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Identification of 2-nonynoic acid, a cosmetic component, as a potential trigger of primary biliary cirrhosis

JOURNAL OF AUTOIMMUNITY 2006年第1期27卷 7-16页

作者： Rieger, Roman Leung, Patrick S. C. Jeddeloh, Melissa R. Kurth, Mark J. Nantz, Michael H. Lam, Kit S. Barsky, Daniel Ansari, Aftab A. Coppel, Ross L. Mackay, Ian R. Gershwin, M. Eric Univ Calif Davis Div Rheumatol Allergy & Clin Immunol Davis CA 95616 USA Univ Calif Davis Ctr Canc Dept Internal Med Div Hematol & Oncol Sacramento CA 95817 USA Univ Calif Davis Dept Chem Davis CA 95616 USA Emory Univ Dept Pathol Atlanta GA 30322 USA Lawrence Livermore Natl Lab Livermore CA 94550 USA Monash Univ Dept Microbiol Clayton Vic 3168 Australia Monash Univ Dept Biochem & Mol Biol Clayton Vic 3168 Australia

Anti mitochondrial antibodies (AMA) are unique among autoimmune serologic reactants because of their extremely high association with the index disease primary biliary cirrhosis (PBC). This autoantibody response is specifically directed only to the lipoyl domain of the mitochondrial 2-oxo-acid dehydrogenase complexes, which prompted us to search for environmental mimotopes in the form of xenobiotics and led to our identification of 2-octynoic acid as a high-affinity reactant for AMA. To focus on the chemical characteristics requisite for binding of AMA to the xenobiotic-modified self-peptide, quantitative structure-activity relationship (QSAR) studies were performed using a panel of alkynoic compounds, including examination of the length of the carbon chain and the location of the triple bond in the identified mimotope. Analyses of octynamides that varied in the position of the triple bond demonstrated that only the 2-octynamide reacted strongly with PBC sera. Furthermore, among 2-alkynamides with varying carbon chain length, 2-octyn-, 2-nonyn- (particularly) and 2-decynamide exhibited the highest reactivity. Thus, an optimal chemical structure of the xenobiotically modified epitope recognized by AMA-positive PBC sera is provided by 2-nonynoic acid. The methyl ester of this compound is ranked 2324th out of 12,945 compounds to which there is occupational exposure, with an 80% female prevalence due to its use in cosmetic products. Our findings illustrate an unusual polyreactivity of anti-PDC-E2 and support the idea of epitope mimicry in the genesis of this autoantibody and perhaps of PBC itself. (c) 2006 Elsevier Ltd. All rights reserved.

关键词： autoepitope microarray platform primary biliary cirrhosis xenobiotics

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Meta-analysis of expression signatures of muscle atrophy: gene interaction networks in early and late stages

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BMC GENOMICS 2008年第1期9卷 1-20页

作者： Calura, Enrica Cagnin, Stefano Raffaello, Anna Laveder, Paolo Lanfranchi, Gerolamo Romualdi, Chiara Univ Padua CRIBI Biotechnol Ctr I-30121 Padua Italy Univ Padua Dept Biol I-30121 Padua Italy Univ Ferrara Dept Biol I-44100 Ferrara Italy

Background: Skeletal muscle mass can be markedly reduced through a process called atrophy, as a consequence of many diseases or critical physiological and environmental situations. Atrophy is characterised by loss of contractile proteins and reduction of fiber volume. Although in the last decade the molecular aspects underlying muscle atrophy have received increased attention, the fine mechanisms controlling muscle degeneration are still incomplete. In this study we applied meta-analysis on gene expression signatures pertaining to different types of muscle atrophy for the identification of novel key regulatory signals implicated in these degenerative processes. Results: We found a general down-regulation of genes involved in energy production and carbohydrate metabolism and up-regulation of genes for protein degradation and catabolism. Six functional pathways occupy central positions in the molecular network obtained by the integration of atrophy transcriptome and molecular interaction data. They are TGF-beta pathway, apoptosis, membrane trafficking/cytoskeleton organization, NFKB pathways, inflammation and reorganization of the extracellular matrix. Protein degradation pathway is evident only in the network specific for muscle short-term response to atrophy. TGF-beta pathway plays a central role with proteins SMAD3/4, MYC, MAX and CDKN1A in the general network, and JUN, MYC, GNB2L1/RACK1 in the short-term muscle response network. Conclusion: Our study offers a general overview of the molecular pathways and cellular processes regulating the establishment and maintenance of atrophic state in skeletal muscle, showing also how the different pathways are interconnected. This analysis identifies novel key factors that could be further investigated as potential targets for the development of therapeutic treatments. We suggest that the transcription factors SMAD3/4, GNB2L1/RACK1, MYC, MAX and JUN, whose functions have been extensively studied in tumours but only marginally

