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Expanding the horizons of targeted protein degradation:A non-small molecule perspective

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Acta Pharmaceutica Sinica B 2024年第6期14卷 2402-2427页

作者： Xiaowei Huang Fengbo Wu jing ye Lian Wang Xiaoyun Wang Xiang Li Gu He Department of Pharmacy and Department of Dermatology&Venerology West China HospitalSichuan UniversityChengdu 610041China Department of Urology West China HospitalSichuan UniversityChengdu 610041China Laboratory of Dermatology Clinical Institute of Inflammation and ImmunologyFrontiers Science Center for Disease-Related Molecular Network and State Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu 610041China

Targeted protein degradation(TPD)represented by proteolysis targeting chimeras(PROTACs)marks a significant stride in drug discovery.A plethora of innovative technologies inspired by PROTAC have not only revolutionized the landscape of TPD but have the potential to unlock functionalities beyond ***-small-molecule-based approaches play an irreplaceable role in this field.A wide variety of agents spanning a broad chemical spectrum,including peptides,nucleic acids,antibodies,and even vaccines,which not only prove instrumental in overcoming the constraints of conventional small molecule entities but also provided rapidly renewing *** we summarize the burgeoning non-small molecule technological platforms inspired by PROTACs,including three major trajectories,to provide insights for the design strategies based on novel paradigms.

关键词： Targeted protein degradation Proteolysis targeting chimera Endocytosis Autophagy Proximity-inducing modality Post-translational modification

Ferroptosis contributes to JEV-induced neuronal damage and neuroinflammation

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Virologica Sinica 2024年第1期39卷 144-155页

作者： Wenjing Zhu Qi Li Yong Yin Huanchun Chen Youhui Si Bibo Zhu Shengbo Cao Zikai Zhao jing ye National Key Laboratory of Agricultural Microbiology Huazhong Agricultural UniversityWuhan430070China Frontiers Science Center for Animal Breeding and Sustainable Production Huazhong Agricultural UniversityWuhan430070China The Cooperative Innovation Center for Sustainable Pig Production Huazhong Agricultural UniversityWuhan430070China Hubei Hongshan Laboratory Wuhan430070China

Ferroptosis is a newly discovered prototype of programmed cell death (PCD) driven by iron-dependent phospholipid peroxidation accumulation, and it has been linked to numerous organ injuries and degenerative pathologies. Although studies have shown that a variety of cell death processes contribute to JEV-induced neuroinflammation and neuronal injury, there is currently limited research on the specific involvement of ferroptosis. In this study, we explored the neuronal ferroptosis induced by JEV infection in vitro and in vivo. Our results indicated that JEV infection induces neuronal ferroptosis through inhibiting the function of the antioxidant system mediated by glutathione (GSH)/glutathione peroxidase 4 (GPX4), as well as by promoting lipid peroxidation mediated by yes-associated protein 1 (YAP1)/long-chain acyl-CoA synthetase 4 (ACSL4). Further analyses revealed that JEV E and prM proteins function as agonists, inducing ferroptosis. Moreover, we found that treatment with a ferroptosis inhibitor in JEV-infected mice reduces the viral titers and inflammation in the mouse brains, ultimately improving the survival rate of infected mice. In conclusion, our study unveils a critical role of ferroptosis in the pathogenesis of JEV, providing new ideas for the prevention and treatment of viral encephalitis.

关键词： Japanese encephalitisvirus(JEV) Ferroptosis Neuron Lipid peroxidation Inflammatory response

Cerebral syphilitic gumma misdiagnosed as brain abscess: A case report

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World Journal of Clinical Cases 2024年第3期12卷 650-656页

作者： Li-Kun Mu Li-Feng Cheng jing ye Meng-Yan Zhao Jin-Long Wang Department of Neurosurgery Shengli Oilfield Central HospitalDongying 257099Shandong ProvinceChina

