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Discovery and engineering of ChCas12b for precise genome editing

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Science Bulletin 2024年第20期69卷 3260-3271页

作者： Jingjing Wei Jingtong Liu Yuwen Tian Ziwen Wang linghui hou Yuan Yang Chen Tao Miaomiao Li Bao-Qing Gao Huanyu Zhou Xixi Zheng Junnan Tang Song Gao Li Yang Renjie Chai Yongming Wang Department of Cardiology The First Affiliated Hospital of Zhengzhou UniversityZhengzhou 450052China Shanghai Pudong Hospital School of Life SciencesShanghai Engineering Research Center of Industrial MicroorganismsFudan UniversityShanghai 200438China State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer MedicineSun Yat-sen University Cancer CenterGuangzhou 510060China Shanghai Institute of Nutrition and Health University of Chinese Academy of SciencesChinese Academy of SciencesShanghai 200031China Center for Molecular Medicine Children’s Hospital of Fudan University and Shanghai Key Laboratory of Medical EpigeneticsInternational Laboratory of Medical Epigenetics and MetabolismMinistry of Science and TechnologyInstitutes of Biomedical SciencesFudan UniversityShanghai 201102China State Key Laboratory of Bioelectronics Department of Otolaryngology Head and Neck SurgeryZhongda HospitalSchool of Life Sciences and TechnologyAdvanced Institute for Life and HealthJiangsu Province High-Tech Key Laboratory for Bio-Medical ResearchSoutheast UniversityNanjing 210096China Co-Innovation Center of Neuroregeneration Nantong UniversityNantong 226001China

Many clustered regularly interspaced short palindromic repeat and CRISPR-associated protein 12b(CRISPR-Cas12b)nucleases have been computationally identified,yet their potential for genome editing remains largely *** this study,we conducted a GFP-activation assay screening 13 Cas12b nucleases for mammalian genome editing,identifying five active *** hydrogenedentes Cas12b(ChCas12b)was found to recognize a straightforward WTN(W=T or A)proto-spacer adjacent motif(PAM),thereby dramatically expanding the targeting *** optimization of the single guide RNA(sgRNA)scaffold,ChCas12b exhibited activity comparable to SpCas9 across a panel of nine endogenous ***,we identified nine mutations enhancing ChCas12b *** importantly,we demonstrated that both ChCas12b and its high-fidelity variant,ChCas12b-D496A,enabled allelespecific disruption of genes harboring single nucleotide polymorphisms(SNPs).These data position ChCas12b and its high-fidelity counterparts as promising tools for both fundamental research and therapeutic applications.

关键词： Genomeediting CRISPR/Cas12b ChCas12b-D496A Allele-specific disruption

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基于熵值法的中国撤县设市潜力评估研究

中国名城 2021年第8期35卷 35-41页

作者：朱建华李文雅侯伶慧东北师范大学地理科学学院长春130024 东北师范大学长白山地理过程与生态安全教育部重点实验室长春130024 东北师范大学中国东北研究院长春130024

撤县设市是行政区划调整的重要方式之一,也是加快新型城镇化建设的推进器。自2013我国重启“撤县设市”审批以来,已有大量的县获批设市,这充分反映了撤县设市将是未来一段时期内中国行政区划调整工作的重要趋势。通过撤县设市,有利于进... 详细信息

撤县设市是行政区划调整的重要方式之一,也是加快新型城镇化建设的推进器。自2013我国重启“撤县设市”审批以来,已有大量的县获批设市,这充分反映了撤县设市将是未来一段时期内中国行政区划调整工作的重要趋势。通过撤县设市,有利于进一步理顺我国行政管理体制,对于培育新生中小城市,优化中国的城镇化空间格局,缩小地区发展差异,缓解大城市发展压力,增强城市活力具有重要意义。从人口、经济、城市建设三个维度出发,选取了10个相关指标构建了撤县设市潜力评价指标体系,通过爛值法对指标进行赋权,得出中国各县综合得分。最终,根据各县得分情况,选取了120个发展潜力较大的县,并将之作为未来一段时期撤县设市的候选对象。通过此项研究,以期为未来中国行政区划调整提供一定的决策依据和参考借鉴。

关键词：撤县设市潜力评估熵值法中国

芳基甲酰胺类Bax激动剂的设计、合成与活性研究

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中国药物化学杂志 2024年第4期34卷 282-293页

作者：侯伶慧张真玮黄敏赵临襄沈阳药科大学基于靶点的药物设计与研究教育部重点实验室辽宁沈阳110016

目的设计合成一类芳基甲酰胺类衍生物,以期发现在多种实体瘤细胞中有效且活性相对于BTSA1显著提高的Bax激动剂。方法以通过虚拟筛选发现的BMC233为先导化合物,经过优化设计合成18个芳基甲酰胺类化合物C1~C18。以4-氨甲基苯甲酸甲酯为起... 详细信息

