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Homologous recombination mediates stable Fah gene integration and phenotypic correction in tyrosinaemia mouse-model

World Journal of Hepatology 2018年第2期10卷 277-286页

作者： Norman Junge Qinggong Yuan Thu Huong Vu Simon Krooss Christien Bednarski Asha Balakrishnan Toni Cathomen michael P Manns Ulrich Baumann Amar Deep Sharma michael ott Department of Pediatric Gastroenterology and Hepatology Hannover Medical School Department of Gastroenterology Hepatology and Endocrinology Hannover Medical School TWINCORE Centre for Experimental and Clinical Infection Research Medical Center University of Freiburg Institute for Cell and Gene Therapy Research Group Micro RNA in Liver Regeneration Cluster of Excellence REBIRTH Hannover Medical School

AIM To stably correct tyrosinaemia in proliferating livers of fumarylacetoacetate-hydrolase knockout(Fah-/-) mice by homologous-recombination-mediated targeted addition of the Fah gene.METHODS C57 BL/6 Fah?exon5 mice served as an animal model for human tyrosinaemia type 1 in our study. The vector was created by amplifying human Fah c DNA including the TTR promoter from a lentivirus plasmid as described. The Fah expression cassette was flanked by homologous arms(620 bp and 749 bp long) of the Rosa26 gene locus. Mice were injected with 2.1 × 108 VP of this vector(r AAV8-ROSA26.HAL-TTR.FahROSA26.HAR) via the tail vein. Mice in the control group were injected with 2.1 × 108 VP of a similar vector but missing the homologous arms(r AAV8-TTR.Fah). Primary hepatocytes from Fah-/-recipient mice, treated with our vectors, were isolated and 1 × 106 hepatocytes were transplanted into secondary Fah-/-recipient mice by injection into the spleen. Upon either vector application or hepatocyte transplantation NTBC treatment was stopped in recipient mice. RESULTS Here, we report successful HR-mediated genome editing by integration of a Fah gene expression cassette into the "safe harbour locus" Rosa26 by recombinant AAV8. Both groups of mice showed long-term survival, weight gain and FAH positive clusters as determined by immunohistochemistry analysis of liver sections in the absence of NTBC treatment. In the group of C57 BL/6 Fah?exon5 mice, which have been transplanted with hepatocytes from a mouse injected with r AAV8-ROSA26.HAL-TTR.Fah-ROSA26.HAR 156 d before, 6 out of 6 mice showed long-term survival, weight gain and FAH positive clusters without need for NTBC treatment. In contrast only 1 out 5 mice, who received hepatocytes from r AAV8-TTR.Fah treated mice, survived and showed few and smaller FAH positive clusters. These results demonstrate that homologous recombinationmediated Fah gene transfer corrects the phenotype in a mouse model of human tyrosinaemia type 1(Fah-/-mice) and is long lasting in a proliferating state of the

关键词： Gene therapy AAV8 Liver based metabolic disease Targeted integration ROSA26 Paediatric liver disease

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Cell atlas of CCl_(4)-induced progressive liver fibrosis reveals stage-specific responses

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Zoological Research 2023年第3期44卷 451-466页

作者： Peng-Cheng Guo Jing Zuo Ke-Ke Huang Guang-Yao Lai Xiao Zhang Juan An Jin-Xiu Li Li Li Liang Wu Yi-Ting Lin Dong-Ye Wang Jiang-Shan Xu Shi-Jie Hao Yang Wang Rong-Hai Li Wen Ma Yu-Mo Song Chang Liu Chuan-Yu Liu Zhen Dai Yan Xu Amar Deep Sharma michael ott Qing Ou-Yang Feng Huo Rong Fan Yong-Yin Li Jin-Lin Hou Giacomo Volpe Long-Qi Liu Miguel A.Esteban Yi-Wei Lai State Key Laboratory for Zoonotic Diseases Key Laboratory for Zoonosis Research of Ministry of EducationInstitute of ZoonosisCollege of Veterinary MedicineJilin UniversityChangchunJilin 130062China BGI-Hangzhou HangzhouZhejiang 310012China BGI-Shenzhen ShenzhenGuangdong 518083China Key Laboratory of Biological Targeting Diagnosis Therapy and Rehabilitation of Guangdong Higher Education InstitutesFifth Affiliated Hospital of Guangzhou Medical UniversityGuangzhouGuangdong 510799China Laboratory of Integrative Biology Guangzhou Institutes of Biomedicine and HealthChinese Academy of SciencesGuangzhouGuangdong 510530China Joint School of Life Sciences Guangzhou Institutes of Biomedicine and Health and Guangzhou Medical UniversityGuangzhouGuangdong 510530China School of Life Sciences Division of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiAnhui 230026China College of Life Sciences University of Chinese Academy of SciencesBeijing 100049China Guangzhou Institutes of Biomedicine and Health Chinese Academy of SciencesGuangzhouGuangdong 510530China Biotherapy Centre Third Affiliated Hospital of Sun Yat-sen UniversityGuangzhouGuangdong 510630China Department of Gastroenterology Hepatology and EndocrinologyHannover Medical SchoolHannover 30625Germany Department of Hepatobiliary Surgery and Liver Transplant Center General Hospital of Southern Theater CommandGuangzhouGuangdong 510010China Department of Infectious Diseases Nanfang HospitalSouthern Medical UniversityGuangdong Provincial Key Laboratory of Viral Hepatitis ResearchGuangzhouGuangdong 510515China Hematology and Cell Therapy Unit IRCCS-Istituto Tumori‘Giovanni Paolo II’Bari 70124Italy Institute of Experimental Hematology Hannover Medical SchoolHannover 30625Germany

