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In vivo evaluation of guide-free Cas9-induced safety risks in a pig model

Signal Transduction and Targeted Therapy 2024年第8期9卷 3493-3506页

作者： Weikai Ge Shixue Gou Xiaozhu Zhao Qin Jin Zhenpeng Zhuang Yu Zhao Yanhui Liang Zhen Ouyang Xiaoyi Liul Fangbing Chen Hui Shi Haizhao Yan Han Wu Liangxue Lai Kepin Wang China-New Zealand Joint Laboratory on Biomedicine and Health CAS Key Laboratory of Regenerative BiologyGuangdong Provincial Key Laboratory of Stem Cell and Regenerative MedicineJoint School of Life SciencesGuangzhou Institutes of Biomedicine and HealthChinese Academy of SciencesGuangzhou Medical UniversityGuangzhou 510530China Sanya institute of Swine resource Hainan Provincial Research Center of Laboratory AnimalsSanya 572000China Guangdong Provincial Key Laboratory of Large Animal models for Biomedicine Wuyi UniversityJiangmen 529020China Guangzhou National Laboratory Guangzhou 510005China SUniversity of Chinese Academy of sciences 100049 BeijingChina Research Unit of Generation of Large Animal disease Models Chinese Academy of Medical Sciences(2019RU015)Guangzhou 510530China

The CRISPR/Cas9 system has shown great potential for treating human genetic diseases through gene ***,there are concerns about the safety of this system,specifically related to the use of guide-free *** studies have shown that guidefree Cas9 can induce genomic instability in ***,the in vivo safety risks associated with guide-free Cas9 have not been evaluated,which is necessary for the development of gene therapy in clinical *** this study,we used doxycycline-inducible Cas9-expressing pigs to evaluate the safety risks of guide-free Cas9 in *** findings demonstrated that expression of guide-free Cas9 could induce genomic damages and transcriptome changes in *** severity of the genomic damages and transcriptome changes were correlate with the expression levels of Cas9 ***,prolonged expression of Cas9 in pigs led to abnormal phenotypes,including a significant decrease in body weight,which may be attributable to genomic damage-induced nutritional absorption and metabolic ***,we observed an increase in whole-genome and tumor driver gene mutations in pigs with long-term Cas9 expression,raising the risk of tumor *** in vivo evaluation of guide-free Cas9 in pigs highlights the necessity of considering and monitoring the detrimental effects of Cas9 alone as genome editing via the CRISPR/Cas9 system is implemented in clinical gene *** research emphasizes the importance of further study and implementation of safety measures to ensure the successful and safe application of the CRiSPR/Cas9 system in clinical practice.

关键词： CRISPR/Cas9 vivo alone

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Synthesis and anti-HIV activities of phorbol derivatives

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Chinese Journal of Natural Medicines 2024年第2期22卷 146-160页

作者： HUANG Xiaolei TANG Chengrun HUANG Xusheng YANG Yun LI Qirun MA Mengdi ZHAO Lei YANG Liumeng CUI Yadong ZHANG Zhenqing ZHENG Yongtang ZHANG Jian College of Pharmaceutical Science Soochow UniversitySuzhou 215123China Key Laboratory of Animal Models and Human disease Mechanisms of the Chinese Academy of sciences/Key Laboratory of Bioactive Peptides of Yunnan Province Kunming Institute of ZoologyChinese Academy of SciencesKunming 650223China Kunming College of Life Science University of Chinese Academy of SciencesKunmingYunnan 650204China

In this study,37 derivatives of phorbol esters were synthesized and their anti-HIV-1 activities evaluated,building upon our previous synthesis of 51 phorbol derivatives.12-Para-electron-acceptor-trans-cinnamoyl-13-decanoyl phorbol derivatives stood out,demonstrating remarkable anti-HIV-1 activities and inhibitory effects on syncytia *** derivatives exhibited a higher safety index compared with the positive control *** them,12-(trans-4-fluorocinnamoyl)-13-decanoyl phorbol,designated as compound 3c,exhibited the most potent anti-HIV-1 activity(EC_(50)2.9 nmol·L^(−1),CC50/EC_(50)11117.24)and significantly inhibited the formation of syncytium(EC_(50)7.0 nmol·L^(−1),CC50/EC_(50)4891.43).Moreover,compound 3c is hypothesized to act both as an HIV-1 entry inhibitor and as an HIV-1 reverse transcriptase *** titration calorimetry and molecular docking studies indicated that compound 3c may also function as a natural activator of protein kinase C(PKC).Therefore,compound 3c emerges as a potential candidate for developing new anti-HIV drugs.

