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Human 8-cell embryos enable efficient induction of disease-preventive mutations without off-target effect by cytosine base editor

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Protein & Cell 2023年第6期14卷 416-432页

作者： Yinghui Wei Meiling Zhang Jing Hu Yingsi Zhou Mingxing Xue Jianhang Yin Yuanhua Liu Hu Feng Ling Zhou Zhifang Li Dongshuang Wang Zhiguo Zhang Yin Zhou Hongbin Liu Ning Yao Erwei Zuo Jiazhi Hu yanzhi du Wen Li Chunlong Xu Hui Yang Center for Reproductive Medicine International Peace Maternity and Child Health HospitalInnovative Research Team of High-level Local Universities in ShanghaiSchool of MedicineShanghai Jiao Tong UniversityShanghai 2000301.Center for Reproductive MedicineInternational Peace Maternity and Child Health HospitalInnovative Research Team of High-level Local Universities in ShanghaiSchool of MedicineShanghai Jiao Tong UniversityShanghai 200030China Institute of Neuroscience State Key Laboratory of NeuroscienceKey Laboratory of Primate NeurobiologyCAS Center for Excellence in Brain Science and Intelligence TechnologyShanghai Institutes for Biological SciencesChinese Academy of SciencesShanghai 200031China Lingang Laboratory Shanghai Research Center for Brain Science and Brain-Inspired Intelligence TechnologyShanghai 200031China Center for Reproductive Medicine Ren Ji HospitalSchool of MedicineShanghai Key Laboratory for Assisted Reproduction and Reproductive GeneticsShanghai Jiao Tong UniversityShanghai 200127China The MOE Key Laboratory of Cell Proliferation and Differentiation School of Life SciencesGenome Editing Research CenterPeking UniversityBeijing 100871China Center for Reproductive Medicine Shandong UniversityJinan 250012China Center for Reproductive Medicine Anhui Provincial Maternal and Child Health HospitalHefei 230001China Shenzhen Branch Guangdong Laboratory for Lingnan Modern AgricultureGenome Analysis Laboratory of the Ministry of AgricultureAgricultural Genomics Institute at ShenzhenChinese Academy of Agricultural SciencesShenzhen 518000China Reproductive Medicine Center Department of Obstetrics and Gynecologythe First Affiliated Hospital of Anhui Medical UniversityHefei 230022China

Approximately 140 million people worldwide are homozygous carriers of APOE4(ε4),a strong genetic risk factor for late onset familial and sporadic Alzheimer’s disease(AD),91%of whom will develop AD at earlier age than heterozygous carriers and noncarriers.Susceptibility to AD could be reduced by targeted editing of APOE4,but a technical basis for controlling the off-target effects of base editors is necessary to develop low-risk personalized gene therapies.Here,we first screened eight cytosine base editor variants at four injection stages(from 1-to 8-cell stage),and found that FNLS-YE1 variant in 8-cell embryos achieved the comparable base conversion rate(up to 100%)with the lowest bystander effects.In particular,80%of AD-susceptibleε4 allele copies were converted to the AD-neutralε3 allele in humanε4-carrying embryos.Stringent control measures combined with targeted deep sequencing,whole genome sequencing,and RNA sequencing showed no DNA or RNA off-target events in FNLS-YE1-treated human embryos or their derived stem cells.Furthermore,base editing with FNLS-YE1 showed no effects on embryo development to the blastocyst stage.Finally,we also demonstrated FNLS-YE1 could introduce known protective variants in human embryos to potentially reduce human susceptivity to systemic lupus erythematosus and familial hypercholesterolemia.Our study therefore suggests that base editing with FNLS-YE1 can efficiently and safely introduce known preventive variants in 8-cell human embryos,a potential approach for reducing human susceptibility to AD or other genetic diseases.

关键词： human embryo APOE4 disease-preventive mutations base editor

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EGF signaling pathway plays an important role in colon cancer stem cell proliferation

EGF signaling pathway plays an important role in colon cance...

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2012中国消化系疾病学术大会

作者： Lu Xia Yanjun Feng Xin Dai Xiaolu Li Haiwei Wang Jiansheng Liu Ji Zhang yanzhi du Department of Gastroenterology Ruijin HospitalShanghai Jiaotong University of Medicine Key Laboratory of Stem Cell Biology Institute of Health SciencesShanghai Institutes for Biological Sciences(SIBS) Chinese Academy of Sciences(CAS) Shanghai Jiao Tong University of Medicine(SJTU-SM)

Objective Cancer stem cells(CSCs) are a subpopulation of cells within a tumor that can self-renew and proliferate.Growth factors,such as epidermal growth factor(EGF),and basic fibroblast growth factor(b-FGF) promote cancer stem cell proliferation in many solid tumors.This study assessed whether EGF,b-FGF and IGF signaling pathways were essential for colon CSCs proliferation and self-renewal.

