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  • 1
    Online Resource
    Online Resource
    Conservation and Rewiring of Functional Modules Revealed by an Epistasis Map in Fission Yeast
    American Association for the Advancement of Science (AAAS) ; 2008
    In:  Science Vol. 322, No. 5900 ( 2008-10-17), p. 405-410
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 322, No. 5900 ( 2008-10-17), p. 405-410
    Abstract: An epistasis map (E-MAP) was constructed in the fission yeast, Schizosaccharomyces pombe , by systematically measuring the phenotypes associated with pairs of mutations. This high-density, quantitative genetic interaction map focused on various aspects of chromosome function, including transcription regulation and DNA repair/replication. The E-MAP uncovered a previously unidentified component of the RNA interference (RNAi) machinery ( rsh1 ) and linked the RNAi pathway to several other biological processes. Comparison of the S. pombe E-MAP to an analogous genetic map from the budding yeast revealed that, whereas negative interactions were conserved between genes involved in similar biological processes, positive interactions and overall genetic profiles between pairs of genes coding for physically associated proteins were even more conserved. Hence, conservation occurs at the level of the functional module (protein complex), but the genetic cross talk between modules can differ substantially.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.1162609
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2008
    detail.hit.zdb_id: 128410-1
    detail.hit.zdb_id: 2066996-3
    detail.hit.zdb_id: 2060783-0
    SSG: 11
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  • 2
    Online Resource
    Online Resource
    Interpretation of cancer mutations using a multiscale map of protein systems
    American Association for the Advancement of Science (AAAS) ; 2021
    In:  Science Vol. 374, No. 6563 ( 2021-10)
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 374, No. 6563 ( 2021-10)
    Abstract: A major goal of cancer research is to understand how mutations distributed across diverse genes affect common cellular systems, including multiprotein complexes and assemblies. Two challenges—how to comprehensively map such systems and how to identify which are under mutational selection—have hindered this understanding. Accordingly, we created a comprehensive map of cancer protein systems integrating both new and published multi-omic interaction data at multiple scales of analysis. We then developed a unified statistical model that pinpoints 395 specific systems under mutational selection across 13 cancer types. This map, called NeST (Nested Systems in Tumors), incorporates canonical processes and notable discoveries, including a PIK3CA-actomyosin complex that inhibits phosphatidylinositol 3-kinase signaling and recurrent mutations in collagen complexes that promote tumor proliferation. These systems can be used as clinical biomarkers and implicate a total of 548 genes in cancer evolution and progression. This work shows how disparate tumor mutations converge on protein assemblies at different scales.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.abf3067
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2021
    detail.hit.zdb_id: 128410-1
    detail.hit.zdb_id: 2066996-3
    detail.hit.zdb_id: 2060783-0
    SSG: 11
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    Online Resource
  • 3
    Online Resource
    Online Resource
    Integrated Genomic and Proteomic Analyses of a Systematically Perturbed Metabolic Network
    American Association for the Advancement of Science (AAAS) ; 2001
    In:  Science Vol. 292, No. 5518 ( 2001-05-04), p. 929-934
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 292, No. 5518 ( 2001-05-04), p. 929-934
    Abstract: We demonstrate an integrated approach to build, test, and refine a model of a cellular pathway, in which perturbations to critical pathway components are analyzed using DNA microarrays, quantitative proteomics, and databases of known physical interactions. Using this approach, we identify 997 messenger RNAs responding to 20 systematic perturbations of the yeast galactose-utilization pathway, provide evidence that approximately 15 of 289 detected proteins are regulated posttranscriptionally, and identify explicit physical interactions governing the cellular response to each perturbation. We refine the model through further iterations of perturbation and global measurements, suggesting hypotheses about the regulation of galactose utilization and physical interactions between this and a variety of other metabolic pathways.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.292.5518.929
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2001
    detail.hit.zdb_id: 128410-1
    detail.hit.zdb_id: 2066996-3
    detail.hit.zdb_id: 2060783-0
    SSG: 11
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    Online Resource
  • 4
    Online Resource
