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Structure-based design of pan-coronavirus inhibitors targeting host cathepsin L and calpain-1

Signal Transduction and Targeted Therapy 2024年第4期9卷 1651-1664页

作者： Xiong Xie Qiaoshuai Lan jinyi zhao Sulin Zhang Lu Liu Yumin Zhang Wei Xu Maolin Shao Jingjing Peng Shuai Xia Yan Zhu Keke Zhang Xianglei Zhang Ruxue Zhang jian Li Wenhao Dai Zhen Ge Shulei Hu Changyue Yu Jiang Wang Dakota Ma Mingyue Zheng Haitao Yang Gengfu Xiao Zihe Rao Lu Lu Leike Zhang Fang Bai Yao zhao Shibo Jiang Hong Liu Drug Discovery and Design Center State Key Laboratory of Drug ResearchCAS Key Laboratory of Receptor ResearchShanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China University of Chinese Academy of Sciences Beijing 100049China Key Laboratory of Medical Molecular Virology(MOE/NHC/CAMS) School of Basic Medical SciencesShanghai Institute of Infectious Disease and BiosecurityFudan UniversityShanghai 200032China Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology ShanghaiTech UniversityShanghai 201210China State Key Laboratory of Virology Wuhan Institute of VirologyCenter for Biosafety Mega-ScienceChinese Academy of SciencesWuhan 430071China School of Chinese Materia Medica Nanjing University of Chinese Medicine138 Xian Lin RoadJiangsu 210023 NanjingChina School of Pharmaceutical Science and Technology Hangzhou Institute for Advanced StudyUCASHangzhou 310024China National Clinical Research Center for Infectious Disease Shenzhen Third People's HospitalShenzhen 518112China

Respiratory disease caused by coronavirus infection remains a global health *** several SARS-CoV-2-specific vaccines and direct-acting antivirals are available,their effcacy on emerging coronaviruses in the future,including SARS-CoV-2 variants,might be ***-targeting antivirals provide preventive and therapeutic strategies to overcome resistance and manage future outbreak of emerging *** L(CTSL)and calpain-1(CAPN1)are host cysteine proteases which play crucial roles in coronaviral entrance into cells and infection-related immune ***,two peptidomimetic a-ketoamide compounds,14a and 14b,were identified as potent dual target inhibitors against CTSL and *** X-ray crystal structures of human CTSL and CAPN1 in complex with 14a and 14b revealed the covalent binding of a-ketoamide groups of 14a and 14b to C25 of CTSL and C115 of *** showed potent and broad-spectrum anticoronaviral activities in vitro,and it is worth noting that they exhibited low nanomolar potency against SARS-CoV-2 and its variants of concern(VOCs)with ECso values ranging from 0.80 to 161.7 nM in various *** mechanistic exploration indicated that they exhibited anticoronaviral activity through blocking viral ***,14a and 14b exhibited good oral pharmacokinetic properties in mice,rats and dogs,and favorable safety in *** addition,both 14a and 14b treatments demonstrated potent antiviral potency against SARS-CoV-2 XBB 1.16 variant infection in a K18-hACE2 transgenic mouse *** 14b also showed effective antiviral activity against HCoV-OC43 infection in a mouse model with a final survival rate of 60%.Further evaluation showed that 14a and 14b exhibited excellent antiinflammatory effects in Raw 264.7 mouse macrophages and in mice with acute *** together,these results suggested that 14a and 14b are promising drug candidates,providing novel insight into developing pan-coronavirus inhibitors with anti

关键词： calpain overcome entrance

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^(40)Ar/^(39)Ar Thermochronological Constraints on the Timing of Collisional Orogeny in the Mian-Lite Collision Belt,Southern Qinling Mountains

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Acta Geologica Sinica(English Edition) 1999年第2期73卷 208-215页

作者： LI jinyi, WANG Zongqi and zhao Min Institute of Geology, Chinese Academy of Geological Sciences, Beijing 100037 Chinese Acad Geol Sci Inst Geol Beijing 100037 Peoples R China

