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Neddylation is a novel therapeutic target for lupus by regulating double negative T cell homeostasis

Signal Transduction and Targeted Therapy 2024年第2期9卷 738-750页

作者： Yun Zhang Lijun Du chenxi Wang Zhangsheng Jiang Qingchi duan Yiping Li Zhijun Xie Zhixing He Yi Sun Lin Huang Liwei Lu Chengping Wen Key Laboratory of Chinese medicine rheumatology of Zhejiang Province Research Institute of Chinese Medical Clinical Foundation and ImmunologyCollege of Basic Medical ScienceZhejiang Chinese Medical UniversityHangzhou 310053China Department of General Surgery Sir Run Run Shaw HospitalZhejiang University School of MedicineHangzhou 310016China Cancer Institute(Key Laboratory of Cancer Prevention and Intervention China National Ministry of Education)of the Second Affiliated Hospital and Institute of Translational MedicineZhejiang University School of MedicineHangzhou 310029China Cancer Center of Zhejiang University Hangzhou 310029China Department of Pathology and Shenzhen Institute of Research and Innovation The University of Hong KongHong KongChina Chongqing International Institute for Immunology Chongqing 400038China

Systemic lupus erythematosus(SLE),a severe autoimmune disorder,is characterized by systemic inflammatory response,autoantibody accumulation and damage to organs.The dysregulation of double-negative(DN)T cells is considered as a crucial commander during SLE.Neddylation,a significant type of protein post-translational modification(PTM),has been well-proved to regulate T cell-mediated immune response.However,the function of neddylation in SLE is still unknown.Here,we reported that neddylation inactivation with MLN4924,a specific inhibitor of NEDD8-activating enzyme E1(NAE1),or genetic abrogation of Ube2m in T cells decreased DN T cell accumulation and attenuated murine lupus development.Further investigations revealed that inactivation of neddylation blocked Bim ubiquitination degradation and maintained Bim level in DN T cells,contributing to the apoptosis of the accumulated DN T cells in lupus mice.Then double knockout(KO)lupus-prone mice(Ube2m-/-Bim-/-lpr)were generated and results showed that loss of Bim reduced Ube2m deficiency-induced apoptosis in DN T cells and reversed the alleviated lupus progression.Our findings identified that neddylation inactivation promoted Bim-mediated DN T cell apoptosis and attenuated lupus progression.Clinically,we also found that in SLE patients,the proportion of DN T cells was raised and their apoptosis was reduced.Moreover,compared to healthy groups,SLE patients exhibited decreased Bim levels and elevated Cullin1 neddylation levels.Meantime,the inhibition of neddylation induced Bim-dependent apoptosis of DN T cells isolated from SLE patients.Altogether,our findings provide the direct evidence about the function of neddylation during lupus,suggesting a promising therapeutic approach for this disease.

关键词： inactivation double finding

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Land cover classification from remote sensing images based on multi-scale fully convolutional network

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Geo-Spatial Information Science 2022年第2期25卷 278-294页

作者： Rui Li Shunyi Zheng chenxi duan Libo Wang Ce Zhang School of Remote Sensing and Information Engineering Wuhan UniversityWuhanChina Faculty of Geo-Information Science and Earth Observation(ITC) University of TwenteEnschedeThe Netherlands The State Key Laboratory of Information Engineering in Surveying Mapping and Remote SensingWuhan UniversityWuhanChina Lancaster Environment Centre Lancaster UniversityLancasterUK UK Centre for Ecology&Hydrology LancasterUK

