human Tissues and Organs Degeneration Shenzhen Institutes of Advanced TechnologyChinese Academy of SciencesShenzhen 518055China Department of Orthopedic Surgery The Johns Hopkins UniversityBaltimoreMD 21205USA

The LIM domain-containing proteins Pinch1/2 regulate integrin activation and cell–extracellular matrix interaction and ***,we report that deleting Pinch1 in limb mesenchymal stem cells(MSCs)and Pinch2 globally(double knockout;dKO)in mice causes severe chondrodysplasia,while single mutant mice do not display marked *** deletion decreases chondrocyte proliferation,accelerates cell differentiation and disrupts column *** loss drastically reduces Smad2/3 protein expression in proliferative zone(PZ)chondrocytes and increases Runx2 and Col10a1 expression in both PZ and hypertrophic zone(HZ)*** loss increases sclerostin and Rankl expression in HZ chondrocytes,reduces bone formation,and increases bone resorption,leading to low bone *** vitro studies revealed that Pinch1 and Smad2/3 colocalize in the nuclei of *** its C-terminal region,Pinch1 interacts with Smad2/3 *** loss increases Smad2/3 ubiquitination and degradation in primary bone marrow stromal cells(BMSCs).Pinch loss reduces TGF-β-induced Smad2/3 phosphorylation and nuclear localization in primary ***,compared to those from single mutant mice,BMSCs from dKO mice express dramatically lower protein levels ofβ-catenin and Yap1/Taz and display reduced osteogenic but increased adipogenic differentiation ***,ablating Pinch1 in chondrocytes and Pinch2 globally causes severe osteopenia with subtle limb ***,our findings demonstrate critical roles for Pinch1/2 and a functional redundancy of both factors in the control of chondrogenesis and bone mass through distinct mechanisms.

关键词： Smad2/3 globally mass

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Kindlin-2 regulates skeletal homeostasis by modulating PTH1R in mice

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Signal Transduction and Targeted Therapy 2021年第1期6卷 131-143页

作者： xuekun fu Bo Zhou Qinnan Yan Chu Tao Lei Qin Xiaohao Wu Sixiong Lin Sheng Chen Yumei Lai Xuenong Zou Zengwu Shao Meiqing Wang Di Chen Wenfei Jin Youqiang Song Huiling Cao Ge Zhang Guozhi Xiao School of Medicine Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Researchand Shenzhen Key Laboratory of Cell MicroenvironmentSouthern University of Science and Technology1088 Xue Yuan Road518055 ShenzhenGuangdongChina Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases School of Chinese MedicineHong Kong Baptist University999077 Hong KongSARChina Department of Biology Southern University of Science and Technology518055 ShenzhenChina School of Biomedical Sciences University of Hong Kong21 Sassoon RoadHong KongChina Department of Spine Surgery Orthopedic Research InstituteThe First Affiliated Hospital of Sun Yat-sen UniversityGuangdong Provincial Key Laboratory of Orthopedics and Traumatology510080 GuangzhouChina Department of Orthopedics Union HospitalTongji Medical CollegeHuazhong University of Science and Technology430022 WuhanChina Department of Orthopedic Surgery Rush University Medical CenterChicagoIL 60612USA State Key Laboratory of Military Stomatology National Clinical Research Center for Oral DiseasesShanxi International Joint Research Center for Oral DiseasesDepartment of Oral Anatomy and Physiology and TMDSchool of Stomatologythe Fourth Military Medical University145 Changle West RoadXi’anChina Research Center for Human Tissues and Organs Degeneration Shenzhen Institutes of Advanced TechnologyChinese Academy of Sciences518055 ShenzhenChina

In vertebrates,the type 1 parathyroid hormone receptor(PTH1R)is a critical regulator of skeletal development and homeostasis;however,how it is modulated is incompletely *** we report that deleting Kindlin-2 in osteoblastic cells using the mouse 10-kb Dmp1-Cre largely neutralizes the intermittent PTH-stimulated increasing of bone volume fraction and bone mineral density by impairing both osteoblast and osteoclast formation in murine adult ***-cell profiling reveals that Kindlin-2 loss increases the proportion of osteoblasts,but not mesenchymal stem cells,chondrocytes and fibroblasts,in non-hematopoietic bone marrow cells,with concomitant depletion of osteoblasts on the bone surfaces,especially those stimulated by ***,haploinsufficiency of Kindlin-2 and Pth1r genes,but not that of either gene,in mice significantly decreases basal and,to a larger extent,PTH-stimulated bone mass,supporting the notion that both factors function in the same genetic ***,Kindlin-2 interacts with the C-terminal cytoplasmic domain of PTH1R via aa 474–475 and Gsα.Kindlin-2 loss suppresses PTH induction of cAMP production and CREB phosphorylation in cultured osteoblasts and in ***,PTH promotes Kindlin-2 expression in vitro and in vivo,thus creating a positive feedback regulatory ***,estrogen deficiency induced by ovariectomy drastically decreases expression of Kindlin-2 protein in osteocytes embedded in the bone matrix and Kindlin-2 loss essentially abolishes the PTH anabolic activity in bone in ovariectomized ***,we demonstrate that Kindlin-2 functions as an intrinsic component of the PTH1R signaling pathway in osteoblastic cells to regulate bone mass accrual and homeostasis.