目的设计合成一类芳基甲酰胺类衍生物,以期发现在多种实体瘤细胞中有效且活性相对于BTSA1显著提高的Bax激动剂。方法以通过虚拟筛选发现的BMC233为先导化合物,经过优化设计合成18个芳基甲酰胺类化合物C1~C18。以4-氨甲基苯甲酸甲酯为起始原料,与不同羧酸依次发生缩合、水解反应得到4-取代苯甲酸中间体,再与经亲核取代反应制得的苯磺酰胺中间体发生缩合反应得到化合物C1~C8;以4-溴-1H-吡咯-2-甲酸甲酯为起始原料,依次发生亲核取代、Suzuki偶联、水解反应,最后与不同的胺发生缩合反应得到化合物C9~C18。对目标化合物进行分子水平和细胞水平活性测试。结果与结论设计并合成18个未见文献报道的芳基甲酰胺类化合物,其结构经^(1)H-NMR、^(13)C-NMR和HR-ESI-MS确证。其中化合物C13对Bcl-2/Bcl-X_(L)/Mcl-1无抑制活性,对多种实体瘤细胞有较高的抗增殖活性并优于阳性对照BTSA1。

关键词： Bax激动剂芳基甲酰胺类化合物抗肿瘤

Analysis on internal mechanism of zedoary turmeric in treatment of liver cancer based on pharmacodynamic substances and pharmacodynamic groups

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Chinese Herbal Medicines 2022年第4期14卷 479-493页

作者： Zeyu Li Erwei Hao Rui Cao Si Lin linghui Zou Tianyan Huang Zhengcai Du Xiaotao hou Jiagang Deng China ASEAN Joint Laboratory for International Cooperation in Traditional Medicine Research Nanning 530200China Guangxi Scientific Experiment Center of Traditional Chinese Medicine Nanning 530000China Guangxi Key Laboratory of Pharmacodynamics of Traditional Chinese Medicine Nanning 530000China

Zedoary tumeric(Curcumae Rhizoma,Ezhu in Chinese)has a long history of application and has great potential in the treatment of liver *** antiliver cancer effect of zedoary tumeric depends on the combined action of multiple pharmacodynamic *** order to clarify the specific mechanism of zedoary tumeric against liver cancer,this paper first analyzes the mechanism of its single pharmacodynamic substance against liver cancer,and then verifies the joint anti liver cancer mechanism of its“pharmacodynamic group”.By searching the research on the antihepatoma effect of active components of zedoary tumeric in recent years,we found that pharmacodynamic substances,including curcumol,zedoarondiol,curcumenol,curzerenone,curdione,curcumin,germacrone,β-elemene,can act on multi-target and multi-channel to play an antihepatoma *** example,curcumin can regulate miR,GLO1,CD133,VEGF,YAP,LIN28B,GPR81,HCAR-1,P53 and PI3K/Akt/mTOR,HSP70/TLR4 and NF-κ***/TGF/EMT,Nrf2/Keap1,JAK/STAT and other pathways play an antihepatoma *** pharmacological analysis showed that the core targets of the“pharmacodynamic group”for anti-life cancer are AKT1,EGFR,MAPK8,etc,and the core pathways are neuroactive live receiver interaction,nitrogen metabolism,HIF-1 signaling pathway,*** the same time,by comparing and analyzing the relationship between the specific mechanisms of pharmacodynamic substance and“pharmacodynamic group”,it is found that they have great reference significance in target,pathway,biological function,determination of core pharmacodynamic components,formation of core target protein interaction,in-depth research of single pharmacodynamic substance,increasing curative effect and so *** analyzing the internal mechanism of zedoary tumeric pharmacodynamic substance and“pharmacodynamic group”in the treatment of liver cancer,this paper intends to provide some ideas and references for the deeper pharmacological research of zedoary tumeric and the relationship between

关键词： action mechanism Curcumae Rhizoma liver cancer pharmacodynamic groups pharmacodynamic substances zedoary turmeric

Working memory deficits in Parkinson′s disease mouse model

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中国药理学与毒理学杂志 2023年第7期37卷 517-518页

作者： ZHAO Tingting GU Huating ZHAO Miao CHEN Tianzhi AN Yingjie ZHANG Xian hou Jincan CAO Peng ZENG linghui LI Chengyu Institute of Neuroscience State Key Laboratory of Neuroscience Chinese Academy of Sciences CAS Center for Excellence in Brain Science and Intelligence TechnologyShanghai Center for Brain Science and Brain-Inspired Technology Hangzhou City University National Institute of Biological Sciences

