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whole-exome sequencing identifies a novel INS mutation causative of maturity-onset diabetes of the young 10

Journal of Molecular Cell Biology 2017年第5期9卷 376-383页

作者： Jing Yan Feng Jiang Rong Zhang Tongfu Xu Zhou Zhou Wei Ren Danfeng Peng Yong Liu Cheng Hu Weiping Jia Shanghai Diabetes Institute Shanghai Key Laboratory of Diabetes MeUitus Shanghai Key Clinical Center for Metabolic Diseases Shanghai Jiao Tong University AffiLiated Sixth People's Hospital Shanghai China The Key Laboratory of Nutrition and Metabolism Institute for Nutritional Sciences Shanghai Institutes for Biological Sciences Chinese Academy of Sciences University of the Chinese Academy of Sciences Shanghai China Institute for Metabolic Disease Fengxian Central Hospital Affiliated to Southern Medical University Shanghai China

Monognnic diabetes is often misdiagnosed with type 2 diabetes due to overlapping characteristics. This study aimed to discover novel causative mutations of monogenic diabetes in patients with clinically diagnosed type 2 diabetes and to explore potential molecular mechanisms. whole-exome sequencing was performed on 31 individuals clinically diagnosed with type 2 diabetes. One novel heterozygnus mutation （p^la2Thr） in INS was identified. It was further gnnotyped in an additional case-control population （6523 cases and 4635 controls）, and this variant was observed in 0.09% of cases. IntraceUular trafficking of insulin proteins was assessed in INSl-E and HEK293T cells, ***2Thr preproinsuUn-GFP was markedly retained in the endoplasmic reticulum （ER） in INS1-E cells. Activation of the PERK-elF2a-ATF4, IREla-XBP1, and ATF6 pathways as well as upregulated ER chaperones were detected in INS1-E cells transfected with the ***2Thr mutant. In conclusion, we identified a causative mutation in IN5 respon- sible for maturity-onset diabetes of the young 10 （MODYIO） in a Chinese population and demonstrated that this mutation affected 13 cell function by inducing ER stress.

关键词： whole-exome sequencing causative mutation MODYIO endoplasmic reticulum stress

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whole-exome sequencing of a multicenter cohort identifies genetic changes associated with clinical phenotypes in pediatric nephrotic syndrome

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Genes & Diseases 2022年第6期9卷 1662-1673页

作者： Jia Jiao Li Wang Fenfen Ni Mo Wang Shipin Feng Xiaojie Gao Han Chan Xueying Yang Hao Lee Huan Chi Xuelan Chen Daoqi Wu Gaofu Zhang Baohui Yang Anshuo Wang Qin Yang Junli Wan Sijie Yu Xiaoqin Li Mei Wang Xiaofeng Chen Xianying Mai Xiongzhong Ruan Haiping Yang Qiu Li Department of Nephrology Children’s Hospital of Chongqing Medical UniversityNational Clinical Research Center for Child Health and DisordersMinistry of Education Key Laboratory of Child Development and DisordersChongqing Key Laboratory of PediatricsChongqing 400015PR China Department of Nephrology Chengdu Women and Children Central HospitalChengduSichuan 610091PR China Department of Nephrology Sheen Children’s HospitalShenzhenGuangdong 518034PR China Centre for Lipid Research&Key Laboratory of Molecular Biology for Infectious Diseases(Ministry of Education) Institute for Viral HepatitisDepartment of Infectious DiseasesThe Second Affiliated Hospital Chongqing Medical UniversityChongqing 400016PR ChinaJohn Moorhead Research LaboratoryCentre for NephrologyUniversity College London Medical SchoolRoyal Free CampusUniversity College LondonLondon WC1E 6BTUnited Kingdom

Understanding the association between the genetic and clinical phenotypes in children with nephrotic syndrome(NS)of different etiologies is critical for early clinical *** employed whole-exome sequencing(WES)to detect monogenic causes of NS in a multicenter cohort of 637 *** this study,a genetic cause was identified in 30.0%of the idiopathic steroid-resistant nephrotic syndrome(SRNS)*** than congenital nephrotic syndrome(CNS),there were no significant differences in the incidence of monogenic diseases based on the age at *** mutations were detected in 39.5%of patients with focal segmental glomerulosclerosis(FSGS)and 9.2%of those with minimal change disease(MCD).In terms of the patterns in patients with different types of steroid resistance,a single gene mutation was identified in 34.8%of patients with primary resistance,2.9%with secondary resistance,and 71.4%of children with multidrug *** the various intensified immunosuppressive therapies,tacrolimus(TAC)showed the highest response rate,with 49.7%of idiopathic SRNS patients achieving complete *** SRNS patients with monogenic disease showed a similar multidrug resistance pattern,and only 31.4%of patients with monogenic disease achieved a partial remission on *** an average 4.1-year follow-up,21.4%of idiopathic SRNS patients with monogenic disease progressed to end-stage renal disease(ESRD).Collectively,this study provides evidence that genetic testing is necessary for presumed steroid-resistant and idiopathic SRNS patients,especially those with primary and/or multidrug resistance.