关键词： homeostasis Kindlin skeletal

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扎实推进成都市场监管现代化

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中国市场监管研究 2023年第1期 6-9页

作者：傅学坤成都市市场监管局

党的二十大报告对全面建设社会主义现代化国家、全面推进中华民族伟大复兴进行了战略部署。市场监管现代化是建设社会主义现代化国家的重要组成部分,成都市市场监管部门要立足职能职责,坚持改革创新,研究把握新形势、新要求,谋实谋细新... 详细信息

党的二十大报告对全面建设社会主义现代化国家、全面推进中华民族伟大复兴进行了战略部署。市场监管现代化是建设社会主义现代化国家的重要组成部分,成都市市场监管部门要立足职能职责,坚持改革创新,研究把握新形势、新要求,谋实谋细新思路、新举措,切实把各项部署贯穿到市场监管现代化建设全过程。

关键词：党的二十大市场监管现代化安全治理市场环境

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一体推进法治监管、信用监管、智慧监管的路径研究

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中国市场监管研究 2023年第8期 33-37页

作者：傅学坤成都市市场监管局

市场监管现代化是中国式现代化的重要组成部分。立足成都市场监管实际,一体推进法治监管、信用监管、智慧监管,是推进市场监管现代化的必由之路,是不断提升与超大规模市场相适应、超大城市治理相匹配的市场监管综合能力的现实要求。本... 详细信息

市场监管现代化是中国式现代化的重要组成部分。立足成都市场监管实际,一体推进法治监管、信用监管、智慧监管,是推进市场监管现代化的必由之路,是不断提升与超大规模市场相适应、超大城市治理相匹配的市场监管综合能力的现实要求。本文界定了法治监管、信用监管、智慧监管的基本内涵,坚持问题导向、目标导向,走访调研经营主体、基层局(所),找准问题症结,提出以法治为根本、以信用为基础、以智慧为手段,提升市场监管综合效能的对策建议。

关键词：系统观念法治监管信用监管智慧监管

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成都构建“4+N”市场安全监管体系的实践与思考

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中国市场监管研究 2022年第8期 21-24页

作者：傅学坤成都市市场监管局

安全是发展的前提。超大城市市场监管对象量大面广,涉及老百姓的生活、市场主体的生产经营,相应的安全工作具有职能整体性、风险系统性、手段前瞻性等特征。本文研究“4+N”市场安全监管体系的内涵外延,总结成都市场安全监管的实践成效... 详细信息

安全是发展的前提。超大城市市场监管对象量大面广,涉及老百姓的生活、市场主体的生产经营,相应的安全工作具有职能整体性、风险系统性、手段前瞻性等特征。本文研究“4+N”市场安全监管体系的内涵外延,总结成都市场安全监管的实践成效,针对安全监管基础依然薄弱、风险防控难度不断加大、市场安全监管能力还有短板等问题,提出健全“4+N”市场安全监管体系的对策建议。

关键词：市场监管风险隐患闭环管理本质安全

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壮大推动高质量发展的市场力量——成都市市场主体培育发展战略研究

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中国市场监管研究 2021年第3期 8-10页

作者：傅学坤成都市市场监管局

党的十九届五中全会通过的《中共中央关于制定国民经济和社会发展第十四个五年规划和二〇三五年远景目标的建议》,将"市场主体更加充满活力"作为我国"十四五"时期经济社会发展的重要目标,将"激发各类市场主体活力"作为全面深化改革、构... 详细信息

党的十九届五中全会通过的《中共中央关于制定国民经济和社会发展第十四个五年规划和二〇三五年远景目标的建议》,将"市场主体更加充满活力"作为我国"十四五"时期经济社会发展的重要目标,将"激发各类市场主体活力"作为全面深化改革、构建高水平社会主义市场经济体制的重要任务。"十三五"时期,成都市市场主体稳健发展,从2015年末的124.7万户增至292.1万户,占全省市场主体总数的42%.

