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Discovery of novel covalent selective estrogen receptor degraders against endocrine-resistant breast cancer

Acta Pharmaceutica Sinica B 2023年第12期13卷 4963-4982页

作者： Yubo Wang Jian Min Xiangping Deng Tian Feng Hebing hu Xinyi Guo Yan Cheng Baohua Xie Yu Yang Chun-Chi Chen Rey-Ting Guo Chune dong Hai-Bing Zhou Department of Gynecological Oncology Zhongnan Hospital of Wuhan UniversitySchool of Pharmaceutical SciencesWuhan UniversityWuhan 430071China State Key Laboratory of Biocatalysis and Enzyme Engineering National&Local Joint Engineering Research Center of High-throughput Drug Screening TechnologyHubei Key Laboratory of Industrial BiotechnologySchool of Life SciencesHubei UniversityWuhan 430062China Frontier Science Center for Immunology and Metabolism State Key Laboratory of VirologyProvincial Key Laboratory of Developmentally Originated DiseaseKey Laboratory of Combinatorial Biosynthesis and Drug Discovery(MOE)and Hubei Province Engineering and Technology Research Center for Fluorinated PharmaceuticalsWuhan UniversityWuhan 430071China Wuhan Research Center for Infectious Diseases and Cancer Chinese Academy of Medical SciencesZhongnan Hospital of Wuhan UniversityWuhan 430071China

Endocrine-resistance remains a major challenge in estrogen receptorαpositive(ERα^(+))breast cancer(BC)treatment and constitutively active somatic mutations in ERαare a common *** is an urgent need to develop novel drugs with new mode of mechanism to fight *** aberrant ERαactivity,we herein report the identification of novel covalent selective estrogen receptor degraders(cSERDs)possessing the advantages of both covalent and degradation strategies.A highly potent cSERD 29c was identified with superior anti-proliferative activity than fulvestrant against a panel of ERa+breast cancer cell lines including mutant ERα.Crystal structure of ERα-29c complex alongside intact mass spectrometry revealed that 29c disrupted ERa protein homeostasis through covalent targeting C530 and strong hydrophobic interaction collied on H11,thus enforcing a unique antagonist conformation and driving the ERα*** significant effects of the cSERD on ERαhomeostasis,unlike typical ERαdegraders that occur directly via long side chains perturbing the morphology of H12,demonstrating a distinct mechanism of action(MoA).In vivo,29c showed potent antitumor activity in MCF-7 tumor xenograft models and low *** proof-of-principle study verifies that novel cSERDs offering new opportunities for the development of innovative therapies for endocrine-resistant BC.

关键词： Covalent strategy Estrogen receptor degraders Endocrine-resistant breast cancer X-ray crystallography

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3-D profile measurement for complex micro-structures

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Optoelectronics Letters 2005年第3期1卷 205-208页

作者： hu Chun-guang hu Xiao-dong XU Lin-yan GUO Tong hu Xiao-tang State Key Laboratory of Precision Measuring Technology and Instruments Tianjin University Tianjin 300072 China

Micro-structures 3-D profile measurement is an important measurement content for research on micro-machining and characterization of micro-dimension. In this paper,a new method involved 2-D structure template, which guides phase unwrapping,is proposed based on phase-shifting microscopic *** is fit not only for static measurement, but also for dynamic measurement,especially for motion of MEMS devices.3-D profile of active comb of micro-resonator is obtained by using the *** theoretic precision in out-of-plane direction is better than 0.5 *** in-plane theoretic precision in micro-structures is better than 0.5 μ*** at the edge of micro-structures,it is on the level of micrometer mainly caused by imprecise edge ***,its disadvantages and the following development are discussed.

关键词：微观结构光检测技术三维测量干涉测量

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KAM Tori for the Derivative Quintic Nonlinear Schrodinger Equation

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Acta Mathematica Sinica,English Series 2020年第2期36卷 153-170页

作者： dong Feng YAN Guang hua SHI School of Mathematics and Statistics Zhengzhou UniversityZhengzhou 450001P.R.China College of Mathematics and Statistics Hu fnan Normal UniversityChangsha 410006P.R.China

This paper is concerned with one-dimensional derivative quintic nonlinear Schrodinger equation,iut—uxx+i(|u|4u)x=0,x *** existence of a large amount of quasi-periodic solutions with two frequencies for this equation is *** proof is based on partial Birkhoff normal form technique and an unbounded KAM *** mention that in the present paper the mean value of u does not need to be zero,but small enough,which is different from the assumption(1.7)in Geng-Wu[***.、53,102702(2012)].

