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文献 2002年第4期 147-156页

作者：赵素文浙江大学人文学院中文系

祁彪佳,字虎子,又字幼文、宏吉,号世培.生于明万历三十年(1602),万历四十六年十七岁举于乡试,天启二年(1622)中进士,选福建兴化府推官,任职五年后丁外忧归,崇祯四年(1631)服满晋京,次年春考选福建道御史,六年出为苏松巡按,八年乞病归养... 详细信息

祁彪佳,字虎子,又字幼文、宏吉,号世培.生于明万历三十年(1602),万历四十六年十七岁举于乡试,天启二年(1622)中进士,选福建兴化府推官,任职五年后丁外忧归,崇祯四年(1631)服满晋京,次年春考选福建道御史,六年出为苏松巡按,八年乞病归养母,此后家居八年,直至崇祯十五年才北上赴河南道御史之命,主掌计典,计事竣外迁为京畿刷卷.南明立国,被公荐为苏松巡抚,因与东林党人关系密切,为马士英、阮大铖所嫉,任事不过半年便不得不辞职告归.

关键词：东书堂祁彪佳稿本乌丝栏

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《鱼儿佛》杂剧改编者寓山居士为祁彪佳考辨

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绍兴文理学院学报（哲学社会科学版） 2001年第2期21卷 8-11页

作者：赵素文浙江大学人文学院，浙江杭州310028

祁彪佳在明末曲坛上有重要地位，他的戏曲论著《远山堂曲品剧品》虽然受到了一些重视，但他本人以及他的戏曲活动却很少受到研究者的关注，同时也存在着一些误解。本文在广泛搜求各方资料的基础上，对学术界以寓山居士为释湛然的传统说... 详细信息

祁彪佳在明末曲坛上有重要地位，他的戏曲论著《远山堂曲品剧品》虽然受到了一些重视，但他本人以及他的戏曲活动却很少受到研究者的关注，同时也存在着一些误解。本文在广泛搜求各方资料的基础上，对学术界以寓山居士为释湛然的传统说法提出质疑，认为《鱼鱼佛》杂剧的改编者寓山居士就是祁彪佳，并进而考订出祁氏改编此剧的大概时间和背景，对祁氏的戏曲活动和创作也作了初步探讨。

关键词：《鱼儿佛》释湛然寓山居士祁彪佳改编者考证戏曲文学研究改编时间明代

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ULK2 deficiency stratifies autophagy-driven molecular subtypes and exacerbates trophoblasts apoptosis in preeclampsia

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PLACENTA 2025年 167卷 42-54页

作者： Gan, Jianfeng Zhou, Wenhan zhao, Huanqiang Shao, Jiejie Cui, Yutong Wu, suwen Xu, Huangfang Wang, Yinan Zhou, Qiongjie Li, Xiaotian Fudan Univ Obstet & Gynecol Hosp Fangxie Rd 419 Shanghai Peoples R China Shanghai Key Lab Female Reprod Endocrine Related D Shanghai Peoples R China Southern Med Univ Affiliated Shenzhen Matern & Child Healthcare Hosp Shenzhen Peoples R China Tongji Univ Shanghai Funiirst Matern & Infant Hosp Sch Med Shanghai Peoples R China Huazhong Univ Sci & Technol Union Hosp Tongji Med Coll Wuhan Peoples R China Zhejiang Univ Affiliated Hosp 2 Sch Med Dept Gynecol Hangzhou Peoples R China