OBJECTIVE Parkinson′s disease(PD) is a progressive neurodegenerative disease clinically characterized by dyskinesia, tremor, rigidity, abnormal gait,whereas 90% of patients with PD suffer from defects of the sense of smell before the appearance of the motor dysfunctions. However, the mechanism of olfactory disorder is still not clear. METHODS We utilized olfaction based delayed paired association task in head-fixed *** focused on functional role of neural circuit using optogenetic techniques. In addition, we viewed the synaptic transmission by slice physiological recording and counted the cell number of targeted circuits. RESULTS AND CONCLUSION In our experiments, olfactory working memory impairments were found in the PD mice, and the working memory impairment appeared before motor dysfunctions. Furthermore, we also investigated the functional role of neural circuit for olfactory working memory in PD mice. Meanwhile, the excitatory post synaptic currents were decreased as a result of presynaptic release probability suppression in PD mice. However cell loss wasn′t found in working memory related circuit recently. These will provide a new idea of clinic diagnosis for PD.

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论著肥胖和消瘦儿童间生活行为对FAIM2启动子甲基化的影响：人群研究

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英国医学杂志中文版 2015年第8期18卷 438-446页

作者： Wu, Lijun Zhao, Xiaoyuan Huang, Guimin Zhang, Meixian Yinkun Yan hou, Dongqing Meng, linghui Liu, Junting Cheng, Hong Mi, Jie Shen, Yue Department of Epidemiology Capital Institute of Pediatrics Beijing China National Research Institute for Family Planning Beijing China

目标肥胖相关基因Fas细胞凋亡抑制分子2（FAIM2）可以被营养状况调控，并且其启动子甲基化水平与肥胖显著相关。生活行为因素，如静态生活行为和运动，可以修饰与肥胖相关的表观遗传状态。但是，FAIM2影响肥胖的分子机制是否与生活行为... 详细信息

目标肥胖相关基因Fas细胞凋亡抑制分子2（FAIM2）可以被营养状况调控，并且其启动子甲基化水平与肥胖显著相关。生活行为因素，如静态生活行为和运动，可以修饰与肥胖相关的表观遗传状态。但是，FAIM2影响肥胖的分子机制是否与生活行为相关还不清楚。本研究检测了肥胖和消瘦儿童间FAIM2启动子甲基化水平与静态生活行为和运动的潜在差异。

关键词：队列研究生活方式甲基化启动子儿童肥胖

一种新型的两态叠加多模叠加态光场的广义非线性等阶N次方H压缩

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光子学报 2000年第4期29卷 293-307页

作者：赵玲慧杨志勇侯瑶张振杰侯洵西北大学光子学与光子技术研究所西北大学光电子技术省级重点开放实验室西北大学现代物理研究所西安710069 西北大学物理学系中国科学院西安光学精密机械研究所瞬态光学技术国家重点实验室西安710068

本文根据量子力学中的线性叠加原理 ,构造了由多模 (即 q模 )相干态的相反态 | {-Zj}〉q及多模虚相干态的相反态 | {-iZj}〉q 这两者的线性叠加所组成的一种新型的两态叠加多模叠加态光场 | ψ(2 )msc〉q 利用新近建立的多模压缩态理论 ... 详细信息

本文根据量子力学中的线性叠加原理 ,构造了由多模 (即 q模 )相干态的相反态 | {-Zj}〉q及多模虚相干态的相反态 | {-iZj}〉q 这两者的线性叠加所组成的一种新型的两态叠加多模叠加态光场 | ψ(2 )msc〉q 利用新近建立的多模压缩态理论 ,详细研究了态 | ψ(2 )msc〉q 的广义非线性等阶N次方H压缩特性结果发现 :1 )当压缩阶数N与腔模总数q这两者之积为偶数 ,亦即当q·N =2 p且p =2m (m =1 ,2 ,3,… ,… )时 ,态 | ψ(2 )msc〉q恒处于等阶N H最小测不准态 ;2 )当q·N =2 p且 p =2m′+ 1 (m′ =0 ,1 ,2 ,3,… ,… )时 ,如果各模的初始相位之和 qj=1φj、态间的初始相位差 (θ(I)nq-θ(R)nq)、各多模相干态光场的总的平均光子数 qj=1R2 j以及 [(θ(I)nq -θ(R)nq) + qj=1R2 j]等满足一定的量子化条件时 ,态 | ψ(2 )msc〉q 总可呈现出周期性变化的、任意阶的等阶N次方H压缩效应 ;3)当压缩阶数N与腔模总数 q这两者之积为奇数时 ,亦即当 q·N =2 p + 1时 ,无论 p =2m(m =0 ,1 ,2 ,3,… ,… )还是 p =2m′ + 1 (m′ =0 ,1 ,2 ,3,… ,… ) ,只要各模初始相位之和 qj =1φj满足一定的量子化条件 ,则当两态叠加几率幅满足r(R)nq =r(I)nq 时 ,态 | ψ(2 )msc〉q 就恒处于N

关键词：两态叠加多模叠加态光场等阶N次方H压缩

Serologic Survey of the Pandemic H1N1 2009 Virus in Guangdong province,China:a cross sectional study

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Serologic Survey of the Pandemic H1N1 2009 Virus in Guangdon...