关键词： Clinical phenotypes Genetic phenotypes Multicenter cohort Nephrotic syndrome Pediatric whole-exome sequencing

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whole-exome sequencing in a patient with synchronous triple primary malignancies involving lung cancer:a case report

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Precision Clinical Medicine 2020年第4期3卷 306-310页

作者： Dan Li Min Yu Ping Zhou Jie Yang Yongsheng Wang Precision Medicine Center Precision Medicine Key Laboratory of Sichuan ProvinceWest China HospitalSichuan UniversityChengdu 610041China Department of Thoracic Oncology West China HospitalSichuan UniversityChengdu 610041China Department of Pathology West China HospitalSichuan UniversityChengdu 610041China YuceBio Technology Co. LtdShenzhen 518081China Institute of Drug Clinical Trial West China HospitalSichuan UniversityChengdu 610041China

The incidence of multiple primary malignancies(MPMs)has been increasing rapidly in recent years,however,the genetic pathogenesis is largely unknown on account of rare cases,especially for those patients who are diagnosed with three or more *** these circumstances,whole-exome sequencing(WES)may help to provide more comprehensive genomic information and guidance to proper therapeutic ***,we presented a rare case of a 66-year-old Chinese male patient who was diagnosed with synchronous triple primary malignancies:esophageal squamous cell carcinoma(ESCC),lung adenocarcinoma(LA),and hepatocellular carcinoma(HCC).Tumors were surgically removed within 3 *** was performed when the patient suffered from cancer recurrence and tumor-specific neoantigens were *** tumor displayed a distinct somatic mutation profile,providing direct evidence of independent *** shared driver gene mutation or neoantigen was detected among the three *** germline alterations of cancer susceptibility genes—SPINK1 c.194+2T>C and JAK3 c.425G>A were *** case is the first report of synchronous primary triple cancers covering the esophagus,lung,and *** findings highlight the complexities of MPMs that even when under identical germline genetic backgrounds,the occurrence of MPMs can be a random event and driven by distinct somatic gene *** multiple primary cancers that originated from different organs may not have common therapeutic gene targets,and it can be difficult to find a treatment to cover all the tumors.

关键词： triple primary malignancies whole-exome sequencing lung adenocarcinoma esophageal squamous cell carcinoma hepatocellular carcinoma somatic mutation germline mutation neoantigen

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Identification of risk genes in Chinese nonobstructive azoospermia patients based on whole-exome sequencing

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Asian Journal of Andrology 2023年第1期25卷 66-72页

作者： Yu-Jun Liu Xin-Jie Zhuang Jian-Ting An Hui Jiang Rong Li Jie Qiao Li-Ying Yan Xu Zhi Center for Reproductive Medicine Department of Obstetrics and GynecologyPeking University Third HospitalBeijing 100191China National Clinical Research Center for Obstetrics and Gynecology Beijing 100191China Key Laboratory of Assisted Reproduction Peking UniversityMinistry of EducationBeijing 100191China Peking-Tsinghua Center for Life Sciences Peking UniversityBeijing 100191China Department of Urology Peking University Third HospitalBeijing 100191China Department of Andrology Peking University Third HospitalBeijing 100191China

Nonobstructive azoospermia(NOA)is a severe condition in infertile men,and increasing numbers of causative genes have been identified during the last few *** certain causative genes can explain the presence of NOA in some patients,a proportion of NOA patients remain to be *** study aimed to investigate potential high-risk genes associated with spermatogenesis in idiopathic NOA patients by whole-exome ***-exome sequencing was performed in 46 male patients diagnosed with ***,screening was performed for 119 genes known to be related to male ***,further screening was performed to determine potential high-risk causative genes for NOA by comparisons with 68 healthy male ***,risk genes with high/specific expression in the testes were selected and their expression fluctuations during spermatogenesis were *** frequency of cystic fibrosis transmembrane conductance regulator(CFTR)gene pathogenic variant carriers was higher in the NOA patients compared with the healthy *** risk genes that may be causes of NOA were identified,including seven genes that were highly/specifically expressed in the *** risk genes previously reported to be involved in spermatogenesis(MutS homolog 5[MSH5],cilia-and flagella-associated protein 54[CFAP54],MAP7 domain containing 3[MAP7D3],and coiled-coil domain containing 33[CCDC33])and three novel risk genes(coiled-coil domain containing 168[CCDC168],chromosome 16 open reading frame 96[C16orf96],and serine protease 48[PRSS48])were identified to be highly or specifically expressed in the testes and significantly different in the 46 NOA patients compared with 68 healthy *** study on clinical NOA patients provides further evidence for the four previously reported risk *** present findings pave the way for further functional investigations and provide candidate risk genes for genetic diagnosis of NOA.