Introduction: Preeclampsia (PE), a placenta-originated hypertensive disorder of pregnancy, lacks targeted therapies despite its significant contribution to maternal and fetal morbidity. Emerging evidence implicates autophagy dysregulation in PE pathogenesis, though its molecular heterogeneity remains unexplored. This study aims to investigate autophagy-related molecular subtypes in PE and identify ULK2 key regulators linking autophagic imbalance to placental dysfunction. Methods: Placental transcriptomic datasets were analyzed to identify autophagy-related differentially expressed genes (ARGs). Unsupervised consensus clustering stratified 80 PE patients into molecular subtypes. Proteinprotein interaction (PPI) networks, machine learning algorithms, and functional enrichment analyses were employed to delineate hub genes and pathways. ULK2's role was validated via qRT-PCR, shRNA knockdown in HTR8/SVneo trophoblasts, and immunofluorescence. A murine PE model was established using the ULK1/2 inhibitor MRT68921 to assess systolic blood pressure, fetal growth, and placental autophagy-apoptosis dynamics. Results: Unsupervised clustering of 45 ARGs classified PE patients into ULK2low and ULK2high subtypes. The ULK2low subtype exhibited severe clinical features: elevated preterm delivery, systolic hypertension, HELLP syndrome incidence and increased proteinuria. ULK2-kncokdown trophoblasts showed impaired autophagy and upregulated apoptosis. Six hub genes correlated with disease severity and inversely with ULK2 expression. In mice, ULK2 inhibition induced PE-like phenotypes: sustained hypertension, fetal growth restriction and severe proteinuria. Discussion: ULK2 deficiency disrupts trophoblast homeostasis, driving placental dysfunction and severe clinical outcomes. The ULK2low subtype highlights autophagy heterogeneity in PE. While pharmacological ULK2 inhibition recapitulates PE in mice, limitations include sample size and MRT68921's dual ULK1/2 activity. Our findings prop

关键词： Preeclampsia Autophagy Subtype Bioinformatics Apoptosis

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Structural Basis of the Diversity of Adrenergic Receptors

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CELL REPORTS 2019年第10期29卷 2929-+页

作者： Qu, Lu Zhou, Qingtong Xu, Yueming Guo, Yu Chen, Xiaoyu Yao, Deqiang Han, Gye Won Liu, Zhi-Jie Stevens, Raymond C. Zhong, Guisheng Wu, Dong zhao, suwen ShanghaiTech Univ iHuman Inst Shanghai 201210 Peoples R China Chinese Acad Sci Inst Biophys Natl Lab Biomacromol Beijing 100101 Peoples R China Univ Chinese Acad Sci Beijing 100049 Peoples R China ShanghaiTech Univ Sch Life Sci & Technol Shanghai 201210 Peoples R China Univ Southern Calif Dept Biol Sci Bridge Inst Los Angeles CA 90089 USA Univ Southern Calif Dept Chem Bridge Inst Los Angeles CA 90089 USA

Adrenergic receptors are highly homologous while at the same time display a wide diversity of ligand and G-protein binding, and understanding this diversity is key for designing selective or biased drugs for them. Here, we determine two crystal structures of the alpha(2A) adrenergic receptor (alpha(2A)AR) in complex with a partial agonist and an antagonist. Key non-conserved residues from the ligand-binding pocket (Phe(7.39) and Tyr(6.55)) to G-protein coupling region (Ile(34.51) and Lys(34.56)) are discovered to play a key role in the interplay between partial agonism and biased signaling of alpha(2A)AR, which provides insights into the diversity of ligand binding and G-protein coupling preference of adrenergic receptors and lays the foundation for the discovery of next-generation drugs targeting these receptors.

关键词： GPCR α2A adrenergic receptor partial agonism biased signaling

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Ugi Reaction Mediated Detergent Assembly for Membrane Protein Studies

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CHEMISTRY-AN ASIAN JOURNAL 2022年第15期17卷 e202200372-e202200372页

作者： Yang, Meifang Luo, Weiling Zhang, Wei Wang, Huixia Xue, Dongxiang Wu, Yiran zhao, suwen zhao, Fei Zheng, Xing Tao, Houchao Univ South China Dept Pharm Grp Lead Compound Hengyang 421001 Hunan Peoples R China Shanghai Univ Tradit Chinese Med Innovat Res Inst Tradit Chinese Med Shanghai Frontiers Sci Ctr TCM Chem Biol Shanghai 201203 Peoples R China ShanghaiTech Univ iHuman Inst Shanghai 201210 Peoples R China ShanghaiTech Univ Sch Life Sci & Technol Shanghai 201210 Peoples R China Univ Chinese Acad Sci Beijing 100049 Peoples R China