关键词：市场主体发展战略研究稳健发展万户远景目标五年规划高质量发展全面深化改革

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牢记初心使命构建市场监管新体系

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中国市场监管研究 2019年第12期 12-16页

作者：傅学坤成都市市场监管局

按照"不忘初心、牢记使命"主题教育调研工作安排,成都市市场监管局牢牢把握"守初心、担使命,找差距、抓落实"的总要求和"把学习教育、调查研究、检视问题、整改落实贯穿全过程"的具体要求,聚焦全局目标任务,坚持问题导向,结合目前市场... 详细信息

按照"不忘初心、牢记使命"主题教育调研工作安排,成都市市场监管局牢牢把握"守初心、担使命,找差距、抓落实"的总要求和"把学习教育、调查研究、检视问题、整改落实贯穿全过程"的具体要求,聚焦全局目标任务,坚持问题导向,结合目前市场监管体制改革融合阶段出现的新情况新问题新任务,围绕市场监管"管什么""怎么管"两大核心问题深入思考,就"探索建立成都市市场监管新体系"开展调研。通过深入企业走访问需,到基层局所座谈问计,组织机关干部研究问策,摸清了全市市场监管的现状,找到了市场监管的短板和问题.

关键词：市场监管基层局问题导向不忘初心整改落实融合阶段教育调研成都市

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Framework and development of data-driven physics based model with application in dimensional accuracy prediction in pocket milling

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Chinese Journal of Aeronautics 2021年第6期34卷 162-177页

作者： Zhanying CHEN Liping WANG Jiabo ZHANG Guoqiang GUO Shuailei fu Chao WANG xuekun LI Department of Mechanical Engineering Tsinghua UniversityBeijing 100084China State Key Lab of Tribology Tsinghua UniversityBeijing 100084China Beijing Spacecrafts China Academy of Space TechnologyBeijing 100094China Shanghai Spaceflight Precision Machinery Institute Shanghai 201600China

In the manufacturing of thin wall components for aerospace industry,apart from the side wall contour error,the Remaining Bottom Thickness Error(RBTE)for the thin-wall pocket component(*** shell)is of the same importance but overlooked in current *** the RBTE reduces by 30%,the weight reduction of the entire component will reach up to tens of kilograms while improving the dynamic balance performance of the large *** RBTE control requires the off-process measurement of limited discrete points on the component bottom to provide the reference value for *** leads to incompleteness in the remaining bottom thickness control and redundant measurement in *** this paper,the framework of data-driven physics based model is proposed and developed for the real-time prediction of critical quality for large components,which enables accurate prediction and compensation of RBTE value for the thin wall *** physics based model considers the primary root cause,in terms of tool deflection and clamping stiffness induced Axial Material Removal Thickness(AMRT)variation,for the RBTE *** to incorporate the dynamic and inherent coupling of the complicated manufacturing system,the multi-feature fusion and machine learning algorithm,*** Principal Component Analysis(kPCA)and kernel Support Vector Regression(kSVR),are incorporated with the physics based ***,the proposed data-driven physics based model combines both process mechanism and the system disturbance to achieve better prediction *** final verification experiment is implemented to validate the effectiveness of the proposed method for dimensional accuracy prediction in pocket milling,and the prediction accuracy of AMRT achieves 0.014 mm and 0.019 mm for straight and corner milling,respectively.

关键词： Data-driven Physics based model Thin-wall component Pocket milling Remaining bottom thickness error

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粘着斑相关蛋白Kindlin-1在血管内皮细胞的表达及功能研究

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生物骨科材料与临床研究 2021年第3期18卷 18-23页

作者：吴晓昊陶楚姚青伏学坤梁超曹惠玲肖国芝南方科技大学医学院广东深圳518055 南方科技大学生命科学学院广东深圳518055

目的探索Kindin-1蛋白在健康骨关节组织及关节炎模型骨关节组织中的表达模式及相关功能。方法分离健康小鼠、经内侧半月板失稳定术(DMM)诱导关节炎小鼠以及经胶原诱导关节炎(CIA)小鼠的骨关节组织,通过抗体免疫荧光标记分析Kindlin-1蛋... 详细信息

目的探索Kindin-1蛋白在健康骨关节组织及关节炎模型骨关节组织中的表达模式及相关功能。方法分离健康小鼠、经内侧半月板失稳定术(DMM)诱导关节炎小鼠以及经胶原诱导关节炎(CIA)小鼠的骨关节组织,通过抗体免疫荧光标记分析Kindlin-1蛋白在骨关节组织内的表达情况。筛选针对Kindlin-1的siRNA序列并进行体外功能验证。结果免疫荧光分析发现Kindlin-1主要表达于健康骨组织的骨髓腔中,进一步发现Kindlin-1信号与骨内H型血管(由CD31和Endomucin共同标记)存在共定位。在DMM和CIA模型中,Kindlin-1表达量均显著升高并可特异性地标记异常的新生血管。在人类脐静脉血管内皮细胞(HUVECs)中也可检测到Kindlin-1的高水平表达。通过siRNA敲除Kindlin-1可显著地增强HUVECs的体外迁移能力。结论粘着斑相关蛋白Kindlin-1表达于血管内皮细胞,并可作为骨关节组织内血管组织及异常血管新生的生物标志及潜在靶点。

关键词： Kindlin-1 内皮细胞骨生物学血管新生 H型血管

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