Although the Convolutional Neural Network(CNN)has shown great potential for land cover classification,the frequently used single-scale convolution kernel limits the scope of informa-tion extraction.Therefore,we propose a Multi-Scale Fully Convolutional Network(MSFCN)with a multi-scale convolutional kernel as well as a Channel Attention Block(CAB)and a Global Pooling Module(GPM)in this paper to exploit discriminative representations from two-dimensional(2D)satellite images.Meanwhile,to explore the ability of the proposed MSFCN for spatio-temporal images,we expand our MSFCN to three-dimension using three-dimensional(3D)CNN,capable of harnessing each land cover category’s time series interac-tion from the reshaped spatio-temporal remote sensing images.To verify the effectiveness of the proposed MSFCN,we conduct experiments on two spatial datasets and two spatio-temporal datasets.The proposed MSFCN achieves 60.366%on the WHDLD dataset and 75.127%on the GID dataset in terms of mIoU index while the figures for two spatio-temporal datasets are 87.753%and 77.156%.Extensive comparative experiments and abla-tion studies demonstrate the effectiveness of the proposed MSFCN.

关键词： Spatio-temporal remote sensing images Multi-Scale Fully Convolutional Network land cover classification

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Delicate chemical structure regulation of nonfullerene acceptor for efficient and large thickness organic solar cells

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Science China Chemistry 2024年第5期67卷 1596-1604页

作者： Zhe Zhang Wanying Feng Yunxin Zhang Shaohui Yuan Yuyang Bai Peiran Wang Zhaoyang Yao chenxi Li Tainan duan Xiangjian Wan Bin Kan Yongsheng Chen State Key Laboratory and Institute of Elemento-Organic Chemistry Frontiers Science Center for New Organic MatterThe Centre of Nanoscale Science and Technology and Key Laboratory of Functional Polymer MaterialsRenewable Energy Conversion and Storage Center(RECAST)College of ChemistryNankai UniversityTianjin 300071China School of Materials Science and Engineering National Institute for Advanced MaterialsNankai UniversityTianjin 300350China Chongqing Institute of Green and Intelligent Technology Chongqing SchoolUniversity of Chinese Academy of Sciences(UCAS Chongqing)Chinese Academy of SciencesChongqing 400722China

Inspired by the success of CH-series acceptors, a small-molecular acceptor, CH-Tz was reported by adopting a new conjugationextended electron-deficient unit([1,2,5]thiadiazolo[3,4-b]pyrazine) on the central core. Owing to the enhanced inter-/intramolecular interactions, CH-Tz exhibited near-infrared absorption and an effective three-dimensional molecular packing network in its single crystal. When blended with polymer donor PM6, the binary device achieved a high power conversion efficiency(PCE) of 18.54%, with a notable short-circuit current density(J_(sc)) of 27.54 m A cm-2and an excellent fill factor(FF) over 80%,which can be partly ascribed to the balanced charge transport properties in the blend film. After employing D18-Cl as the third component, an enhanced PCE of 18.85% was achieved due to a more obvious fiber network. Impressively, the CH-Tz-based OSC devices show excellent thermal stability and thickness insensitivity. Record-breaking Jscof 28.92 m A cm-2was reached for PM6:D18-Cl:CH-Tz ternary device with a thickness of 560 nm. Besides, CH-Tz shows potential in fabricating multicomponent high-performance organic solar cells, where over 19% efficiency could be realized in the quaternary device. Our work advances the strong influence of electron-deficient central units on molecular photovoltaic properties and guides the design of acceptors for stable and large-thickness organic solar cells.

关键词： organic solar cells non-fullerene acceptor central unit large thickness molecular packing

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A case study of comparing two dimerized acceptor molecules built by different branch-connected and terminal-connected approaches

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Science China Chemistry 2024年第5期67卷 1687-1696页

作者： Kangqiao Ma Huazhe Liang Yuxin Wang Tengfei He Tainan duan Xiaodong Si Wendi Shi Guankui Long Xiangjian Cao Zhaoyang Yao Xiangjian Wan chenxi Li Bin Kan Yongsheng Chen State Key Laboratory and Institute of Elemento-Organic Chemistry Frontiers Science Center for New Organic MatterThe Centre of Nanoscale Science and Technology and Key Laboratory of Functional Polymer MaterialsInstitute of Polymer ChemistryRenewable Energy Conversion and Storage Center(RECAST)College of ChemistryNankai UniversityTianjin 300071China School of Materials Science and Engineering National Institute for Advanced MaterialsRenewable Energy Conversion and Storage Center(RECAST)Nankai UniversityTianjin 300350China Chongqing Institute of Green and Intelligent Technology Chongqing SchoolUniversity of Chinese Academy of Sciences(UCAS Chongqing)Chinese Academy of SciencesChongqing 400015China