Chronic liver injury leads to progressive liver fibrosis and ultimately cirrhosis,a major cause of morbidity and mortality worldwide.However,there are currently no effective anti-fibrotic therapies available,especially for latestage patients,which is partly attributed to the major knowledge gap regarding liver cell heterogeneity and cellspecific responses in different fibrosis stages.To reveal the multicellular networks regulating mammalian liver fibrosis from mild to severe phenotypes,we generated a single-nucleus transcriptomic atlas encompassing 49919nuclei corresponding to all main liver cell types at different stages of murine carbon tetrachloride(CCl_(4))-induced progressive liver fibrosis.Integrative analysis distinguished the sequential responses to injury of hepatocytes,hepatic stellate cells and endothelial cells.Moreover,we reconstructed the cell-cell interactions and gene regulatory networks implicated in these processes.These integrative analyses uncovered previously overlooked aspects of hepatocyte proliferation exhaustion and disrupted pericentral metabolic functions,dysfunction for clearance by apoptosis of activated hepatic stellate cells,accumulation of pro-fibrotic signals,and the switch from an anti-angiogenic to a pro-angiogenic program during CCl_(4)-induced progressive liver fibrosis.Our dataset thus constitutes a useful resource for understanding the molecular basis of progressive liver fibrosis using a relevant animal model.

关键词： Liver fibrosis Toxicity Single-cell and single-nucleus RNA-sequencing Hepatocytes Hepatic stellate cells Angiogenesis Cell-cell interactions Gene regulatory networks

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通过沙盘作业实现储运培训

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机电信息（北京） 2001年第1期 82-84页

作者： CHRISTIAN DILLING MARTIN LEGGEWIE michael ott 德国Dortmund大学仓储和运输领域的科研专家

为了提高中小型企业在国际上的竞争能力,应当力争提高储运业的工作能力。同时必须着眼于整个储运链,首先应对操作一级的员工提出要求。这些人员的进修与培训可以采用沙盘作业技术来进行。

关键词：物流储运培训沙盘作业中小企业

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Multitarget Thiol-Activated Tetrapyridyl Gold(Ⅲ)Complexes for Hypoxic Cancer Therapy

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CCS Chemistry 2024年第3期6卷 783-797页

作者： Xue-Quan Zhou Selda Abyar Imma Carbo-Bague Lan Wang Sebastian Türck Maxime ASiegler Uttara Basu Ingo ott Rongfang Liu Adriaan PIJzerman Sylvestre Bonnet Institute of Biopharmaceutical and Health Engineering Tsinghua Shenzhen International Graduate School(SIGS)Tsinghua UniversityShenzhen 518055 Leiden Institute of Chemistry Leiden University2333 CC Leiden Department of Chemistry Simon Fraser UniversityBurnabyBritish Columbia V5A 1S6 Institute of Medicinal and Pharmaceutical Chemistry Technische Universität Braunschweig38106 Braunschweig Department of Chemistry Johns Hopkins UniversityBaltimoreMaryland 21218 Division of Drug Discovery&Safety Leiden Academic Centre for Drug ResearchLeiden University2333 CC Leiden

Gold complexes have emerged as promising anticancer metallodrugs due to their efficient thioredoxin reductase(TrxR)inhibition,which disturbs the redox balance of cancer cells.However,in this model,the role of the ligand(s)coordinated to gold is often overlooked.In this work,we present a series of tetrapyridyl Au(Ⅲ)complexes that exhibit thiol-induced release of a Au(Ⅰ)ion and a tetrapyridyl ligand.The formation of a free Au(Ⅰ)center is responsible for the expected TrxR inhibition.Additionally,the released ligand,which was visible in cells due to its intense blue fluorescence,showed excellent binding properties to the hERG potassium channel.Moreover,these ligands ended up in the lysosomes,resulting in significant lysosome damage.Altogether,the Au(Ⅲ)complexes presented in this work showed broad-spectrum anticancer properties,both in hypoxic 2D monolayers and 3D tumor spheroids.We suggest that the interaction of the released Au(Ⅰ)center and the tetrapyridyl ligand with two different protein targets may combine into prodrugs that overcome hypoxia-induced drug deactivation.

