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Science China Life Sciences 2024年第12期67卷 2575-2586页

作者： Dexin Zhang Rui Zheng Zhoutong Chen Liren Wang Xi Chen Lei Yang Yanan Huo Shuming Yin Dan Zhang Jiaxin Huang Xingang Cui Dali Li hongquan geng Department of Urology Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine Department of Urology Children's Hospital of Fudan University Shanghai Frontiers Science Center of Genome Editing and Cell Therapy Shanghai Key Laboratory of Regulatory Biology Institute of Biomedical Sciences and School of Life Sciences East China Normal University

Primary hyperoxaluria type 1(PH1) is a severe hereditary disease, leading to the accumulation of oxalate in multiple organs, particularly the kidney. Hydroxyacid oxidase 1(HAO1), a pivotal gene involved in oxalate production, is an approved target for the treatment of PH1. In this study, we demonstrated the discovery of several novel therapeutic sites of the Hao1 gene and the efficient editing of Hao1c.290-2 A in vivo with lipid nanoparticles(LNP) delivered adenine base editing(ABE) mRNA. A single infusion of LNP-ABE resulted in a near-complete knockout of Hao1 in the liver, leading to the sustainable normalization of urinary oxalate(for at least 6 months) and complete rescue of the pathophysiology in PH1 rats. Additionally, a significant correlation between Hao1 editing efficiency and urinary oxalate levels was observed and over 60% Hao1 editing efficiency was required to achieve the normalization of urinary oxalate in PH1 rats. These findings suggest that the LNP-mediated base-editing of Hao1c.290-2 A is an efficient and safe approach to PH1 therapy, highlighting its potential utility in clinical settings.

关键词： primary hyperoxaluria type 1 lipid nanoparticles hydroxyacid oxidase 1 base editing

Enhanced genome editing to ameliorate a genetic metabolic liver disease through co-delivery of adeno-associated virus receptor

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Science China(Life Sciences) 2022年第4期65卷 718-730页

作者： Shuming Yin Lie Ma Tingting Shao Mei Zhang Yuting Guan Liren Wang Yaqiang Hu Xi Chen Honghui Han Nan Shen Wenjuan Qiu hongquan geng Yongguo Yu Shichang Li Weishi Yu Mingyao Liu Dali Li Shanghai Key Laboratory of Regulatory Biology Institute of Biomedical Sciences and School of Life SciencesEast China Normal UniversityShanghai200241China Bioray Laboratories Inc. Shanghai200241China Xinhua Hospital Shanghai Jiao Tong University School of MedicineShanghai200092China College of Physical Education and Health East China Normal UniversityShanghai200241China Key Laboratory of Adolescent Health Assessment and Exercise Intervention Ministry of EducationCollege of Physical Education and HealthEast China Normal UniversityShanghai200241China CIPHER GENE LLC Beijing100089China

Genome editing through adeno-associated viral(AAV) vectors is a promising gene therapy strategy for various diseases,especially genetic disorders. However, homologous recombination(HR) efficiency is extremely low in adult animal models. We assumed that increasing AAV transduction efficiency could increase genome editing activity, especially HR efficiency, for in vivo gene therapy. Firstly, a mouse phenylketonuria(PKU) model carrying a pathogenic R408W mutation in phenylalanine hydroxylase(Pah) was generated. Through co-delivery of the general AAV receptor(AAVR), we found that AAVR could dramatically increase AAV transduction efficiency in vitro and in vivo. Furthermore, co-delivery of SaCas9/sgRNA/donor templates with AAVR via AAV8 vectors increased indel rate over 2-fold and HR rate over 15-fold for the correction of the single mutation in Pah;mice. Moreover, AAVR co-injection successfully increased the site-specific insertion rate of a 1.4 kb Pah cDNA by 11-fold, bringing the HR rate up to 7.3% without detectable global off-target effects. Insertion of Pah cDNA significantly decreased the Phe level and ameliorated PKU symptoms. This study demonstrates a novel strategy to dramatically increase AAV transduction which substantially enhanced in vivo genome editing efficiency in adult animal models, showing clinical potential for both conventional and genome editing-based gene therapy.