Dimerized small-molecule acceptors(SMAs) built by the conventional connection of terminal groups of monomers have contributed to exciting long-term stabilities of organic solar cells(OSCs). However, device efficiencies, especially fill factors(FFs), still need to be improved. This probably originates from unsymmetrical molecular structure/conformation-determined less compact/ordered molecular stackings, such as ineffective stackings of constraint terminals. Herein, an exotic dimerized SMA of BC-Th is established by bridging the branched groups(BC-type, branch coupling) of two monomers rather than conventional terminal units(TC-type, terminal coupling). Benefiting from the three-dimensional conformation and more uncurbed terminals,BC-Th exhibits multiple molecular orientations along with a larger dielectric constant and electron mobility compared with TCTh. Finally, an efficiency of 17.43% is achieved by BC-Th-based OSCs, along with the highest FF of 79.13% among all dimerized SMAs-based OSCs to date. When introducing L8-BO as the third component, overall enhanced efficiency of 18.05%and FF of 80.11% are further afforded. Contrarily, TC-Th-based OSCs exhibit much inferior PCE of 16.29% and FF of 74.81%,demonstrating the great advantages of “branch coupling” over “terminal coupling” when building dimerized SMAs.

关键词： organic solar cells dimerized acceptor molecules branch coupling morphology control stability

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Synthetic biology-inspired cell engineering in diagnosis,treatment,and drug development

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Signal Transduction and Targeted Therapy 2023年第4期8卷 1524-1544页

作者： Ninglin Zhao Yingjie Song Xiangqian Xie Ziqi Zhu chenxi duan Cheng Nong Huan Wang Rui Bao Division of Infectious Diseases State Key Laboratory of Biotherapy and Center of Infectious DiseasesWest China HospitalSichuan UniversityChengduChina College of Life Science Sichuan Normal UniversityChengduChina State Key Laboratory of Coordination Chemistry Chemistry and Biomedicine Innovation Center of Nanjing UniversityJiangsu Key Laboratory of Advanced Organic MaterialsSchool of Chemistry and Chemical EngineeringNanjing UniversityNanjingChina

The fast-developing synthetic biology(SB)has provided many genetic tools to reprogram and engineer cells for improved performance,novel functions,and diverse applications.Such cell engineering resources can play a critical role in the research and development of novel therapeutics.However,there are certain limitations and challenges in applying genetically engineered cells in clinical practice.This literature review updates the recent advances in biomedical applications,including diagnosis,treatment,and drug development,of SB-inspired cell engineering.It describes technologies and relevant examples in a clinical and experimental setup that may significantly impact the biomedicine field.At last,this review concludes the results with future directions to optimize the performances of synthetic gene circuits to regulate the therapeutic activities of cell-based tools in specific diseases.

关键词： diagnosis treatment directions

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斜入射下四光幕精度靶着靶位置测量原理误差分析

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兵工学报 2024年第6期45卷 1965-1973页

作者：李敬孙忠辉倪晋平段晨曦崔长青西安工业大学光电工程学院陕西西安710021 63853部队吉林白城137001 陕西省光电测试与仪器技术重点实验室陕西西安710021 中国兵器装备集团公司黑龙江北方工具有限公司黑龙江牡丹江157000

为研究飞行弹丸斜入射时着靶坐标测量原理误差的分布规律,根据四光幕精度靶几何结构,建立了斜入射下着靶坐标测量原理误差模型,研究有效探测靶面内不同着靶位置与不同入射角下原理误差分布规律;分析工程应用中发射位置确定下,不同散布... 详细信息

