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An SNP-based second-generation genetic map of Daphnia magna and its application to QTL analysis of phenotypic traits

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BMC GENOMICS 2014年第1期15卷 1-15页

作者： Routtu, Jarkko Hall, Matthew D. Albere, Brian Beisel, Christian Bergeron, R. Daniel Chaturvedi, Anurag Choi, Jeong-Hyeon Colbourne, John De Meester, Luc Stephens, Melissa T. Stelzer, Claus-Peter Solorzano, Eleanne Thomas, W. Kelley Pfrender, Michael E. Ebert, Dieter Univ Basel Inst Zool CH-4051 Basel Switzerland Univ New Hampshire Dept Comp Sci Durham NH 03824 USA Swiss Fed Inst Technol Dept Biosyst Sci & Engn CH-4058 Basel Switzerland Univ Leuven Lab Aquat Ecol Evolut & Conservat B-3000 Louvain Belgium Georgia Regents Univ Dept Biostat Augusta GA 30912 USA Univ Birmingham Sch Biosci Birmingham B15 2TT W Midlands England Galvin Life Sci Ctr Dept Biol Sci Notre Dame IN 46556 USA Univ Innsbruck Forschungsinst Limnol A-5310 Mondsee Austria Univ New Hampshire Hubbard Ctr Genome Studies Durham NH 03824 USA Univ New Hampshire Peter T Paul Coll Business & Econ Durham NH 03824 USA Tel Aviv Univ George S Wise Fac Life Sci Dept Zool IL-69978 Tel Aviv Israel Monash Univ Sch Biol Sci Melbourne Vic 3800 Australia

Background: Although Daphnia is increasingly recognized as a model for ecological genomics and biomedical research, there is, as of yet, no high-resolution genetic map for the genus. Such a map would provide an important tool for mapping phenotypes and assembling the genome. Here we estimate the genome size of Daphnia magna and describe the construction of an SNP array based linkage map. We then test the suitability of the map for life history and behavioural trait mapping. The two parent genotypes used to produce the map derived from D. magna populations with and without fish predation, respectively and are therefore expected to show divergent behaviour and life-histories. Results: Using flow cytometry we estimated the genome size of D. magna to be about 238 mb. We developed an SNP array tailored to type SNPs in a D. magna F2 panel and used it to construct a D. magna linkage map, which included 1,324 informative markers. The map produced ten linkage groups ranging from 108.9 to 203.6 cM, with an average distance between markers of 1.13 cM and a total map length of 1,483.6 cM (Kosambi corrected). The physical length per cM is estimated to be 160 kb. Mapping infertility genes, life history traits and behavioural traits on this map revealed several significant QTL peaks and showed a complex pattern of underlying genetics, with different traits showing strongly different genetic architectures. Conclusions: The new linkage map of D. magna constructed here allowed us to characterize genetic differences among parent genotypes from populations with ecological differences. The QTL effect plots are partially consistent with our expectation of local adaptation under contrasting predation regimes. Furthermore, the new genetic map will be an important tool for the Daphnia research community and will contribute to the physical map of the D. magna genome project and the further mapping of phenotypic traits. The clones used to produce the linkage map are maintained in a stock coll

关键词： Linkage Group single nucleotide polymorphism Marker single nucleotide polymorphism array Parent Clone Transmission Ratio Distortion

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Bivariate segmentation of SNP-array data for allele-specific copy number analysis in tumour samples

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BMC BIOINFORMATICS 2013年第1期14卷 1-10页

作者： Mosen-Ansorena, David Maria Aransay, Ana CIC bioGUNE & CIBERehd Genome Anal Platform Derio 48160 Spain