关键词： CRISPR/Cas9 gene therapy adeno-associated virus(AAV) AAVR Pah PKU

Increasing targeting scope of adenosine base editors in mouse and rat embryos through fusion of TadA deaminase with Cas9 variants

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Protein & Cell 2018年第9期9卷 814-819页

作者： Lei Yang Xiaohui Zhang Liren Wang Shuming Yin Biyun Zhu Ling Xie Qiuhui Duan Huiqiong Hu Rui Zheng Yu Wei Liangyue Peng Honghui Han Jiqin Zhang Wenjuan Qiu hongquan geng Stefan Siwko Xueli Zhang Mingyao Liu Dali Li East China Normal University and Shanghai Fengxian DistrictCentral Hospital Joint Center for Translational Medicine ShanghaiKey Laboratory of Regulatory Biology School of Life SciencesEast China Normal University Shanghai 200241 China Fengxian Hospital Affiliated to Southern Medical University Shanghai 201499 China Xinhua Hospital Shanghai Jiao Tong University School ofMedicine Shanghai 200092 China School of Life Sciences Hunan Normal University Changsha 410081 China Bioray Laboratories Inc. Shanghai 200241 China Department of Molecular and Cellular Medicine The Institute of Biosciences and Technology Texas AM University Health Science Center Houston TX 77030 USA

Dear Editor, The clustered regularly interspaced short palindromic repeat （CRISPR） system has been widely adapted to genome editing to either introduce or correct genetic mutations （Wang et al., 2016）. However, due to competition with the dominant non-homologous end-joining （NHEJ） pathway, precise genome modifications through Cas9-stimulated homologous recombination （HR） is inefficient. Through fusion of cytidine deaminases, APOBEC1 （apolipoprotein B editing complex 1） or AID （activation-induced deaminase）, with Cas9 variants, several groups have developed the cytidine base editor （BE） systems （Komor et al., 2016; Li et al., 2018; Nishida et al., 2016）. The BE system achieves programmable conversion of C-G base pairs to T.A without double-stranded DNA cleavage （Zhou et al., 2017）. More recently, adenine base editors （ABEs）, which efficiently convert A-T base pairs to G-C in genomic DNA, have been developed via fusion of an engineered tRNA adenosine deaminase （ecTadA from Escherichia coh） with nCas9 （Gaudelli et al., 2017）. The ABE system has quickly been adapted to generate disease models and correction of genetic disease in mice （Ryu et al., 2017; Liu et al, 2018）. However, whether the editing efficiency and the targeting scope of ABE could be improved is largely unexplored. In this study, we describe the efficient generation of base-edi- ted mice and rats modeling human diseases through ABEs with highest efficiency up to 100%. We also demonstrate an increase of ABE activity through injection of chemically modified tracrRNA and crRNA in mouse zygotes, and the expansion of editing scope by fusion of an ecTadA mutant to SaCas9n-KKH and Casgn-VQR variants in both cells and embryos. Our study suggests that the ABE system is a powerful and convenient tool to introduce precise base conversions in rodents.

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单根输尿管膀胱再植术与输尿管端侧吻合术治疗小儿输尿管重复畸形的疗效对比研究

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临床小儿外科杂志 2022年第4期21卷 341-346页

作者：王锦斌方晓亮陈周彤耿红全上海交通大学医学院附属新华医院小儿泌尿外科上海200082 山东省青岛妇女儿童医院小儿泌尿外科青岛266034

目的比较单根输尿管膀胱再植术与输尿管端侧吻合术治疗小儿输尿管重复畸形的安全性与疗效。方法回顾性分析2010年1月至2018年12月上海交通大学医学院附属新华医院收治的采用单根输尿管膀胱再植术与输尿管端侧吻合术治疗的小儿输尿管重... 详细信息