关键词： cystic fibrosis transmembrane conductance regulator nonobstructive azoospermia potential risk genes spermatogenesis whole-exome sequencing

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Targeted gene panel provides advantages over whole-exome sequencing for diagnosing obesity and diabetes mellitus

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Journal of Molecular Cell Biology 2023年第6期15卷 40-52页

作者： Hairong Yu Haoyong Yu Rong Zhang Danfeng Peng Dandan Yan Yunjuan Gu Yuqian Bao Weiping Jia Hong Zhang Cheng Hu Shanghai Diabetes Institute Shanghai Key Laboratory of Diabetes MellitusShanghai Clinical Center for DiabetesShanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai 200233China Department of Endocrinology Affiliated Hospital of Nantong UniversityNantong 226001China Institute for Metabolic Disease Fengxian Central Hospital Affiliated to Southern Medical UniversityShanghai 201499China

A small fraction of patients diagnosed with obesity or diabetes mellitus has an underlying monogenic ***,we constructed a targeted gene panel consisting of 83 genes reported to be causative for monogenic obesity or *** performed this panel in 481 patients to detect causative variants and compared these results with whole-exome sequencing(WES)data available for 146 of these *** coverage of targeted gene panel sequencing was significantly higher than that of *** diagnostic yield in patients sequenced by the panel was 32.9%with subsequent WES leading to three additional diagnoses with two novel *** total,178 variants in 83 genes were detected in 146 patients by targeted *** of the 178 variants were missed by WES,although the WES-only approach had a similar diagnostic *** the 335 samples only receiving targeted sequencing,the diagnostic yield was 32.2%.In conclusion,taking into account the lower costs,shorter turnaround time,and higher quality of data,targeted sequencing is a more effective screening method for monogenic obesity and diabetes compared to ***,this approach could be routinely established and used as a first-tier test in clinical practice for specific patients.

关键词： molecular diagnosis monogenic diabetes mellitus monogenic obesity targeted panel whole-exome sequencing

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Identification of de novo Mutations in the Chinese Autism Spectrum Disorder Cohort via whole-exome sequencing Unveils Brain Regions Implicated in Autism

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Neuroscience Bulletin 2023年第10期39卷 1469-1480页

作者： Bo Yuan Mengdi Wang Xinran Wu Peipei Cheng Ran Zhang Ran Zhang Shunying Yu Jie Zhang Yasong Du Xiaoqun Wang Zilong Qiu Songjiang Research Institute Songjiang HospitalShanghai Jiao Tong University School of MedicineShanghai 201600China Shanghai Mental Health Center Shanghai Jiao Tong University School of MedicineShanghai 200032China Institute of Neuroscience State Key Laboratory of NeuroscienceCAS Center for Excellence in Brain Science and Intelligence TechnologyShanghai Center for Brain Science and Brain-Inspired Intelligence TechnologyChinese Academy of SciencesShanghai 200032China Beijing Normal University Beijing 100875China Institute of Biophysics Chinese Academy of SciencesBeijing 100101China Institute of Science and Technology for Brain-Inspired Intelligence Fudan UniversityShanghai 200433China

Autism spectrum disorder(ASD)is a highly heritable neurodevelopmental disorder characterized by deficits in social interactions and repetitive *** hundreds of ASD risk genes,implicated in synaptic formation and transcriptional regulation,have been identified through human genetic studies,the East Asian ASD cohorts are still under-represented in genome-wide genetic ***,we applied whole-exome sequencing to 369 ASD trios including probands and unaffected parents of Chinese *** a joint-calling analytical pipeline based on GATK toolkits,we identified numerous de novo mutations including 55 high-impact variants and 165 moderate-impact variants,as well as de novo copy number variations containing known ASD-related ***,combined with single-cell sequencing data from the developing human brain,we found that the expression of genes with de novo mutations was specifically enriched in the pre-,post-central gyrus(PRC,PC)and banks of the superior temporal(BST)regions in the human *** further analyzing the brain imaging data with ASD and healthy controls,we found that the gray volume of the right BST in ASD patients was significantly decreased compared to healthy controls,suggesting the potential structural deficits associated with ***,we found a decrease in the seed-based functional connectivity between BST/PC/PRC and sensory areas,the insula,as well as the frontal lobes in ASD *** work indicated that combinatorial analysis with genome-wide screening,single-cell sequencing,and brain imaging data reveal the brain regions contributing to the etiology of ASD.