为研究飞行弹丸斜入射时着靶坐标测量原理误差的分布规律,根据四光幕精度靶几何结构,建立了斜入射下着靶坐标测量原理误差模型,研究有效探测靶面内不同着靶位置与不同入射角下原理误差分布规律;分析工程应用中发射位置确定下,不同散布半径与不同射击距离对测量原理误差的影响,给出着靶坐标测量的修正公式,并进行实弹射击试验。试验结果表明:飞行弹丸斜入射时必然存在原理误差,必须修正着靶坐标;射击距离一定时,发射枪散布半径越大,原理误差越大;散布半径确定时,原理误差随射击距离增加而减小;在发射位置确定下,采用修正公式后,四光幕精度靶测量误差小于1 mm。

关键词：外弹道测试四光幕精度靶着靶坐标误差修正

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公众上呼吸道感染症状的潜在模式及其对抗生素使用行为的影响研究

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中国全科医学 2024年第5期27卷 527-534页

作者：张欣怡王茜王丹段立霞林如娇刘晨曦华中科技大学同济医学院医药卫生管理学院湖北省武汉市430000 湖北中医药大学管理学院湖北省武汉市430000

背景抗生素滥用导致的耐药问题已成全球重大公共卫生议题,减少公众上呼吸道感染的抗生素不合理使用是我国治理抗生素滥用的重要策略,识别上呼吸道感染疾病病症特点及其对抗生素不合理使用行为的影响有助于临床医生设计更为精准的干预政... 详细信息

背景抗生素滥用导致的耐药问题已成全球重大公共卫生议题,减少公众上呼吸道感染的抗生素不合理使用是我国治理抗生素滥用的重要策略,识别上呼吸道感染疾病病症特点及其对抗生素不合理使用行为的影响有助于临床医生设计更为精准的干预政策。目的定量分析公众上呼吸道感染症状的潜在模式,探究其对抗生素使用行为的影响。方法本研究采用整群随机抽样调查,于2022-07-20—08-02选取重庆市三个县(区)的人群作为调查对象。调查公众上呼吸道感染疾病症状、公众上呼吸道感染抗生素使用行为、公众抗生素使用知识及人口学特征。采用潜在类别分析方法鉴别公众上呼吸道感染疾病症状的潜在模式,采用多因素Logistic回归分析探索不同潜在症状模式对抗生素使用行为的影响。结果815位公众参与本研究。其中,30.06%(245/815)受访者存在无处方从药店购买抗生素,14.72%(120/815)受访者使用过抗生素自我药疗以应对上呼吸道感染。公众抗生素合理使用知识水平较低[(2.3±1.7)分]。上呼吸道感染疾病发病模式方面,潜在类别分析共识别4种症状模式,包括多重症状组93例(11.41%)、全身症状组124例(15.21%)、鼻咽症状组282例(34.60%)和轻微症状组316例(38.77%)。多因素Logistic回归分析结果显示:相较于轻微症状组,鼻咽症状组出现无处方购买抗生素行为的概率更高(OR=1.538,P<0.05),该结果在调整知识与人口学变量后仍显著。除个体疾病症状潜在模式外,年龄和医保类型也对公众无处方抗生素购药行为有影响(P<0.05)。抗生素使用知识水平对抗生素自我药疗行为有影响(OR=0.869,P<0.05),对公众无处方抗生素购药行为也有影响(OR=1.155,P<0.05)。结论公众上呼吸道感染症状存在4种潜在模式,疾病病症模式影响公众抗生素的合理使用,应着重关注出现鼻咽症状患者的抗生素不合理使用行为。

关键词：呼吸道感染抗菌药抗生素合理使用体征和症状潜在类别分析 Logistic模型

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Local administration of liposomal-based Plekhf1 gene therapy attenuates pulmonary fibrosis by modulating macrophage polarization

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Science China(Life Sciences) 2023年第11期66卷 2571-2586页