Silurian, Devonian and Carboniferous geological bodies in the Mianxian-Lueyang (Mian-Lue) collisional belt (MLB) and its neighbouring areas, southern Qinling Mountains, China, show similar characteristics of having undergone deformation of two stages. The earlier one, which is inferred to be related to collisional orogeny between the Yangtze and Sino-Korean palaeocontinents based on previous geological data, is responsible for large-scale, north-verging recumbent folds and overthrusts, and associated with low greenschist fades metamorphism. 40Ar/39Ar dating of three muscovite samples taken from different localities yields plateau ages of 226.9±0.9 and 219.5±1.4 Ma and an apparent age of 194.5±3.0 Ma. Thus, the late Triassic collision between the Yangtze and Sino-Korean palaeocontinents has been constrained.

关键词： Qinling Mountains Mian-Lue collision belt muscovite 40Ar/39Ar dating collisional orogeny

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基于肛提肌剪切波弹性成像参数的列线图模型预测初产妇发生盆腔脏器脱垂的临床价值

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临床超声医学杂志 2024年第8期26卷 623-629页

作者：赵津艺张玉玲胥卉苹刘婷李蔚周江英四川省人民医院温江医院超声医学科成都市610000 成都医学院第一附属医院超声医学科

目的基于肛提肌剪切波弹性成像(SWE)参数构建列线图模型,探讨其预测初产妇发生盆腔脏器脱垂(POP)的临床应用价值。方法选取我院产后42 d经阴道分娩的初产妇107例,以盆腔脏器脱垂定量分期法(POP-Q)评分作为POP诊断依据,将其分为POP阳性... 详细信息

目的基于肛提肌剪切波弹性成像(SWE)参数构建列线图模型,探讨其预测初产妇发生盆腔脏器脱垂(POP)的临床应用价值。方法选取我院产后42 d经阴道分娩的初产妇107例,以盆腔脏器脱垂定量分期法(POP-Q)评分作为POP诊断依据,将其分为POP阳性组65例和POP阴性组42例,应用SWE测量两组静息状态下右侧和左侧耻骨直肠肌杨氏模量值(rE1和rE2)、右侧和左侧髂尾肌杨氏模量值(rE3和rE4),以及缩肛状态下右侧和左侧耻骨直肠肌杨氏模量值(cE1和cE2)、右侧和左侧髂尾肌杨氏模量值(cE3和cE4),并计算两种状态下右侧和左侧耻骨直肠肌杨氏模量差值(ΔE1和ΔE2)、右侧和左侧髂尾肌杨氏模量差值(ΔE3和ΔE4),比较两组上述各参数的差异。应用二元Logistic回归分析筛选预测初产妇发生POP的独立影响因素;绘制受试者工作特征(ROC)曲线分析各独立影响因素预测初产妇发生POP的诊断效能,选取其中曲线下面积(AUC)>0.850的参数作为优选参数,并基于优选参数构建预测初产妇发生POP的列线图模型。绘制ROC曲线分析列线图模型预测初产妇发生POP的诊断效能,并采用Bootstrap法对该模型进行内部验证;采用C-index评价模型的区分度;校准曲线评价模型的校准度。结果POP阳性组rE1、rE2、rE3、rE4、cE1、cE2、cE3、cE4、ΔE1、ΔE2、ΔE3、ΔE4均小于POP阴性组,差异均有统计学意义(均P0.850,基于此3个参数建立初产妇发生POP的列线图模型。ROC曲线分析显示,当列线图模型截断值为0.48时,预测初产妇发生POP的灵敏度和特异度分别为93.8%、90.5%,AUC为0.952(95%可信区间:0.910~0.993);采用Bootstrap法对列线图模型进行内部验证显示,C-index为0.952,提示该模型具有良好的区分度;校准曲线显示,列线图模型预测结果与真实结果之间符合度的平均绝对误差为0.014,提示该模型校准度较好。结论基于肛提肌SWE参数的列线图模型在预测初产妇发生POP中有一定的临床应用价值。

