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

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 ***,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 *** 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 *** analysis distinguished the sequential responses to injury of hepatocytes,hepatic stellate cells and endothelial ***,we reconstructed the cell-cell interactions and gene regulatory networks implicated in 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 *** 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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Recent advances in targeting the“undruggable”proteins:from drugdiscover to clinical trials

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Signal Transduction and Targeted Therapy 2023年第10期8卷 4477-4547页

作者： Xin Xie Tingting yu Xiang Li Nan Zhang Leonard J.Foster Cheng Peng Wei Huang Gu He State Key Laboratory of Southwestern Chinese Medicine Resources College of Medical Technology and School of PharmacyChengdu University of Traditional Chinese Medicine611137 ChengduChina michael Smith Laboratories University of British ColumbiaVancouverBC V6T 1Z4Canada Department of Dermatology and State Key Laboratory of Biotherapy West China HospitalSichuan University610041 ChengduChina

Undruggable proteins are a class of proteins that are often characterized by large,complex structures or functions that are diffcult to interfere with using conventional drug design *** such undruggable targets has been considered also a great opportunity for treatment of human diseases and has attracted substantial efforts in the field of ***,in this review,we focus on the recent development of drug discovery targeting"undruggable"proteins and their application in *** make this review well organized,we discuss the design strategies targeting the undruggable proteins,including covalent regulation,allosteric inhibition,protein-protein/DNA interaction inhibition,targeted proteins regulation,nucleic acid-based approach,immunotherapy and others.

关键词： drug diseases clinical

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Retinoic acid signaling acts as a rheostat to balance Treg function

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Cellular & Molecular Immunology 2022年第7期19卷 820-833页

作者： Govindarajan Thangavelu Gabriela Andrejeva Sara Bolivar-Wagers Sujeong Jin michael C.Zaiken michael Loschi Ethan G.Aguilar Scott N.Furlan Chrysothemis C.Brown yu-Chi Lee Cameron McDonald Hyman Colby J.Feser Angela Panoskaltsis-Mortari Keli L.Hippen Kelli P.MacDonald William J.Murphy Ivan Maillard Geoffrey R.Hill David H.Munn Robert Zeiser Leslie S.Kean Jeffrey C.Rathmell Hongbo Chi Randolph J.Noelle Bruce R.Blazar Department of Pediatrics Center for ImmunologyUniversity of MinnesotaMinneapolisMNUSA Center for Immunobiology Vanderbilt University Medical CenterNashville TNUSA Department of Pediatrics University of WashingtonSeattleWAUSA Fred Hutchinson Cancer Research Center SeattleWAUSA Howard Hughes Medical Institute Immunology Program and Ludwig CenterSloan Kettering InstituteMemorial Sloan Kettering Cancer CenterNew YorkNYUSA Department of Microbiology and Immunology.Geisel School of Medicine at Dartmouth Norris Cotton Cancer CenterLebanonUSA Department of Immunology Queensland Institute of Medical Research(QIMR)Berghofer Medical Research Institute and School of MedicineUniversity of QueenslandBrisbaneQLDAustralia Departmentof Dermatology School of MedicineUniversity of California DavisSacramentoCAUSA Division of Hematology/Oncology Department of MedicineUniversity of Pennsylvania Perelman School of MedicinePhiladelphiaPAUSA Georgia Cancer Center Augusta UniversityAugustaGAUSA Department of Haematology Oncology and Stem Cell TransplantationFaculty of MedicineFreiburg University Medical CentreFreiburgGermany Boston Children's Hospital and the Dana-Farber Cancer Institute BostonMAUSA Department of Immunology St.Jude Children's ResearchHospitalMemphisTNUSA