关键词： Phorbol esters Anti-HIV-1 activity Syncytia formation 12-(Trans-4-fluorocinnamoyl)-13-decanoyl phorbol Safety index HIV-1 entry inhibitor HIV-1 reverse transcriptase inhibitor PKC activator

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TBK1:a new target for overcoming cancer immunotherapy resistance

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Science China(Life sciences) 2024年第1期67卷 217-218页

作者： Jizhong Guan Long Zhang Fangfang Zhou institutes of Biology and Medical Science Soochow UniversitySuzhou 215123China MOE Laboratory of Biosystems Homeostasis and Protection and Innovation Center for Cell Signaling Network Life Sciences InstituteZhejiang UniversityHangzhou 310058China

In a recent study published in Nature,Sun et al.(2023)discovered that targeting TANK-binding kinase 1(TBK1)can successfully overcome resistance to immune checkpoint blockade(ICB)treatment and the study revealed its potential *** authors provided evidence that the disruption of TBK1 signal enhances the blockade of programmed cell death protein-1(PD-1)and promotes anti-tumor immunity in the tumor microenvironment(TME).Tumor cells rely on Janus kinase(JAK)and signal transducer as well as activator of transcription(STAT)signals to elicit an immune response by perceiving tumor necrosis factorα(TNF-α)and interferon-γ(IFN-γ),resulting in receptor-interacting protein kinase(RIPK)-caspase-mediated cell death in tumor cells(Figure 1).

关键词： TBK1 immunity

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Deepening International Cooperation in Digital Sector

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China News Release 2024年第9期 26-32页

作者： Wan Jinbo Liu Mingxi the institutes of Science and Development Chinese Academy of Sciences(CASISD) CASISD

At present, digital technologies,such as artificial intelligence, cloud computing, blockchain and big data,are advancing at an unprecedented pace, spearheading a new scientific and technological revolution and industrial transformation. These technologies are rapidly permeating every facet of social and economic development, profoundly reshaping ways of production and life, as well as governance models, and accelerating the transition of human society toward the digital age.

关键词： transformation. heading profound

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Manure substitution improves maize yield by promoting soil fertility and mediating the microbial community in lime concretion black soil

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Journal of Integrative Agriculture 2024年第2期23卷 698-710页

作者： Minghui Cao Yan Duan Minghao Li Caiguo Tang Wenjie Kan Jiangye Li Huilan Zhang Wenling Zhong Lifang Wu The Center for Ion Beam Bioengineering&Green Agriculture Hefei Institutes of Physical ScienceChinese Academy of SciencesHefei 230031China University of Science and Technology of China Hefei 230026China Zhongke Taihe Experimental Station Taihe 236626China Institute of Resources and Environment Jiangsu Academy of Agricultural SciencesNanjing 210014China

Synthetic nitrogen(N)fertilizer has made a great contribution to the improvement of soil fertility and productivity,but excessive application of synthetic N fertilizer may cause agroecosystem risks,such as soil acidification,groundwater contamination and biodiversity ***,organic substitution has received increasing attention for its ecologically and environmentally friendly and productivity ***,the linkages between manure substitution,crop yield and the underlying microbial mechanisms remain *** bridge this gap,a three-year field experiment was conducted with five fertilization regimes:i)Control,non-fertilization;CF,conventional synthetic fertilizer application;CF_(1/2)M_(1/2),1/2 N input via synthetic fertilizer and 1/2 N input via manure;CF_(1/4)M_(3/4),1/4 N input synthetic fertilizer and 3/4 N input via manure;M,manure *** fertilization treatments were designed to have equal N *** results showed that all manure substituted treatments achieved high soil fertility indexes(SFI)and productivities by increasing the soil organic carbon(SOC),total N(TN)and available phosphorus(AP)concentrations,and by altering the bacterial community diversity and composition compared with ***,AP,and the soil C:N ratio were mainly responsible for microbial community *** co-occurrence network revealed that SOC and AP had strong positive associations with Rhodospirillales and Burkholderiales,while TN and C:N ratio had positive and negative associations with Micromonosporaceae,*** specific taxa are implicated in soil macroelement *** Forest analysis predicted that both biotic(bacterial composition and Micromonosporaceae)and abiotic(AP,SOC,SFI,and TN)factors had significant effects on crop *** present work strengthens our understanding of the effects of manure substitution on crop yield and provides theoretical support for optimizing fertilization strategies.