目的比较单根输尿管膀胱再植术与输尿管端侧吻合术治疗小儿输尿管重复畸形的安全性与疗效。方法回顾性分析2010年1月至2018年12月上海交通大学医学院附属新华医院收治的采用单根输尿管膀胱再植术与输尿管端侧吻合术治疗的小儿输尿管重复畸形患儿临床资料。共92例患儿,其中实施单根输尿管膀胱再植术42例,为单根输尿管膀胱再植术组,输尿管端侧吻合术50例,为输尿管端侧吻合术组。比较两组手术时间、术后住院天数、患侧肾盂前后径、患侧输尿管直径、患肾分肾功能、术后并发症等情况。结果单根输尿管膀胱再植术组手术时间显著少于输尿管端侧吻合术组(Z=-2.28,P=0.023),置入输尿管支架管病例数多于输尿管端侧吻合术组(χ^(2)=26.799,P<0.0001)。两组术后平均住院时间差异无统计学意义(Z=-1.639,P=0.101)。单根输尿管膀胱再植术组出现远期并发症2例(尿路感染、吻合口狭窄各1例),输尿管端侧吻合术组出现远期并发症4例(吻合口狭窄2例、尿路感染和膀胱输尿管反流各1例),差异无统计学意义(χ^(2)=0.041,P=0.839)。两组手术前后患肾部肾盂前后径、输尿管直径、分肾功能均有显著改善,手术前后患肾部肾盂前后径改善值ΔAPD(t=0.021,P=0.983)、分肾功能改善值ΔDRF(Z=-1.859,P=0.063)差异无统计学意义,两组手术前后患侧输尿管直径改善值ΔUD(t=2.697,P=0.008)差异有统计学意义。结论单根输尿管膀胱再植术和输尿管端侧吻合术治疗小儿输尿管重复畸形均安全、有效。输尿管端侧吻合术不涉及膀胱,导管相关并发症更少。

关键词：输尿管膀胱再植输尿管-输尿管吻合肾重复畸形输尿管重复畸形外科手术/方法治疗结果

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肾积水患儿的肾功能评估与结局预判

临床小儿外科杂志 2020年第3期19卷 193-198页

作者：张君颀耿红全上海交通大学医学院附属新华医院小儿泌尿外科上海市200092

儿童肾积水目前的诊疗方案以保守观察为主,出现明确手术指征的肾积水患儿才进行手术治疗。然而,该诊疗方案历经几十年仍存在争议,各项检查对梗阻和肾功能受损的诊断能力、手术干预的指征和时机等问题尚未达成共识。目前肾积水的主要检... 详细信息

儿童肾积水目前的诊疗方案以保守观察为主,出现明确手术指征的肾积水患儿才进行手术治疗。然而,该诊疗方案历经几十年仍存在争议,各项检查对梗阻和肾功能受损的诊断能力、手术干预的指征和时机等问题尚未达成共识。目前肾积水的主要检查手段包括超声、同位素肾图、核磁共振等。基于对患者数据的观察分析得出的临界值、比值、分级和积分系统有助于判断哪些先天性肾盂输尿管连接部梗阻(ureteropelvic junction obstruction,UPJO)情况需要手术,而哪些可以继续观察随访;目前没有哪一项指标在诊断的敏感度和特异度上占据绝对优势。机器学习等较新的数据分析方法也正在被应用于肾积水的诊断,帮助提高超声和肾动态显像的诊断价值。此外,对尿液生物标志物诊断价值的探索工作也正在开展。本文将总结儿童肾积水的诊断方法在肾功能评估和结局预测中的价值,并对其最新进展进行评述。

关键词：肾积水肾盂输尿管连接部梗阻超声检查利尿肾图磁共振成像

后尿道瓣膜中pop-off现象对肾脏功能的长期保护作用

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中华小儿外科杂志 2014年第9期35卷 666-670页