关键词： Autism Cohorts whole-exome sequencing Single-cell sequencing

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A novel CRX mutation by whole-exome sequencing in an autosomal dominant cone-rod dystrophy pedigree

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International Journal of Ophthalmology(English edition) 2015年第6期8卷 1112-1117页

作者： Qin-Kang Lu Na Zhao Ya-Su Lv Wei-Kun Gong Hui-Yun Wang Qi-Hu Tong Xiao-Ming Lai Rong-Rong Liu Ming-Yan Fang Jian-Guo Zhang Zhen-Fang Du Xian-Ning Zhang Ophthalmology Center Yinzhou People's Hospital Yinzhou Hospital Affiliated to Medical School of Ningbo University Department of Cell Biology and Medical Genetics Research Center for Molecular Medicine Institute of Cell BiologyZhejiang University School of Medicine BGI-Shenzhen

AIMTo identify the disease-causing gene mutation in a Chinese pedigree with autosomal dominant cone-rod dystrophy (adCORD).METHODSA southern Chinese adCORD pedigree including 9 affected individuals was studied. whole-exome sequencing (WES), coupling the Agilent whole-exome capture system to the Illumina HiSeq 2000 DNA sequencing platform was used to search the specific gene mutation in 3 affected family members and 1 unaffected member. After a suggested variant was found through the data analysis, the putative mutation was validated by Sanger DNA sequencing of samples from all available family *** results of both WES and Sanger sequencing revealed a novel nonsense mutation c.C766T (p.Q256X) within exon 5 of CRX gene which was pathogenic for adCORD in this family. The mutation could affect photoreceptor-specific gene expression with a dominant-negative effect and resulted in loss of the OTX tail, thus the mutant protein occupies the CRX-binding site in target promoters without establishing an interaction and, consequently, may block *** modes of Mendelian inheritance in CORD have been observed, and genetic heterogeneity is a hallmark of CORD. Therefore, conventional genetic diagnosis of CORD would be time-consuming and labor-intensive. Our study indicated the robustness and cost-effectiveness of WES in the genetic diagnosis of CORD.

关键词： cone-rod dystrophy autosomal dominant cone-rod dystrophy whole-exome sequencing Sanger sequencing CRX gene mutation

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CTCs Detection and whole-exome sequencing Might Be Used to Differentiate Benign and Malignant Pulmonary Nodules

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中国肺癌杂志 2023年第6期26卷 449-460页

作者： Changdan XU Xiaohong XU Weipeng SHAO Hongliang SUN Xiaohong LIU Hongxiang FENG Xianbo ZUO Jingyang GAO Guohui WANG Xiongtao YANG Runchuan GU Shutong GE Shijie WANG Liwei GAO Guangying ZHU Department of Radiation Oncology Peking University China-Japan Friendship School of Clinical MedicineBeijing 100029China Department of Radiation Oncology Zhongshan HospitalFudan UniversityShanghai 200032China Department of Thoracic Surgery China-Japan Friendship HospitalBeijing 100029China Department of Radiology China-Japan Friendship HospitalBeijing 100029China Department of Information Science and Technology Beijing University of Chemical TechnologyBeijing 100029China Department of Dermatology China-Japan Friendship HospitalBeijing 100029China Department of Pharmacy China-Japan Friendship HospitalBeijing 100029China Department of Radiation Oncology Tianjin First Central HospitalTianjin 300070China Department of Oncology Beijing Changping District HospitalBeijing 102200China Faculty of Medicine Lund University Lund SE-22100Sweden Department of Radiation Oncology China-Japan Friendship HospitalChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100029China Department of Radiation Oncology Center of Respiratory MedicineChina-Japan Friendship HospitalBeijing 100029China