关键词：剪切波弹性成像盆腔脏器脱垂肛提肌经阴道分娩初产妇

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Microbial diversity and functionally distinct groups in produced water from the Daqing Oilfield,China

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Petroleum Science 2012年第4期9卷 469-484页

作者： Li Hui Ai Mingqiang Han Siqin Guo Yanling Li Nana Shi Rongjiu Zeng Xiangling Leng Shengbing zhao jinyi Liu Xiaobo Zhang Ying Key Laboratory of Pollution Ecology and Environment Engineering Institute of Applied EcologyChinese Academy of SciencesShenyangLiaoning 110016China Daqing Oilfield Co.Ltd. DaqingHeilongjiang 163414China

The microbial community structure and functionally distinct groups in three kinds of produced water samples from the shallow,mesothermic and low-salinity Daqing oil reservoir were systematically evaluated using both culture-dependent and culture-independent *** analysis of the 16S rRNA genes indicated that the bacterial library was dominated by Acinetobacter and Arcobacter and the archaeal community was dominated by Methanosaeta and *** isolated methanogens were closely related with Methanothermobacter thermautotrophicus and Methanoculleus *** fermentative bacteria were identified as Pseudomonas,Haloanaerobium,Alcalibacter,Arcobacter,and *** predominant nitrate-reducing bacteria fell within the genus *** dominant members of the cultured hydrocarbon-oxidizing bacteria were phylogenetically associated with Micrococcus,Pseudomonas,and *** of biosurfactants and biopolymer producing groups mainly yielded Pseudomonas,Bacillus,and Acenitobacter-related *** functional groups related to polymer degradation were also affiliated with Pseudomonas and *** from this study provide the fresh insight into the diversity of microbial communities in Daqing petroleum *** vast pool of functional strains retrieved in this study was presumed to include the promising strains that could be applied in microbial-enhanced oil recovery in future.

关键词： Petroleum microbiology 16S rRNA gene diversity methanogens bio-surfactants producing bacteria biopolymer-producing bacteria nitrate-reducing bacteria

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Crystal structure of SARS-CoV-2 main protease in complex with protease inhibitor PF-07321332

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Protein & Cell 2022年第9期13卷 689-693页

作者： Yao zhao Chao Fang Qi Zhang Ruxue Zhang Xiangbo zhao Yinkai Duan Haofeng Wang Yan Zhu Lu Feng jinyi zhao Maolin Shao Xiuna Yang Leike Zhang Chao Peng Kailin Yang Dawei Ma Zihe Rao Haitao Yang Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology ShanghaiTech UniversityShanghai 201210China State Key Laboratory of Bioorganic&Natural Products Chemistry Center for Excellence in Molecular SynthesisShanghai Institute of Organic ChemistryUniversity of Chinese Academy of SciencesChinese Academy of SciencesShanghai 200032China CAS Center for Excellence in Molecular Cell Science Shanghai Institute of Biochemistry and Cell BiologyChinese Academy of SciencesShanghai 200031China University of Chinese Academy of Sciences Beijing 100049China State Key Laboratory of Virology Wuhan Institute of VirologyCenter for Biosafety Mega-ScienceChinese Academy of SciencesWuhan 430071China National Facility for Protein Science in Shanghai Zhangjiang LabShanghai Advanced Research InstituteChinese Academy of SciencesShanghai 201210China Taussig Cancer Center Cleveland ClinicClevelandOH 44195USA Laboratory of Structural Biology School of Life Sciences and School of MedicineTsinghua UniversityBeijing 100091China State Key Laboratory of Medicinal Chemical Biology Frontiers Science Center for Cell ResponseCollege of Life SciencesNankai Universityand Tianjin Key Laboratory of Protein SciencesTianjin 300071China