作者：徐国锋耿红全林厚维方晓亮徐卯升上海交通大学医学院附属新华医院小儿科上海200092

目的探讨后尿道瓣膜病例中pop-off现象对肾脏功能的长期保护作用。方法回顾性分析2003年1月至2013年12月确诊为后尿道瓣膜且年龄小于3个月，并获长期随访的24例患儿的临床资料。根据患儿有、无pop-off现象分为pop-off组（7例）和无pop-... 详细信息

目的探讨后尿道瓣膜病例中pop-off现象对肾脏功能的长期保护作用。方法回顾性分析2003年1月至2013年12月确诊为后尿道瓣膜且年龄小于3个月，并获长期随访的24例患儿的临床资料。根据患儿有、无pop-off现象分为pop-off组（7例）和无pop-off组（17例）。分析病史及随访中的血肌酐值、放射性核素肾图、排泄性膀胱尿道造影（VCUG）、尿动力学结果。通过比较pop-off组和无pop-off组后尿道瓣膜患儿的血清肌酐值，来评价肾脏功能情况。膀胱功能通过临床症状和尿动力学结果进行评价。结果pop-off组人院、出院、术后第2年的血肌酐值分别为（28.6±9.0）／μmol／L、（29.4±7.7）μmol／L和（27.7±5.4）／μmol／L，无pop-off组人院、出院、术后第2年的血肌酐值分别为（62.3±44.3）μmol／L、（34.1±9.8）μmol／L和（28.2±6.5）μmol／L，两组入院时血清肌酐值比较，差异有统计学意义（P〈0.05），出院和术后第2年的血清肌酐值差异无统计学意义（P〉0.05）。pop-off组病例中没有出现肾功能不全及衰竭情况；无pop-off组有1例随访中肾功能严重受损需要透析，1例死于尿毒症并发症。pop-off组无尿失禁、尿储留；无pop-off组有3例有尿储留，需要清洁导尿和夜间留置导尿，另1例尿失禁经药物和导尿治疗后膀胱功能无改善需要行膀胱扩大术。尿动力学检查结果显示，pop-off组最大逼尿肌收缩压（***）、最大膀胱容量（MBC）分别为（86.1±20.4）ml和（78.2±18.2）ml，无pop-off组分别为（67.5±16.8）ml和（92.4±13.3）ml，两组间比较***、MBC的差异有统计学意义（P〈O.05）。结论Pop-off机制通过牺牲一侧肾脏保护另一侧肾脏功能以及尿液外渗等自行减压方式来降低尿路的压力，保护了膀胱的功能以及肾脏的长期预后。

关键词：尿道梗阻肾膀胱放射性核素显像尿动力学

A promising approach for quantifying focal stroke modeling and assessing stroke progression:optical resolution photoacoustic microscopy photothrombosis

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Neural Regeneration Research 2025年第7期20卷 2029-2037页

作者： Xiao Liang Xingping Quan Xiaorui geng Yujing Huang Yonghua Zhao Lei Xi Zhen Yuan Ping Wang Bin Liu Faculty of Health Sciences University of MacaoMacao Special Administrative RegionChina Center for Cognitive and Brain Sciences University of MacaoMacao Special Administrative RegionChina Department of Biomedical Engineering Southern University of Science and TechnologyShenzhenGuangdong ProvinceChina State Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical SciencesUniversity of MacaoTaipaMacao Special Administrative RegionChina Department of Emergency Zhujiang HospitalSouthern Medical UniversityGuangzhouGuangdong ProvinceChina

To investigate the mechanisms underlying the onset and progression of ischemic stroke,some methods have been proposed that can simultaneously monitor and create embolisms in the animal cerebral ***,these methods often require complex systems and the effect of age on cerebral embolism has not been adequately studied,although ischemic stroke is strongly *** this study,we propose an optical-resolution photoacoustic microscopy-based visualized photothrombosis methodology to create and monitor ischemic stroke in mice simultaneously using a 532 nm pulsed *** observed the molding process in mice of different ages and presented age-dependent vascular embolism ***,we integrated optical coherence tomography angiography to investigate age-associated trends in cerebrovascular variability following a *** imaging data and quantitative analyses underscore the differential cerebrovascular responses to stroke in mice of different ages,thereby highlighting the technique's potential for evaluating cerebrovascular health and unraveling age-related mechanisms involved in ischemic strokes.