关键词： Proliferate Cell Nuclear Antigen Transcription Factor Binding Site Muscle Atrophy Skeletal Muscle Mass microarray platform

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Global regulatory architecture of human, mouse and rat tissue transcriptomes

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BMC GENOMICS 2013年第1期14卷 1-12页

作者： Prasad, Ajay Kumar, Suchitra Suresh Dessimoz, Christophe Bleuler, Stefan Laule, Oliver Hruz, Tomas Gruissem, Wilhelm Zimmermann, Philip ETH Dept Biol CH-8092 Zurich Switzerland Nebion AG CH-8048 Zurich Switzerland Swiss Inst Bioinformat CH-8092 Zurich Switzerland ETH Dept Comp Sci CH-8092 Zurich Switzerland UCL London WC1E 6BT England

Background: Predicting molecular responses in human by extrapolating results from model organisms requires a precise understanding of the architecture and regulation of biological mechanisms across species. Results: Here, we present a large-scale comparative analysis of organ and tissue transcriptomes involving the three mammalian species human, mouse and rat. To this end, we created a unique, highly standardized compendium of tissue expression. Representative tissue specific datasets were aggregated from more than 33,900 Affymetrix expression microarrays. For each organism, we created two expression datasets covering over 55 distinct tissue types with curated data from two independent microarray platforms. Principal component analysis (PCA) revealed that the tissue-specific architecture of transcriptomes is highly conserved between human, mouse and rat. Moreover, tissues with related biological function clustered tightly together, even if the underlying data originated from different labs and experimental settings. Overall, the expression variance caused by tissue type was approximately 10 times higher than the variance caused by perturbations or diseases, except for a subset of cancers and chemicals. Pairs of gene orthologs exhibited higher expression correlation between mouse and rat than with human. Finally, we show evidence that tissue expression profiles, if combined with sequence similarity, can improve the correct assignment of functionally related homologs across species. Conclusion: The results demonstrate that tissue-specific regulation is the main determinant of transcriptome composition and is highly conserved across mammalian species.

关键词： Tissue Type Degree Distribution microarray platform Tissue Expression Profile Scale Free Property

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Bimodal gene expression patterns in breast cancer

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BMC GENOMICS 2010年第1期11卷 1-14页

作者： Bessarabova, Marina Kirillov, Eugene Shi, Weiwei Bugrim, Andrej Nikolsky, Yuri Nikolskaya, Tatiana Genego Inc St Joseph MI 49085 USA Russian Acad Sci Vavilov Inst Gen Genet Moscow Russia

We identified a set of genes with an unexpected bimodal distribution among breast cancer patients in multiple studies. The property of bimodality seems to be common, as these genes were found on multiple microarray platforms and in studies with different end-points and patient cohorts. Bimodal genes tend to cluster into small groups of four to six genes with synchronised expression within the group (but not between the groups), which makes them good candidates for robust conditional descriptors. The groups tend to form concise network modules underlying their function in cancerogenesis of breast neoplasms.

关键词： Breast Cancer Close Neighbor microarray platform Group Expression cDNA Array

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Gene expression in a paleopolyploid: a transcriptome resource for the ciliate Paramecium tetraurelia

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BMC GENOMICS 2010年第1期11卷 1-13页

作者： Arnaiz, Olivier Gout, Jean-Francois Betermier, Mireille Bouhouche, Khaled Cohen, Jean Duret, Laurent Kapusta, Aurelie Meyer, Eric Sperling, Linda Univ Paris Sud Ctr Genet Mol CNRS FRE3144 Gif Sur Yvette France Univ Lyon 1 CNRS UMR 5558 Lab Biometrie & Biol Evolut F-69622 Villeurbanne France Ecole Normale Super CNRS Inst Biol INSERMUMR8197U1024 Paris France Indiana Univ Dept Biol Bloomington IN 47405 USA