Regulatory T cells(Tregs)promote immune homeostasis by maintaining self-tolerance and regulating inflammatory *** certain inflammatory conditions,Tregs can lose their lineage stability and *** studies have reported that ex vivo exposure to retinoic acid(RA)enhances Treg function and ***,it is unknown how RA receptor signaling in Tregs influences these processes in ***,we employed mouse models in which RA signaling is silenced by the expression of the dominant negative receptor(DN)RARαin all T *** the fact that DNRARαconventional T cells are hypofunctional,Tregs had increased CD25 expression,STAT5 pathway activation,mTORC1 signaling and supersuppressor ***,DNRARαTregs had increased inhibitory molecule expression,amino acid transporter expression,and metabolic fitness and decreased antiapoptotic *** function was observed when wild-type mice were treated with a pharmacologic pan-RAR ***,Treg-specific expression of DNRARαresulted in distinct phenotypes,such that a single allele of DNRARαin Tregs heightened their suppressive function,and biallelic expression led to loss of suppression and *** loss of Treg function was not cell intrinsic,as Tregs that developed in a noninflammatory milieu in chimeric mice reconstituted with DNRARαand wild-type bone marrow maintained the enhanced suppressive *** mapping suggested that maintaining Treg stability in an inflammatory milieu requires RA *** findings indicate that RA signaling acts as a rheostat to balance Treg function in inflammatory and noninflammatory conditions in a dose-dependent manner.

关键词： Retinoic acid Tregulatory cells Autoimmunity Metabolism mTORC1 STAT5

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Lack of association between lysyl oxidase-like 1 polymorphisms and primary open angle glaucoma: a meta-analysis

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International Journal of Ophthalmology(English edition) 2014年第3期7卷 550-556页

作者： Wen Sun Yan Sheng yu Weng Chun-Xiao Xu Susan E.I.Williams yu-Tao Liu michael A.Hauser R.Rand Allingham Ming-Juan Jin Guang-Di Chen Department of Ophthalmology the First Affiliated HospitalZhejiang University School of Medicine Department of Clinical Laboratory Sir Run Run Shaw Hospital Zhejiang University School of Medicine Department of Public Health Zhejiang University School of Medicine Division of Ophthalmology Department of NeurosciencesUniversity of the Witwatersrand Center for Human Genetics Duke University Medical Center Durham North Carolina 27710 USA Department of Ophthalmology Duke University Eye CenterDurham North Carolina 27710 USA

AIM:To study the associations between lysyl oxidaselike 1(LOXL1)polymorphisms and primary open angle glaucoma(POAG)remain *** this study,we have performed a meta-analysis to investigate the association of LOXL1 polymorphisms with POAG ***:Published literature from PubMed and other databases were *** studies evaluating the association between LOXL1 polymorphisms(rs2165241,rs1048661,rs3825942)and POAG risk were *** odds ratio(OR)and 95%confidence interval(CI)were calculated using random-or fixed-effects ***:Twelve studies were identified as eligible articles,with thirteen(2098 cases and 16 473 controls),thirteen(1795 cases and 2916 controls)and sixteen population cohorts(2456 cases and 2846 controls)for the association of rs2165241,rs1048661 and rs3825942with POAG risk *** analyses showed noassociation between each LOXL1 polymorphism and POAG risk,and the negative associations were remained when the subjects were stratified as Caucasian and *** heterozygote of rs2165241 was associated with reduced POAG risk in hospital-based populations(TC vs CC:OR,0.79,95%CI:0.63-0.99),and rs1048661was associated with increased POAG risk in hospitalbased populations in a dominant model(TT vs CC+CT:OR,1.23,95%CI:1.01-1.50);however,these associations were not found in population-based ***:This meta-analysis suggests that LOXL1 polymorphisms are not associated with POAG *** the limited sample size,the associations of LOXL1 polymorphisms with POAG risk in hospital-based populations await further investigation.

关键词： glaucoma gene polymorphism metaanalysis lysyl oxidase-like 1

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Circular smooth muscle contributes to esophageal shortening during peristalsis

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World Journal of Gastroenterology 2012年第32期18卷 4317-4322页

作者： Anil K Vegesna Keng-yu Chuang Ramashesai Besetty Steven J Phillips Alan S Braverman Mary F Barbe michael R Ruggieri Larry S Miller Department of Medicine Section of GastroenterologyHofstra Northshore Long Island Jewish HospitalHofstra University School of MedicineManhassetNY 11030United States Department of Medicine Section of GastroenterologyTemple University School of MedicinePhiladelphiaPA 19140United States Department of Anatomy and Cell Biology Temple University School of MedicinePhiladelphiaPA 19140United States Department of Urology Temple University School of MedicinePhiladelphiaPA 19140United States Department of Anatomy and Cell Biology and Department of Urology Temple University School of MedicinePhiladelphiaPA 19140United States