Despite the continuous efforts, the current repertoire of detergents is still far from sufficient for the biophysics studies of membrane proteins (MPs). Toward the rapid expansion of detergent diversity, we herein report a new strategy based on Ugi reaction mediated modular assembly. Structural varieties, including hydrophobic tails and hydrophilic heads, could be conveniently introduced from the multiple reaction components. New detergents then were comprehensively evaluated in the physical properties and preliminarily screened by the thermal stabilization for a transporter MsbA and a spectrum of G protein-coupled receptors (GPCRs). For the glucagon-like peptide-1 receptor (GLP-1R), a class B GPCR, detergent M-23-M finally stood out in a second evaluation for the maintenance of homogeneity and was further illustrated its application in the improvement of NMR study. Besides the promising utility in the MP study, the current results exhibit intriguing structural-physical relationship that would allow the guidance in the tuning of detergent properties in the future.

关键词： detergent membrane proteins micelle NMR study Ugi reaction

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Molecular Basis for the Final Oxidative Rearrangement Steps in Chartreusin Biosynthesis

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JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 2018年第34期140卷 10909-10914页

作者： Wang, Yi Shuang Zhang, Bo Zhu, Jiapeng Yang, Cheng Long Guo, Yu Liu, Cheng Li Liu, Fang Huang, Huiqin zhao, suwen Liang, Yong Jiao, Rui Hua Tan, Ren Xiang Ge, Hui Ming Nanjing Univ Inst Funct Biomol Sch Life Sci State Key Lab Pharmaceut Biotechnol Nanjing 210023 Jiangsu Peoples R China Nanjing Univ Chinese Med Sch Med & Life Sci State Key Lab Cultivat Base TCM Qual & Efficacy Nanjing 210023 Jiangsu Peoples R China Shanghai Tech Univ iHuman Inst Shanghai 201210 Peoples R China Chinese Acad Trop Agr Sci Minist Agr Key Lab Biol & Genet Resources Trop Crops Inst Trop Biosci & Biotechnol Haikou 571101 Hainan Peoples R China Nanjing Univ Sch Chem & Chem Engn Jiangsu Key Lab Adv Organ Mat State Key Lab Coordinat Chem Nanjing 210023 Jiangsu Peoples R China

Oxidative rearrangements play key roles in introducing structural complexity and biological activities of natural products biosynthesized by type II polyketide synthases (PKSs). Chartreusin (1) is a potent antitumor polyketide that contains a unique rearranged pentacyclic aromatic bilactone aglycone derived from a type II PKS. Herein, we report an unprecedented dioxygenase, ChaP, that catalyzes the final a-pyrone ring formation in 1 biosynthesis using flavin-activated oxygen as an oxidant. The X-ray crystal structures of ChaP and two homologues, docking studies, and site-directed mutagenesis provided insights into the molecular basis of the oxidative rearrangement that involves two successive C-C bond cleavage steps followed by lactonization. ChaP is the first example of a dioxygenase that requires a flavin-activated oxygen as a substrate despite lacking flavin binding sites, and represents a new class in the vicinal oxygen chelate enzyme superfamily.

关键词： Peptides and proteins Monomers Biosynthesis Aromatic compounds Rearrangement

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Alleviation effect of macrophage depletion on hepatotoxicity of triptolide: A new insight based on metabolomics and proteomics

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JOURNAL OF ETHNOPHARMACOLOGY 2025年 343卷 119485页