    Online Resource
    Conserved pathways within bacteria and yeast as revealed by global protein network alignment
    Proceedings of the National Academy of Sciences ; 2003
    In:  Proceedings of the National Academy of Sciences Vol. 100, No. 20 ( 2003-09-30), p. 11394-11399
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 100, No. 20 ( 2003-09-30), p. 11394-11399
    Abstract: We implement a strategy for aligning two protein–protein interaction networks that combines interaction topology and protein sequence similarity to identify conserved interaction pathways and complexes. Using this approach we show that the protein–protein interaction networks of two distantly related species, Saccharomyces cerevisiae and Helicobacter pylori , harbor a large complement of evolutionarily conserved pathways, and that a large number of pathways appears to have duplicated and specialized within yeast. Analysis of these findings reveals many well characterized interaction pathways as well as many unanticipated pathways, the significance of which is reinforced by their presence in the networks of both species.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1534710100
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2003
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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    Online Resource
  • 5
    Online Resource
    Online Resource
    Beyond Agar: Gel Substrates with Improved Optical Clarity and Drug Efficiency and Reduced Autofluorescence for Microbial Growth Experiments
    American Society for Microbiology ; 2015
    In:  Applied and Environmental Microbiology Vol. 81, No. 16 ( 2015-08-15), p. 5639-5649
    Details
    In: Applied and Environmental Microbiology, American Society for Microbiology, Vol. 81, No. 16 ( 2015-08-15), p. 5639-5649
    Abstract: Agar, a seaweed extract, has been the standard support matrix for microbial experiments for over a century. Recent developments in high-throughput genetic screens have created a need to reevaluate the suitability of agar for use as colony support, as modern robotic printing systems now routinely spot thousands of colonies within the area of a single microtiter plate. Identifying optimal biophysical, biochemical, and biological properties of the gel support matrix in these extreme experimental conditions is instrumental to achieving the best possible reproducibility and sensitivity. Here we systematically evaluate a range of gelling agents by using the yeast Saccharomyces cerevisiae as a model microbe. We find that carrageenan and Phytagel have superior optical clarity and reduced autofluorescence, crucial for high-resolution imaging and fluorescent reporter screens. Nutrient choice and use of refined Noble agar or pure agarose reduce the effective dose of numerous selective drugs by 〉 50%, potentially enabling large cost savings in genetic screens. Using thousands of mutant yeast strains to compare colony growth between substrates, we found no evidence of significant growth or nutrient biases between gel substrates, indicating that researchers could freely pick and choose the optimal gel for their respective application and experimental condition.
    Type of Medium: Online Resource
    ISSN: 0099-2240 , 1098-5336
    URL: Article
    DOI: 10.1128/AEM.01327-15
    RVK:
    WA 15000
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2015
    detail.hit.zdb_id: 223011-2
    detail.hit.zdb_id: 1478346-0
    SSG: 12
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  • 6
    Online Resource
    Online Resource
    Correcting for gene-specific dye bias in DNA microarrays using the method of maximum likelihood
    Oxford University Press (OUP) ; 2008
    In:  Bioinformatics Vol. 24, No. 1 ( 2008-01-01), p. 71-77
    Details
    In: Bioinformatics, Oxford University Press (OUP), Vol. 24, No. 1 ( 2008-01-01), p. 71-77
    Abstract: Motivation: In two-color microarray experiments, well-known differences exist in the labeling and hybridization efficiency of Cy3 and Cy5 dyes. Previous reports have revealed that these differences can vary on a gene-by-gene basis, an effect termed gene-specific dye bias. If uncorrected, this bias can influence the determination of differentially expressed genes. Results: We show that the magnitude of the bias scales multiplicatively with signal intensity and is dependent on which nucleotide has been conjugated to the fluorescent dye. A method is proposed to account for gene-specific dye bias within a maximum-likelihood error modeling framework. Using two different labeling schemes, we show that correcting for gene-specific dye bias results in the superior identification of differentially expressed genes within this framework. Improvement is also possible in related ANOVA approaches. Availability: A software implementation of this procedure is freely available at http://cellcircuits.org/VERA Contact:  rmkelley@ucsd.edu Supplementary information: Supplementary data are available at Bioinformatics online.