作者： Lifeng Yan Chenchen Hou Juan Liu Yi Wang chenxi Zeng Jun Yu Tianyu Zhou Qing Zhou Shengzhong duan Weining Xiong Department of Respiratory and Critical Care Medicine Shanghai Ninth People’s HospitalShanghai Jiao Tong University School of MedicineShanghai 200011China Department of Pulmonary and Critical Care Medicine The Center for Biomedical ResearchTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China Department of Thoracic Surgery Tongji HospitalTongji Medical CollegeHuazhong University of Sciences and TechnologyWuhan 430030China Shanghai Key Laboratory of Tissue Engineering Shanghai Ninth People’s HospitalShanghai Jiao Tong University School of MedicineShanghai 200011China Laboratory of Oral Microbiota and Systemic Diseases Shanghai Ninth People’s HospitalCollege of StomatologyShanghai Jiao Tong University School of MedicineShanghai 200011China National Center for Stomatology National Clinical Research Center for Oral DiseasesShanghai Key Laboratory of StomatologyShanghai 200011China

Idiopathic pulmonary fibrosis(IPF)is a fatal interstitial lung disease with limited therapeutic options.Macrophages,particularly alternatively activated macrophages(M2),have been recognized to contribute to the pathogenesis of pulmonary fibrosis.Therefore,targeting macrophages might be a viable therapeutic strategy for IPF.Herein,we report a potential nanomedicinebased gene therapy for IPF by modulating macrophage M2 activation.In this study,we illustrated that the levels of pleckstrin homology and FYVE domain containing 1(Plekhf1)were increased in the lungs originating from IPF patients and PF mice.Further functionality studies identified the pivotal role of Plekhf1 in macrophage M2 activation.Mechanistically,Plekhf1 was upregulated by IL-4/IL-13 stimulation,after which Plekhf1 enhanced PI3K/Akt signaling to promote the macrophage M2 program and exacerbate pulmonary fibrosis.Therefore,intratracheal administration of Plekhf1 siRNA-loaded liposomes could effectively suppress the expression of Plekhf1 in the lungs and notably protect mice against BLM-induced lung injury and fibrosis,concomitant with a significant reduction in M2 macrophage accumulation in the lungs.In conclusion,Plekhf1 may play a crucial role in the pathogenesis of pulmonary fibrosis,and Plekhf1 siRNA-loaded liposomes might be a promising therapeutic approach against pulmonary fibrosis.

关键词： idiopathic pulmonary fibrosis macrophages alternatively activated macrophages Plekhf1 liposomes

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棘脑通的抗抑郁作用及机制研究

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中国医院用药评价与分析 2024年第1期24卷 55-61页

作者：黄雯高雄夏辰希段然董婷霞詹华强广州医科大学附属肿瘤医院药学部广州510095 香港科技大学生命科学部暨中药研发中心中国香港特别行政区999007

目的:考察主成分为沙棘和花生壳提取物的棘脑通的抗抑郁药效及作用机制。方法:(1)动物水平上,采用慢性不可预知温和应激(CUMS)抑郁模型小鼠,随机分为空白组、模型组、棘脑通给药组(棘脑通低浓度组、棘脑通高浓度组)和氟西汀组。通过体... 详细信息

