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Overview of epigenetic degraders based on PROTAC, molecular glue, and hydrophobic tagging technologies

Acta Pharmaceutica Sinica B 2024年第2期14卷 533-578页

作者： Xiaopeng Peng Zhihao Hu limei zeng Meizhu Zhang Congcong Xu Benyan Lu Chengpeng Tao Weiming Chen Wen Hou Kui Cheng Huichang Bi Wanyi Pan Jianjun Chen College of Pharmacy Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases of Ministry of EducationGannan Medical UniversityGanzhou 314000China College of Basic Medicine Gannan Medical UniversityGanzhou 314000China Guangdong Provincial Key Laboratory of New Drug Screening NMPA Key Laboratory for Research and Evaluation of Drug MetabolismSchool of Pharmaceutical SciencesSouthern Medical UniversityGuangzhou 510515China

Epigenetic pathways play a critical role in the initiation, progression, and metastasis of cancer. Over the past few decades, significant progress has been made in the development of targeted epigenetic modulators(e.g., inhibitors). However, epigenetic inhibitors have faced multiple challenges,including limited clinical efficacy, toxicities, lack of subtype selectivity, and drug resistance. As a result,the design of new epigenetic modulators(e.g., degraders) such as PROTACs, molecular glue, and hydrophobic tagging(Hy T) degraders has garnered significant attention from both academia and pharmaceutical industry, and numerous epigenetic degraders have been discovered in the past decade. In this review,we aim to provide an in-depth illustration of new degrading strategies(2017-2023) targeting epigenetic proteins for cancer therapy, focusing on the rational design, pharmacodynamics, pharmacokinetics, clinical status, and crystal structure information of these degraders. Importantly, we also provide deep insights into the potential challenges and corresponding remedies of this approach to drug design and development. Overall, we hope this review will offer a better mechanistic understanding and serve as a useful guide for the development of emerging epigenetic-targeting degraders.

关键词： Epigenetic Degrader PROTAC Molecularglue Hydrophobic tagging

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血栓通注射液联合阿替普酶治疗急性缺血性脑血管病临床疗效

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辽宁中医杂志 2024年第4期51卷 80-83页

作者：曾莉梅杨盛贤崔伟班毓徽高策蒙喜斯广西医科大学附属武鸣医院广西南宁530199

目的观察血栓通注射液联合阿替普酶治疗急性缺血性脑血管病临床效果及对血清肿瘤坏死因子-α(TNF-α)及白细胞介素-1β(IL-1β)的影响。方法纳入医院2018年3月—2021年5月期间90例急性缺血性脑血管病患者,采用随机数字表法分为观察组和... 详细信息

目的观察血栓通注射液联合阿替普酶治疗急性缺血性脑血管病临床效果及对血清肿瘤坏死因子-α(TNF-α)及白细胞介素-1β(IL-1β)的影响。方法纳入医院2018年3月—2021年5月期间90例急性缺血性脑血管病患者,采用随机数字表法分为观察组和对照组各45例。对照组予以阿替普酶治疗,观察组联合血栓通注射液治疗,两组用药疗程均为2周。比较两组临床疗效,治疗前、治疗2周后神经功能缺损(NIHSS)与生活能力[Barthel指数(BI)]量表评分、血液流变学、血清生化指标(TNF-α、IL-1β)水平变化。结果治疗2周后,观察组治疗总有效率高于对照组(P<0.05);两组NIHSS评分、血液流变学指标及血清TNF-α、IL-1β均较治疗前降低,且观察组低于对照组,BI评分均较治疗前升高,且观察组高于对照组(P<0.05)。结论血栓通注射液联合阿替普酶治疗急性缺血性脑血管病疗效确切,可改善血液流变学指标,抑制炎症反应,减轻神经功能损伤。

关键词：血栓通注射液阿替普酶急性缺血性脑血管病肿瘤坏死因子-α 白细胞介素-1β

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Genetic and lipidomic analyses reveal the key role of lipid metabolism for cold tolerance in maize

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Journal of Genetics and Genomics 2024年第3期51卷 326-337页

作者： Lei Gao Haifang Jiang Minze Li Danfeng Wang Hongtao Xiang Rong zeng limei Chen Xiaoyan Zhang Jianru Zuo Shuhua Yang Yiting Shi State Key Laboratory of Plant Environmental Resilience College of Biological SciencesFrontiers Science Center for Molecular Design BreedingCenter for Crop Functional Genomics and Molecular BreedingChina Agricultural UniversityBeijing 100193China State Key Laboratory of Wheat&Maize Crop Science College of Life SciencesHenan Agricultural UniversityZhengzhouHenan 450002China State Key Laboratory of Plant Genomics Institute of Genetics and Developmental BiologyChinese Academy of SciencesBeijing 100101China University of Chinese Academy of Sciences Beijing 100049China Suihua Branch of Heilongjiang Academy of Agricultural Machinery Sciences SuihuaHeilongjiang 152052China