BACKGROUND Cerebral syphilitic gumma is a relatively rare clinical *** clinical manifest-ations are non-specific,and the imaging manifestations are similar to other in-tracranial occupying lesions,often misdiagnosed as tumors or *** are few reports on this disease in the relevant *** our knowledge,we have reported the first case of cerebral syphilitic gumma misdiagnosed as a brain *** report this case and provide useful information for clinical doctors on neurosyphilis *** SUMMARY We report the case to explore the diagnostic essentials of cerebral syphilitic gumma and attempt to mitigate the rates of misdiagnosis and missed diagnosis by equipping physicians with knowledge of neurosyphilis *** cli-nical diagnosis and treatment of a patient with cerebral syphilitic gumma were *** manifestations,classifications,and diagnostic points were retro-spectively *** patient was admitted to the hospital with fever and limb *** magnetic resonance imaging showed multiple space-occupying lesions and a positive serum Treponema pallidum gelatin agglutination *** patient was misdiagnosed as having a brain abscess and underwent a craniotomy.A postoperative pathological diagnosis of syphilis gumma was *** patient improved and was discharged after penicillin anti-syphilis ***-up recovery was *** Cerebral syphilitic gumma is rare in clinical practice,and it is often misdiagnosed and *** diagnosis should be considered in combination with multiple examinations.

关键词： Neurosyphilis Cerebral syphilitic gumma Brain abscess Misdiagnosis Treatment Case report

基于扎根理论的乳制品安全综合治理机制政策分析

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食品科学 2024年第8期45卷 272-282页

作者：叶璟李艳南京财经大学管理科学与工程学院江苏南京210023 南京航空航天大学自动化学院江苏南京210016

为提高乳制品安全治理效能,从政策视角探究我国乳制品安全治理的发展脉络和作用机制是必要的。以2002—2021年乳制品政策文本为研究对象,运用扎根理论量化政策文本形成包括治理要素和治理行为的乳制品安全保障体系,并基于量化结果和社... 详细信息

为提高乳制品安全治理效能,从政策视角探究我国乳制品安全治理的发展脉络和作用机制是必要的。以2002—2021年乳制品政策文本为研究对象,运用扎根理论量化政策文本形成包括治理要素和治理行为的乳制品安全保障体系,并基于量化结果和社会网络分析对我国乳制品安全治理演化过程和作用机制进行深入探究。研究发现,我国乳制品安全治理经历了从政府强制监管、应急治理、政主企辅治理到社会共治治理模式的演变过程;整个演变过程体现了国家对治理行动者治理行为与方式的侧重,揭示了乳制品安全综合治理作用机制,治理行动者通过治理行为的相互配合共同作用于治理要素,并经治理要素将其治理作用体现在乳制品安全上,从而保障了乳制品质量安全。

关键词：乳制品安全演化分析政策文本扎根理论社会网络

Severe pediatric COVID‑19:a review from the clinical and immunopathophysiological perspectives

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World Journal of Pediatrics 2024年第4期20卷 307-324页

作者： Yi‑Kan Sun Can Wang Pei‑Quan Lin Lei Hu jing ye Zhi‑Gang Gao Ru Lin Hao‑Min Li Qiang Shu Li‑Su Huang Lin‑Hua Tan Children's Hospital Zhejiang University School of MedicineHangzhou 310052China The Second Affiliated Hospital Zhejiang University School of MedicineHangzhou 310030China Surgical Intensive Care Unit Children’s HospitalZhejiang University School of MedicineHangzhou 310052China Department of General Surgery Children’s HospitalZhejiang University School of MedicineHangzhou 310052China Department of Cardiopulmonary and Extracorporeal Life Support Children’s HospitalZhejiang University School of MedicineHangzhou 310052China Clinical Data Center Children’s HospitalZhejiang University School of MedicineHangzhou 310052China Department of Cardiac Surgery Children’s HospitalZhejiang University School of MedicineHangzhou 310052China National Clinical Research Center for Child Health Children’s HospitalZhejiang University School of MedicineHangzhou 310052China Department of Infectious Diseases Children’s HospitalZhejiang University School of MedicineHangzhou 310052China

