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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

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

Genomic differentiation with isolation by distance along a latitudinal gradient in the spotted-leg treefrog Polypedates megacephalus

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Integrative Zoology 2023年第3期18卷 569-580页

作者： Long JIN Yuchi zheng xiaofeng LUAN Wenbo LIAO Key Laboratory of Southwest China Wildlife Resources Conservation(Ministry of Education) China West Normal UniversityNanchongChina Chengdu Institute of Biology Chinese Academy of SciencesChengduChina School of Ecology and Nature Conservation Beijing Forestry UniversityBeijingChina

The patterns of isolation by distance(IBD)entailing increased genetic differentiation among populations have aroused extensive concerns for evolutionary biologists.Although the IBD may act on spatial processes contribut-ing to the genetic differentiation among populations in anuran species,the factors shaping the IBD of frogs among populations in natural systems are largely unknown.Here,we studied the genetic differentiation among six popula-tions with 24 individuals of the spotted-leg treefrog along a latitudinal gradient(1860.31 km)based on 1020 single nucleotide polymorphisms from restriction site-associated DNA sequencing.The results showed that the genetic diversity differed signiﬁcantly among populations and that the insular populations had higher genetic diversity than the mainland populations.Furthermore,we also found a signiﬁcant genetic differentiation among populations(FST=0.277)and no sign of inbreeding(FUNI=-0.145).The IBD was detected for all populations,and a higher degree of the IBD was indicated when controlling for the effects of the isolation between Hainan and mainland populations caused by the Qiongzhou Strait.Ourﬁndings suggest that the form of the Qiongzhou Strait plays a key role in shaping the genetic diversity and population differentiation in treefrogs.

关键词： genetic diversity isolation by distance Polypedates megacephalus population differentiation single nucleotide polymorphisms

Characterization of size-resolved effective density of atmospheric particles in an urban atmosphere in Southern China

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Journal of Environmental Sciences 2024年第7期141卷 194-204页

作者： Tingting Xie Liming Cao Jinyi zheng Peng Xuan xiaofeng Huang Laboratory of Atmospheric Observation Supersite School of Environment and EnergyPeking University Shenzhen Graduate SchoolShenzhen 518055China

Effective density(ρ_(eff))is one of the most important physical properties of atmospheric particles,providing important references in exploring the emissions and aging processes of fresh particles.In this study,a combined system of differential mobility analyzer,centrifugal particle mass analyzer,and condensation particle counter was used to periodically measure theρ_(eff)of atmospheric particles in Shenzhen from Oct.2021 to Jan.2022.Results showed that theρ_(eff)of particles with various size presented a bimodal distribution,which could be divided into main density(ρ_(m),main peak,corresponding to relatively dense particles after aging)and sub density(ρ_(s),sub peak,corresponding to fresh particles).The occurrence frequencies ofρ_(s)of particles with diameters of 50 and 80 nm were less than 20%,but were as high as about 40%of that with diameters from 120 to 350 nm.Theρ_(m)showed increasing trend with the size of particles,whileρ_(s)decreased as the increasing of the size of particles.Theρ_(eff)on pollution day varied significantly with chemical compositions.The increasing of the proportion of sulfate could promote the increasing ofρ_(eff),while black carbon and organic matter caused opposite effects,which may be related to various factors,including the difference of the material density and morphology of various chemical components.Theρ_(eff)of 50,80 and 120 nm particles decreased considerably during the new particle formation event,indicating that organic condensation was an important contributor to new particle growth.

关键词： DMA-CPMA-CPC Effective density Main/sub density Size distribution

hCINAP negatively regulates NF-κB signaling by recruiting the phosphatase PP1 to deactivate IKK complex

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分子细胞生物学报:英文版 2015年第6期7卷 529-542页

作者： Linglong Qu Yapeng Ji Xi Zhu Xiaofeng Zheng State Key Lab of Protein and Plant Gene Research Beijing 100871China Department of Biochemistry and Molecular Biology School of Life SciencesPeking UniversityBeijing 100871China Department of Critical Care Medicine Peking University Third HospitalBeijing 100191China

Tight regulation of nuclear factor-kB(NF-kB)signaling is essential to maintain homeostasis in immune system in response to various stimuli,which hasbeen studied extensivelyand deeply.However,the molecularmechanisms responsible for its negative regulation are not completely understood.Here we demonstrate that human coilin-interacting nuclear ATPase protein(hCINAP)is a novel negative regulator in NF-kB signaling by deactivating IkB kinase(IKK)complex.In response to TNF stimulation,hCINAP dynamically associates with IKKa and IKKb and inhibits IKK phosphorylation.Notably,hCINAP directly interacts with the catalytic subunits of protein phosphatase 1(PP1)and mediates the formation of IKK–hCINAP–PP1 complex,serving as an adaptor protein that recruits PP1 to dephosphorylate IKK.Furthermore,decreased levels of hCINAP are observed in several inflammatory diseases with NF-kB hyperactivity.Our study suggests a novel mechanism underlying deactivation of IKK and provides new insight into the negative regulation of NF-kB signaling.

