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Frontiers of Medicine 2023年第5期17卷 805-822页

作者： Liming Liao Huilin Xu Yuhan Zhao xiaofeng zheng State Key Laboratory of Protein and Plant Gene Research Department of Biochemistry and Molecular BiologySchool of Life SciencesPeking UniversityBeijing100871China

Immunotherapies based on immune checkpoint blockade(ICB)have significantly improved patient outcomes and offered new approaches to cancer therapy over the past decade.To date,immune checkpoint inhibitors(ICIs)of CTLA-4 and PD-1/PD-L1 represent the main class of immunotherapy.Blockade of CTLA-4 and PD-1/PD-L1 has shown remarkable efficacy in several specific types of cancers,however,a large subset of refractory patients presents poor responsiveness to ICB therapy;and the underlying mechanism remains elusive.Recently,numerous studies have revealed that metabolic reprogramming of tumor cells restrains immune responses by remodeling the tumor microenvironment(TME)with various products of metabolism,and combination therapies involving metabolic inhibitors and ICIs provide new approaches to cancer therapy.Nevertheless,a systematic summary is lacking regarding the manner by which different targetable metabolic pathways regulate immune checkpoints to overcome ICI resistance.Here,we demonstrate the generalized mechanism of targeting cancer metabolism at three crucial immune checkpoints(CTLA-4,PD-1,and PD-L1)to influence ICB therapy and propose potential combined immunotherapeutic strategies co-targeting tumor metabolic pathways and immune checkpoints.

关键词： CTLA-4 PD-1 PD-L1 immune checkpoint blockade(ICB) metabolic reprogramming combined tumor therapeutic strategies

Tip-to-tip interaction in the crystal packing of PACSIN 2 is important in regulating tubulation activity

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Protein & Cell 2013年第9期4卷 695-701页

作者： Xiaoyun Bai xiaofeng zheng State Key Lab of Protein and Plant Gene Research School of Life SciencesPeking UniversityBeijing 100871China Department of Biochemistry and Molecular Biology School of Life SciencesPeking UniversityBeijing 100871China

The F-BAR domain containing proteins PACSINs are cytoplasmic phosphoproteins involved in various mem-brane deformations,such as actin reorganization,vesicle transport and microtubule movement.Our previous study shows that all PACSINs are composed of crescent shaped dimers with two wedge loops,and the wedge loop-mediated lateral interaction between neighboring dimers is important for protein packing and tubulation activity.Here,from the crystal packing of PACSIN 2,we observed a tight tip-to-tip interaction,in addition to the wedge loop-mediated lateral interaction.With this tip-to-tip interaction,the whole packing of PACSIN 2 shows a spiral-like assem-bly with a central hole from the top view.Elimination of this tip-to-tip connection inhibited the tubulation function of PACSIN 2,indicating that tip-to-tip interaction plays an important role in membrane deformation activity.Together with our previous study,we proposed a packing model for the assembly of PACSIN 2 on membrane,where the pro-teins are connected by tip-to-tip and wedge loop-mediated lateral interactions on the surface of membrane to gener-ate various diameter tubules.

关键词： PACSIN 2 crystal packing tip-to-tip interac-tion tubulation wedge loop

ASFV transcription reporter screening system identifies ailanthone as a broad antiviral compound

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Virologica Sinica 2023年第3期38卷 459-469页

作者： Yuhang Zhang Zhenjiang Zhang Fan Zhang Jiwen Zhang Jun Jiao Min Hou Nianchao Qian Dongming Zhao xiaofeng zheng Xu Tan College of Veterinary Medicine Hunan Agricultural UniversityChangsha 410128China State Key Laboratory of Veterinary Biotechnology Harbin Veterinary Research InstituteChinese Academy of Agricultural SciencesHarbin 150009China Beijing Advanced Innovation Center for Structural Biology Beijing Frontier Research Center for Biological StructureMOE Key Laboratory of Bioorganic Phosphorus Chemistry&Chemical BiologySchool of Pharmaceutical SciencesTsinghua-Peking Center for Life SciencesTsinghua UniversityBeijing 100084China Institute of Health and Medicine Hefei Comprehensive National Science CenterHefei 230601 China