Background: The genome of Paramecium tetraurelia, a unicellular model that belongs to the ciliate phylum, has been shaped by at least 3 successive whole genome duplications (WGD). These dramatic events, which have also been documented in plants, animals and fungi, are resolved over evolutionary time by the loss of one duplicate for the majority of genes. Thanks to a low rate of large scale genome rearrangement in Paramecium, an unprecedented large number of gene duplicates of different ages have been identified, making this organism an outstanding model to investigate the evolutionary consequences of polyploidization. The most recent WGD, with 51% of pre-duplication genes still in 2 copies, provides a snapshot of a phase of rapid gene loss that is not accessible in more ancient polyploids such as yeast. Results: We designed a custom oligonucleotide microarray platform for P. tetraurelia genome-wide expression profiling and used the platform to measure gene expression during 1) the sexual cycle of autogamy, 2) growth of new cilia in response to deciliation and 3) biogenesis of secretory granules after massive exocytosis. Genes that are differentially expressed during these time course experiments have expression patterns consistent with a very low rate of subfunctionalization (partition of ancestral functions between duplicated genes) in particular since the most recent polyploidization event. Conclusions: A public transcriptome resource is now available for Paramecium tetraurelia. The resource has been integrated into the ParameciumDB model organism database, providing searchable access to the data. The microarray platform, freely available through NimbleGen Systems, provides a robust, cost-effective approach for genome-wide expression profiling in P. tetraurelia. The expression data support previous studies showing that at short evolutionary times after a whole genome duplication, gene dosage balance constraints and not functional change are the major determinants

关键词： microarray platform Whole Genome Duplication Gene Retention Limma Package Whole Genome Duplication Event

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Performance evaluation of commercial short-oligonucleotide microarrays and the impact of noise in making cross-platform correlations

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BMC GENOMICS 2004年第1期5卷 1-15页

作者： Shippy, R Sendera, TJ Lockner, R Palaniappan, C Kaysser-Kranich, T Watts, G Alsobrook, J GE Healthcare Chandler AZ 85248 USA Univ Arizona Arizona Canc Ctr Microarray Shared Serv Tucson AZ 85724 USA Yale Univ Sch Med Ctr Child Study New Haven CT 06510 USA

Background: Despite the widespread use of microarrays, much ambiguity regarding data analysis, interpretation and correlation of the different technologies exists. There is a considerable amount of interest in correlating results obtained between different microarray platforms. To date, only a few cross-platform evaluations have been published and unfortunately, no guidelines have been established on the best methods of making such correlations. To address this issue we conducted a thorough evaluation of two commercial microarray platforms to determine an appropriate methodology for making cross-platform correlations. Results: In this study, expression measurements for 10,763 genes uniquely represented on Affymetrix U133A/B GeneChips(R) and Amersham CodeLink(TM) UniSet Human 20 K microarrays were compared. For each microarray platform, five technical replicates, derived from the same total RNA samples, were labeled, hybridized, and quantified according to each manufacturers' standard protocols. The correlation coefficient (r) of differential expression ratios for the entire set of 10,763 overlapping genes was 0.62 between platforms. However, the correlation improved significantly (r = 0.79) when genes within noise were excluded. In addition to levels of interplatform correlation, we evaluated precision, statistical-significance profiles, power, and noise levels for each microarray platform. Accuracy of differential expression was measured against real-time PCR for 25 genes and both platforms correlated well with r values of 0.92 and 0.79 for CodeLink and GeneChip, respectively. Conclusions: As a result of this study, we recommend using only genes called 'present' in cross-platform correlations. However, as in this study, a large number of genes may be lost from the correlation due to differing levels of noise between platforms. This is an important consideration given the apparent difference in sensitivity of the two platforms. Data from microarray analysis need to

关键词： Perfect Match microarray platform Probe Pair UniGene Cluster Target Preparation

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Establishment of the epithelial-specific transcriptome of normal and malignant human breast cells based on MPSS and array expression data

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BREAST CANCER RESEARCH 2006年第5期8卷 1-15页

作者： Grigoriadis, Anita Mackay, Alan Reis-Filho, Jorge S. Steele, Dawn Iseli, Christian Stevenson, Brian J. Jongeneel, C. Victor Valgeirsson, Haukur Fenwick, Kerry Iravani, Marjan Leao, Maria Simpson, Andrew J. G. Strausberg, Robert L. Jat, Parmjit S. Ashworth, Alan Neville, A. Munro O'Hare, Michael J. UCL Ludwig Inst Canc Res Breast Canc Lab London W1W 7BS England Inst Canc Res Breakthrough Breast Canc Res Ctr London SW3 6JB England Ludwig Inst Canc Res Off Informat Technol CH-1015 Lausanne Switzerland Swiss Inst Bioinformat CH-1015 Lausanne Switzerland Mem Sloan Kettering Canc Ctr Ludwig Inst Canc Res New York Branch New York NY 10021 USA J Craig Venter Inst Rockville MD 20850 USA Inst Neurol Dept Neurodegenerat Dis London WC1N 3BG England