Dear Editor,Since December 2019,the pandemic of coronavirus disease 2019(COVID-19)has taken a heavy toll on global health,creating an urgent need to develop effective strategies for prevention and *** etiological agent,known as severe acute respiratory syndrome coronavirus 2(SARSCoV-2),has infected nearly 229.2 million people worldwide with more than 4.7 million deaths as of September 15,*** age and preexisting health conditions are associated with worse clinical prognosis including higher mortality rates(Zhou et al.,2020).The global race to combat this pandemic has led to rapid deployment of numerous effective vaccines against SARS-CoV-2(Tregoning et al.,2021).However,the emergence of viral variants,including the Delta variant(B.1.617.2),compromised vaccine effectiveness with resurgence of SARS-CoV-2 infection among highly vaccinated population(Keehner et al.,2021).Therefore,development of therapeutics against the more conserved viral targets would be essential to contain the spread of COVID-19 and reduce mortality.

关键词： mortality prevention Crystal

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高动态环境下数据链信号载波频率估计算法

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系统工程与电子技术 2023年第9期45卷 2965-2970页

作者：赵晋毅尚佳栋杨健中国长峰机电技术研究设计院北京100854 北京遥感设备研究所北京100854

针对高动态环境下Link16数据链信号载波同步问题,设计了一种基于相邻符号相位差与两步式频率估计相结合的多普勒频率估计算法。该算法引入一种导频插入式数据结构,然后在此基础上对接收信号进行取辐角处理,再借助相邻符号位的相位差去... 详细信息

针对高动态环境下Link16数据链信号载波同步问题,设计了一种基于相邻符号相位差与两步式频率估计相结合的多普勒频率估计算法。该算法引入一种导频插入式数据结构,然后在此基础上对接收信号进行取辐角处理,再借助相邻符号位的相位差去除一阶频率偏移量,最后对观测序列求和得到变化率估计值。一阶多普勒频偏估计采用快速傅里叶变换与自相关结合方式来完成。理论分析和仿真结果表明,所提算法在频偏估计算法的基础上消除了多普勒变化率的影响,能实现多普勒变化率的有效估计。与其他算法相比,所提算法进一步增强了数据链系统传输的可靠性与动态环境适应能力,并且在估计精度方面具有优越的性能。

关键词：高动态 Link16数据链相邻符号相位差频偏估计多普勒变化率估计

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冷变形和固溶温度对HR3C钢中σ相析出行为的影响

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金属学报 2020年第5期56卷 673-682页

作者：曹铁山赵津艺程从前孟宪明赵杰大连理工大学材料科学与工程学院大连116024 大连理工大学工业装备结构分析国家重点实验室大连116024 中国汽车技术研究中心天津300300

结合HR3C钢制备工艺,综合研究冷变形和固溶处理工艺对其在时效过程中σ相的析出动力学和相关力学性能的影响。结果表明:冷变形和固溶温度均对该钢中σ相的析出有着较大的影响,变形量的增加会促进σ相的时效析出,升高固溶处理温度有助于... 详细信息

结合HR3C钢制备工艺,综合研究冷变形和固溶处理工艺对其在时效过程中σ相的析出动力学和相关力学性能的影响。结果表明:冷变形和固溶温度均对该钢中σ相的析出有着较大的影响,变形量的增加会促进σ相的时效析出,升高固溶处理温度有助于抑制HR3C钢中σ相的析出行为,但却在一定程度上增大晶粒尺寸。σ相析出量随时间延长先缓慢增加,后快速析出,最后达到稳态值约5.7%(体积分数)。变形量的增加使HR3C钢时效过程中冲击韧性显著降低,而固溶温度的升高虽然增加了固溶态试样的冲击韧性但降低了时效过程中的冲击韧性。

关键词： HR3C钢 σ 相冷变形固溶处理

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考虑SSI效应的核电厂SSC耦合体系模型主余震易损性分析

