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Id2 epigenetically controls CD8^(+)T-cell exhaustion by disrupting the assembly of the Tcf3-LSD1 complex

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Cellular & Molecular Immunology 2024年第3期21卷 292-308页

作者： Yiming Li Mingwei Han Haolin Wei Wan Huang Zhinan chen Tianjiao Zhang Meirui Qian Lin Jing Gang Nan Xiuxuan Sun Shuhui Dai Kun Wang Jianli Jiang Ping Zhu Liang chen Department of Cell Biology of National Translational Science Center for Molecular Medicine and Department of Clinical Immunology of Xijing Hospital Fourth Military Medical UniversityXi’anShaanxi 710032China State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases GanzhouJiangxi341000Xi’anShaanxi 710032China School of Medicine Shanghai UniversityShanghai 200444China

CD8^(+)T-cell exhaustion is a state of dysfunction that promotes tumor progression and is marked by the generation of Slamf6^(+)progenitor exhausted(Tex^(prog))and tim-^(3+)terminally exhausted(Tex^(term))*** of DNA binding protein 2(Id2)has been shown to play important roles in T-cell development and CD8^(+)T-cell ***,the role of Id2 in CD8^(+)T-cell exhaustion is ***,we found that Id2 transcriptionally and epigenetically regulates the generation of Texprog cells and their conversion to Texterm *** deletion of Id2 dampens CD8^(+)T-cell-mediated immune responses and the maintenance of stem-like CD8^(+)T-cell subpopulations,suppresses PD-1 blockade and increases tumor ***,through its HLH domain,Id2 binds and disrupts the assembly of the Tcf3-Tal1 transcriptional regulatory complex,and thus modulates chromatin accessibility at the Slamf6 promoter by preventing the interaction of Tcf3 with the histone lysine demethylase ***,Id2 increases the abundance of the permissive H3K4me2 mark on the Tcf3-occupied E-boxes in the Slamf6 promoter,modulates chromatin accessibility at the Slamf6 promoter and epigenetically regulates the generation of Slamf6+Texprog *** LSD1 inhibitor GSK2879552 can rescue the Id2 knockout phenotype in tumor-bearing *** of LSD1 increases the abundance of Slamf6^(+)tim-3^(−)Tex^(prog) cells in tumors and the expression level of Tcf1 in Id2-deleted CD8+T *** study demonstrates that Id2-mediated transcriptional and epigenetic modification drives hierarchical CD8^(+)T-cell exhaustion,and the mechanistic insights gained may have implications for therapeutic intervention with tumor immune evasion.

关键词： Id2 T-cell exhaustion Epigenetic modification Immune evasion

Three-type MJO Initiation processes over the Western Equatorial Indian Ocean

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Advances in Atmospheric Sciences 2015年第9期32卷 1208-1216页

作者： MEI Shuangli tim LI chen Wen Center for Monsoon System Research Institute of Atmospheric PhysicsChinese Academy of Sciences University of Chinese Academy of Sciences International Laboratory on Climate and Environment Change and Key Laboratory of Meteorological Disaster of Ministry of Education Nanjing University of Information Science and Technology International Pacific Research Center Department of MeteorologySchool of Ocean and Earth Science and TechnologyUniversity of Hawaii at Manoa

Thirty strong Madden–Julian Oscillation（MJO） events in boreal winter 1982–2001 are selected to investigate the triggering processes of MJO convection over the western equatorial Indian Ocean（IO）.These MJO events are classified into three types,according to their dynamic and thermodynamic precursor signals in *** Type I,a remarkable increase in low-level moisture occurs,on average,7 days prior to the convection *** low-level moistening is mainly due to the advection of the background mean moisture by easterly wind anomalies over the equatorial *** Type II,lower-tropospheric ascending motion anomalies develop,on average,4 days prior to the *** cause of this ascending motion anomaly is attributed to the anomalous warm advection,set up by a suppressed MJO phase in the equatorial *** Type III,there are no clear dynamic and thermodynamic precursor signals in *** convection might be triggered by energy accumulation in the upper layer associated with Rossby wave activity fluxes originated from the midlatitudes.