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Fusion of Ground-Based and Spaceborne Radar Precipitation Based on Spatial Domain Regularization

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Journal of Meteorological Research 2024年第2期38卷 285-302页

作者： Anfan HUANG Leilei KOU yanzhi LIANG Ying MAO Haiyang GAO Zhigang CHU School of Atmospheric Physics Nanjing University of Information Science&TechnologyNanjing 210044 Collaborative Innovation Center on Forecast and Evaluation of Meteorological Disasters Nanjing University of Information Science&TechnologyNanjing 210044

High-quality and accurate precipitation estimations can be obtained by integrating precipitation information measures using ground-based and spaceborne radars in the same target area.Estimating the true precipitation state is a typical inverse problem for a given set of noisy radar precipitation observations.The regularization method can appropriately constrain the inverse problem to obtain a unique and stable solution.For different types of precipitation with different prior distributions,the L_(1) and L_(2) norms were more effective in constraining stratiform and convective precipitation,respectively.As a combination of L_(1) and L_(2) norms,the Huber norm is more suitable for mixed precipitation types.This study uses different regularization norms to combine precipitation data from the C-band dual-polarization ground radar(CDP)and dual-frequency precipitation radar(DPR)on the Global Precipitation Measurement(GPM)mission core satellite.Compared to single-source radar data,the fused figures contain more information and present a comprehensive precipitation structure encompassing the reflectivity and precipitation fields.In 27 precipitation cases,the fusion results utilizing the Huber norm achieved a structural similarity index measure(SSIM)and a peak signal-to-noise ratio(PSNR)of 0.8378 and 30.9322,respectively,compared with the CDP data.The fusion results showed that the Huber norm effectively amalgamate the features of convective and stratiform precipitation,with a reduction in the mean absolute error(MAE;16.1%and 22.6%,respectively)and root-mean-square error(RMSE;11.7%and 13.6%,respectively)compared to the 1-norm and 2-norm.Moreover,in contrast to the fusion results of scale recursive estimation(SRE),the Huber norm exhibits superior capability in capturing the localized precipitation intensity and reconstructing the detailed features of precipitation.

关键词： dual-frequency precipitation radar(DPR) dual-polarization radar data fusion regularization Huber norm

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Metagenomic analysis identified microbiome alterations and pathological association between intestinal microbiota and polycystic ovary syndrome

Metagenomic analysis identified microbiome alterations and p...

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2019中国生理学会学术年会暨张锡钧基金第十五届全国青...

作者：储维薇 Qixin Han Jieying Xu Juan Wang Yun Sun Weiping Li Zi-Jiang Chen yanzhi du Center for Reproductive Medicine Ren Ji HospitalSchool of MedicineShanghai Jiao Tong University Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics National Research Center for Assisted Reproductive Technology and Reproductive Genetics The Key Laboratory for Reproductive Endocrinology of Ministry of EducationShandong Provincial Key Laboratory of Reproductive MedicineCenter for Reproductive MedicineShandong Provincial HospitalShandong University

Background: Polycystic ovary syndrome（PCOS） is the most common metabolic and endocrinal disorder in women of childbearing age.Although some studies have investigated the microbiota of women with PCOS, the functions and underlying mechanisms of microbes associated with PCOS have not yet been identified.Methods: Subjects were recruited at the Centre for Reproductive Medicine.We collected faecal samples from women in the control group（n = 14） and women with PCOS（n = 14） and performed shotgun metagenomic sequencing.Clinical parameters, including body mass index, endocrine hormone, and blood glucose level, were gathered for correlation analysis.Findings: In this study, we found several microbial strains were significantly more abundant in the PCOS group, including Parabacteroides merdae, Bacteroides fragilis, and strains of Escherichia and Shigella, whereas Faecalibacterium prausnitzii was enriched in the control group.Metagenomic species（MGS） analysis revealed that the microbes which enrich the PCOS group were negatively correlated with those of the control group.Of note, we observed a positive correlation between MGSs relevant to PCOS and endocrine disorder, including elevated levels of serum testosterone（T）, luteinising hormone（LH）, anti-Müllerian hormone（AMH）, and body mass index（BMI）.Functional alterations, reflected by KEGG orthologues, could imply potential mechanisms of microbial involvement in the developmental progress of PCOS.Interpretation: Our findings suggest an intimate association and potential mechanisms linking microbial dysbiosis and pathophysiology changes of PCOS.We address the importance of monitoring and modulating microbial composition and functional shifts in future clinical practice.