Background: SNP arrays output two signals that reflect the total genomic copy number (LRR) and the allelic ratio (BAF), which in combination allow the characterisation of allele-specific copy numbers (ASCNs). While methods based on hidden Markov models (HMMs) have been extended from array comparative genomic hybridisation (aCGH) to jointly handle the two signals, only one method based on change-point detection, ASCAT, performs bivariate segmentation. Results: In the present work, we introduce a generic framework for bivariate segmentation of SNP array data for ASCN analysis. For the matter, we discuss the characteristics of the typically applied BAF transformation and how they affect segmentation, introduce concepts of multivariate time series analysis that are of concern in this field and discuss the appropriate formulation of the problem. The framework is implemented in a method named CnaStruct, the bivariate form of the structural change model (SCM), which has been successfully applied to transcriptome mapping and aCGH. Conclusions: On a comprehensive synthetic dataset, we show that CnaStruct outperforms the segmentation of existing ASCN analysis methods. Furthermore, CnaStruct can be integrated into the workflows of several ASCN analysis tools in order to improve their performance, specially on tumour samples highly contaminated by normal cells.

关键词： single nucleotide polymorphism array Allelic Ratio Bivariate Case Affymetrix Platform Minkowski Distance

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SH3GL2 is frequently deleted in non-small cell lung cancer and downregulates tumor growth by modulating EGFR signaling

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JOURNAL OF MOLECULAR MEDICINE-JMM 2013年第3期91卷 381-393页

作者： Dasgupta, Santanu Jang, Jin Sung Shao, Chunbo Mukhopadhyay, Nitai D. Sokhi, Upneet K. Das, Swadesh K. Brait, Mariana Talbot, Conover Yung, Rex C. Begum, Shahnaz Westra, William H. Hoque, Mohammad Obaidul Yang, Ping Yi, Joanne E. Lam, Stephan Gazdar, Adi F. Fisher, Paul B. Jen, Jin Sidransky, David Virginia Commonwealth Univ VCU Inst Mol Med VCU Massey Canc Ctr Dept Human & Mol GenetSch Med Richmond VA 23220 USA Mayo Clin Div Pulm & Crit Care Med Dept Med Rochester MN USA Johns Hopkins Univ Dept Otolaryngol Head & Neck Surg Baltimore MD USA Virginia Commonwealth Univ Dept Biostat Richmond VA USA Johns Hopkins Univ Inst Basic Biomed Sci Baltimore MD USA Johns Hopkins Univ Dept Pulm & Crit Care Med Baltimore MD USA Mayo Clin Dept Hlth Sci Res Rochester MN USA Mayo Clin Dept Lab Med & Pathol Rochester MN USA British Columbia Canc Res Ctr Dept Integrat Oncol Vancouver BC V5Z 1L3 Canada Univ Texas SW Med Ctr Dallas Hamon Ctr Therapeut Oncol Res Dallas TX 75390 USA

The purpose of this study was to identify key genetic pathways involved in non-small cell lung cancer (NSCLC) and understand their role in tumor progression. We performed a genome wide scanning using paired tumors and corresponding 16 mucosal biopsies from four follow-up lung cancer patients on Affymetrix 250K-NSpI array platform. We found that a single gene SH3GL2 located on human chromosome 9p22 was most frequently deleted in all the tumors and corresponding mucosal biopsies. We further validated the alteration pattern of SH3GL2 in a substantial number of primary NSCLC tumors at DNA and protein level. We also overexpressed wild-type SH3GL2 in three NSCLC cell lines to understand its role in NSCLC progression. Validation in 116 primary NSCLC tumors confirmed frequent loss of heterozygosity of SH3GL2 in overall 51 % (49/97) of the informative cases. We found significantly low (p = 0.0015) SH3GL2 protein expression in 71 % (43/60) primary tumors. Forced overexpression of wild-type (wt) SH3GL2 in three NSCLC cell lines resulted in a marked reduction of active epidermal growth factor receptor (EGFR) expression and an increase in EGFR internalization and degradation. Significantly decreased in vitro (p = 0.0015-0.030) and in vivo (p = 0.016) cellular growth, invasion (p = 0.029-0.049), and colony formation (p = 0.023-0.039) were also evident in the wt-SH3GL2-transfected cells accompanied by markedly low expression of activated AKT(Ser(473)), STAT3 (Tyr(705)), and PI3K. Downregulation of SH3GL2 interactor USP9X and activated -catenin was also evident in the SH3GL2-transfected cells. Our results indicate that SH3GL2 is frequently deleted in NSCLC and regulates cellular growth and invasion by modulating EGFR function.