African swine fever(ASF)is an acute,highly contagious and deadly viral disease in swine that jeopardizes the worldwide pig industry.Unfortunately,there are no authoritative vaccine and antiviral drug available for ASF control.African swine fever virus(ASFV)is the etiological agent of ASF.Among the ASFV proteins,p72 is the most abundant component in the virions and thus a potential target for anti-ASFV drug design.Here,we con-structed a luciferase reporter system driven by the promoter of p72,which is transcribed by the co-transfected ASFV RNA polymerase complex.Using this system,we screened over 3200 natural product compounds and obtained three potent candidates against ASFV.We further evaluated the anti-ASFV effects and proved that among the three candidates,ailanthone(AIL)inhibits the replication of ASFV at the nanomolar concentration(IC_(50)=15 nmol/L).Our in vitro experiments indicated that the antiviral effect of AIL is associated with its inhibition of the HSP90-p23 cochaperone.Finally,we showed the antiviral activity of AIL on Zika virus and hepatitis B virus(HBV),which supports that AIL is a potential broad-spectrum antiviral agent.

关键词： African swine fever virus(ASFV) Replication inhibition Broad-spectrum antiviral drugs Ailanthone(AIL)

多发性肌炎/皮肌炎相关间质性肺病治疗的研究进展

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上海交通大学学报（医学版） 2024年第4期44卷 531-536页

作者：郑晓峰徐凌上海交通大学医学院附属第六人民医院呼吸与危重症医学科上海200233

多发性肌炎/皮肌炎(polymyositis/dermatomyositis,PM/DM)是一组病因未明,以骨骼肌炎症浸润为特征的异质性自身免疫性疾病。PM/DM患者中间质性肺病(interstitial lung disease,ILD)的发病率较高,合并ILD是影响PM和DM患者预后的最重要因... 详细信息

多发性肌炎/皮肌炎(polymyositis/dermatomyositis,PM/DM)是一组病因未明,以骨骼肌炎症浸润为特征的异质性自身免疫性疾病。PM/DM患者中间质性肺病(interstitial lung disease,ILD)的发病率较高,合并ILD是影响PM和DM患者预后的最重要因素。现有证据表明PM/DM相关ILD异质性大,需要结合ILD的起病形式、进展速度、病变受累范围、实验室检查、是否存在预后不良因素以及对治疗的反应等进行个体化施治。文章总结了近年来PM/DM相关ILD在治疗方面的研究进展,包括传统治疗药物的选择、用药时机、临床上在该领域尝试的新的相关用药(如生物制剂、Janus激酶抑制剂)、静脉输注免疫球蛋白、抗纤维化药物,以及潜在的有效的非药物治疗方法,旨在帮助临床医师更好地制定PM/DMILD治疗方案,从而改善患者的预后。

关键词：多发性肌炎皮肌炎间质性肺病药物治疗

NEDDylation antagonizes ubiquitination of proliferating cell nuclear antigen and regulates the recruitment of polymerase rl in response to oxidative DNA damage

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Protein & Cell 2018年第4期9卷 365-379页

作者： Junhong Guan Shuyu Yu xiaofeng zheng State Key Lab of Protein and Plant Gene Research School of Life Sciences Peking University Beijing 100871 China Department of Biochemistry and Molecular Biology School of Life Sciences Peking University Beijing 100871 China

NEDDylation has been shown to participate in the DNA damage pathway, but the substrates of neural precursor cell expressed developmentally downregulated 8 （NEDD8） and the roles of NEDDylation involved in the DNA damage response （DDR） are largely unknown. Translesion synthesis （TLS） is a damage-tolerance mechanism, in which RAD181RAD6-mediated monoubiq- uitinated proliferating cell nuclear antigen （PCNA） pro- motes recruitment of polymerase q （polq） to bypass lesions. Here we identify PCNA as a substrate of NEDD8, and show that E3 ligase RAD18-catalyzed PCNA NEDDylation antagonizes its ubiquitination. In addition, NEDP1 acts as the deNEDDylase of PCNA, and NEDP1 deletion enhances PCNA NEDDylation but reduces its ubiquitination. In response to H202 stimulation, NEDP1 disassociates from PCNA and RAD18-dependent PCNA NEDDylation increases markedly after its ubiquitination. impairment of NEDDylation by Ubc12 knockout enhances PCNA ubiquitination and promotes PCNA-polη interaction, while up-regulation of NEDDylation by NEDD8 overexpression or NEDP1 deletion reduces the excessive accumulation of ubiquitinated PCNA, thus inhibits PCNA-polη interaction and blocks polη foci formation. Moreover, Ubc12 knockout decreases cell sensitivity to H2O2-induced oxidative stress, but NEDP1 deletion aggravates this sensitivity. Collectively, our study elucidates the important role of NEDDylation in the DDR as a modulator of PCNA monoubiquitination and polη recruitment.