Background Coronavirus disease 2019(COVID-19)tends to have mild presentations in ***,severe and critical cases do arise in the pediatric population with debilitating systemic impacts and can be fatal at times,meriting further attention from ***,the intricate interactions between the pathogen virulence factors and host defense mechanisms are believed to play indispensable roles in severe COVID-19 pathophysiology but remain incompletely *** sources A comprehensive literature review was conducted for pertinent publications by reviewers independently using the PubMed,Embase,and Wanfang *** keywords included“COVID-19 in children”,“severe pediatric COVID-19”,and“critical illness in children with COVID-19”.Results Risks of developing severe COVID-19 in children escalate with increasing numbers of co-morbidities and an unvaccinated *** respiratory distress stress and necrotizing pneumonia are prominent pulmonary manifestations,while various forms of cardiovascular and neurological involvement may also be *** immunological processes are implicated in the host response to COVID-19 including the type I interferon and inflammasome pathways,whose dysregulation in severe and critical diseases translates into adverse clinical *** inflammatory syndrome in children(MIS-C),a potentially life-threatening immune-mediated condition chronologically associated with COVID-19 exposure,denotes another scientific and clinical conundrum that exemplifies the complexity of pediatric *** the considerable dissimilarities between the pediatric and adult immune systems,clinical trials dedicated to children are lacking and current management recommendations are largely adapted from adult *** Severe pediatric COVID-19 can affect multiple organ *** dysregulated immune pathways in severe COVID-19 shape the disease course,epitomize the vast functional diversity of the

关键词： Immunopathophysiology MIS-C Pediatric critical care Severe pediatric COVID-19

基于文献计量学的中医创伤救治研究回顾与展望

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中国中药杂志 2024年第2期49卷 559-564页

作者：李静叶菁菁杨磊杭州师范大学公共卫生学院浙江杭州311121 北京大学人民医院创伤救治中心/国家创伤医学中心/创伤救治与神经再生教育部重点实验室(北京大学) 北京100044

为梳理总结现阶段我国中医创伤救治的研究热点和未来发展趋势,为我国开展中西医协同创伤救治相关研究提供参考和建议,该文采用文献计量学,检索中国知网(CNKI)、万方(Wanfang)、维普(VIP)、Web of Science、PubMed自建库至2022年12月31... 详细信息

为梳理总结现阶段我国中医创伤救治的研究热点和未来发展趋势,为我国开展中西医协同创伤救治相关研究提供参考和建议,该文采用文献计量学,检索中国知网(CNKI)、万方(Wanfang)、维普(VIP)、Web of Science、PubMed自建库至2022年12月31日中医创伤救治的相关文献进行分析。经筛选共纳入315篇中文文献,34篇英文文献。文献主要发表在中医类杂志;发文作者尚未形成核心作者群;作者单位分布呈现以医疗机构为主,高校及科研院所、政府机关等为辅的特征;研究内容主要聚焦于中医及中医药技术在创伤救治领域的临床实践及临床研究。中医创伤救治兴起较早,但目前尚处于起步发展阶段,未来研究可围绕中医创伤救治的服务模式创新、临床研究能力提升、医疗质量管理提升和强化综合医院中医药人才队伍建设等方面进一步深化。在创伤救治领域,西医更为精准、有效,而中医以其独特的治疗手段和效果,能起到很好的补充,所以中西医协同创伤救治发展潜力较大。

关键词：中医创伤文献计量学回顾展望

IDH1 mutation inhibits differentiation of astrocytes and glioma cells with low oxoglutarate dehydrogenase expression by disturbingα-ketoglutarate-related metabolism and epigenetic modification

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Life Metabolism 2024年第2期3卷 24-37页

作者： Yuanlin Zhao Ying Yang Risheng Yang Chao Sun Xing Gao Xiwen Gu Yuan Yuan Yating Nie Shenhui Xu Ruili Han Lijun Zhang jing Li Peizhen Hu Yingmei Wang Huangtao Chen Xiangmei Cao jing Wu Zhe Wang Yu Gu jing ye State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers Department of PathologyXijing Hospital and School of Basic MedicineFourth Military Medical UniversityXi’anShaanxi 710032China Department of Pathology Air Force Hospital of Southern Theater CommandGuangzhouGuangdong 510000China Department of Neurology Tangdu HospitalFourth Military Medical UniversityXi’anShaanxi 710038China Department of Clinical Diagnosis Tangdu HospitalFourth Military Medical UniversityXi’anShaanxi 710038China Department of Neurosurgery the Second Affiliated Hospital of Xi’an Jiaotong UniversityXi’anShaanxi 710004China Department of Pathology School of Basic Medical SciencesNingxia Medical UniversityYinchuanNingxia 750004China Institute of Analytical Chemistry and Instrument for Life Science The Key Laboratory of Biomedical Information Engineering of Ministry of EducationSchool of Life Science and TechnologyXi’an Jiaotong UniversityXi’anShaanxi 710049China