关键词： Derivative nonlinear Schrodinger equation KAM theorem quasi-periodic solutions BirkhofF normal form

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人-任务互动的并行集成模拟

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系统工程理论与实践 2009年第8期29卷 127-133页

作者：董升平胡斌武汉理工大学交通学院武汉430063 华中科技大学管理学院武汉430074

管理者与任务的人-任务互动问题源于管理者自我效能感演化和任务进程间的相互作用.在讨论了Visual ***和Arena间基于消息通信实现并行集成的基础上,分别针对管理者行为过程和任务处理过程建立基于改进QSIM算法的定性模拟模型和基于事件... 详细信息

管理者与任务的人-任务互动问题源于管理者自我效能感演化和任务进程间的相互作用.在讨论了Visual ***和Arena间基于消息通信实现并行集成的基础上,分别针对管理者行为过程和任务处理过程建立基于改进QSIM算法的定性模拟模型和基于事件驱动的离散事件模拟模型,提出并实现了人-任务互动的并行集成模拟方法,开发了PSMS-SMMPT并行集成模拟系统原型.最后通过一个示例,确认了该方法及系统可用来分析复杂管理系统人-任务互动规律.

关键词：人-任务互动并行集成模拟定性模拟离散事件模拟自我效能感

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Enhanced resistance to Botrytis cinerea and Rhizoctonia solani in transgenic broccoli with a Trichoderma viride endochitinase gene

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Journal of Integrative Agriculture 2015年第3期14卷 430-437页

作者： YU Ya ZHANG Lei LIAN Wei-ran XU Feng-feng LI Shuang-tao XIANG Juan ZHANG Guo-zhen hu Zan-min ZHAO Bing REN Shu-xin GUO Yang-dong College of Agriculture & Biotechnology China Agricultural University Department of Biology Science & Technology Wuhan Institute of Bioengineering Institute of Genetics & Developmental Biology Chinese Academy of Sciences School of Agriculture Virginia State University

A endochitinase gene（Tch） from the fungus Trichoderma viride was introduced into broccoli（Brassica oleracea var. italica） by Agrobacterium-mediated transformation. Sixty-eight putative transformants were obtained and the presence of the Tch gene was confirmed by both PCR and Southern blot analysis. RT-PCR analysis showed an accumulation of the transcript encoding the endochitinase protein in the transgenic plants. Using real-time quantitative PCR, the expression profiling of endochitinase gene was analyzed. Primary transformants and selfed progeny were examined for expression of the endochitinase using a fluorometric assay and for their resistance to the pathogenic fungi Botrytis cinerea and Rhizoctonia solani. The endochitinase activities in T0 in vitro plants, T0 mature plants and T1 mature plants were correlated with leaf lesions, and the transgenic line T618 had high endochitinse activities of 102.68, 114.53 and 120.27 nmol L–1 MU min–1 mg–1 protein in the three kinds of plants, respectively. The endochitinase activity showed a positive correlation with the resistance to the pathogens. Most transgenic T0 broccoli had increased resistance to the pathogens of B. cinerea and R. solani in leaf assays and this resistance was confirmed to be inheritable. These findings suggested that expression of the Tch gene from T. viride could enhance resistance to pathogenic fungi in Brassica species.