关键词： NEDDylation ubiquitination PCNA,oxidative stress DNA damage response

hCINAP alleviates senescence by regulating MDM2 via p14ARF and the HDAC1/CoREST complex

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Journal of Molecular Cell Biology 2023年第2期15卷 58-71页

作者： Xinping Huang Yan Zhao Min Wei Ruipeng Zhuge xiaofeng zheng State Key Laboratory of Protein and Plant Gene Research School of Life SciencesPeking UniversityBeĳing 100871China Department of Biochemistry and Molecular Biology School of Life SciencesPeking UniversityBeĳing 100871China

Cellular senescence is a major process affected by multiple signals and coordinated by a complex signal response network.Identification of novel regulators of cellular senescence and elucidation of their molecular mechanisms will aid in the discoveryof new treatment strategies for aging-related diseases. In the present study, we identified human coilin-interacting nuclear ATPaseprotein (hCINAP) as a negative regulator of aging. Depletion of cCINAP significantly shortened the lifespan of Caenorhabditiselegans and accelerated primary cell aging. Moreover, mCINAP deletion markedly promoted organismal aging and stimulatedsenescence-associated secretory phenotype in the skeletal muscle and liver from mouse models of radiation-induced senescence.Mechanistically, hCINAP functions through regulating MDM2 status by distinct mechanisms. On the one hand, hCINAP decreasesp53 stability by attenuating the interaction between p14ARF and MDM2;on the other hand, hCINAP promotes MDM2 transcriptionvia inhibiting the deacetylation of H3K9ac in the MDM2 promoter by hindering the HDAC1/CoREST complex integrity. Collectively,our data demonstrate that hCINAP is a negative regulator of aging and provide insight into the molecular mechanisms underlyingthe aging process.

关键词： hCINAP HDAC1/CoREST complex p14ARF MDM2 transcription senescence

“三言”中城市民居书写的叙事作用与文化意蕴

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学术交流 2024年第3期 181-192页

作者：张萌郑晓峰哈尔滨师范大学文学院哈尔滨150025

如果说城市园林的书写体现了章回小说文人化的叙事风格,那么城市民居就是拟话本小说民间化叙事的典型环境。在拟话本小说集“三言”中,城市民居空间兼具了自然环境和社会环境的双重身份,产生了重要的叙事作用,使故事环境更加生动具体、... 详细信息

如果说城市园林的书写体现了章回小说文人化的叙事风格,那么城市民居就是拟话本小说民间化叙事的典型环境。在拟话本小说集“三言”中,城市民居空间兼具了自然环境和社会环境的双重身份,产生了重要的叙事作用,使故事环境更加生动具体、人物关系更加贴近世俗、故事情节更加曲折多变。从文化的角度看,一方面,城市民居书写彰显了明代市民社会的思想新变,民宅空间的开放暗示了男女情欲的放纵,商铺空间的繁华体现出市民物欲的勃发;另一方面,城市民居书写中暗含了传统思想的观念固守,民居秩序象征了传统的婚姻方式,民居结构昭示出家庭伦理观念,商人住宅的细节则揭示出根深蒂固的重农抑商观念。可见,明代城市社会虽然出现了思想文化的变革,但传统价值观念仍然占据着主流地位。

关键词：拟话本 “三言” 城市民居叙事文化意蕴

Switched-capacitor Multi-level Inverter with Equal Distribution of the Capacitors Discharging Phases

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Chinese Journal of Electrical Engineering 2020年第4期6卷 42-52页

作者： Zhiyuan Xu xiaofeng zheng Tong Lin Jia Yao Adrian Ioinovici College of Automation Nanjing University of Science and TechnologyNanjing 210014China College of Automation Nanjing University of Aeronautics and AstronauticsNanjing 210016China