    Type of Medium: Online Resource
    ISSN: 1367-4811 , 1367-4803
    URL: Article
    DOI: 10.1093/bioinformatics/btm347
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2008
    detail.hit.zdb_id: 1468345-3
    SSG: 12
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    Online Resource
  • 7
    Online Resource
    Online Resource
    Papers on normalization, variable selection, classification or clustering of microarray data
    Oxford University Press (OUP) ; 2009
    In:  Bioinformatics Vol. 25, No. 6 ( 2009-03-15), p. 701-702
    Details
    In: Bioinformatics, Oxford University Press (OUP), Vol. 25, No. 6 ( 2009-03-15), p. 701-702
    Type of Medium: Online Resource
    ISSN: 1367-4811 , 1367-4803
    URL: Article
    DOI: 10.1093/bioinformatics/btp038
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2009
    detail.hit.zdb_id: 1468345-3
    SSG: 12
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  • 8
    Online Resource
    Online Resource
    Discovering regulatory and signalling circuits in molecular interaction networks
    Oxford University Press (OUP) ; 2002
    In:  Bioinformatics Vol. 18, No. suppl_1 ( 2002-07-01), p. S233-S240
    Details
    In: Bioinformatics, Oxford University Press (OUP), Vol. 18, No. suppl_1 ( 2002-07-01), p. S233-S240
    Abstract: Motivation: In model organisms such as yeast, large databases of protein–protein and protein-DNA interactions have become an extremely important resource for the study of protein function, evolution, and gene regulatory dynamics. In this paper we demonstrate that by integrating these interactions with widely-available mRNA expression data, it is possible to generate concrete hypotheses for the underlying mechanisms governing the observed changes in gene expression. To perform this integration systematically and at large scale, we introduce an approach for screening a molecular interaction network to identify active subnetworks, i.e., connected regions of the network that show significant changes in expression over particular subsets of conditions. The method we present here combines a rigorous statistical measure for scoring subnetworks with a search algorithm for identifying subnetworks with high score. Results: We evaluated our procedure on a small network of 332 genes and 362 interactions and a large network of 4160 genes containing all 7462 protein–protein and protein-DNA interactions in the yeast public databases. In the case of the small network, we identified five significant subnetworks that covered 41 out of 77 (53%) of all significant changes in expression. Both network analyses returned several top-scoring subnetworks with good correspondence to known regulatory mechanisms in the literature. These results demonstrate how large-scale genomic approaches may be used to uncover signalling and regulatory pathways in a systematic, integrative fashion. Availability: The methods presented in this paper are implemented in the Cytoscape software package which is available to the academic community at http://www.cytoscape.org. Contact: trey@wi.mit.edu Keywords: molecular interactions; gene expression; data integration; simulated annealing; Monte carlo methods. *To whom correspondence should be addressed.