关键词： polycystic ovary syndrome gut microbiota metagenomic sequencing microbial dysbiosis,metabolic pathways

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德语广告中的“会话含义”

德语广告中的“会话含义”

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作者： du yanzhi 西安外国语大学

学位级别：硕士

广告充斥着现代社会的各个角落，特别是商业广告，已在经济全球化和信息时代扮演着越来越重要的角色。广告尤其是商业广告的最终目的是劝说人们购买产品，为实现这一最终目的，广告商（说话人）千方百计地吸引人们的注意力，鼓动、诱导... 详细信息

广告充斥着现代社会的各个角落，特别是商业广告，已在经济全球化和信息时代扮演着越来越重要的角色。广告尤其是商业广告的最终目的是劝说人们购买产品，为实现这一最终目的，广告商（说话人）千方百计地吸引人们的注意力，鼓动、诱导、劝服消费者（听话人）花钱购买其商品，关键就是充分利用语言。由于广告的普遍性，广告语言已经引起了众多语言学者的关注。本文在现有研究的启发下，从语用学角度对德语印刷商业广告进行研究分析。在广告这种单向隐含的语言交际方式中，广告语言往往是间接的，会话含义经常被广告商作为一个策略来使用。通过对会话准则的遵守或违反产生“言外之意”可以加深消费者对广告的印象，引起他们的兴趣，从而诱导其购买商品。本文旨在运用格赖斯提出的合作原则分析德语广告中遵守和违背其原则的现象和规律（其中重点探讨广告语对会话准则的违反），阐释广告文案深层含义产生的方式。进一步探讨广告商如何利用会话含义吸引消费者的注意力，从而达到劝服其购买产品的目的。

关键词：广告合作原则会话准则会话含义

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从西北国际运输线看抗战时期边疆交通的功能

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史林 2024年第1期 72-79,103,218页

作者：李艳枝杜佳辽宁大学社会科学研究院辽宁大学历史学院 110136

西北国际运输线是抗日战争时期开辟的、连接内地与西北边疆的重要国际运输通道。从晚清到抗战爆发,国民对于内地和边疆之间的交通认知,经历了由稳定边疆到抵御外侮再到交通救国的转变。基于认知的转变和特殊的政治环境,南京国民政府采... 详细信息

西北国际运输线是抗日战争时期开辟的、连接内地与西北边疆的重要国际运输通道。从晚清到抗战爆发,国民对于内地和边疆之间的交通认知,经历了由稳定边疆到抵御外侮再到交通救国的转变。基于认知的转变和特殊的政治环境,南京国民政府采用全方位部署与重点兼顾的方式,将边疆交通建设纳入国家整体规划,中央政府与边疆省份积极配合,开辟了包括公路运输、驿运、空运、水陆联运的西北国际运输线。国民政府依托西北国际运输线,加快边疆交通网络雏形构建,密切边疆省份与中央政府的关系,实现国家对边疆的有效管控,进而推动对边疆治理的长远谋划。西北国际运输线兼具救国与治边的双重使命,既是抗战时期的物资运输之路,更是时代孕育的国家进行边疆整合的重要途径。

关键词：西北国际运输线治边救国南京国民政府新疆

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The effects of selenium on the translation efficiency of selenoproteins Gpx1， Gpx4， and Txnrd1 in oxLDL-induced EA.hy926 cells

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Food Science and Human Wellness 2024年

作者： Jiaqi Lu Jing Meng yanzhi Lang Abdul Rehman Yamei Yan Linwu Ran School of Public Health Ningxia Medical University Key Laboratory of Environmental Factors and Chronic Disease Control Yinchuan School of Clinical Medicine Ningxia Medical University Goji Berry Research Institute Ningxia Academy of Agriculture and Forestry Sciences

Selenium is a crucial trace element that contributes to physiological processes in the body as selenoproteins. Selenoproteins serve as an integral role in the body in controlling the redox state of cells and protecting against damage induced by oxidative stress. This study aimed to investigate the effects and possible mechanism of selenium on selenoproteins expression in EA.hy926 cells induced by oxLDL. The impact of selenium on the viability of EA.hy926 cells was detected by the MTT method， and intracellular ROS level and mitochondrial membrane potential were assessed by fluorescent probe DCFH-DA and JC-1， respectively. RNA-seq， quantitative real-time PCR (RT-qPCR)， and western blot were used to investigate the selenoprotein expression. Selenoprotein mRNA translation efficiency was analyzed by ribosome profiling (Ribo-Seq) coupled with transcriptomics. Our data showed that selenium supplementation (0.5 μmol/L) significantly decreased ROS production， reduced mitochondrial inner membrane potential and increased the proliferative activity of EA.hy926 cells induced by oxLDL. Moreover， The protective effects of selenium against oxLDL-induced EA.hy926 cell injury were associated with the upregulation of the expressions of selenoproteins GPX1， GPX4， and TXNRD1. Furthermore， the expressions of selenoproteins GPX1 and GPX4 were hierarchically controlled， but the expressions of selenoproteins TXNRD1 were mainly regulated by oxLDL. Finally， Ribo-Seq coupled with transcriptomics results demonstrated that the expressions of selenoproteins GPX1， GPX4， and TXNRD1 were regulated at the translation process level. These findings suggested that selenium could have preventive effects in oxLDL induced EA.hy926 cell injury by regulating the selenoprotein expression， and the selenoproteins expressions at the translation level in vascular endothelial cells need further study.