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核动力工程 2023年第5期44卷 85-94页

作者：赵锦一宋雷周志光同济大学土木工程学院上海200092

核电厂体系的地震易损性分析能够反映耦合的结构、系统和部件(SSC)在不同地震强度下的失效概率,土-结构相互作用(SSI)和主余震作用是地震易损性分析中2个非常重要的因素。本文建立了AP1000核电厂SSC耦合体系模型,选用典型软岩石地基作... 详细信息

核电厂体系的地震易损性分析能够反映耦合的结构、系统和部件(SSC)在不同地震强度下的失效概率,土-结构相互作用(SSI)和主余震作用是地震易损性分析中2个非常重要的因素。本文建立了AP1000核电厂SSC耦合体系模型,选用典型软岩石地基作为场地条件,根据AP1000设计谱选取主余震记录,采用增量动力分析(IDA)方法对耦合体系模型进行考虑SSI效应的地震易损性分析。经计算分析可知,主余震作用对结构和设备的破坏可能大于单一主震的作用效应。考虑SSI效应普遍增大了SSC主余震易损性的条件失效概率。由典型SSC抗震性能结果可知,耦合体系的失效模式为屏蔽厂房混凝土首先开裂,随后蒸汽发生器管道屈服,最后主蒸汽管道进入屈服。考虑SSI效应时,破坏状态基本完好与一般破坏之间的极限状态下屏蔽厂房、蒸汽发生器、管道的高置信度低失效概率(HCLPF)值分别为0.48g、0.68g和0.92g。由本文研究可知,在核电厂易损性评估过程中,SSI效应和主余震作用的影响不容忽视。

关键词： AP1000核电厂SSC耦合模型土-结构相互作用(SSI) 主余震作用地震易损性分析

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AP1000核电厂模型基底隔震振动台试验研究

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地震工程与工程振动 2020年第2期40卷 64-72页

作者：周志光周龙定赵锦一同济大学土木工程学院上海200092

为研究AP1000核电厂基底隔震性能,设计了缩尺比为1/40的AP1000核电厂模型结构,进行了AP1000核电厂模型基底隔震振动台试验。试验中采用铅芯橡胶隔震支座进行隔震,并选取RG1.60人工波、El Centro波和Kobe波作为地震动输入。本文从加速度... 详细信息

为研究AP1000核电厂基底隔震性能,设计了缩尺比为1/40的AP1000核电厂模型结构,进行了AP1000核电厂模型基底隔震振动台试验。试验中采用铅芯橡胶隔震支座进行隔震,并选取RG1.60人工波、El Centro波和Kobe波作为地震动输入。本文从加速度响应、楼层加速度反应谱、加速度峰值放大系数、减震率等方面对隔震与非隔震核电厂结构的地震响应特性进行了研究。试验结果表明:隔震能明显减小上部结构水平向加速度响应和加速度反应谱峰值,而在隔震频率处隔震模型加速度反应谱有所增加;隔震模型由于摇摆效应在隔震频率处的水平向楼层加速度反应谱随楼层高度的升高先减小后增大;在三向输入地震动作用下,隔震和非隔震AP1000模型各楼层在竖向基频附近的竖向加速度反应谱较竖向输入的地震动放大较为明显。

关键词：核电厂隔震振动台试验加速度反应谱摇摆效应

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Synergistic efficacy of meropenem and rifampicin in a murine model of sepsis caused by multidrug-resistant Acinetobacter baumannii

Synergistic efficacy of meropenem and rifampicin in a murine...

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中华医学会临床药学分会2014年全国学术会议

作者：孙渊 Wang Lei Li Jiankang zhao Chongbo zhao jinyi Liu Meiyou Wang Shan Lu Chengtao Shang Gangwei Jia Yanyan Wen Aidong Department of Pharmacy Xijing Hospital Fourth Military Medical University

Aims To investigate the synergistic activity of meropenem combined with other antibiotics in vitro and in *** Checkerboard assay and time-kill assay were performed to study the combination effects in vitro.A murine sepsis model was used and the survival rate and bacterial clearance from blood were recorded to evaluate the combination

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