关键词： fertilization manure substitution soil fertility maize yield bacterial community

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On the evolutionary trail of MagRs

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Zoological Research 2024年第4期45卷 821-830页

作者： Jing Zhang Yafei Chang Peng Zhang Yanqi Zhang Mengke Wei Chenyang Han Shun Wang Hui-Meng Lu Tiantian Cai Can Xie High Magnetic Field Laboratory Hefei Institutes of Physical ScienceChinese Academy of SciencesScience IslandHefeiAnhui 230031China Science Island Branch of Graduate School University of Science and Technology of ChinaHefeiAnhui 230036China institutes of Physical Science and Information Technology Anhui UniversityHefeiAnhui 230039China School of Life sciences Key Laboratory for Space Bioscience and BiotechnologyNorthwestern Polytechnical UniversityXi’anShaanxi 710072China Institute of Quantum Sensing Zhejiang UniversityHangzhouZhejiang 310027China

Magnetic sense,or termed magnetoreception,has evolved in a broad range of taxa within the animal kingdom to facilitate orientation and ***,highly conserved A-type iron-sulfur proteins,are widely distributed across all phyla and play essential roles in both magnetoreception and iron-sulfur cluster ***,the evolutionary origins and functional diversification of MagRs from their prokaryotic ancestor remain *** this study,MagR sequences from 131 species,ranging from bacteria to humans,were selected for analysis,with 23 representative sequences covering species from prokaryotes to Mollusca,Arthropoda,Osteichthyes,Reptilia,Aves,and mammals chosen for protein expression and *** studies revealed a gradual increase in total iron content in MagRs during *** types of MagRs were identified,each with distinct iron and/or iron-sulfur cluster binding capacity and protein stability,indicating continuous expansion of the functional roles of MagRs during speciation and *** evolutionary biochemical study provides valuable insights into how evolution shapes the physical and chemical properties of biological molecules such as MagRs and how these properties influence the evolutionary trajectories of MagRs.

关键词： Magnetoreception Magnetoreceptor(MagR) Iron-sulfur cluster Stability Evolutionary biochemistry

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从快照到电影:捕捉单核苷酸分辨率的真核生物转录起始过程

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Science Bulletin 2024年第7期69卷 853-855页

作者：尚雪莹徐从玲陈飞 Fudan University Shanghai Cancer Center Institutes of Biomedical SciencesShanghai Key Laboratory of Radiation OncologyShanghai Key Laboratory of Medical EpigeneticsShanghai Medical College of Fudan UniversityShanghai 200032China Shanghai Key Laboratory of Anesthesiology and brain Functional Modulation Clinical Research Center for Anesthesiology and Perioperative MedicineTranslational Research Institute of Brain and Brain-Like IntelligenceShanghai Fourth People’s HospitalSchool of Life Sciences and TechnologyTongji UniversityShanghai 200092China

The process of transcription is generally delineated into three sequential phases:initiation,elongation,and *** transition between these phases,particularly from initiation to elongation,requires substantial conformational and compositional reconfigurations within the transcription machinery to enable functional *** initiation is characterized by the assembly of a preinitiation complex(PIC).

关键词： figuration enable termination

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Role of cancer stem cell ecosystem on breast cancer metastasis and related mouse models

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Zoological Research 2024年第3期45卷 506-517页

作者： Xilei Peng Haonan Dong Lixing Zhang Suling Liu Fudan University Shanghai Cancer Center&institutes of Biomedical sciences/State Key Laboratory of Genetic Engineering/Cancer institutes/Department of Oncology/Key Laboratory of Breast Cancer in Shanghai/Shanghai Key Laboratory of Medical Epigenetics/Shanghai Key Laboratory of Radiation Oncology/International Co-laboratory of Medical Epigenetics and Metabolism Ministry of Science and Technology/Shanghai Medical College/Fudan UniversityShanghai 200032China

Breast cancer metastasis is responsible for most breast cancer-related deaths and is influenced by many factors within the tumor ecosystem,including tumor cells and *** cancer stem cells(BCSCs)constitute a small population of cancer cells with unique characteristics,including their capacity for self-renewal and *** have shown that BCSCs not only drive tumorigenesis but also play a crucial role in promoting metastasis in breast *** tumor microenvironment(TME),composed of stromal cells,immune cells,blood vessel cells,fibroblasts,and microbes in proximity to cancer cells,is increasingly recognized for its crosstalk with BCSCs and role in BCSC survival,growth,and dissemination,thereby influencing metastatic ***,a thorough understanding of BCSCs and the TME is critical for unraveling the mechanisms underlying breast cancer *** this review,we summarize current knowledge on the roles of BCSCs and the TME in breast cancer metastasis,as well as the underlying regulatory ***,we provide an overview of relevant mouse models used to study breast cancer metastasis,as well as treatment strategies and clinical trials addressing BCSC-TME interactions during ***,this study provides valuable insights for the development of effective therapeutic strategies to reduce breast cancer metastasis.