AIM:To study the angle between the circular smooth muscle(CSM) and longitudinal smooth muscle(LSM) fibers in the distal ***:In order to identify possible mechanisms for greater shortening in the distal compared to proximal esophagus during peristalsis,the angles between the LSM and CSM layers were measured in 9 *** outer longitudinal layer of the muscularis propria was exposed after stripping the outer *** inner circular layer of the muscularis propria was then revealed after dissection of the esophageal mucosa and the underlying muscularis *** of each specimen were taken with half of the open esophagus folded back showing both the outer longitudinal and inner circular muscle *** were measured every one cm for 10 cm proximal to the squamocolumnar junction(SCJ) by two independent *** human esophagi were obtained from organ transplant donors and the angles between the circular and longitudinal smooth muscle layers were measured using micro-computed tomography(micro CT) and Image J ***:All data are presented as mean ± *** CSM to LSM angle at the SCJ and 1 cm proximal to SCJ on the autopsy specimens was 69.3 ± 4.62 degrees vs 74.9 ± 3.09 degrees,P = *** CSM to LSM angle at SCJ were statistically significantly lower than at 2,3,4 and 5 cm proximal to the SCJ,69.3 ± 4.62 degrees vs 82.58 ± 1.34 degrees,84.04 ± 1.64 degrees,84.87 ± 1.04 degrees and 83.72 ± 1.42 degrees,P = 0.013,P = 0.008,P = 0.004,P = 0.009 *** CSM to LSM angle at SCJ was also statistically significantly lower than the angles at 6,7 and 8 cm proximal to the SCJ,69.3 ± 4.62 degrees vs 80.18 ± 2.09 degrees,81.81 ± 1.75 degrees and 80.96 ± 2.04 degrees,P = 0.05,P = 0.02,P = 0.03 *** CSM to LSM angle at 1 cm proximal to SCJ was statistically significantly lower than at 3,4 and 5 cm proximal to the SCJ,74.94 ± 3.09 degrees vs 84.04 ± 1.64 degrees,84.87 ± 1.04 degrees and 83.72 ± 1.42 degrees,P =

关键词：平滑肌食管蠕动计算机断层扫描圆形 CSM LSM 角度测量

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scDPN for High-throughput Single-cell CNV Detection to Uncover Clonal Evolution During HCC Recurrence

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Genomics, Proteomics & Bioinformatics 2021年第3期19卷 346-357页

作者： Liang Wu Miaomiao Jiang yuzhou Wang Biaofeng Zhou yunfan Sun Kaiqian Zhou Jiarui Xie yu Zhong Zhikun Zhao michael Dean Yong Hou Shiping Liu BGI Education Center University of Chinese Academy of SciencesShenzhen 518083China BGI-Shenzhen Beishan Industrial ZoneShenzhen 518083China Shenzhen Key Laboratory of Single-Cell Omics BGI-ShenzhenShenzhen 518100China Department of Liver Surgery&Transplantation Liver Cancer InstituteZhongshan HospitalFudan UniversityMOE Key Laboratory of Carcinogenesis and Cancer InvasionShanghai 200032China School of Biology and Biological Engineering South China University of TechnologyGuangzhou 510640China Laboratory of Translational Genomics Division of Cancer Epidemiology&GeneticsNational Cancer InstituteGaithersburgMD 20877USA

Single-cell genomics provides substantial resources for dissecting cellular heterogeneity and cancer ***,classical DNA amplification-based methods have low throughput and introduce coverage bias during sample *** developed a single-cell DNA library preparation method without preamplification in nanolitre scale(scDPN)to address these *** method achieved a throughput of up to 1800 cells per run for copy number variation(CNV)***,our approach demonstrated a lower level of amplification bias and noise than the multiple displacement amplification(MDA)method and showed high sensitivity and accuracy for cell line and tumor tissue *** used this approach to profile the tumor clones in paired primary and relapsed tumor samples of hepatocellular carcinoma(HCC).We identified three clonal subpopulations with a multitude of aneuploid alterations across the ***,we observed that a minor clone of the primary tumor containing additional alterations in chromosomes 1q,10q,and 14q developed into the dominant clone in the recurrent tumor,indicating clonal selection during recurrence in ***,this approach provides a comprehensive and scalable solution to understand genome heterogeneity and evolution.