作者： Zhang, Xiaoguang Zhang, Jia Xun, Ge Gao, Yanhua zhao, Jie Fu, Yan Su, suwen Kong, Dezhi Wang, Qiao Wang, Xu Hebei Med Univ Core Facil & Ctr Shijiazhuang Hebei Peoples R China Hebei Med Univ Sch Pharm Shijiazhuang Hebei Peoples R China China Acad Chinese Med Sci Inst Chinese Mat Med Beijing Peoples R China Henan Univ Chinese Med Acad Chinese Med Sci Zhengzhou Henan Peoples R China Hebei Med Univ Dept Pharmacol Key Lab Neural & Vasc Biol Key Lab New Drug Pharmacol & ToxicolMinist Educ Shijiazhuang Hebei Peoples R China Hebei Med Univ Inst Chinese Integrat Med Shijiazhuang Hebei Peoples R China

Ethnopharmacological relevance: Triptolide (TP) is an abietane-type diterpenoid isolated from the traditional Chinese herb Tripterygium wilfordii Hook. F, which is used to relieve rheumatism, alleviate joint pain and swelling, and promote blood circulation for more than 600 years in China. The most common preparations containing TP from Tripterygium wilfordii Hook F, which are Tripterygium tablets and Tripterygium glycoside tablets, are widely used in clinical for treating rheumatoid arthritis and other autoimmune diseases at present. However, the clinical application is hindered by severe systemic toxicity induced by TP, especially hepatotoxicity. It is crucial to discover potent and specific detoxification strategy for TP. Aim of study: According to our previous study, TP-induced hepatotoxicity is primarily related to macrophages. This study aimed to investigate the alleviation effects of macrophage depletion on the TP-induced liver injury in mice and to explore the related mechanisms by integration of metabolomics and proteomics. Materials and methods: Mice were treated with clodronate liposomes to deplete macrophage before administration of triptolide. The alleviation effects were evaluated by biochemical analysis of serum and histopathology observation of the hepatic tissues. Metabolomics and proteomics were carried out to explore the mechanism of macrophage depletion on triptolide-induced liver injury. The levels of mRNA and protein of TLR4- MyD88-NF-kappa B axis were further detected. Results: The altered levels of biochemistry indicators, including aminotransferase (ALT) and aspartate aminotransferase (AST), albumin (ALB), and gamma-glutamyltranspeptidase (GGT) were significantly recovered, and histopathological liver injury also showed restoring tendency in mice with macrophage depletion compared to mice with TP-treatment. The inflammation indicator interleukin-6 (IL-6) and interleukin-1 beta (IL-1 beta) were recovered significantly after depletion of macro

关键词： Macrophages Triptolide Hepatotoxicity Multi-omics

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Genome-wide CRISPR screen identifies FAM49B as a key regulator of actin dynamics and T cell activation

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2018年第17期115卷 E4051-E4060页

作者： Shang, Wanjing Jiang, Yong Boettcher, Michael Ding, Kang Mollenauer, Marianne Liu, Zhongyi Wen, Xiaofeng Liu, Chang Hao, Piliang zhao, suwen McManus, Michael T. Wei, Lai Weiss, Arthur Wang, Haopeng ShanghaiTech Univ Sch Life Sci & Technol Shanghai 201210 Peoples R China Chinese Acad Sci Shanghai Inst Biol Sci Inst Biochem & Cell Biol Shanghai 200031 Peoples R China Univ Chinese Acad Sci Beijing 100049 Peoples R China Univ Calif San Francisco Dept Microbiol & Immunol WM Keck Ctr Noncoding RNAs Ctr Diabet San Francisco CA 94143 USA ShanghaiTech Univ iHuman Inst Shanghai 201210 Peoples R China Univ Calif San Francisco Dept Med Rosalind Russell & Ephraim P Engleman Rheumatol R Div Rheumatol San Francisco CA 94143 USA Univ Calif San Francisco Howard Hughes Med Inst San Francisco CA 94143 USA Sun Yat Sen Univ Zhongshan Ophthalm Ctr State Key Lab Ophthalmol Guangzhou 510060 Guangdong Peoples R China