Lipid remodeling is crucial for cold tolerance in ***,the precise alternations of lipidomics during cold responses remain elusive,especially in maize(Zea mays L.).In addition,the key genes responsible for cold tolerance in maize lipid metabolism have not been ***,we integrate lipidomic,transcriptomic,and genetic analysis to determine the profile of lipid remodeling caused by cold *** find that the homeostasis of cellular lipid metabolism is essential for maintaining cold tolerance of ***,we detect 210 lipid species belonging to 13 major classes,covering phospholipids,glycerides,glycolipids,and free fatty *** lipid metabolites undergo specific and selective alterations in response to cold stress,especially mono-/di-unsaturated lysophosphatidic acid,lysophosphatidylcholine,phosphatidylcholine,and phosphatidylinositol,as well as polyunsaturated phosphatidic acid,monogalactosyldiacylglycerol,diacylglycerol,and *** addition,we identify a subset of key enzymes,including ketoacyl-acyl-carrier protein synthase II(KAS II),acyl-carrier protein 2(ACP2),male sterility33(Ms33),and stearoyl-acyl-carrier protein desaturase 2(SAD2)involved in glycerolipid biosynthetic pathways are positive regulators of maize cold *** results reveal a comprehensive lipidomic profile during the cold response of maize and provide genetic resources for enhancing cold tolerance in crops.

关键词： Maize Cold stress Lipid metabolism Transcriptome Lipidomic

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An Outbreak of Serogroup Y Meningococcal Meningitis in a Private Secondary Vocational School-Guangzhou City,Guangdong Province,China,2023

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China CDC weekly 2024年第12期6卷 242-246,I0005页

作者： Xiang zeng Qing He Yilan Li Yong Zhou Xiaoping Shao Pei Hu Jian Liang Yudan Song Chao Ma Lijie Zhang limei Sun Lei Luo Chinese Field Epidemiology Training Program Chinese Center for Disease Control and PreventionBeijingChina Zhuhai Center for Disease Control and Prevention Zhuhai CityGuangdong ProvinceChina Guangdong Center for Disease Control and Prevention Guangzhou CityGuangdong ProvinceChina Guangzhou Center for Disease Control and Prevention Guangzhou CityGuangdong ProvinceChina Institute of Public Health Guangzhou Medical University&Guangzhou Center for Disease Control and PreventionGuangzhou CityGuangdong ProvinceChina Department of the National Immunization Programme Chinese Center for Disease Control and PreventionBeijingChina

What is already known about this topic?The inclusion of meningococcal vaccines in the National Immunization Program(NIP)over several years has significantly reduced the incidence of meningococcal meningitis in China to historic ***,there has been a diversification of meningococcal serogroups,leading to a shift in dominant serogroups in China from serogroup A to serogroups C and B,accompanied by a rise in reports of serogroups Y and *** is added by this report?An outbreak of serogroup Y Neisseria meningitidis(Nm)in a secondary vocational school involved a single confirmed severe case and 24 individuals with laboratory-confirmed Nm *** investigation revealed that the outbreak was localized to the classroom of the confirmed *** close contact within a confined space was identified as a significant risk factor for Nm *** genotype sequence identified was type 1655(ST-1655),which is categorized under clonal complex 23(CC-23)and bears resemblance to 8 previously confirmed cases of serogroup Y meningococcal meningitis within Guangdong *** suggests that serogroup Y infections continue to sporadically emerge and have become prevalent *** are the implications for public health practice?This outbreak underscores the critical need to enhance surveillance of meningococcal serogroups and population carrier,and advocate for vaccination with MenY-containing vaccines.

关键词： break Secondary Guangdong

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Comparative Study on Different Methods for Prediction of Thermal Insulation Performance of Thermal Barrier Coating Used on Turbine Blades

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Journal of Thermal Science 2024年第1期33卷 172-189页

作者： ZHANG Zhixin zeng Wu ZHANG Xiaodong zeng Yuntao Advanced Gas Turbine Laboratory Institute of Engineering ThermophysicsChinese Academy of SciencesBeijing 100190China Key Laboratory of Advanced Energy and Power Institute of Engineering ThermophysicsChinese Academy of SciencesBeijing 100190China Innovation Academy for Light-duty Gas Turbine Chinese Academy of SciencesBeijing 100190China University of Chinese Academy of Sciences Beijing 100049China