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长链非编码RNA在卵泡发育及其相关疾病中的研究进展

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中华生殖与避孕杂志 2020年第11期40卷 958-963页

作者：黄家语杜艳芝上海交通大学医学院附属仁济医院生殖医学中心上海市辅助生殖与优生重点实验室200135

长链非编码RNA(LncRNAs)的表达异常与许多卵泡发育异常疾病密切相关,包括多囊卵巢综合征(PCOS)和原发性卵巢功能不全(POI)等。随着对LncRNAs的深入研究,越来越多研究表明,LncRNAs在卵泡发育异常疾病中差异表达并发挥功能。研究结果显示L... 详细信息

长链非编码RNA(LncRNAs)的表达异常与许多卵泡发育异常疾病密切相关,包括多囊卵巢综合征(PCOS)和原发性卵巢功能不全(POI)等。随着对LncRNAs的深入研究,越来越多研究表明,LncRNAs在卵泡发育异常疾病中差异表达并发挥功能。研究结果显示LncRNAs可能参与女性卵泡发育、卵丘扩张、卵子成熟和黄体形成等多个过程,可能影响PCOS患者颗粒细胞的增殖、迁移和凋亡,并且参与其调控内分泌和代谢过程。本文综述了LncRNAs参与卵泡发育及相关疾病的研究,通过揭示疾病发生发展的机制,发现新的生物标志物和治疗靶点,为卵泡发育异常相关疾病的诊断和治疗提供新思路。

关键词：长链非编码RNA 多囊卵巢综合征原发性卵巢功能不全卵泡发育

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飞行器飞行大气数据传感技术发展现状与展望

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航空学报 2024年第5期45卷 202-217页

作者：熊亮张睿龙彦志西北工业大学自动化学院西安710129 成都凯天电子股份有限公司大气数据系统研究室成都610091

飞行器飞行大气数据传感技术是现代飞行器全包线飞行控制、通信导航和武器打击轨迹精确控制获取飞行大气参数测量的关键或重要途径。回顾了飞行器飞行大气数据传感技术发展历程,阐述了技术跨代发展的驱动因素和系统架构设计、压力受感... 详细信息

飞行器飞行大气数据传感技术是现代飞行器全包线飞行控制、通信导航和武器打击轨迹精确控制获取飞行大气参数测量的关键或重要途径。回顾了飞行器飞行大气数据传感技术发展历程,阐述了技术跨代发展的驱动因素和系统架构设计、压力受感与传递转换、参数解算模型设计、复杂气象环境适应性设计、系统校准与飞行验证五项关键技术解决情况,分析了现有技术的不足与缺陷,从现代飞行器发展与应用需要出发,结合工程技术研究成果,提出了飞行器飞行大气数据传感技术未来重点发展方向。

关键词：大气数据系统大气参数测量大气参数解算压力受感技术气象环境适应性

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金融集聚能有效提升县域经济韧性吗?——基于湖南省88个县(市)的空间效应分析

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湖南师范大学社会科学学报 2024年第2期53卷 88-103页

作者：谭燕芝海霞湘潭大学商学院湖南湘潭411105

面对日趋严峻的外部环境和内部新旧动能转换的冲击,县域经济韧性的提升已成为实现城乡融合可持续发展、实现乡村振兴的重要着力点。运用熵值法从抵抗力和恢复力两个方面测算了2011—2020年湖南88个县(市)的经济韧性,并采用空间杜宾模型... 详细信息

面对日趋严峻的外部环境和内部新旧动能转换的冲击,县域经济韧性的提升已成为实现城乡融合可持续发展、实现乡村振兴的重要着力点。运用熵值法从抵抗力和恢复力两个方面测算了2011—2020年湖南88个县(市)的经济韧性,并采用空间杜宾模型检验了金融集聚对县域经济韧性的影响。研究表明:县域金融资源的空间集聚对本地区的经济韧性有显著的正向直接效应,对周边地区有显著的空间溢出效应,且空间溢出效应大于直接效应;金融集聚的空间溢出效应在经济发展水平较高的县更加明显,存在显著的“效益依赖性”;金融集聚通过增加创业、激发创新提升县域经济韧性。县域金融发展应该突破区域限制,在经济发展水平较好的县设立区域性金融中心,集聚金融资源提高整体配置效率。

关键词：县域经济韧性金融集聚空间溢出效应区域差异

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