关键词： MJO Indian Ocean dynamic precursor signal thermodynamic precursor signal

Asymmetry of Atmospheric Responses to Two-Type El Nino and La Nina over Northwest Pacific

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Journal of Meteorological Research 2019年第5期33卷 826-836页

作者： Mingcheng chen tim LI Xiaohui WANG Key Laboratory of Meteorological Disaster Ministry of Education(KLME)/Joint International Research Laboratory of Climate and Environmental Change(ILCEC)/Collaborative Innovation Center on Forecast and Evaluation of Meteorological Disasters(CIC-FEMD)Nanjing University of Information Science&TechnologyNanjing 210044China International Pacific Research Center and Department of Atmospheric Sciences School of Ocean and Earth Science and TechnologyUniversity of Hawaii at ManoaHonoluluHI96822USA

The mechanism for asymmetric atmospheric responses to the central Pacific(CP) El Ni?o and La Ni?a over the western North Pacific(WNP) is studied in this paper. The negative anomalies of rainfall over the key region of WNP are explained by diagnosing the column-integrated equations of moisture and moist static energy(MSE). It is revealed that the nonlinear advection of moist enthalpy is critical to introduce negative rainfall anomalies over the region. The anomalous easterly(westerly) in La Ni?a(CP El Ni?o) causes negative advection of anomalous moist enthalpy, inducing negative heating anomaly and an anticyclone anomaly in the WNP, which weakens(strengthens) the cyclone(anticyclone) in La Ni?a(CP El Ni?o). The MSE budget analysis shows a larger nonlinear term in CP El Ni?o than in eastern Pacific(EP) El Ni?o, inconsistent with the amplitudes of sea surface temperature anomalies. The reason is that the nonlinear term transforms to positive above 700 h Pa in EP El Ni?o, offsetting the negative advection below 700 h Pa and thus making the nonlinear term smaller. The nonlinear term is negative at low levels in CP El Ni?o, resulting in a larger nonlinear term. The stronger precipitation anomalies in the WNP during EP El Ni?o can be attributed to the linear moist enthalpy advection. The mean easterly wind at mid levels causes a larger(smaller) positive moist enthalpy advection in CP(EP) El Ni?o, due to a larger(smaller) moist enthalpy gradient, resulting in a positive(negative) linear moist enthalpy advection, which weakens(strengthens) the negative precipitation anomalies in the key region.

关键词： asymmetry La Nina eastern Pacific(EP) El Nino central Pacific(CP) El Nino moist enthalpy

How Frequently Will the Persistent Heavy Rainfall over the Middle and Lower Yangtze River Basin in Summer 2020 Happen under Global Warming?

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Advances in Atmospheric Sciences 2022年第10期39卷 1673-1692,I0016,I0017页

作者： Zi-An GE Lin chen tim LI Lu WANG Key Laboratory of Meteorological Disaster Ministry of Education(KLME)/Joint International Research Laboratory of Climate and Environmental Change(ILCEC)/Collaborative Innovation Center on Forecast and Evaluation of Meteorological Disasters(CIC-FEMD)Nanjing University of Information Science and TechnologyNanjing 210044China International Pacific Research Center and Department of Atmospheric Sciences School of Ocean and Earth Science and TechnologyUniversity of Hawaii at ManoaHonoluluHawaii 96822USA

The middle and lower Yangtze River basin(MLYRB)suffered persistent heavy rainfall in summer 2020,with nearly continuous rainfall for about six consecutive *** the likelihood of persistent heavy rainfall resembling that which occurred over the MLYRB in summer 2020(hereafter 2020PHR-like event)would change under global warming is *** index that reflects maximum accumulated precipitation during a consecutive five-week period in summer(Rx35day)is *** accumulated precipitation index in summer 2020 is 60%stronger than the climatology,and a statistical analysis further shows that the 2020 event is a 1-in-70-year *** model projection results derived from the 50-member ensemble of CanESM2 and the multimodel ensemble(MME)of the CMIP5 and CMIP6 models show that the occurrence probability of the 2020PHR-like event will dramatically increase under global *** on the Kolmogorov-Smirnoff test,one-third of the CMIP5 and CMIP6 models that have reasonable performance in reproducing the 2020PHR-like event in their historical simulations are selected for the future projection *** CMIP5 and CMIP6 MME results show that the occurrence probability of the 2020PHR-like event under the present-day climate will be double under lower-emission scenarios(CMIP5 RCP4.5,CMIP6 SSP1-2.6,and SSP2-4.5)and 3-5 times greater under higher-emission scenarios(3.0 times for CMIP5 RCP8.5,2.9 times for CMIP6 SSP3-7.0,and 4.8 times for CMIP6 SSP5-8.5).The inter-model spread of the probability change is small,lending confidence to the projection *** results provide a scientific reference for mitigation of and adaptation to future climate change.