关键词： Botrytis cinerea broccoli endochitinase gene genetic transformation Rhizoctonia solani

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Cloning and Sequence Analysis of the 28.5ku Movement Protein of Frangipani Mosaic Virus (FMV)

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Agricultural Sciences in China 2001年第1期 148-150页

作者： DENG Xiao-dong FEI Xiao-wen LIU Zhi-xin hu Xin-wen ZHENG Xue-qin National Key Biotechnology Laboratory of Tropical Crop CA TAS Haikou 571101 National Key Biotechnology Laboratory of Tropical Crop CA TAS Haikou 571101 National Key Biotechnology Laboratory of Tropical Crop CA TAS Haikou 571101 National Key Biotechnology Laboratory of Tropical Crop CA TAS Haikou 571101 National Key Biotechnology Laboratory of Tropical Crop CA TAS Haikou 571101

Based on conserved regions among genomic RNA of tobamoviruses, a pair of primers spanning the sequence encoding the movement protein were synthesized. A cDNA fragment of 1700bp was thus amplified by RT-PCR(reverse transcription-polymerase chain reaction). The fragment was cloned into pGEM-T easy vector and sequenced. DNA sequence analysis showed that the fragment contained a region of 768 nucleotides encoding protein of 256 amino acid of frangipani mosaic virus (FMV) and also partial sequence corresponding to 180ku and 17. 5ku protein.

关键词： Plumeria acutifolia FMV Movement protein gene Sequence analysis

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Femtosecond laser direct writing of functional stimulus-responsive structures and applications

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International Journal of Extreme Manufacturing 2023年第4期5卷 375-414页

作者： Yuxuan Zhang dong Wu Yachao Zhang Yucheng Bian Chaowei Wang Jiawen Li Jiaru Chu Yanlei hu CAS Key Laboratory of Mechanical Behavior and Design of Materials Key Laboratory of Precision Scientific Instrumentation of Anhui Higher Education InstitutesDepartment of Precision Machinery and Precision InstrumentationUniversity of Science and Technology of ChinaHefei 230027People’s Republic of China

Diverse natural organisms possess stimulus-responsive structures to adapt to the surrounding *** by nature,researchers have developed various smart stimulus-responsive structures with adjustable properties and functions to address the demands of ever-changing application environments that are becoming more *** many fabrication methods for stimulus-responsive structures,femtosecond laser direct writing(FsLDW)has received increasing attention because of its high precision,simplicity,true three-dimensional machining ability,and wide applicability to almost all *** paper systematically outlines state-of-the-art research on stimulus-responsive structures prepared by *** on the introduction of femtosecond laser-matter interaction and mainstream FsLDW-based manufacturing strategies,different stimulating factors that can trigger structural responses of prepared intelligent structures,such as magnetic field,light,temperature,pH,and humidity,are emphatically *** applications of functional structures with stimuli-responsive dynamic behaviors fabricated by FsLDW,as well as the present obstacles and forthcoming development opportunities,are discussed.

关键词： stimulus-responsive structures femtosecond laser direct writing laser–matter interaction multifunctionality

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Functional Analysis of Three Rice Chloroplast Transit Peptides

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Rice science 2019年第1期26卷 11-20页

作者： HE Lei CHEN Guang ZHANG Sen QIU Zhennan hu Jiang ZENG Dali ZHANG Guangheng dong Guojun GAO Zhenyu REN Deyong SHEN Lan GUO Longbiao QIAN Qian Zhu Li State Key Laboratory of Rice Biology China National Rice Research Institute

Chloroplast transit peptides(CTPs) can be used to transport non-chloroplastic proteins into the chloroplasts. Here, we studied the CTPs of three rice(Oryza sativa L.) chloroplast-localized proteins and found that their CTPs could be used to transport non-chloroplast-localized proteins into the chloroplasts. Fusion proteins lacking the CTP remained located in the cytoplasm. Furthermore, we constructed green fluorescent protein fusion vectors with the three CTPs and three non-chloroplast-localized proteins, Ghd10, MULTI-FLORET SPIKELET1(MFS1), and SHORTENED UPPERMOST INTERNODE 1(SUI1). After transforming these constructs into rice protoplasts, the fusion proteins all localized in the chloroplasts. Collectively, our results showed that these CTPs can transport non-chloroplast-localized proteins into the chloroplasts, and more importantly, these CTPs can be applied to engineer chloroplast metabolism.