关键词： age-dependent cerebral cortex ischemic stroke mouse model optical coherence tomography angiography photoacoustic microscopy photothrombosis vascular imaging

Crystallization Modulation and Holistic Passivation Enables Efficient Two‑Terminal Perovskite/CuIn(Ga)Se_(2)Tandem Solar Cells

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Nano-Micro Letters 2025年第1期17卷 205-215页

作者： Cong geng Kuanxiang Zhang Changhua Wang Chung Hsien Wu Jiwen Jiang Fei Long Liyuan Han Qifeng Han Yi‑Bing Cheng Yong Peng State Key Laboratory of Advanced Technology for Materials Synthesis and Processing Wuhan University of TechnologyWuhan 430070People’s Republic of China Triumph Photovoltaic Materials Co. Ltd.No.1001 Yannan AvenueHigh‑Tech Development DistrictBengbuAnhui 233000People’s Republic of China College of Materials Science and Engineering Guilin University of TechnologyGuilin 541004People’s Republic of China State Key Laboratory of Metal Matrix Composites Shanghai Jiao Tong UniversityShanghai 200240People’s Republic of China

Two-terminal(2-T)perovskite(PVK)/CuIn(Ga)Se_(2)(CIGS)tandem solar cells(TSCs)have been considered as an ideal tandem cell because of their best bandgap matching regarding to Shockley–Queisser(S–Q)***,the nature of the irregular rough morphology of commercial CIGS prevents people from improving tandem device *** this paper,D-homoserine lactone hydrochloride is proven to improve coverage of PVK materials on irregular rough CIGS surfaces and also passivate bulk defects by modulating the growth of PVK *** addition,the minority carriers near the PVK/C60 interface and the incompletely passivated trap states caused interface recombination.A surface reconstruction with 2-thiopheneethylammonium iodide and N,N-dimethylformamide assisted passivates the defect sites located at the surface and grain ***,LiF is used to create this field effect,repelling hole carriers away from the PVK and C60 interface and thus reducing *** a result,a 2-T PVK/CIGS tandem yielded a power conversion efficiency of 24.6%(0.16 cm^(2)),one of the highest results for 2-T PVK/CIGS TSCs to our *** validation underscores the potential of our methodology in achieving superior performance in PVK/CIGS tandem solar cells.

关键词： PVK/CIGS TSCs Irregular rough surfaces Modulating the growth PVK/C60 interface recombination

A Flexible Smart Healthcare Platform Conjugated with Artificial Epidermis Assembled by Three‑Dimensionally Conductive MOF Network for Gas and Pressure Sensing

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Nano-Micro Letters 2025年第2期17卷 601-620页

作者： Qingqing Zhou Qihang Ding Zixun geng Chencheng Hu Long Yang Zitong Kan Biao Dong Miae Won Hongwei Song Lin Xu Jong Seung Kim State Key Laboratory of Integrated Optoelectronics College of Electronic Science and EngineeringJilin UniversityChangchun 130012People’s Republic of China Department of Chemistry Korea UniversitySeoul 02841Republic of Korea TheranoChem Incorporation Seoul 02856Republic of Korea