    Type of Medium: Online Resource
    ISSN: 1367-4811 , 1367-4803
    URL: Article
    DOI: 10.1093/bioinformatics/18.suppl_1.S233
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2002
    detail.hit.zdb_id: 1468345-3
    SSG: 12
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  • 9
    Online Resource
    Online Resource
    NDEx IQuery: a multi-method network gene set analysis leveraging the Network Data Exchange
    Oxford University Press (OUP) ; 2023
    In:  Bioinformatics Vol. 39, No. 3 ( 2023-03-01)
    Details
    In: Bioinformatics, Oxford University Press (OUP), Vol. 39, No. 3 ( 2023-03-01)
    Abstract: The investigation of sets of genes using biological pathways is a common task for researchers and is supported by a wide variety of software tools. This type of analysis generates hypotheses about the biological processes that are active or modulated in a specific experimental context. Results The Network Data Exchange Integrated Query (NDEx IQuery) is a new tool for network and pathway-based gene set interpretation that complements or extends existing resources. It combines novel sources of pathways, integration with Cytoscape, and the ability to store and share analysis results. The NDEx IQuery web application performs multiple gene set analyses based on diverse pathways and networks stored in NDEx. These include curated pathways from WikiPathways and SIGNOR, published pathway figures from the last 27 years, machine-assembled networks using the INDRA system, and the new NCI-PID v2.0, an updated version of the popular NCI Pathway Interaction Database. NDEx IQuery’s integration with MSigDB and cBioPortal now provides pathway analysis in the context of these two resources. Availability and implementation NDEx IQuery is available at https://www.ndexbio.org/iquery and is implemented in Javascript and Java.
    Type of Medium: Online Resource
    ISSN: 1367-4811
    URL: Article
    DOI: 10.1093/bioinformatics/btad118
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
    detail.hit.zdb_id: 1468345-3
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  • 10
    Online Resource
    Online Resource
    Unveiling Complexity and Multipotentiality of Early Heart Fields
    Ovid Technologies (Wolters Kluwer Health) ; 2021
    In:  Circulation Research Vol. 129, No. 4 ( 2021-08-06), p. 474-487
    Details
    In: Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 129, No. 4 ( 2021-08-06), p. 474-487
    Abstract: Extraembryonic tissues, including the yolk sac and placenta, and the heart within the embryo, work to provide crucial nutrients to the embryo. The association of congenital heart defects with extraembryonic tissue defects further supports the potential developmental relationship between the heart and extraembryonic tissues. Although the development of early cardiac lineages has been well-studied, the developmental relationship between cardiac lineages, including epicardium, and extraembryonic mesoderm remains to be defined. Objective: To explore the developmental relationships between cardiac and extraembryonic lineages. Methods and Results: Through high-resolution single-cell and genetic lineage/clonal analyses, we show an unsuspected clonal relationship between extraembryonic mesoderm and cardiac lineages. Single-cell transcriptomics and trajectory analyses uncovered 2 mesodermal progenitor sources contributing to left ventricular cardiomyocytes, 1 embryonic and the other with an extraembryonic gene expression signature. Additional lineage-tracing studies revealed that the extraembryonic-related progenitors reside at the embryonic/extraembryonic interface in gastrulating embryos and produce distinct cell types forming the pericardium, septum transversum, epicardium, dorsolateral regions of the left ventricle and atrioventricular canal myocardium, and extraembryonic mesoderm. Clonal analyses demonstrated that these progenitors are multipotent, giving rise to not only cardiomyocytes and serosal mesothelial cell types but also, remarkably, extraembryonic mesoderm. Conclusions: Overall, our results reveal the location of previously unknown multipotent cardiovascular progenitors at the embryonic/extraembryonic interface and define the earliest embryonic origins of serosal mesothelial lineages, including the epicardium, which contributes fibroblasts and vascular support cells to the heart. The shared lineage relationship between embryonic cardiovascular lineages and extraembryonic mesoderm revealed by our studies underscores an underappreciated blurring of boundaries between embryonic and extraembryonic mesoderm. Our findings suggest unexpected underpinnings of the association between congenital heart disease and placental insufficiency anomalies and the potential utility of extraembryonic cells for generating cardiovascular cell types for heart repair.
    Type of Medium: Online Resource
    ISSN: 0009-7330 , 1524-4571
    URL: Article
    DOI: 10.1161/CIRCRESAHA.121.318943
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2021
    detail.hit.zdb_id: 1467838-X
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