关键词： single nucleotide polymorphism array Lung cancer SH3GL2 Deletion

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Response to lenalidomide in myelodysplastic syndromes with del(5q): influence of cytogenetics and mutations

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BRITISH JOURNAL OF HAEMATOLOGY 2013年第1期162卷 74-86页

作者： Mallo, Mar del Rey, Monica Ibanez, Mariam Jose Calasanz, Ma Arenillas, Leonor Jose Larrayoz, Ma Pedro, Carmen Jerez, Andres Maciejewski, Jaroslaw Costa, Dolors Nomdedeu, Meritxell Diez-Campelo, Maria Lumbreras, Eva Gonzalez-Martinez, Teresa Marugan, Isabel Such, Esperanza Cervera, Jose Cigudosa, Juan C. Alvarez, Sara Florensa, Lourdes Hernandez, Jesus Ma Sole, Francesc Hosp del Mar Res Inst Lab Citogenet Mol Lab Citol HematolServ PatolGRETNHEIMIM Barcelona Spain Inst Recerca Leucemia Josep Carreras IJC Grp Recerca SMD Badalona Barcelona Spain Univ Autonoma Barcelona Dept Biol Cellular Fisiol & Immunol Fac Biociencies Bellaterra Spain Univ Salamanca IBSAL Inst Biomed Salamanca Ctr Invest Canc Serv Hematol E-37008 Salamanca Spain Univ Salamanca IBMCC E-37008 Salamanca Spain Hosp Univ La Fe Serv Hematol Valencia Spain Univ Navarra Dept Genet E-31080 Pamplona Spain Hosp del Mar Res Inst Serv Hematol Clin GRETNHEIMIM Barcelona Spain Cleveland Clin Dept Translat Hematol & Oncol Res Taussig Canc Inst Cleveland OH 44106 USA Hosp Clin Barcelona Serv Hematopatol Barcelona Spain Hosp Clin Barcelona Serv Hematol Clin Barcelona Spain Hosp Clin Univ Fdn Publ Galega Med Xenom Santiago De Compostela Spain Hosp Clin Univ Valencia Serv Hematol & Oncol Med Valencia Spain Ctr Nacl Invest Oncol Grp Citogenet Mol Madrid Spain

Lenalidomide is an effective drug in low-risk myelodysplastic syndromes (MDS) with isolated del(5q), although not all patients respond. Studies have suggested a role for TP53 mutations and karyotype complexity in disease progression and outcome. In order to assess the impact of complex karyotypes on treatment response and disease progression in 52 lenalidomide-treated patients with del(5q) MDS, conventional G-banding cytogenetics (CC), single nucleotide polymorphism array (SNP-A), and genomic sequencing methods were used. SNP-A analysis (with control sample, lymphocytes CD3+, in 30 cases) revealed 5q losses in all cases. Other recurrent abnormalities were infrequent and were not associated with lenalidomide responsiveness. Low karyotype complexity (by CC) and a high baseline platelet count (>280x109/l) were associated with the achievement of haematological response (P=0020, P=0013 respectively). Unmutated TP53 status showed a tendency for haematological response (P=0061). Complete cytogenetic response was not observed in any of the mutated TP53 cases. By multivariate analysis, the most important predictor for lenalidomide treatment failure was a platelet count <280x109/l (Odds Ratio=617, P=0040). This study reveals the importance of a low baseline platelet count, karyotypic complexity and TP53 mutational status for response to lenalidomide treatment. It supports the molecular study of TP53 in MDS patients treated with lenalidomide.