Isocitrate dehydrogenase(IDH)mutations frequently occur in lower-grade gliomas and secondary *** IDHs exhibit a gain-of-function activity,leading to the production of D-2-hydroxyglutarate(D-2HG)by reducingα-ketoglutarate(α-KG),a central player in metabolism and epigenetic ***,the role ofα-KG homeostasis in IDH-mutated gliomagenesis remains *** this study,we found that low expression of oxoglutarate dehydrogenase(OGDH)was a common feature in IDH-mutated gliomas,***α-***,IDH1 mutation significantly reducedα-KG levels and increased glutaminolysis and DNA/histone methylation in *** metabolic and epigenetic alterations inhibited astrocyte maturation and led to cortical dysplasia in ***,our results also indicated that reduced OGDH expression can promote the differentiation of glioma cells,while IDH1 mutations impeded the differentiation of glioma cells with low OGDH by reducing the accumulation ofα-KG and increasing ***,we found that l-glutamine increasedα-KG levels and augmented the differentiation-promoting effects of AGI5198,an IDH1-mutant inhibitor,in IDH1-mutant glioma ***,this study reveals that low OGDH expression is a crucial metabolic characteristic of IDH-mutant gliomas,providing a potential strategy for the treatment of IDH-mutant gliomas by targetingα-KG homeostasis.

关键词： α-ketoglutarate IDH1 mutation OGDH l-glutamine gliomas

Neutron star core-crust transition and the crustal moment of inertia in the nonlinear relativistic Hartree approximation

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Chinese Physics C 2024年第3期48卷 133-141页

作者：李牛韦斯纳杨荣瑶叶婧蒋维洲 School of Physics Southeast UniversityNanjing 211189China School of Physics and Optoelectronics South China University of TechnologyGuangzhou 510640China

We investigate the effects of theσmeson mass(m_(σ)),symmetry energy,and slope of the symmetry energy on the neutron star core-crust transition density and the crustal moment of inertia(ΔI/I)in the nonlinear relativistic Hartree approach(RHA),which includes vacuum *** the core-crust transition density(ρ_(t)),pressure(P_(t)),and neutron star radius(R),which are all dependent on the symmetry energy,contribute to determiningΔI/I,we find that changing only the slope of symmetry energy within a reasonable range is not sufficient to reachΔI/I≥7%to achieve the large glitches of the Vela ***,since all three factors(ρ_(t),P_(t),and R)increase with the increase in mσthrough scalar vacuum polarization,adjusting mσcan easily achieveΔI/I≥7%.

关键词： symmetry energy relativistic Hartree approximation random phase approximation core-crust transition density pulsar glitch

R141b在烧结高通量管外流动沸腾换热实验研究

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工程热物理学报 2024年第8期45卷 2389-2395页

作者：王科赵学智叶晶揭涛中国石油大学(北京)机械与储运工程学院北京102249 中国船舶集团有限公司第七一一研究所上海201100

烧结型高通量管是一种新型的强化换热元件,能在较低的壁面过热度条件下产生剧烈的核态沸腾,促进工质的相变换热。为探究烧结多孔层对流动沸腾换热特性的影响规律,本文以制冷剂R141b为实验工质,对外径为25 mm、涂层厚度为0.3mm、孔隙度... 详细信息

烧结型高通量管是一种新型的强化换热元件,能在较低的壁面过热度条件下产生剧烈的核态沸腾,促进工质的相变换热。为探究烧结多孔层对流动沸腾换热特性的影响规律,本文以制冷剂R141b为实验工质,对外径为25 mm、涂层厚度为0.3mm、孔隙度分别为65%和75%的外烧结型高通量管开展了实验研究。结果表明,在相同的壁面过热度条件下,高通量管较光管能大幅提高壁面热流密度,且孔隙率更高的高通量管其壁面热流密度更高。增加高通量管的孔隙度能增加汽化核心的数量和汽泡脱离的频率,但当加热壁面温度升高到一定程度时,汽泡无法及时从多孔层中逃逸而形成局部汽膜,导致高通量管的换热系数降低。

关键词：高通量管强化换热流动沸腾过冷沸腾 R141b