气候变化和物候变动对东北黑土区农业生产的协同作用及未来粮食生产风险

2011广东省预防医学会学术年会

作者： Xin Zhang Jianfeng He linghui Li Xiaolan Zhu Changwen Ke Hanzhong Ni Nianmei hou Haojie Zhong Jie Wu Center for Disease Control and Prevention of Guangdong Province

Background:Relying on surveillance of clinical cases limits the ability to understand the full impact and severity of an epidemic,which urges a deep insight into the serological evidence of infection and transmission feature of pandemic H1N1 2009(pH1N1) virus in Guangdong province. Methods:In this cross-sectional serological survey,serum samples were collected by multi-stage stratified random sampling in Jan *** titers were measured by hemagglutination inhibition(HI) ***-specific and region-specific prevalence were calculated based on the results of HI assay(positive,HI titer≥1:40). Results:A total of 4,319 serum samples had been collected from subjects without vaccination with pH1N1 *** seroprevalence was 22.82%(985/4,319).By contrast,there was a marked spatial heterogeneity in *** seroprevalence was 27.3%in large city,21.4% in medium cities,higher than that of 20.2%in rural *** seroprevalence was highest in 11-20 age group(32.8%),however,in those above 60 years of age group,which was 12.6%, lower than other age *** the other hand,antibody titers to pH1N1 virus were highest in school children,which were followed by a gradual decrease in ***,in the elderly groups from cities,especially from large city,the antibody titer to pH1N1 increased significantly and reached a much higher level. Conclusion:Our results showed that the prevalence for pH1N1 was correlated with age and population *** antibody may have protected the very old from pH1NI infection,while original antigenic sin and immunosenescence may have contributed to greater severity once *** should be considered when studying the pathogenesis and transmission of influenza virus and formulating strategies on vaccination and treatment.

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地理学报 2022年第7期77卷 1681-1700页

作者：高江波刘路路郭灵辉孙东琪刘婉露侯文娟吴绍洪中国科学院地理科学与资源研究所中国科学院陆地表层格局与模拟重点实验室北京100101 河南理工大学测绘与国土信息学院焦作454000 中国科学院地理科学与资源研究所中国科学院区域可持续发展分析与模拟重点实验室北京100101 中国科学院大学资源与环境学院北京100049

东北黑土区是中国重要的粮食生产基地,也是中国气候变化最敏感的地区之一。然而,气候变化背景下东北黑土区气候及物候变化对农业生产力的综合影响并不清晰,未来农业生产风险评估的定量化程度不够,风险等级制定缺乏依据。本文借助遥感产... 详细信息

东北黑土区是中国重要的粮食生产基地,也是中国气候变化最敏感的地区之一。然而,气候变化背景下东北黑土区气候及物候变化对农业生产力的综合影响并不清晰,未来农业生产风险评估的定量化程度不够,风险等级制定缺乏依据。本文借助遥感产品、气候资料和模拟数据等资料,综合运用多元线性回归、相关分析及干旱危险性指数等方法,探究东北黑土区作物物候动态及其气候响应特征,辨识气候与物候变化对农业生产的复合效应及未来可能风险。结果表明:(1)2000—2017年东北黑土区29.76%的区域作物生长季开始期呈显著延后趋势,16.71%的区域作物生长季结束期呈提前态势,生长季开始期受气温的影响范围广,且滞后时间长;生长季结束期与前期气候变化关系更加密切,且带状差异性响应格局尤其明显。(2)气候变化和物候期改变对作物生产的解释能力较生长季同期气候变化的解释能力增加了70.23%,解释面积扩大了85.04%。(3)RCP8.5情景下东北黑土区粮食总产量呈现上升趋势,粮食生产风险表现出“南增北减”的演变特征,风险区面积不断扩大,全球温升2.0℃时,松嫩黑土亚区南部粮食减产量可能达到10%。研究有助于深入认识气候—物候—作物生产的关联机理及未来粮食生产风险,对制定气候变化应对策略,保障国家粮食安全具有重要意义。

关键词：东北黑土区植被物候植被生产力滞后效应未来风险