As turbine inlet temperature gets higher and higher,thermal barrier coating(TBC) is more and more widely used in turbine *** turbine blades with TBC,it is of great significance to evaluate the temperature distribution of its substrate metal quickly and accurately,especially during the design *** different degrees of simplification such as whether to consider the change of the geometric size of the fluid domain by TBC and whether to consider the planar heat conduction in TBC,three different methods used in conjugate heat transfer(CHT) simulation to model the TBC of the turbine blades have been developed and widely used by ***,little research has been conducted to investigate the influence of the three methods on the temperature distribution of turbine *** fill this gap,three geometric models were *** are a solid conduction model with a substrate metal layer and a TBC layer,a transonic turbine vane with internal cooling and TBC,and a plate cylindrical film hole cooling model with *** methods were used in these geometric models and their differences were carefully analyzed and *** result shows that for the conduction model used in this paper,with the same TBC surface temperature distribution,the difference between the three methods is very small and can be *** a transonic turbine vane with internal cooling,regarding the local maximum temperature of the substrate-TBC interface,the largest difference between the method in which TBC is considered as a thermal resistance or a virtual layer of cells and the method in which three-dimensional heat conduction equation of TBC is solved occurs at the trailing *** difference near the leading edge is below *** employed to the film cooling model,the difference of the laterally averaged temperature of the substrate-TBC interface can be 8 K which is mainly due to the change of the length to diameter ratio of the film cooling hole by *** the substrate

关键词： turbine blade thermal barrier coating conjugate heat transfer film cooling hole

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Nested Saturated Control of Uncertain Complex Cascade Systems Using Mixed Saturation Levels

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IEEE/CAA Journal of Automatica Sinica 2024年第5期11卷 1163-1174页

作者： Meng Li Zhigang zeng Wuhan National Laboratory for Optoelectronics Wuhan 430074 School of Artificial Intelligence and Automation Huazhong University of Science and TechnologyWuhan 430074China School of Artificial Intelligence and Automation Huazhong University of Science and TechnologyWuhan 430074 Key Laboratory of Image Processing and Intelligent Control of Education Ministry of China Wuhan 430074China

This study addresses the problem of global asymptotic stability for uncertain complex cascade systems composed of multiple integrator systems and non-strict feedforward nonlinear systems. To tackle the complexity inherent in such structures, a novel nested saturated control design is proposed that incorporates both constant saturation levels and state-dependent saturation levels. Specifically, a modified differentiable saturation function is proposed to facilitate the saturation reduction analysis of the uncertain complex cascade systems under the presence of mixed saturation levels. In addition, the design of modified differentiable saturation function will help to construct a hierarchical global convergence strategy to improve the robustness of control design scheme. Through calculation of relevant inequalities, time derivative of boundary surface and simple Lyapunov function,saturation reduction analysis and convergence analysis are carried out, and then a set of explicit parameter conditions are provided to ensure global asymptotic stability in the closed-loop systems. Finally, a simplified system of the mechanical model is presented to validate the effectiveness of the proposed method.

关键词： method saturation differentiable

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Aggregation-regulated bioreduction process of graphene oxide by Shewanella bacteria

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Chinese Journal of Chemical Engineering 2024年第5期69卷 56-62页

作者： Kaixin Han Yibo zeng Yinghua Lu Ping zeng Liang Shen Department of Chemical and Biochemical Engineering College of Chemistry and Chemical EngineeringXiamen UniversityXiamen 361005China Pen-Tung Sah Institute of Micro-Nano Science and Technology Xiamen UniversityXiamen 361005China Chinese Research Academy of Environmental Sciences Beijing 100012China

The bioreduction of graphene oxide(GO)using environmentally functional bacteria such as Shewanella represents a green approach to produce reduced graphene oxide(rGO).This process differs from the chemical reduction that involves instantaneous molecular *** bioreduction,the contact of bacterial cells and GO is considered the rate-limiting *** reveal how the bacteria-GO integration regulates rGO production,the comparative experiments of GO and three Shewanella strains were carried ***-transform infrared spectroscopy,X-ray photoelectron spectroscopy,Raman spectroscopy,and atomic force microscopy were used to characterize the reduction degree and the aggregation *** results showed that a spontaneous aggregation of GO and Shewanella into the condensed entity occurred within 36 h.A positive linear correlation was established,linking three indexes of the aggregation potential,the bacterial reduction ability,and the reduction degree(ID/IG)comprehensively.