关键词： myelodysplastic syndrome deletion 5q lenalidomide TP53 single nucleotide polymorphism array

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Diplotyper: diplotype-based association analysis

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BMC MEDICAL GENOMICS 2013年第2期6卷 1-8页

作者： Kim, Sunshin Park, KyungChae Shin, Chol Cho, Nam H. Ko, Jeong-Jae Koh, InSong Kwack, KyuBum CHA Univ Coll Life Sci Dept Biomed Sci Songnam South Korea CHA Univ CHA Bundang Med Ctr Dept Family Med Songnam South Korea Korea Univ Ansan Hosp Dept Internal Med Div Pulm & Crit Care Med Ansan South Korea Ajou Univ Sch Med Dept Prevent Med Suwon 441749 South Korea Hanyang Univ Coll Med Dept Physiol Seoul 133791 South Korea

Background: It was previously reported that an association analysis based on haplotype clusters increased power over single-locus tests, and that another association test based on diplotype trend regression analysis outperformed other, more common association approaches. We suggest a novel algorithm to combine haplotype cluster-and diplotype-based analyses. Methods: Diplotyper combines a novel algorithm designed to cluster haplotypes of interest from a given set of haplotypes with two existing tools: Haploview, for analyses of linkage disequilibrium blocks and haplotypes, and PLINK, to generate all possible diplotypes from given genotypes of samples and calculate linear or logistic regression. In addition, procedures for generating all possible diplotypes from the haplotype clusters and transforming these diplotypes into PLINK formats were implemented. Results: Diplotyper is a fully automated tool for performing association analysis based on diplotypes in a population. Diplotyper was tested through association analysis of hepatic lipase (LIPC) gene polymorphisms or diplotypes and levels of high-density lipoprotein (HDL) cholesterol. Conclusions: Diplotyper is useful for identifying more precise and distinct signals over single-locus tests.

关键词： Hepatic Lipase single nucleotide polymorphism Genotype Linkage Disequilibrium Block single nucleotide polymorphism array Haplotype Pair

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Investigation of transferability of BovineSNP50 BeadChip from cattle to water buffalo for genome wide association study

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MOLECULAR BIOLOGY REPORTS 2013年第2期40卷 743-750页

作者： Wu, Jun Jing Song, Li Jun Wu, Fang Jie Liang, Xian Wei Yang, Bing Zhuang Wathes, D. Claire Pollott, Geoff E. Cheng, Zhangrui Shi, De Shun Liu, Qing You Yang, Li Guo Zhang, Shu Jun Huazhong Agr Univ Minist Educ Key Lab Agr Anim Genet Breeding & Reprod Wuhan 430070 Peoples R China Hubei Prov Acad Agr Sci Inst Anim Husb & Vet Wuhan 430064 Peoples R China Guangxi Buffalo Res Inst Guangxi Key Lab Buffalo Genet Reprod & Breeding Nanning 530001 Peoples R China Univ London Royal Vet Coll Hatfield AL9 7TA Herts England Guangxi Univ Dept Anim Sci Nanning 530005 Peoples R China

Cattle and water buffalo belong to the same subfamily Bovinae and share chromosome banding and gene order homology. In this study, we used genome-wide Illumina BovineSNP50 BeadChip to analyze 91 DNA samples from three breeds of water buffalo (Nili-Ravi, Murrah and their crossbred with local GuangXi buffalos in China), to demonstrate the genetic divergence between cattle and water buffalo through a large single nucleotide polymorphism (SNP) transferability study at the whole genome level, and performed association analysis of functional traits in water buffalo as well. A total of 40,766 (75.5 %) bovine SNPs were found in the water buffalo genome, but 49,936 (92.5 %) were with only one allele, and finally 935 were identified to be polymorphic and useful for association analysis in water buffalo. Therefore, the genome sequences of water buffalo and cattle shared a high level of homology but the polymorphic status of the bovine SNPs varied between these two species. The different patterns of mutations between species may associate with their phenotypic divergence due to genome evolution. Among 935 bovine SNPs, we identified a total of 9 and 7 SNPs significantly associated to fertility and milk production traits in water buffalo, respectively. However, more works in larger sample size are needed in future to verify these candidate SNPs for water buffalo.