Background and objective Low-density computed tomography(LDCT)improved early lung cancer diagnosis but introduces an excess of false-positive pulmonary nodules ***,accurate diagnosis of early-stage lung cancer remains *** purpose of the study was to assess the feasibility of using circulating tumour cells(CTCs)to differentiate malignant from benign pulmonary *** and methods 122 patients with suspected malignant pulmonary nodules detected on chest CT in preparation for surgery were prospectively *** blood samples were collected before surgery,and CTCs were identified upon isolation by size of epithelial tumour cells and morphological *** capture microdissection,MALBAC amplification,and whole-exome sequencing were performed on 8 *** diagnostic efficacy of CTCs counting,and the genomic variation profile of benign and malignant CTCs samples were *** Using 2.5 cells/5 m L as the cut-off value,the area under the receiver operating characteristic curve was of 0.651(95%confidence interval:0.538-0.764),with a sensitivity and specificity of 0.526 and 0.800,respectively,and positive and negative predictive values of 91.1%and 30.3%,*** sequence variations differences in DNA damage repair-related and driver genes were observed in benign and malignant ***53 mutations were identified in CTCs of four malignant cases;in particular,g.7578115T>C,g.7578645C>T,and g.7579472G>C were exclusively detected in all four malignant *** CTCs play an ancillary role in the diagnosis of pulmonary ***53 mutations in CTCs might be used to identify benign and malignant pulmonary nodules.

关键词： Chest computed tomography Circulating tumour cells Lung nodule TP53 whole-exome sequencing

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Identification of A Novel SBF2 Frameshift Mutation in Charcot–Marie–Tooth Disease Type 4B2 Using whole-exome sequencing

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Genomics, Proteomics & Bioinformatics 2014年第5期12卷 221-227页

作者： Meiyan Chen Jing Wu Ning Liang Lihui Tang Yanhua Chen Huishuang Chen Wei Wei Tianying Wei Hui Huang Xin Yi Ming Qi BGI-Shenzhen School of Life Sciences The Chinese University of Hong Kong NT Center for Genetic and Genomic Medicine Zhejiang University School of Medicine First Affiliated Hospital and James D. Watson Institute of Genome Sciences Department of Pathology University of Rochester Medical Center

Abstract Charcot-Marie-Tooth disease type 4B2 with early-onset glaucoma （CMT4B2, OMIM 604563） is a genetically-heterogeneous childhood-onset neuromuscular disorder. Here, we report the case of a 15-year-old male adolescent with lower extremity weakness, gait abnormalities, foot deformities and early-onset glaucoma. Since clinical diagnosis alone was insufficient for providing pathogenetic evidence to indicate that the condition belonged to a consanguineous family, we applied whole-exome sequencing to samples from the patient, his parents and his younger brother, assuming that the patient＇s condition is transmitted in an autosomal recessive pattern. A frame-shift mutation, c.4571delG （***1524Glufs＊42）, was revealed in the CMT4B2-related gene SBF2 （also known as MTMR13, MIM 607697）, and this mutation was found to be homozygous in the proband and heterozygous in his parents and younger brother. Together with the results of clinical diagnosis, this case was diagnosed as CMT4B2. Our finding further demonstrates the use of whole-exome sequencing in the diagnosis and treatment of rare diseases.

关键词： whole-exome sequencing Charcot-Marie--Toothdisease Early-onset glaucoma SBF2

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Comprehensive analysis of genetic variations in strictly-defined Leber congenital amaurosis with whole-exome sequencing in Chinese

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International Journal of Ophthalmology(English edition) 2016年第9期9卷 1260-1264页

作者： Shi-Yuan Wang Qi Zhang Xiang Zhang Pei-Quan Zhao Department of Ophthalmology Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine

AIM：To make a comprehensive analysis of the potential pathogenic genes related with Leber congenital amaurosis（LCA） in ***：LCA subjects and their families were retrospectively collected from 2013 to ***,whole-exome sequencing was performed in patients who had underwent gene mutation screening with nothing found,and then homozygous sites was selected,candidate sites were annotated,and pathogenic analysis was conducted using softwares including Sorting Tolerant from Intolerant（SIFT）,Polyphen-2,Mutation assessor,Condel,and Functional Analysis through Hidden Markov Models（FATHMM）.Furthermore,Gene Ontology function and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses of pathogenic genes were performed followed by co-segregation analysis using Fisher exact *** sequencing was used to validate single-nucleotide variations（SNVs）.Expanded verification was performed in the rest ***：Totally 51 LCA families with 53 patients and24 family members were recruited.A total of 104 SNVs（66 LCA-related genes and 15 co-segregated genes）were submitted for expand *** frequencies of homozygous mutation of KRT12 and CYP1A1 were simultaneously observed in 3 *** analysis showed that the potential pathogenic genes were mainly enriched in functions related to cell adhesion,biological adhesion,retinoid metabolic process,and eye development biological ***,WFS7 and STAU2 had the highest homozygous ***：LCA is a highly heterogeneous *** in KRT12,CVP1A1,WFS1,and STAU2 may be involved in the development of LCA.

关键词： Leber congenital amaurosis whole-exome sequencing targeted next-generation sequencing

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