Introduction Diverse microarray and sequencing technologies have been widely used to characterise the molecular changes in malignant epithelial cells in breast cancers. Such gene expression studies to identify markers and targets in tumour cells are, however, compromised by the cellular heterogeneity of solid breast tumours and by the lack of appropriate counterparts representing normal breast epithelial cells. Methods Malignant neoplastic epithelial cells from primary breast cancers and luminal and myoepithelial cells isolated from normal human breast tissue were isolated by immunomagnetic separation methods. Pools of RNA from highly enriched preparations of these cell types were subjected to expression profiling using massively parallel signature sequencing ( MPSS) and four different genome wide microarray platforms. Functional related transcripts of the differential tumour epithelial transcriptome were used for gene set enrichment analysis to identify enrichment of luminal and myoepithelial type genes. Clinical pathological validation of a small number of genes was performed on tissue microarrays. Results MPSS identified 6,553 differentially expressed genes between the pool of normal luminal cells and that of primary tumours substantially enriched for epithelial cells, of which 98% were represented and 60% were confirmed by microarray profiling. Significant expression level changes between these two samples detected only by microarray technology were shown by 4,149 transcripts, resulting in a combined differential tumour epithelial transcriptome of 8,051 genes. microarray gene signatures identified a comprehensive list of 907 and 955 transcripts whose expression differed between luminal epithelial cells and myoepithelial cells, respectively. Functional annotation and gene set enrichment analysis highlighted a group of genes related to skeletal development that were associated with the myoepithelial/ basal cells and upregulated in the tumour sample. One of the mos

关键词： Myoepithelial Cell microarray platform Breast Epithelial Cell Cartilage Oligomeric Matrix Protein Massively Parallel Signature Sequencing

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The Colorectal cancer disease-specific transcriptome may facilitate the discovery of more biologically and clinically relevant information

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BMC CANCER 2010年第1期10卷 1-14页

作者： Allen, Wendy L. Jithesh, Puthen V. Oliver, Gavin R. Proutski, Irina Longley, Daniel B. Lenz, Heinz-Josef Proutski, Vitali Harkin, Paul Johnston, Patrick G. Queens Univ Belfast Ctr Canc Res & Cell Biol Belfast BT9 7BL Antrim North Ireland Almac Diagnost Ltd Craigavon BT63 5QD North Ireland Univ So Calif Norris Comprehens Canc Ctr Div Med Oncol Keck Sch Med Los Angeles CA 90033 USA

Background: To date, there are no clinically reliable predictive markers of response to the current treatment regimens for advanced colorectal cancer. The aim of the current study was to compare and assess the power of transcriptional profiling using a generic microarray and a disease-specific transcriptome-based microarray. We also examined the biological and clinical relevance of the disease-specific transcriptome. Methods: DNA microarray profiling was carried out on isogenic sensitive and 5-FU-resistant HCT116 colorectal cancer cell lines using the Affymetrix HG-U133 Plus2.0 array and the Almac Diagnostics Colorectal cancer disease specific Research tool. In addition, DNA microarray profiling was also carried out on pre-treatment metastatic colorectal cancer biopsies using the colorectal cancer disease specific Research tool. The two microarray platforms were compared based on detection of probesets and biological information. Results: The results demonstrated that the disease-specific transcriptome-based microarray was able to outperform the generic genomic-based microarray on a number of levels including detection of transcripts and pathway analysis. In addition, the disease-specific microarray contains a high percentage of antisense transcripts and further analysis demonstrated that a number of these exist in sense: antisense pairs. Comparison between cell line models and metastatic CRC patient biopsies further demonstrated that a number of the identified sense: antisense pairs were also detected in CRC patient biopsies, suggesting potential clinical relevance. Conclusions: Analysis from our in vitro and clinical experiments has demonstrated that many transcripts exist in sense: antisense pairs including IGF2BP2, which may have a direct regulatory function in the context of colorectal cancer. While the functional relevance of the antisense transcripts has been established by many studies, their functional role is currently unclear;however, the numbers that hav

关键词： Pathway Analysis Insulin Signaling Sensitive Experiment Full Length Sequence microarray platform

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Distinct molecular mechanisms underlying clinically relevant subtypes of breast cancer: gene expression analyses across three different platforms