Despite decades of research, mechanisms controlling T cell activation remain only partially understood, which hampers T cell-based immune cancer therapies. Here, we performed a genome-wide CRISPR screen to search for genes that regulate T cell activation. Our screen confirmed many of the known regulators in proximal T cell receptor signaling and, importantly, also uncovered a previously uncharacterized regulator, FAM49B (family with sequence similarity 49 member B). FAM49B deficiency led to hyperactivation of Jurkat T cells following T cell receptor stimulation, as indicated by enhancement of CD69 induction, PAK phosphorylation, and actin assembly. FAM49B directly interacted with the active form of the small GTPase Rac, and genetic disruption of the FAM49BRac interaction compromised FAM49B function. Thus, FAM49B inhibits T cell activation by repressing Rac activity and modulating cytoskeleton reorganization.

关键词： genome-wide CRISPR screen TCR signaling FAM49B Rac1 actin cytoskeleton

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Glutaryl-CoA dehydrogenase suppresses tumor progression and shapes an anti-tumor microenvironment in hepatocellular carcinoma

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JOURNAL OF HEPATOLOGY 2024年第5期81卷 847-861页

作者： Lao, Yuanxiang Cui, Xiaohan Xu, Zhu Yan, Hongyao Zhang, Zechuan Zhang, Zhenwei Geng, Longpo Li, Binghua Lu, Yijun Guan, Qifei Pu, Xiaohong zhao, suwen Zhu, Jiapeng Qin, Xihu Sun, Beicheng Anhui Med Univ Affiliated Hosp 1 Affiliated Drum Tower Hosp Dept Hepatobiliary Surg Hefei Peoples R China Nanjing Univ Med Sch Affiliated Drum Tower Hosp Dept Hepatobiliary Surg Nanjing Peoples R China Innovat Inst Tumor Immun & Med ITIM Hefei Anhui Peoples R China Anhui Prov Key Lab Tumor Immune Microenvironm & Im Hefei Anhui Peoples R China Shandong Univ Qilu Hosp Cheeloo Coll Med Dept Gastrointestinal Surg Jinan Shandong Peoples R China Sichuan Univ West China Hosp Dept Rheumatol & Immunol Chengdu Sichuan Peoples R China Nanjing Univ Affiliated Drum Tower Hosp Med Sch Dept Pathol Nanjing Jiangsu Peoples R China Shanghai Tech Univ iHuman Inst Shanghai Peoples R China Nanjing Univ Chinese Med Sch Med & Holist Integrat Med Nanjing Jiangsu Peoples R China Nanjing Med Univ Affiliated Changzhou Peoples Hosp 2 Dept Hepatobiliary Pancreat Surg Changzhou Jiangsu Peoples R China Anhui Med Univ Affiliated Hosp 1 218 Jixi Rd Hefei 230022 Peoples R China

Background & aims: Crotonylation, a crotonyl-CoA-based non-enzymatic protein translational modification, affects diverse biological processes, such as spermatogenesis, tissue injury, inflammation, and neuropsychiatric diseases. Crotonylation is decreased in hepatocellular carcinomas (HCCs), but the mechanism remains unknown. In this study, we aim to describe the role of glutaryl-CoA dehydrogenase (GCDH) in tumor suppression. Methods: Three cohorts containing 40, 248 and 17 pairs of samples were used to evaluate the link between GCDH expression levels and clinical characteristics of HCC, as well as responses to anti-programmed cell death protein 1 (PD-1) treatment. Subcutaneous xenograft, orthotopic xenograft, Trp53(Delta hep/Delta hep);MYC- and Ctnnb(oe);METoe-driven mouse models were adopted to validate the effects of GCDH on HCC suppression. Results: GCDH depletion promoted HCC growth and metastasis, whereas its overexpression reversed these processes. As GCDH converts glutaryl-CoA to crotonyl-CoA to increase crotonylation levels, we performed lysine crotonylome analysis and identified the pentose phosphate pathway (PPP) and glycolysis-related proteins PGD, TKT, and ALDOC as GCDH-induced crotonylation targets. Crotonyl-bound targets showed allosteric effects that controlled their enzymatic activities, leading to decreases in ribose 5-phosphate and lactate production, further limiting the Warburg effect. PPP blockade also stimulated peroxidation, synergizing with senescent modulators to induce senescence in GCDH(high) cells. These cells induced the infiltration of immune cells by the SASP (senescence-associated secretory cell phenotype) to shape an anti-tumor immune microenvironment. Meanwhile, the GCDH(low) population was sensitized to anti-PD-1 therapy. Conclusion: GCDH inhibits HCC progression via crotonylation-induced suppression of the PPP and glycolysis, resulting in HCC cell senescence. The senescent cell further shapes an anti-tumor microenvironment via the