关键词： single nucleotide polymorphism array Water buffalo Bovine Association analysis Genomic divergence

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A Case of Toriello-Carey Syndrome With Severe Congenital Tracheal Stenosis

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AMERICAN JOURNAL OF MEDICAL GENETICS PART A 2013年第9期161卷 2291-2293页

作者： Yokoo, Noritaka Marumo, Chieko Nishida, Yoshinobu Iio, Jun Maeda, Shinji Nonaka, Michiko Maihara, Toshiro Chujoh, Satoru Katayama, Tetsuo Sakazaki, Hisanori Matsumoto, Naomichi Okamoto, Nobuhiko Hyogo Prefectural Tsukaguchi Hosp Dept Pediat Amagasaki Hyogo Japan Hyogo Prefectural Tsukaguchi Hosp Dept Pediat Surg Amagasaki Hyogo Japan Hyogo Kenritsu Amagasaki Hosp Dept Pediat Cardiol Amagasaki Hyogo Japan Yokohama City Univ Grad Sch Med Dept Human Genet Yokohama Kanagawa 232 Japan Osaka Med Ctr Dept Med Genet Izumi Osaka Japan Res Inst Maternal & Children Hlth Izumi Osaka Japan

Toriello-Carey syndrome is rare condition characterized by agenesis of the corpus callosum, the Pierre Robin sequence, and facial anomalies such as telecanthus, short palpebral fissures, and a small nose with anteverted nares [Toriello and Carey, 1988]. In addition, tracheal and laryngeal anomalies are common complications in patients with Toriello-Carey syndrome, and these anomalies can lead to death [Kataoka et al., 2003]. Congenital tracheal stenosis is a life-threatening condition with high mortality. Even if surgery is successful, several serious complications can result in a high risk of mortality. We describe a case of a Japanese boy with Toriello-Carey syndrome who had severe congenital tracheal stenosis, in whom surgical tracheal plasty was avoided because of adequate respiratory care, allowing the patient to be alive at 18 months of age. (c) 2013 Wiley Periodicals, Inc.

关键词： Toriello-Carey syndrome congenital tracheal stenosis single nucleotide polymorphism array corpus callosum agenesis Pierre Robin sequence

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Small Intestinal Neuroendocrine Tumor: A Rare Malignancy with Favorable Outcome

Small Intestinal Neuroendocrine Tumor: A Rare Malignancy wit...

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作者： OLOV NORLEN Uppsala University

学位级别：博士

Small intestinal neuroendocrine tumor (SI-NET) is the most common small bowel tumor in Europe and USA, with an annual incidence of around 0.3-1.3/100000 persons. SI-NETs are the most common type of gastroenteropancreatic NETs (GEP-NETs), and they are known for their ability to produce hormones such as tachykinins and serotonin, as well as for their favorable long-term prognosis in comparison to gastrointestinal adenocarcinoma. The overall aim of the thesis was to investigate unknown or unclear aspects of SI-NET disease, in connection with prognosis, treatment and follow-up. Paper I confirmed several known negative prognostic factors and also showed, for the first time, that para-aortal lymph node metastases and peritoneal carcinomatosis were associated with worse survival by multivariable analyses. Locoregional surgery was associated with a low post-operative mortality, and a prolonged long-term survival by multivariable analysis. In Paper II we continued to investigate peritoneal carcinomatosis and found it be a risk factor not only for death, but also for emergency re-surgery. Furthermore, genetic analyses of samples from primary tumors in patients with and without peritoneal carcinomatosis showed a difference in the DNA between these two groups. In Paper III the outcome after liver surgery and/or radiofrequency ablation of liver metastases was investigated. To summarize, no difference in survival was seen in patients treated with surgery/radiofrequency ablation in comparison with matched controls. However, a superior radiological response of liver metasases and lower U-5-HIAA values were seen in patients subjected to liver surgery and/ or radiofrequency ablation compared to matched controls. Paper IV compared ultrasonography, computed tomography and 11 C-5HTP-PET in the follow-up after radiofrequency ablation of NET liver metastases. The study concluded that 11 C-5HTP-PET depicted all residual tumors after RFA and that it, if used, should be combined with compute

关键词： Neuroendocrine tumor peritoneal carcinomatosis single nucleotide polymorphism array liver metastases radiofrequency ablation liver surgery positron emission tomography somatostatin analogs cholecystectomy