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BMC GENOMICS 2006年第1期7卷 1-15页

作者： Sorlie, Therese Wang, Yulei Xiao, Chunlin Johnsen, Hilde Naume, Bjorn Samaha, Raymond R. Borresen-Dale, Anne-Lise Radiumhosp Med Ctr Rikshosp Dept Genet Inst Canc Res N-0310 Oslo Norway Appl Biosyst Inc Foster City CA 94404 USA Celera Gen Rockville MD 20850 USA Rikshosp Radiumhosp Med Ctr Dept Oncol N-0310 Oslo Norway Univ Oslo Fac Med N-0310 Oslo Norway

Background: Gene expression profiling has been used to define molecular phenotypes of complex diseases such as breast cancer. The luminal A and basal-like subtypes have been repeatedly identified and validated as the two main subtypes out of a total of five molecular subtypes of breast cancer. These two are associated with distinctly different gene expression patterns and more importantly, a significant difference in clinical outcome. To further validate and more thoroughly characterize these two subtypes at the molecular level in tumors at an early stage, we report a gene expression profiling study using three different DNA microarray platforms. Results: Expression data from 20 tumor biopsies of early stage breast carcinomas were generated on three different DNA microarray platforms;Applied Biosystems Human Genome Survey microarrays, Stanford cDNA microarrays and Agilent's Whole Human Genome Oligo microarrays, and the resulting gene expression patterns were analyzed. Both unsupervised and supervised analyses identified the different clinically relevant subtypes of breast tumours, and the results were consistent across all three platforms. Gene classification and biological pathway analyses of the genes differentially expressed between the two main subtypes revealed different molecular mechanisms descriptive of the two expression-based subtypes: Signature genes of the luminal A subtype were over-represented by genes involved in fatty acid metabolism and steroid hormone-mediated signaling pathways, in particular estrogen receptor signaling, while signature genes of the basal-like subtype were over-represented by genes involved in cell proliferation and differentiation, p21-mediated pathway, and G1-S checkpoint of cell cycle-signaling pathways. A minimal set of 54 genes that best discriminated the two subtypes was identified using the combined data sets generated from the three different array platforms. These predictor genes were further verified by TaqMan (R) Gene E

关键词： microarray platform Gene Expression Assay Predictor Gene Intrinsic Gene Distinct Disease Entity

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Comparison of hybridization-based and sequencing-based gene expression technologies on biological replicates

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BMC GENOMICS 2007年第1期8卷 1-14页

作者： Liu, Fang Jenssen, Tor-Kristian Trimarchi, Jeff Punzo, Claudio Cepko, Connie L. Ohno-Machado, Lucila Hovig, Eivind Kuo, Winston Patrick Brigham & Womens Hosp Decis Syst Grp Boston MA 02115 USA Natl Hosp Norway Dept Tumor Biol Radiumhosp Med Ctr NO-0310 Oslo Norway Natl Hosp Norway Dept Med Informat Radiumhosp Med Ctr NO-0310 Oslo Norway PubGene AS NO-0319 Oslo Norway Harvard Univ Sch Med Dept Genet Boston MA 02115 USA Harvard Univ Sch Med Howard Hughes Med Inst Boston MA 02115 USA Harvard Univ Sch Dent Med Dept Dev Biol Boston MA 02115 USA Harvard Univ Fac Arts & Sci Dept Organism & Evolutionary Biol Cambridge MA 02138 USA

Background: High-throughput systems for gene expression profiling have been developed and have matured rapidly through the past decade. Broadly, these can be divided into two categories: hybridization-based and sequencing-based approaches. With data from different technologies being accumulated, concerns and challenges are raised about the level of agreement across technologies. As part of an ongoing large-scale cross-platform data comparison framework, we report here a comparison based on identical samples between one-dye DNA microarray platforms and MPSS (Massively Parallel Signature Sequencing). Results: The DNA microarray platforms generally provided highly correlated data, while moderate correlations between microarrays and MPSS were obtained. Disagreements between the two types of technologies can be attributed to limitations inherent to both technologies. The variation found between pooled biological replicates underlines the importance of exercising caution in identification of differential expression, especially for the purposes of biomarker discovery. Conclusion: Based on different principles, hybridization-based and sequencing-based technologies should be considered complementary to each other, rather than competitive alternatives for measuring gene expression, and currently, both are important tools for transcriptome profiling.

关键词： microarray platform Mouse Retina UniGene Cluster Biological Theme Mouse Cortex

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