The rising flexible and intelligent electronics greatly facilitate the noninvasive and timely tracking of physiological information in telemedicine *** building bionic-sensitive moieties is vital for designing efficient electronic skin with advanced cognitive functionalities to pluralistically capture external ***,realistic mimesis,both in the skin’s three-dimensional interlocked hierarchical structures and synchronous encoding multistimuli information capacities,remains a challenging yet vital need for simplifying the design of flexible logic ***,we construct an artificial epidermal device by in situ growing Cu_(3)(HHTP)_(2) particles onto the hollow spherical Ti_(3)C_(2)T_(x) surface,aiming to concurrently emulate the spinous and granular layers of the skin’s *** bionic Ti_(3)C_(2)T_(x)@Cu_(3)(HHTP)_(2) exhibits independent NO_(2) and pressure response,as well as novel functionalities such as acoustic signature perception and Morse code-encrypted message ***,a wearable alarming system with a mobile application terminal is self-developed by integrating the bimodular senor into flexible printed *** system can assess risk factors related with asthmatic,such as stimulation of external NO_(2) gas,abnormal expiratory behavior and exertion degrees of fingers,achieving a recognition accuracy of 97.6%as assisted by a machine learning *** work provides a feasible routine to develop intelligent multifunctional healthcare equipment for burgeoning transformative telemedicine diagnosis.

关键词： Ti_(3)C_(2)T_(x)@Cu_(3)(HHTP)_(2)composites NO_(2)/pressure flexible sensors Health-monitoring Machine learning

Repetitive transcranial magnetic stimulation in Alzheimer’s disease:effects on neural and synaptic rehabilitation

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Neural Regeneration Research 2025年第2期20卷 326-342页

作者： Yi Ji Chaoyi Yang Xuerui Pang Yibing Yan Yue Wu Zhi geng Wenjie Hu Panpan Hu Xingqi Wu Kai Wang Department of Neurology The First Affiliated Hospital of Anhui Medical UniversityHefeiAnhui ProvinceChina Anhui Province Key Laboratory of Cognition and Neuropsychiatric Disorders HefeiAnhui ProvinceChina Collaborative Innovation Center of Neuropsychiatric Disorders and Mental Health HefeiAnhui ProvinceChina Institute of Artificial Intelligence Hefei Comprehensive National Science CenterHefeiAnhui ProvinceChina Department of Psychology and Sleep Medicine The Second Affiliated Hospital of Anhui Medical UniversityHefeiAnhui ProvinceChina

Alzheimer’s disease is a neurodegenerative disease resulting from deficits in synaptic transmission and *** Alzheimer’s disease brain tends to be hyperexcitable and hypersynchronized,thereby causing neurodegeneration and ultimately disrupting the operational abilities in daily life,leaving patients *** transcranial magnetic stimulation is a cost-effective,neuro-modulatory technique used for multiple neurological *** the past two decades,it has been widely used to predict cognitive decline;identify pathophysiological markers;promote neuroplasticity;and assess brain excitability,plasticity,and *** has also been applied to patients with dementia,because it can yield facilitatory effects on cognition and promote brain recovery after a neurological ***,its therapeutic effectiveness at the molecular and synaptic levels has not been elucidated because of a limited number of *** study aimed to characterize the neurobiological changes following repetitive transcranial magnetic stimulation treatment,evaluate its effects on synaptic plasticity,and identify the associated *** review essentially focuses on changes in the pathology,amyloidogenesis,and clearance pathways,given that amyloid deposition is a major hypothesis in the pathogenesis of Alzheimer’s *** mechanisms associated with repetitive transcranial magnetic stimulation procedures and different pathways mediating gene transcription,which are closely related to the neural regeneration process,are also ***,we discuss the outcomes of animal studies in which neuroplasticity is modulated and assessed at the structural and functional levels by using repetitive transcranial magnetic stimulation,with the aim to highlight future directions for better clinical translations.

关键词： Alzheimer’s disease amyloid deposition apoptotic mechanisms biomarker neural regeneration neurodegeneration repetitive transcranial magnetic stimulation synaptic plasticity