关键词： persistent heavy rainfall middle and lower Yangtze River basin future projection CMIP5 and CMIP6 models generalized extreme value(GEV)distribution

Moxibustion of Zusanli(ST36)and Shenshu(BL23)alleviates the inflammation of rheumatoid arthritis in rats through regulating macrophage migration inhibitory factor/glucocorticoids signaling

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Journal of Traditional Chinese Medicine 2024年第2期44卷 353-361页

作者： ZHANG Linlin ZHONG Yumei LU Wenting SHANG Yanan GUO Yanding LUO Xiaochao chen Yang LUO Kun HU Danhui YU Huiling ZHOU Haiyan Acupuncture and Moxibustion College Chengdu University of Traditional Chinese MedicineChengdu 610075China Department of Painology First People's Hospital of ChengduChengdu 610095China Chinese Evidence-Based Medicine Centre West China HospitalSichuan UniversityChengdu 610044China Traditional Chinese Medicine College Chongqing Medical UniversityChongqing 400016China External treatment center First People's Hospital of ChengduChengdu 610095China

OBJECTIVE:To test the hypothesis that moxibustion may inhibit rheumatoid arthritis(RA)synovial inflammation by regulating the expression of macrophage migration inhibitory factor(MIF)/glucocorticoids(GCs).METHODS:Fifty male Sprague-Dawley rats were randomly divided into five groups(n=10 each):blank Control(CON)group,RA Model(RA)group,Moxibustion(MOX)group,MIF inhibitor(S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester(ISO-1)group,and Moxibustion+MIF inhibitor ISO-1(MOX+ISO-1)*** in the ISO-1 group and ISO-1+MOX group were intraperitoneally injected with the inhibitor *** rats in the RA group,ISO-1 group,MOX group,and ISO-1+MOX group were injected with Freund's complete adjuvant(FCA)in the right hind footpad to establish an experimental RA rat *** the MOX group and MOX+ISO-1 group,rats were treated with *** thickness of the footpads of the rats in each group was measured at three-time points before,after modeling and after moxibustion *** contents of serum MIF,corticosterone(CORT),tumor necrosis factor-α(TNF-α)and interleukin-1β(IL-1β)were detected by enzyme-linked immunosorbent assay;and the contents of synovial MIF were detected by Western ***-eosin(HE)staining method was used to observe the pathological changes of synovial tissue under a section light microscope,and pathological scoring was performed according to the grading standard of the degree of synovial tissue ***:Moxibustion was found to reduce the level of MIF and alleviate inflammation in RA rats in this *** addition,after inhibiting the expression of MIF,the level of CORT increased,and the level of TNF-α *** RA rats with inhibited MIF by moxibustion,the level of CORT was almost unchanged,but the level of TNF-α further *** correlation analysis data suggested that MIF was positively related to the expression of TNF-α and negatively correlated with the expression of ***:Reducing MIF to

关键词： rheumatoid arthritis macrophage migration inhibitory factor moxibustion corticosterone glucocorticoids

Tumor-derived exosomes induce initial activation by exosomal CD19 antigen but impair the function of CD19-specific CAR T-cells via TGF-βsignaling

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Frontiers of Medicine 2024年第1期18卷 128-146页

作者： Yuanyuan Hao Panpan chen Shanshan Guo Mengyuan Li Xueli Jin Minghuan Zhang Wenhai Deng Ping Li Wen Lei Aibin Liang Wenbin Qian Department of Hematology The Second Affiliated HospitalCollege of MedicineZhejiang UniversityHangzhou310009China Department of Hematology Henan Provincial People’s HospitalZhengzhou University People’s HospitalZhengzhou450003China Key Laboratory of Laboratory Medicine Ministry of EducationSchool of Laboratory Medicine and Life SciencesWenzhou Medical UniversityWenzhou325000China Department of Hematology Tongji Hospital of Tongji UniversityShanghai200065China

Tumor-derived exosomes (TEXs) enriched in immune suppressive molecules predominantly drive T-cell dysfunction and impair antitumor immunity. Chimeric antigen receptor (CAR) T-cell therapy has emerged as a promising treatment for refractory and relapsed hematological malignancies, but whether lymphoma TEXs have the same impact on CAR T-cell remains unclear. Here, we demonstrated that B-cell lymphoma-derived exosomes induce the initial activation of CD19-CAR T-cells upon stimulation with exosomal CD19. However, lymphoma TEXs might subsequently induce CAR T-cell apoptosis and impair the tumor cytotoxicity of the cells because of the upregulated expression of the inhibitory receptors PD-1, tim3, and LAG3 upon prolonged exposure. Similar results were observed in the CAR T-cells exposed to plasma exosomes from patients with lymphoma. More importantly, single-cell RNA sequencing revealed that CAR T-cells typically showed differentiated phenotypes and regulatory T-cell (Treg) phenotype conversion. By blocking transforming growth factor β (TGF-β)-Smad3 signaling with TGF-β inhibitor LY2109761, the negative effects of TEXs on Treg conversion, terminal differentiation, and immune checkpoint expression were rescued. Collectively, although TEXs lead to the initial activation of CAR T-cells, the effect of TEXs suppressed CAR T-cells, which can be rescued by LY2109761. A treatment regimen combining CAR T-cell therapy and TGF-β inhibitors might be a novel therapeutic strategy for refractory and relapsed B-cell lymphoma.