关键词： Single-cell sequencing Hepatocellular carcinoma Heterogeneity Clonal evolution Relapse

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Novel strategies for the biocontrol of noctuid pests(Lepidoptera)based on improving ascovirus infectivity using Bacillus thuringiensis

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Insect Science 2021年第5期28卷 1452-1467页

作者： Huan yu Chang-Jin Yang Ni Li Ying Zhao Zhuang-Mei Chen Si-Jia Yi Zi-Qi Li michael J.Adang Guo-Hua Huang Hunan Provincial Key Laboratory for Biology and Control of Plant Diseases and Insect Pests Hunan Agricultural UniversityChangshaHunan410128China College of Plant Protection Hunan Agricultural UniversityChangshaHunan410128China Department of Entomology University of GeorgiaAthensGA30602USA

ldentifying novel biocontrol agents and developing new strategies are urgent goals in insect pest *** are potential competent insect viruses that may be developed into bioinsecticides,but this aim is impeded by their poor oral *** improve the per os infectivity of ascovirus,Bacillus thuringiensis kurstaki(Btk)was employed as a helper to damage the midgut of lepidopteran larvae(Helicoverpa armigera,Mythimna separata,Spodoptera frugiperda,and ***)in formulations with Heliothis virescens ascovirus isolates(HvAV-3h and HvAV-3j).Btk and ascovirus mixtures(Btk/HvAV-3h and B1k/HvAV-3j)were fed to insect larvae(3rd instar).With the exception of *** larvae,which exhibited low mortality after ingesting Btk,the larvae of the other tested species showed three types of response to feeding on the formulas:type I,the tested larvae(***)were killed by Btk infection so quickly that insufficient time and resources remained for ascoviral invasion;type II,both Btk and the ascovirus were depleted by their competition,such that neither was successfully released or colonized the tissue;type II,Btk was eliminated by the ascovirus,and the ascovirus achieved systemic infection in the tested *** feeding of Btk/ascovirus formulas led to a great reduction in larval diet consumption and resulted in a significant decrease in the emergence rate of ***,***,and *** larvae,which suggested that the formulas exerted marked oral control effects on both the contemporary individuals and the next generation of these tested pest species.

关键词： ascovirus Bacillus thuringiensis formulation Heliothis virescens ascovirus 3h(HvAV-3h) Heliothis virescens ascovirus 3j(HvAV-3j) per os infectivity

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Yes-associated protein contributes to magnesium alloy-derivedinflammation in endothelial cells

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Regenerative Biomaterials 2022年第1期9卷 130-142页

作者： Hongchi yu Zhe Hou Nuoya Chen Rifang Luo Li Yang michael Miao Xiaoyi Ma Lifeng Zhou Fugui He Yang Shen Xiaoheng Liu yunbing Wang National Engineering Research Center for Biomaterials Sichuan UniversityChengdu 610065China Institute of Biomedical Engineering West China School of Basic Medical Sciences&Forensic MedicineSichuan UniversityChengdu 610041China Division of Oral&Craniofacial Health Sciences University of North Carolina Adams School of DentistryChapel HillNC 27599USA Beijing Key Laboratory of Cardiac Drug Device Technology and Evidence Based Medicine Beijing 100021China