关键词： rice chloroplast transit peptide translocated function subcellular location

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Major Miocene geological events in southern Tibet and eastern Asia induced by the subduction of the Ninetyeast Ridge

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Acta Geochimica 2018年第3期37卷 395-401页

作者： Xinlei Sun Wei-dong Sun Yong-bin hu Wei Ding Trevor Ireland Mei-zhen Zhan Ji-qiang Liu Ming-xing Ling Xing Ding Zhao-feng Zhang Wei-ming Fan State Key Laboratory of Isotope Geochemistry Guangzhou Institute of Geochemistry Chinese Academy of SciencesGuangzhou 510640 China Center of Deep Sea Research Institute of OceanographyChinese Academy of Sciences Qingdao 266071 China Laboratory for Marine Mineral Resources Qingdao National Laboratory for Marine Science and TechnologyQingdao 266237 China CAS Center for Excellence in Tibetan Plateau Earth Sciences Chinese Academy of Sciences Beijing 100101China CAS Key Laboratory of Mineralogy and Metallogeny Guangzhou Institute of Geochemistry Chinese Academy of Sciences Guangzhou 510640 China University of the Chinese Academy of Sciences Beijing 100049 China Research School of Earth Sciences The Australian National University Canberra ACT 2601 Australia

Cenozoic adakitic rocks in the Gangdese changed from barren continental melts to ore-forming slab melts at * 23 Ma. The distribution and chemical characteristics of the ore-forming adakites point to an association with the Ninetyeast Ridge. The subduction of the thick,rigid Ninetyeast Ridge changed the geometry and rheology of the eastern Tibetan Plateau lithosphere and asthenosphere, restrained the eastward escape of asthenospheric mantle as well as continental fragments, and promoted the uplift and building of the Tibetan Plateau, which consequently changed the tectonic and climatic regimes in eastern Asia.

关键词： Ridge subduction Eastern Tibetan Plateau Cenozoic mineralization Seismic anomaly

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Electroacupuncture and moxibustion promote regeneration of injured sciatic nerve through Schwann cell proliferation and nerve growth factor secretion

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Neural Regeneration Research 2018年第3期13卷 477-483页

作者： Lin-na hu Jin-xin Tian Wei Gao Jing Zhu Fang-fang Mou Xiao-chun Ye Yu-pu Liu Ping-ping Lu Shui-jin Shao Hai-dong Guo Department of Anatomy School of Basic Medicine Shanghai University of Traditional Chinese Medicine Department of Internal Medicine Shanghai Changhang Hospital Department of Gynaecology and Obstetrics Heze Hospital of Traditional Chinese Medicine

Using electroacupuncture and moxibustion to treat peripheral nerve injury is highly efficient with low side effects. However, the electroacupuncture-and moxibustion-based mechanisms underlying nerve repair are still unclear. Here, in vivo and in vitro experiments uncovered one mechanism through which electroacupuncture and moxibustion affect regeneration after peripheral nerve injury. We first established rat models of sciatic nerve injury using neurotomy. Rats were treated with electroacupuncture or moxibustion at acupoints huantiao （GB30） and Zusanli （ST36）. Each treatment lasted 15 minutes, and treatments were given six times a week for 4 consecutive weeks. Behavioral testing was used to determine the sciatic functional index. We used electrophysiological detection to measure sciatic nerve conduction velocity and performed hematoxylin-eosin staining to determine any changes in the gastrocnemius muscle. We used immunohistochemistry to observe changes in the expression of S100—a specific marker for Schwann cells—and an enzyme-linked immunosorbent assay to detect serum level of nerve growth factor. Results showed that compared with the model-only group, sciatic functional index, recovery rate of conduction velocity, diameter recovery of the gastrocnemius muscle fibers, number of S100-immunoreactive cells,and level of nerve growth factor were greater in the electroacupuncture and moxibustion groups. The efficacy did not differ between treatment groups. The serum from treated rats was collected and used to stimulate Schwann cells cultured in vitro. Results showed that the viability of Schwann cells was much higher in the treatment groups than in the model group at 3 and 5 days after treatment. These findings indicate that electroacupuncture and moxibustion promoted nerve regeneration and functional recovery; its mechanism might be associated with the enhancement of Schwann cell proliferation and upregulation of nerve growth factor.

关键词： nerve regeneration peripheral nerve injury electroacupuncture moxibustion acupuncture serum Schwann cells nerve growth factor proliferation regeneration sciatic functional index neural regeneration

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