A new switched-capacitor(2n+1)levels inverter with a single input source and equal charge of the capacitors at the input voltage V_(in) is presented.Compared with its peers from the same class of inverters,the proposed one features an equal or lower components count referred to the boost factor.And,it presents an additional advantage:each voltage level can be obtained by using different capacitors in the discharging phase,such that the decreasing part of the staircase output waveform can be synthesized with different switching topologies than those used in the increasing part.As a consequence,all the capacitors are discharged at the same voltage value at the end of each half-cycle,allowing for the use of smaller capacitors of equal values.When the capacitors are connected in parallel in the charging phase,there is no need to equalize their voltages,so no additional current spikes appear.This also implies less electromagnetic emission(EMI).Two types of modulation strategies are proposed.A half-height fundamental switching frequency modulation strategy allows for reaching the desired peak of the output voltage during the highest voltage level operation.It is advantageous in application of the inverter as a front end of a grid supplied by green sources of energy.A high frequency(f_(s)=200 kHz)modulation strategy accompanied by a duty-cycle control is advantageous for applications which require miniaturization.A 9-level switched-capacitor multi-level inverter(SCMLI)is analyzed and designed.The power losses are calculated.The experimental results for a 9-level inverter with V_(in)=40 V,V_(out)=110 Vrms 50 Hz,200 W confirm the theoretical expectations.

关键词： Switched-capacitor multi-level inverter half-height frequency modulation

Recent progress in liquid desiccant dehumidification and air-conditioning:A review

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能源与人工环境(英文)

能源与人工环境(英文) 2020年第1期1卷 106-130页

作者： Xiangjie Chen Saffa Riffat Hongyu Bai xiaofeng zheng David Reay Department of Architecture and Built Environment University of NottinghamUniversity ParkNG72JQ NottinghamUnited Kingdom David Reay&Associates PO Box 25Whitley BayTyne&Wear NE261QTUnited Kingdom Department of Energy and Power Engineering University of Shanghai for Science and TechnologyJungong Road No.516Shanghai 200031China Centre for Renewable Energy Systems Technologies(CREST) Wolfson School of MechanicalElectrical and Manufacturing EngineeringLoughborough UniversityLeicestershire LE113TUUnited Kingdom

This paper presents a literature review on the recent research progress in liquid desiccant dehumidification and air conditioning systems.The physical features of various liquid desiccant materials and their dehumidification performances have been summarized.With the aim to improve the dehumidification characteristics,mixed sol-vents desiccants have become research hot topics recently.Various types of dehumidifiers and their integration with liquid desiccant dehumidification system have been reviewed.The combination of liquid desiccant dehumid-ification system with solar collector,vapour compression system,heat pump system,CHP system,etc.have been grouped and compared.It is shown that the majority of the recent research work for liquid desiccant dehumid-ification systems has concentrated on numerical simulations,a considerable amount of works are still required for the practical investigations of innovative material(mixed solvents)and hybrid systems.

关键词： Dehumidification Hybrid system Liquid desiccant Model Review

The crystal structure of LidA,a translocated substrate of the Legionella pneumophila type IV secretion system

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Protein & Cell 2013年第12期4卷 897-900页

作者： Geng Meng Xiaojing An Sheng Ye Yong Liu Wenzhuang Zhu Rongguang Zhang xiaofeng zheng State Key Lab of Protein and Plant Gene Research School of Life SciencesPeking UniversityBeijing 100871China Department of Biochemistry and Molecular Biology School of Life SciencesPeking UniversityBeijing 100871China National Laboratory of Biomacromolecules Institute of BiophysicsChinese Academy of SciencesBeijing 100101China

Dear Editor,Legionella pneumophila,a gram-neg-ative bacterium,is the causative agent of Legionnaires’pneumonia by infecting human lung macrophages(Muder et al.,1986).Upon uptake into macrophages,the bacteria are internalized to escape the endocytic pathway and lysosomal network,and establish the Legionella-containing vacuole(LCV)as an intracel-lular replicative organelle(Roy et al.,1998).The LCV hijacks and recruits the early secretory ER-derived vesicles and transforms them into ER-like vacuole.Within the specialized ER-like vacuole,L.pneumophila replicates to a high den-sity and subsequently kills the host cell by lysing the host cell membrane.The released bacteria can infect neighboring cells to initiate a new round of infection(Tilney et al.,2001).

关键词： agent system specialized