关键词： anticancer Au(Ⅲ)complexes enzyme inhibtion potassium channel affinity lysosome damage cell imaging prodrug

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Investigation of the heat distribution in dry friction systems during fade and recovery using fiber-optic sensing and infrared technology

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Friction 2022年第3期10卷 422-435页

作者： Albert ALBERS Thomas KLOTZ Chris FINK Sascha ott IPEK–Institute of Product Engineering Karlsruhe Institute of TechnologyBaden Wurttemberg 76131Germany

The design of dry-running friction pairings and systems determines not only their installation space and costs,but also their reliability under critical load conditions,for example in emergencies,in the case of faults,and in the event of misuse.While knowledge of the contact pattern is highly important for the development of clutches and brakes,the contact-related measurement of the temperature of these systems has not yet been solved in a satisfactory manner.Despite its importance,the temperature distribution has only been measured in a few studies.Typically,temperature measurements of complete clutches and brakes are carried out using thermocouples only.In this study,a new innovative test setup is presented.This setup is able to measure the heat distribution of the lining and the steel disk of a brake with high spatial resolution by means of fiber optic sensing technology and thermography.As a novelty,it enables measurement of the heat distribution and allows to correlate it with the fade and recovery behavior.Contrary to the expectations,the contact pattern is heterogeneous in circumferential direction.Possible causes are discussed using simulation results.Along with surface analysis,the new setup contributes to the investigation of the causes of fade and recovery.

关键词： dry-running clutch and brake fade and recovery high-resolution spatial temperature distribution measurement

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Multiple phenotypes in genome-wide genetic mapping studies

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Protein & Cell 2011年第7期2卷 519-522页

作者： Jurg ott Jing Wang Key Laboratory of Mental Health Institute of Psychology Chinese Academy of SciencesBeijing 100101China

For many psychiatric and other traits,diagnoses are based on a number of different criteria or phenotypes.Rather than carrying out genetic analyses on the final diagnosis,it has been suggested that relevant phenotypes should be analyzed directly.We provide an overview of statistical methods for the joint analysis of multiple phenotypes in case-control association studies.

关键词： multiple phenotypes genetic mapping case-control statistical method

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Decline of semen quality during IVF is not associated with subjective male stress

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Asian Journal of Andrology 2014年第4期16卷 597-601页

作者： Kazem Nouri Brigitte Litschauer michael Sator Denise Tiringer Johannes ott Katherina Walch Lukas A Hefler Clemens B Tempfer Department of Obstetrics and Gynecolog Department of Clinical Pharmacology Medical University of Vienna Vienna Department of Obstetrics and Gynecology Krankenhaus Barmherzige Schwestern Linz Austria Department of Obstetrics and Gynecology Ruhr University Bochum Bochum Germany.

The aim of the present study was to assess if semen quality declines during in vitro fertilization （IVF） and whether or not this phenomenon is triggered by chronic male stress. In order to test this hypothesis, we first investigated a retrospective cohort of 155 male IVF patients （testing cohort）. Subsequently, we started a prospective cohort study in men undergoing their first IVF and assessed semen quality and subjective male chronic stress using a validated tool, i.e. the Fertility Problem Inventory （FPI） questionnaire. The association between stress and sperm quality decline measured 4-6weeks before the start of IVF （T1） and at the day of oocyte retrieval （T2） was the primary outcome. Live birth rate, first trimester abortion and rate of poor responders were secondary outcomes. In the testing cohort, mean progressive motility, but not mean sperm density significantly declined. There were 78/154 （51%） men who showed a decline in semen density and 50/154 （32%） men who showed a decline in progressive motility. In the validation cohort, progressive motility declined, whereas, sperm density increased from T1 to T2. Of 78 men, 27 men had increased stress （FPI-score 〉 146）. Sperm density and progressive motility were not significantly different in men with and without stress. However, in the presence of male stress, couples had a higher rate of poor responders, miscarriages and a lower rate of live births. Subjective stress is not associated with a decline in semen quality observed during IVF but may be associated with adverse ore^nancv outcome.