关键词： hCINAP NF-κB IKK complex phosphatase PP1 inflammatory diseases

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

The impact of consistency between the emotional feature of advertising music and brand personality on brand experience

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Journal of Management Analytics 2019年第3期6卷 250-268页

作者： Jianrong Hou xiaofeng Zhao Jiahao zheng Department of Marketing Antai College of Economics and ManagementShanghai Jiao Tong UniversityShanghaiPeople’s Republic of China College of Business University of Mary WashingtonFredericksburgVAUSA

Music in advertising plays a crucial role in making the audience feel beyond the multi-level visual experience.The intrinsic link between brand publicity and advertising music has long been a puzzle.This paper discusses the impact of the consistency between the emotional characteristics of music and brand personality on brand experience and expands the discussion to brand experience under market competition.We use the examples of Canon and Apple for our study.The results shows that:(1)the higher the degree of consistency between the emotional experience from music and brand personality,the greater the positive effect on brand experience;(2)this positive effect is not as significant for functional brands as it is for representative brands;(3)the consistency between the emotional experience from music and brand personality has a greater impact on brand experience for representative brands than functional brands.The results provide practical guidance for branding campaigns.

关键词： music emotional feature brand personality consistency brand experience

空肠间置术能快速改善非肥胖2型糖尿病大鼠的糖耐量并缓慢改善胰岛素抵抗

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Gastroenterology Report 2018年第4期6卷 291-297,I0002页

作者： Hengliang Zhu Huaiming Wang Zhihai zheng Bailiang Ye Xiaojiao Ruan Xiaofeng Zheng Guoxin Li Department of General Surgery Nanfang HospitalSouthern Medical UniversityGuangzhouGuangdongChina Department of Gastrointestinal Surgery The Seventh Affiliated HospitalSun Yat-sen UniversityShenzhenGuangdongChina Department of Colorectal Surgery The Sixth Affiliated HospitalSun Yat-sen UniversityGuangzhouGuangdongChina Department of Gastrointestinal Surgery The First Affiliated Hospital of Wenzhou Medical UniversityWenzhouZhejiangChina

背景:许多研究已证实,回肠间置术能改善2型糖尿病(T2DM),同时胰高血糖素样肽-1(GLP-1)水平上升。我们采用糖尿病大鼠模型进行研究,评估回肠间置术对糖代谢的影响及其机制。方法:20只GK大鼠被随机分为回肠间置组和假手术组。分别于术前... 详细信息

背景:许多研究已证实,回肠间置术能改善2型糖尿病(T2DM),同时胰高血糖素样肽-1(GLP-1)水平上升。我们采用糖尿病大鼠模型进行研究,评估回肠间置术对糖代谢的影响及其机制。方法:20只GK大鼠被随机分为回肠间置组和假手术组。分别于术前及术后1、4、8、16、24周检测大鼠体重、进食量、空腹血糖(FPG)、空腹胰岛素(F-ins)、口服葡萄糖耐量试验(OGTT)和GLP-1水平。计算稳态模型胰岛素抵抗指数(HOMA-IR)和OGTT曲线下面积(AUC)。术后24周处死大鼠,检测胰腺和回肠组织中GLP-1受体(GLP-1R)的表达水平。结果:与假手术组相比,回肠间置组大鼠术后4、8、16和24周血GLP-1水平更高(均P<0.05),术后8、16和24周FPG、F-ins和HOMAIR水平更低(均P<0.05)。与术前相比,回肠间置组术后各个时间点均可观察到血GLP-1、AUC和FPG水平的下降(均P<0.05);术后8、16和24周F-ins和HOMA-IR也显著下降(均P<0.05)。术后24周,无论是胰腺还是回肠组织,回肠间置组大鼠的GLP-1R表达水平均显著高于假手术组(均P<0.05)。结论:回肠间置可改善GK大鼠的糖代谢,且不会导致体重的下降和进食量的减少,这可能与GLP-1水平升高有关。而后期胰岛素抵抗的改善和胰岛素水平的下降可能并不直接受益于GLP-1水平的升高。

关键词： GK大鼠空肠间置术胰岛素抵抗进食量 FPG 糖尿病大鼠模型糖代谢糖耐量

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

Vertical nanowires enhanced X-ray radiation damage of cells

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Journal of Materials Science & Technology 2023年第14期145卷 7-13页

作者： Liyuan zheng Qingxuan Li Shandong Xu xiaofeng Meng Xinqi Chen Ming Su Department of Chemical Engineering Northeastern UniversityBostonMassachusetts 02115United States Wenzhou Institute of Biomaterials and Engineering Chinese Academy of Sciencesand Wenzhou Medical UniversityWenzhou 325001China College of Sciences Beijing Forestry UniversityBeijing 100083China Department of Mechanical Engineering Northwestern UniversityEvanstonIllinois 60208United States

Cell behavior is affected by nanostructured surface,but it remains unknown how ionizing radiation af-fects cells on nanostructured surface.This paper reports an experimental investigation of X-ray radiation induced damage of cells placed on an array of vertically aligned silicon nanowires.X-ray photoelectrons and secondary electrons produced from nanowire array are measured and compared to those from flat silicon substrate.The cell functions including morphology,viability,adhesion and proliferation have been examined and found to be drastically affected when cells are exposed to X-ray radiation,compared to those sitting on flat substrate and those only exposed to X-ray.The enhanced cell damage on nanowires upon X-ray exposure is attributed to nanowire enhanced production of photoelectrons including Auger electrons and secondary electrons,which have high escaping probability from sharp tips of nanowires.The escaped photoelectrons ionize water molecules and generate hydroxyl free radicals that can damage DNAs of cells.An inference of this work is that the contrast in scanning electron microscopy is useful in assessing the effects of nanomaterials for enhanced X-ray radiation therapy.

关键词： Edge enhancement Silicon nanowire array X-ray radiation Photoelectron Cell damage