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Comparison of methods to detect copy number alterations in cancer using simulated and real genotyping data

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BMC BIOINFORMATICS 2012年第1期13卷 1-12页

作者： Mosen-Ansorena, David Maria Aransay, Ana Rodriguez-Ezpeleta, Naiara CIC BioGUNE CIBERehd Derio 48160 Spain AZTI Tecnalia Marine Res Div Sukarrieta 48395 Spain

Background: The detection of genomic copy number alterations (CNA) in cancer based on SNP arrays requires methods that take into account tumour specific factors such as normal cell contamination and tumour heterogeneity. A number of tools have been recently developed but their performance needs yet to be thoroughly assessed. To this aim, a comprehensive model that integrates the factors of normal cell contamination and intra-tumour heterogeneity and that can be translated to synthetic data on which to perform benchmarks is indispensable. Results: We propose such model and implement it in an R package called CnaGen to synthetically generate a wide range of alterations under different normal cell contamination levels. Six recently published methods for CNA and loss of heterozygosity (LOH) detection on tumour samples were assessed on this synthetic data and on a dilution series of a breast cancer cell-line: ASCAT, GAP, GenoCNA, GPHMM, MixHMM and OncoSNP. We report the recall rates in terms of normal cell contamination levels and alteration characteristics: length, copy number and LOH state, as well as the false discovery rate distribution for each copy number under different normal cell contamination levels. Assessed methods are in general better at detecting alterations with low copy number and under a little normal cell contamination levels. All methods except GPHMM, which failed to recognize the alteration pattern in the cell-line samples, provided similar results for the synthetic and cell-line sample sets. MixHMM and GenoCNA are the poorliest performing methods, while GAP generally performed better. This supports the viability of approaches other than the common hidden Markov model (HMM)-based. Conclusions: We devised and implemented a comprehensive model to generate data that simulate tumoural samples genotyped using SNP arrays. The validity of the model is supported by the similarity of the results obtained with synthetic and real data. Based on these results an

关键词： Synthetic Data Recall Rate single nucleotide polymorphism array Allelic Ratio Baseline Shift

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Chromosome microarrays in human reproduction

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HUMAN REPRODUCTION UPDATE 2012年第5期18卷 555-567页

作者： Rajcan-Separovic, Evica Univ British Columbia Dept Pathol & Lab Med Cytogenet Childrens & Womens Hlth Ctr BC Vancouver BC V5Z 4H4 Canada Child & Family Res Inst Vancouver BC V5Z 4H4 Canada

Chromosome microarray (CMA) testing allows automatic and easy identification of large chromosomal abnormalities detectable by conventional cytogenetics as well as the detection of submicroscopic chromosomal imbalances. A PubMed search was performed in order to review the current use of CMA testing in the field of human reproduction. Articles discussing the use of CMA in the preimplantation setting, ongoing pregnancies, miscarriages and patients with reproductive disorders were considered. A high rate of concordance between conventional methods of detecting chromosomal abnormalities [e.g. fluorescence in situ hybridization (FISH), karyotyping] and CMA was reported in the prenatal setting with CMA providing more comprehensive and detailed results as it investigates the whole genome at higher resolution. In preimplantation genetic screening, CMA is replacing FISH and the selection of embryos based on CMA has already resulted in live births. For ongoing pregnancies and miscarriages, CMA eliminates tissue culture failures and artifacts and allows a quick turnaround time. The detection of submicroscopic imbalances [or copy number variants (CNVs)] is beneficial when the imbalance has a clear clinical consequence but is challenging for previously undescribed imbalances, particularly for ongoing pregnancies. Recurrent CNVs have been documented in patients with reproductive disorders;however, the application of CMA in this field is still limited. CMA enhances reproductive medicine as it facilitates better understanding of the genetic aspects of human development and reproduction and more informed patient management. Further clinical validation of CMA in the prenatal setting, creation of practice guidelines and catalogs of newly discovered submicroscopic imbalances with clinical outcomes are areas that will require attention in the future.

关键词： array comparative genomic hybridization single nucleotide polymorphism array PGD PGS miscarriage prenatal diagnosis

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