关键词： Graphene oxide Reduced graphene oxide Bioreduction Aggregation Shewanella

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Cluster analysis reveals a homogeneous subgroup of PCOS women with metabolic disturbance associated with adverse reproductive outcomes

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Chinese Medical Journal 2024年第5期137卷 604-612页

作者： Hanxiao Chen Rujun zeng Xun zeng Lang Qin The Reproductive Medical Center Department of Obstetrics and GynecologyWest China Second University HospitalSichuan UniversityChengduSichuan 610041China Key Laboratory of Birth Defects and Related of Women and Children of Ministry of Education West China Second University HospitalSichuan UniversityChengduSichuan 610041China

Background:Polycystic ovarian syndrome(PCOS)is a heterogeneous and complex reproductive endocrinological disease that could lead to *** were many attempts to classify PCOS but it remains unclear whether there is a specific subgroup of PCOS that is associated with the best or worst reproductive outcomes of assisted reproductive techniques(ART).Methods:Infertile PCOS patients who underwent their first cycle of in vitro fertilization(IVF)in West China Second University Hospital,Sichuan University from January 2019 to December 2021 were *** clinical and laboratory information of each individual were *** cluster analysis was *** ovarian stimulation parameters and reproductive outcomes were collected and compared between the different clusters of ***:Our analysis clustered women with PCOS into"reproductive","metabolic",and"balanced"clusters based on nine *** group was characterized by high levels of testosterone(T),sex hormone-binding globulin(SHBG),follicular stimulation hormone(FSH),luteinizing hormone(LH),and anti-Müllerian hormone(AMH).Metabolic group was characterized by high levels of body mass index(BMI),fasting insulin,and fasting *** group was characterized by low levels of the aforementioned reproductive and metabolic parameters,except for *** with PCOS patients in reproductive and balanced clusters,those in metabolic cluster had lower rates of good quality day 3 embryo and blastocyst ***,PCOS patients in the reproductive cluster had greater fresh embryo transfer(ET)cancelation rate and clinical pregnancy rate after fresh ET than metabolic cluster(odds ratio[OR]=3.37,95%confidence interval[CI]:1.77-6.44,and OR=6.19,95%CI:1.58-24.24,respectively).And compared with PCOS of metabolic cluster,PCOS of balanced cluster also had higher chance for fresh ET cancelation(OR=2.83,95%CI:1.26-6.35).Conclusion:Our study suggested that PCOS patients in met

关键词： Polycystic ovarian syndrome Assisted reproductive techniques Clustering analysis Metabolic disturbance Clinical pregnancy

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Analysis of gravity wave activity during stratospheric sudden warmings in the northern hemisphere

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Earth and Planetary Physics 2024年第2期8卷 415-422页

作者： XuanYun zeng Guang Zhong School of Physics and Electronic Sciences Changsha University of Science and TechnologyChangsha 410000China Key Laboratory of Geospace Environment Chinese Academy of SciencesUniversity of Science&Technology of ChinaHefei 230026China

Due to the significant changes they bring to high latitude stratospheric temperature and wind,stratospheric sudden warmings(SSWs)can have an impact on the propagation and energy distribution of gravity waves(GWs).The variation characteristics of GWs during SSWs have always been an important *** temperature data from January to March in 2014−2016,provided by the Constellation Observing System for Meteorology,Ionosphere and Climate(COSMIC)mission,we have analyzed global GW activity at 15−40 km in the Northern Hemisphere during SSW *** the SSWs that we studied,the stratospheric temperature rose in one or two longitudinal regions in the Northern Hemisphere;the areas affected extended to the east of 90°*** these SSWs,the potential energy density(E_(p)of GWs expanded and covered a larger range of longitude and altitude,exhibiting an eastward and downward *** E_(p)usually increased,while partially filtered by the eastward zonal *** zonal winds weakened or turned westward,E_(p)began to *** SSWs,the E_(p)usually *** observations can serve as a reference for analyzing the interaction mechanism between SSWs and GWs in future work.

关键词： stratospheric sudden warming gravity wave wind filter

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Equivariant Chern Classes of Orientable Toric Origami Manifolds

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Chinese Annals of Mathematics,Series B 2024年第2期45卷 221-234页

作者： Yueshan XIONG Haozhi zeng School of Mathematics and StatisticsHuazhong University of Science and Technology Wuhan 430074China

A toric origami manifold,introduced by Cannas da Silva,Guillemin and Pires,is a generalization of a toric symplectic *** a toric symplectic manifold,its equivariant Chern classes can be described in terms of the corresponding Delzant polytope and the stabilization of its tangent bundle splits as a direct sum of complex line *** in general a toric origami manifold is not simply connected,so the algebraic topology of a toric origami manifold is more difficult than a toric symplectic *** this paper they give an explicit formula of the equivariant Chern classes of an oriented toric origami manifold in terms of the corresponding origami ***,they prove the stabilization of the tangent bundle of an oriented toric origami manifold also splits as a direct sum of complex line bundles.

关键词： Equivariant Chern classes Toric origami manifolds Unitary structures Spin structures

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