关键词： Breast cancer Metastasis Cancer stem cell Ecosystem Tumor microenvironment Mouse model

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Integration of HiBiT into enteroviruses:A universal tool for advancing enterovirus virology research

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Virologica Sinica 2024年第3期39卷 422-433页

作者： Rui Yu Xiaohong Li Peng Zhang Minghao Xu Jitong Zhao Jingjing Yan Chenli Qiu Jiayi Shu Shuo Zhang Miaomiao Kang Xiaoyan Zhang Jianqing Xu Shuye Zhang School of Medicine Shanghai UniversityShanghai200444China Clinical Center for Biotherapy Zhongshan HospitalFudan UniversityShanghai200433China Guangzhou institutes of Biomedicine and Health The Chinese Academy of SciencesGuangzhou510530China institutes of Biomedical sciences Fudan UniversityShanghai200032China Shanghai Geriatric Medical Center Shanghai201104China Clinical Center for Biotherapy Zhongshan Hospital/Zhongshan Hospital(Xiamen)Fudan University361015China Shanghai Public Health Clinical Center Fudan UniversityShanghai201508China

The utilization of enteroviruses engineered with reporter genes serves as a valuable tool for advancing our understanding of enterovirus biology and its applications,enabling the development of effective therapeutic and preventive *** this study,our initial attempts to introduce a NanoLuc luciferase(NLuc)reporter gene into recombinant enteroviruses were unsuccessful in rescuing viable *** hypothesized that the size of the inserted tag might be a determining factor in the rescue of the ***,we inserted the 11-amino-acid HiBiT tag into the genomes of enterovirus A71(EV-A71),coxsackievirus A10(CVA10),coxsackievirus A7(CVA7),coxsackievirus A16(CVA16),namely EV-A71-HiBiT,CVA16-HiBiT,CVA10-HiBiT,CVA7-HiBiT,and observed that the HiBiT-tagged viruses exhibited remarkably high rescue ***,the HiBiT-tagged enteroviruses displayed comparable characteristics to the wild-type viruses.A direct comparison between CVA16-NLuc and CVA16-HiBiT recombinant viruses revealed that the tiny HiBiT insertion had minimal impact on virus infectivity and replication ***,these HiBiT-tagged enteroviruses demonstrated high genetic stability in different cell lines over multiple *** addition,the HiBiT-tagged viruses were successfully tested in antiviral drug assays,and the sensitivity of the viruses to drugs was not affected by the HiBiT ***,our findings provide definitive evidence that the integration of HiBiT into enteroviruses presents a universal,convenient,and invaluable method for advancing research in the realm of enterovirus ***,HiBiT-tagged enteroviruses exhibit great potential for diverse applications,including the development of antivirals and the elucidation of viral infection mechanisms.

关键词： Enterovirus Infectious clones Reporter genes Luciferase Drug screening

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Spatial differences of Sustainable Development Goals(SDGs)among counties(cities)on the northern slope of the Kunlun Mountains

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Regional Sustainability 2024年第1期5卷 1-10页

作者： WANG Tao ZHOU Daojing FAN Jie School of Economics and Management University of Chinese Academy of SciencesBeijing100190China Xinjiang Arts University Urumqi830049China institutes of Science and Development Chinese Academy of SciencesBeijing100190China Institute of Geographic sciences and Natural Resources Research Chinese Academy of SciencesBeijing100101China

The county(city)located on the northern slope of the Kunlun Mountains is the primary area to solidify and extend the success of Xinjiang Uygur Autonomous Region,China in poverty *** Sustainable Development Goals(SDGs)are intertwined with the concerted economic and social development of Xinjiang and the objective of achieving shared prosperity within the *** study established a sustainable development evaluation framework by selecting 15 SDGs and 20 secondary indicators from the United Nations’*** aim of this study is to quantitatively assess the progress of SDGs at the county(city)level on the northern slope of the Kunlun *** results indicate that there are substantial variations in the scores of SDGs among the nine counties and one city located on the northern slope of the Kunlun *** high scores of SDGs are observed in the central and eastern regions,whereas lower scores are prevalent in the western *** scores of SDGs,in descending order,are as follows:62.22 for Minfeng County,54.22 for Hotan City,50.21 for Qiemo County,42.54 for Moyu County,41.56 for Ruoqiang County,41.39 for Qira County,39.86 for Lop County,38.25 for Yutian County,38.10 for Pishan County,and 36.87 for Hotan *** performances of SDGs reveal that Hotan City,Lop County,Minfeng County,and Ruoqiang County have significant sustainable development capacity because they have three or more SDGs ranked as green ***,Hotan County,Moyu County,Qira County,and Yutian County show the poorest performance,as they lack SDGs with green *** is important to establish and enhance mechanisms that can ensure sustained income growth among poverty alleviation beneficiaries,sustained improvement in the capacity of rural governance,and the gradual improvement of social security *** measures will facilitate the effective implementation of ***,this study offers a valuable support for governmental authorities and relevant departments i

关键词： Sustainable Development Goals(SDGs) Northern slope of the Kunlun Mountains Poverty alleviation Arid lands Sustainable development capacity

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