关键词： tumor-derived exosome chimeric antigen receptor T-cell lymphoma TGF-β

Sub-synchronous Oscillations in Power Systems Caused by Grid-connected Wind Farms--A Survey of Mechanism Studies

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CSEE Journal of Power and Energy Systems 2018年第4期4卷 495-503页

作者： chen chen Wenjuan Du Haifeng Wang tim Littler North China Electric Power University Beijing 102206China

Sub-synchronous oscillation(SSO)incidents caused by dynamic interaction between wind farms and power system grids can threaten safe and reliable *** paper investigates mechanism studies of SSOs in power systems induced by grid-connected wind ***,characteristics of several severe SSO incidents encountered by real power systems caused by grid-connected wind farms are ***,in terms of principles and responses,this paper illustrates the most commonly adopted mechanism investigation methods for SSOs,which include impedance-based analysis(IMA)and the openloop modal analysis(OMA)*** reviews that summarize existing studies using the IMA and OMA methods are discussed in this ***,a discussion of the current research gaps in the investigation of SSOs in power systems caused by grid-connected wind farms is presented.

关键词： Doubly-fed induction generator(DFIG) impedance-based analysis modal analysis permanent magnetic synchronous generator(PMSG) sub-synchronous oscillation

Distinctive Precursory Air–Sea Signals between Regular and Super El Ni os

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Advances in Atmospheric Sciences 2016年第8期33卷 996-1004页

作者： Lin chen tim LI Swadhin K.BEHERA Takeshi DOI Key Laboratory of Meteorological Disaster Joint International Research Laboratory of Climate and Environmental Changeand Collaborative Innovation Center on Forecast and Evaluation of Meteorological DisastersNanjing University of Information Science and Technology International Pacific Research Center School of Ocean and Earth Science and Technology University of Hawaii Application Laboratory Japan Agency for Marine-Earth Science and Technology

Statistically different precursory air–sea signals between a super and a regular El Ni no group are investigated, using observed SST and rainfall data, and oceanic and atmospheric reanalysis data. The El Ni no events during 1958–2008 are first separated into two groups： a super El Ni no group（S-group） and a regular El Ni no group（R-group）. Composite analysis shows that a significantly larger SST anomaly（SSTA） tendency appears in S-group than in R-group during the onset phase[April–May（0）], when the positive SSTA is very small. A mixed-layer heat budget analysis indicates that the tendency difference arises primarily from the difference in zonal advective feedback and the associated zonal current anomaly（u）.This is attributed to the difference in the thermocline depth anomaly（D） over the off-equatorial western Pacific prior to the onset phase, as revealed by three ocean assimilation products. Such a difference in D is caused by the difference in the wind stress curl anomaly in situ, which is mainly regulated by the anomalous SST and precipitation over the Maritime Continent and equatorial Pacific.

关键词： super El Ni no precursory air–sea signals thermocline depth anomaly ENSO

Alignment control for a long span urban rail-transit cable-stayed bridge considering dynamic train loads

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Science China(Technological Sciences) 2016年第11期59卷 1759-1770页

作者： chen ZengShun ZHOU JianTing TSE Kim tim HU Gang LI Yong WANG Xu State Key Laboratory Breeding Base of Mountain Bridge and Tunnel Engineering and Engineering Research Center of Bridge Structure and Material in the Mountainous Area Chongqing Jiaotong University Department of Civil and Environmental Engineering Hong Kong University of Science and Technology Shenzhen Bridge Design & Research Institute Co. Ltd.

In this paper, bridge alignment control with considering dynamic train loads was experimentally and theoretically *** process of bridge dynamics and the self-adaptive Kalman filter bridge alignment control method with considering the dynamic train loads were briefly introduced. The static measurement, the dynamic test, the field alignment measurement as well as the finite element analysis(FEA) of the second longest rail transit cable-stayed bridge in the world were carried *** on the results, the train dynamic load effect on the bridge alignment was obtained quantitatively. Subsequently, alignment control of the rail transit bridge with considering this effect using a self-adaptive Kalman filter method was analyzed. The results show that:(a) the dynamic train loads have effects on alignment control of the bridge and therefore cannot be neglected;(b) the self-adaptive Kalman filter method is applicable and reliable for alignment control of bridges during construction. The analytical method and whole process contribute to develop a related specification and further engineering applications.

关键词： dynamic train loads alignment control self-adaptive Kalman filter rail transit cable-stayed bridge