目的:考察主成分为沙棘和花生壳提取物的棘脑通的抗抑郁药效及作用机制。方法:(1)动物水平上,采用慢性不可预知温和应激(CUMS)抑郁模型小鼠,随机分为空白组、模型组、棘脑通给药组(棘脑通低浓度组、棘脑通高浓度组)和氟西汀组。通过体重测试、糖水偏嗜实验和悬尾不动时间测试等行为学研究,考察棘脑通的抗抑郁作用。(2)细胞水平上,将不同浓度的棘脑通应用于PC12细胞、SH-SY5Y细胞、BV2细胞和RAW 264.7细胞,研究棘脑通对神经营养因子功能的促进作用,保护神经细胞、诱导神经分化的作用,以及抗氧化、抗炎作用。结果:(1)与空白组相比,模型组小鼠糖水偏嗜率、体重显著降低,悬尾不动时间、强迫游泳不动时间显著延长(P<0.01);棘脑通给药组小鼠糖水偏嗜率较模型组显著升高(P<0.05),棘脑通给药组、氟西汀组小鼠体重较模型组显著升高(P<0.01),棘脑通低、高浓度组小鼠悬尾不动时间较模型组显著缩短(P<0.01、P<0.05),棘脑通给药组小鼠强迫游泳不动时间较模型组显著缩短(P<0.01),上述差异均有统计学意义。(2)棘脑通与神经生长因子(5、50 ng/mL)协同使用时,PC12细胞分化程度、pNF200-Luc表达荧光素酶活性显著提高。棘脑通与脑源性神经营养因子、神经营养因子-3和神经营养因子-4(5 ng/mL)协同使用时,荧光素酶的活性显著提高。100~1 000μg/mL的棘脑通可显著降低β-淀粉样蛋白的聚集。采用叔丁基过氧化氢诱导PC12细胞的氧化损伤后,应用棘脑通可提高PC12细胞活性,且浓度越高,效果越好。采用Erastin诱导SH-SY5Y细胞铁死亡后,应用棘脑通可提高SH-SY5Y细胞活性,且浓度越高,效果越好。将脂多糖用于BV2、RAW 264.7细胞后,应用棘脑通可降低白细胞介素1β的mRNA水平、核因子κB转录活性,且具有浓度依赖性。结论:棘脑通具有抗炎、抗氧化,保护神经细胞,诱导神经微丝表达,增强神经营养因子样的作用;该药通过以上作用发挥抗抑郁效果。

关键词：沙棘和花生壳提取物棘脑通抗抑郁

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温通化瘀散结法联合箍围-火针法治疗头部脓肿性穿掘性毛囊炎5例

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皮肤科学通报 2024年第3期41卷 323-326页

作者：李凯吴娟李婧娇李晨茜章建兰曾宪玉陈柳青段逸群武汉市第一医院皮肤科湖北武汉430022

目的分析头部脓肿性穿掘性毛囊炎的临床特征及中医证候特点,提高对本病的诊断及中医辨证水平。方法对5例头部脓肿性穿掘性毛囊炎的临床表现、中医证候、中医治则、方药、预后进行回顾性分析。结果5例患者均为青年男性,年龄为19~26岁,平... 详细信息

目的分析头部脓肿性穿掘性毛囊炎的临床特征及中医证候特点,提高对本病的诊断及中医辨证水平。方法对5例头部脓肿性穿掘性毛囊炎的临床表现、中医证候、中医治则、方药、预后进行回顾性分析。结果5例患者均为青年男性,年龄为19~26岁,平均年龄22.62岁,5例患者皮损以头皮大量结节、囊肿、融合性脓肿为主,伴有明显脓性分泌物、压痛、脱发明显等临床特点。5例患者中2例肥胖(BMI≥30.0 kg/m 2)。5例患者皮疹辨证均符合痰瘀互结证。中医内治均采用温通化瘀散结之法,局部红肿者仙方活命饮加减。外治采用箍围-火针法,箍围使用自制消炎膏配合冲和散,火针针刺后按压排脓。中医药治疗时间为56~180 d,平均时间为101.20 d,5例中3例结节、囊肿完全消退,脓性分泌物消失,遗留色减斑及瘢痕(病例1~3);1例结节消失,囊肿变平,硬化性囊肿缩小(病例4);1例硬化性囊肿略缩小(病例5)。随访6个月后,2例肥胖患者均有复发,继续治疗后复发皮损消失。结论温通化瘀散结法联合箍围-火针法治疗头部脓肿性穿掘性毛囊炎临床疗效较好,值得进一步研究和推广。

关键词：头部脓肿性穿掘性毛囊炎温通化瘀散结法箍围-火针法

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