Magnesium alloy(Mg alloy)has attracted massive attention in the potential applications of cardiovascular stents because of its good biocompatibility and ***,whether and how the Mg alloy induces inflammation in endothelial cells remains *** the present work,we investigated the activation of Yes-associated protein(YAP)upon Mg alloy stimuli and unveiled the transcriptional function in Mg alloy-induced *** RT–PCR,western blotting and immunofluorescence staining showed that Mg alloy inhibited the Hippo pathway to facilitate nuclear shuttling and activation of YAP in human coronary artery endothelial cells(HCAECs).Chromatin immunoprecipitation followed sequencing was carried out to explore the transcriptional function of YAP in Mg alloy-derived *** led to the observation that nuclear YAP further bonded to the promoter region of inflammation transcription factors and co-transcription *** binding event activated their transcription and modified mRNA methylation of inflammation-related genes through regulating the expression of N6-methyladenosine modulators(METTL3,METTL14,FTO and WTAP).This then promoted inflammation-related gene expression and aggravated inflammation in *** YAP deficiency cells,Mg alloy-induced inflammation was ***,our data suggest that YAP contributes to the Mg alloy-derived inflammation in HCAECs and may provide a potential therapeutic target that alleviates inflammation after Mg alloy stent implantation.

关键词： magnesium alloy Yes-associated protein inflammation

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Indoor Allergen Levels and Household Distributions in Nine Cities Across China

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Biomedical and Environmental Sciences 2015年第10期28卷 709-717页

作者： ZHENG Yi Wu LAI Xu Xin ZHAO De yu ZHANG Chun Qing CHEN Jian Jun ZHANG Luo WEI Qing yu CHEN Shi LIU En Mei NORBACK Dan GJESING Birgitte ZHONG Nan Shan SPANGFORT D.michael Research Asia Pacific ALK Department of Respiratory Medicine the Affiliated Children's Hospital of Nanjing Medical University State Key Laboratory of Respiratory Disease the First Affiliated HospitalGuangzhou Medical University ENT Department of Wuhan Union Hospital ENT Department of Beijing Tongren Hospital Allergology Department of Shenyang 202 Hospital Asthmatic Children's Immunotherapy Center of People's Hospital of Hainan Province Respiratory Department Children's Hospital of Chongqing Medical University Department of Medical Science and Occupational and Environmental Medicine University HospitalUppsala University

Objective Chinese allergic subjects have high levels of sensitization to house dust mite （HDM） and other indoor allergens. This study quantifies common indoor allergen levels in Chinese households. Methods Dust samples were collected from nine cities. Major allergens Der p 1 and Der f I from Dermatophagoides pteronyssinus and D. farinae, and specific antigens of Blomia tropicalis, Tyrophagus putrescentiae, Acarus siro, and cockroach species Blattella germanica and Periplaneta americana were measured by *** HDM allergens were found in dust samples from bedding in 95% of the Chinese households. The median levels varied from 〈0.006 to 9.2 μg/g of dust, depending on the city. The percentages of households having HDM allergen levels associated with the risk of developing allergy sensitization and asthma were 65% and 25%, respectively. Specific antigens of the storage mite and cockroach were only found in samples from the southern and tropical regions of China. Levels of mite allergens were generally higher in samples from bedding compared to samples from the living room, even for storage mites, whereas levels of cockroach antigens were higher in the living room *** HDM allergens are present in bedding dust samples from most Chinese households. Cities in southern and central China have relatively high levels of HDM major allergens compared to cities in northern and western China. Antigens of storage mites and cockroaches are not as common as HDM allergens.

关键词： Dermatophagoides pteronyssinus D. farinae House dust mite Indoor allergen Storage mite

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Topology Optimization with Domain Derivatives and Level Set Methods

Topology Optimization with Domain Derivatives and Level Set ...

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The Sixth World Congress on Computational Mechanics in Conjunction with the Second Asian-Pacific Congress on Computational MechanicsⅠ

作者： michael yu Wang Department of Automation & Computer-Aided Engineering The Chinese University of Hong Kong Shatin NT China

Topology optimization of structures with unknown a-priori knowledge of the topology of the solution is a great challenge in the field of structural design and optimization. While homogenization-based methods have been widely used in the past decade, level set methods have emerged recently as an attractive alternative to solve the basic problem without homogenization. As a true geometric model, a level set representation describes concisely the geometric and material boundaries of the structure. More importantly, it is capable of performing topological changes of geometric components, especially merging and splitting of components. These properties are highly desirable for topology optimization.

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