关键词： in vitro fertilization questionnaire semen quality stress

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High prevalence of urinary schistosomiasis in a desert population: results from an exploratory study around the Ounianga lakes in Chad

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Infectious Diseases of Poverty 2022年第1期11卷 86-87页

作者： Wendelin Moser Annour Adoum Batil Rebekka ott Moussa Abderamane Ruth Clements Rahel Wampfler Sven Poppert Peter Steinmann Fiona Allan Helena Greter Swiss Tropical and Public Health Institute BaselSwitzerland 不详

Background Researching a water-borne disease in the middle of the Sahara desert might not seem the most relevant concern.However,nomadic Sahelian pastoralists health concerns regarding their livestock and anecdotal reports about trematode infections of Fasciola spp.and Schistosoma spp.in desert-raised animals justified an exploratory study focusing on the lakes of Ounianga in Northern Chad.The aim was to test whether trematode parasites such as Schistosoma spp.occur in human populations living around the Sahara desert lakes of Ounianga Kebir and Ounianga Serir in northern Chad.Methods The study was carried out in January 2019 and comprised of three components.First,a cross sectional survey based on a random sample drawn from the population to detect infections with S.haematobium and S.mansoni;second,focus group discussions exploring disease priorities,access to health and health seeking behaviour;and third,surveying water contact sites for intermediate host snails.Samples of trematode parasites and snails were confirmed on species level by molecular genetic methods.For parasitological and malacological surveys descriptive statistics were performed.Qualitative data analysis included the full review of all transcripts,followed by a descriptive and explorative thematic analysis.Results Among 258 participants,the overall S.haematobium prevalence using urine filtration was 39.2%[95%confidence interval(CI):33.5–45.1%],with 51.5%of the infected suffering from heavy infection.The intermediate host snail of S.haematobium(Bulinus truncatus)occurred at water contact sites near both study villages,revealing the potential for local transmission.Although a positive S.mansoni point-of-care circulating cathodic antigen(POC-CCA)test result was obtained from 8.6%(95%CI 5.7–12.8%)of the samples,no intermediate host snails of S.mansoni were found,and the relevance of S.mansoni remains uncertain.Qualitative findings underline the importance of morbidity caused by urinary schistosomiasis,and the lack of access to diagnostics and treat

关键词： Bulinus truncatus Chad Malacology Ounianga POC-CCA Prevalence Sahara Schistosoma bovis Schistosoma haematobium Schistosomiasis

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A Comparative Study of the Local Heat Transfer Distributions Around Various Surface Mounted Obstacles

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Journal of Thermal Science 2014年第2期23卷 169-176页

作者： Robert Wyssmann Dirk Ullmer Alexandros Terzis Peter ott Group of Thermal Turbomachinery(GTT) cole Polytechnique Fédérale de Lausanne (EPFL)SCI-STI-POCH-1015LausanneSwitzerland

In many engineering applications,heat transfer enhancement techniques are of vital importance in order to ensure reliable thermal designs of convective heat transfer applications.This study examines experimentally the heat transfer characteristics on the base plate around various surface mounted obstacles.Local convection coefficients are evaluated in the vicinity of each individual protruding body with great spatial resolution using the transient liquid crystal technique.Five different obstacles of constant height-to-hydraulic diameter ratio(~1.3) are considered.These include:a cylinder,a square,a triangle,a diamond and a vortex generator of delta wing shape design.The experiments were carried out over a range of freestream Reynolds numbers,based on the hydraulic diameter of each obstacle,varying from 4,000 to 13,000.The results indicate a negligible effect of the flow speed on the heat transfer topological structure and a considerable effect of the obstacle geometry on the level and distribution of heat transfer enhancement.

关键词：表面贴装强化传热技术热分布空间分辨率涡流发生器障碍物对流换热对流系数

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Eccentric error and compensation in rotationally symmetric laser triangulation

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仪器仪表学报 2007年第9期28卷 1548-1553页

作者： Wang Lei Gao Jun Wang Xiaojia Johannes Eckstein Peter ott Lab of Image Information Processing School of Computer and Information Hefei University of Technology Hefei 230009 China Optical Engineering Lab. Heilbronn University Heilbronn D-74081 Germany Dep. of Mechanical and Electrical Engineering Xiamen University Xiamen 361005 China

Rotationally symmetric triangulation(RST)sensor has more flexibility and less uncertainty limits because of the abaxial rotationally symmetric optical system.But if the incident laser is eccentric,the symmetry of the image will descend,and it will result in the eccentric error especially when some part of the imaged ring is blocked.The model of rotationally symmetric triangulation that meets the Schimpflug condition is presented in this paper.The error from eccentric incident laser is analysed.It is pointed out that the eccentric error is composed of two parts,one is a cosine in circumference and proportional to the eccentric departure factor,and the other is a much smaller quadric factor of the departure.When the ring is complete,the first error factor is zero because it is integrated in whole ring, but if some part of the ring is blocked,the first factor will be the main error.Simulation verifies the result of the a- nalysis.At last,a compensation method to the error when some part of the ring is lost is presented based on neural network.The results of experiment show that the compensation will make the absolute maximum error descend to half,and the standard deviation of error descends to 1/3.

关键词：补偿作用旋转对称激光三角测量法偏心因子视力测量神经网络

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