关键词： Glutaryl-CoA dehydrogenase Hepatocellular carcinoma Lysine crotonylation Pentose phosphate pathway

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Structural basis for activation of the growth hormone-releasing hormone receptor

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NATURE COMMUNICATIONS 2020年第1期11卷 5205-5205页

作者： Zhou, Fulai Zhang, Huibing Cong, zhaotong zhao, Li-Hua Zhou, Qingtong Mao, Chunyou Cheng, Xi Shen, Dan-Dan Cai, Xiaoqing Ma, Cheng Wang, Yuzhe Dai, Antao Zhou, Yan Sun, Wen zhao, Fenghui zhao, suwen Jiang, Hualiang Jiang, Yi Yang, Dehua Xu, H. Eric Zhang, Yan Wang, Ming-Wei Chinese Acad Sci Shanghai Inst Mat Med CAS Key Lab Receptor Res Shanghai 201203 Peoples R China Chinese Acad Sci Shanghai Inst Mat Med Natl Ctr Drug Screening Shanghai 201203 Peoples R China Zhejiang Univ Sir Run Run Shaw Hosp Sch Med Dept Biophys Hangzhou 310058 Peoples R China Zhejiang Univ Sir Run Run Shaw Hosp Sch Med Dept Pathol Hangzhou 310058 Peoples R China Fudan Univ Sch Pharm Shanghai 201203 Peoples R China ShanghaiTech Univ iHuman Inst Shanghai 201210 Peoples R China Chinese Acad Sci Shanghai Inst Mat Med State Key Lab Drug Res Shanghai 201203 Peoples R China Chinese Acad Sci Shanghai Inst Mat Med Drug Discovery & Design Ctr Shanghai 201203 Peoples R China Univ Chinese Acad Sci Beijing 100049 Peoples R China ShanghaiTech Univ Sch Life Sci & Technol Shanghai 201210 Peoples R China Fudan Univ Sch Basic Med Sci Shanghai 200032 Peoples R China

Growth hormone-releasing hormone (GHRH) regulates the secretion of growth hormone that virtually controls metabolism and growth of every tissue through its binding to the cognate receptor (GHRHR). Malfunction in GHRHR signaling is associated with abnormal growth, making GHRHR an attractive therapeutic target against dwarfism (e.g., isolated growth hormone deficiency, IGHD), gigantism, lipodystrophy and certain cancers. Here, we report the cryo-electron microscopy (cryo-EM) structure of the human GHRHR bound to its endogenous ligand and the stimulatory G protein at 2.6 angstrom. This high-resolution structure reveals a characteristic hormone recognition pattern of GHRH by GHRHR, where the alpha-helical GHRH forms an extensive and continuous network of interactions involving all the extracellular loops (ECLs), all the transmembrane (TM) helices except TM4, and the extracellular domain (ECD) of GHRHR, especially the N-terminus of GHRH that engages a broad set of specific interactions with the receptor. Mutagenesis and molecular dynamics (MD) simulations uncover detailed mechanisms by which IGHD-causing mutations lead to the impairment of GHRHR function. Our findings provide insights into the molecular basis of peptide recognition and receptor activation, thereby facilitating the development of structure-based drug discovery and precision medicine.

关键词： G protein-coupled receptors Cryoelectron microscopy Cryoelectron microscopy

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