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Institute for Systems Biology

NonprofitSeattle, Washington, United States
About: Institute for Systems Biology is a nonprofit organization based out in Seattle, Washington, United States. It is known for research contribution in the topics: Population & Proteomics. The organization has 1277 authors who have published 2777 publications receiving 353165 citations.


Papers
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Journal ArticleDOI
TL;DR: The identification of CCL1 as a gene involved in host susceptibility to TB and the first study to combine microarray and DNA polymorphism studies to identify genes associated with TB susceptibility suggest that genome-wide studies can provide an unbiased method to identify critical macrophage response genes that are associated with different clinical outcomes.
Abstract: Although host genetics influences susceptibility to tuberculosis (TB), few genes determining disease outcome have been identified. We hypothesized that macrophages from individuals with different clinical manifestations of Mycobacterium tuberculosis (Mtb) infection would have distinct gene expression profiles and that polymorphisms in these genes may also be associated with susceptibility to TB. We measured gene expression levels of >38,500 genes from ex vivo Mtb-stimulated macrophages in 12 subjects with 3 clinical phenotypes: latent, pulmonary, and meningeal TB (n = 4 per group). After identifying differentially expressed genes, we confirmed these results in 34 additional subjects by real-time PCR. We also used a case-control study design to examine whether polymorphisms in differentially regulated genes were associated with susceptibility to these different clinical forms of TB. We compared gene expression profiles in Mtb-stimulated and unstimulated macrophages and identified 1,608 and 199 genes that were differentially expressed by >2- and >5-fold, respectively. In an independent sample set of 34 individuals and a subset of highly regulated genes, 90% of the microarray results were confirmed by RT-PCR, including expression levels of CCL1, which distinguished the 3 clinical groups. Furthermore, 6 single nucleotide polymorphisms (SNPs) in CCL1 were found to be associated with TB in a case-control genetic association study with 273 TB cases and 188 controls. To our knowledge, this is the first identification of CCL1 as a gene involved in host susceptibility to TB and the first study to combine microarray and DNA polymorphism studies to identify genes associated with TB susceptibility. These results suggest that genome-wide studies can provide an unbiased method to identify critical macrophage response genes that are associated with different clinical outcomes and that variation in innate immune response genes regulate susceptibility to TB.

141 citations

Journal ArticleDOI
TL;DR: A genome-wide analysis of the acquisition of stress cross-tolerance shows that reduction of growth rate is an important determinant of severe stress survival.
Abstract: All organisms have evolved to cope with changes in environmental conditions, ensuring the optimal combination of proliferation and survival. In yeast, exposure to a mild stress leads to an increased tolerance for other stresses. This suggests that yeast uses information from the environment to prepare for future threats. We used the yeast knockout collection to systematically investigate the genes and functions involved in severe stress survival and in the acquisition of stress (cross-) tolerance. Besides genes and functions relevant for survival of heat, acid, and oxidative stress, we found an inverse correlation between mutant growth rate and stress survival. Using chemostat cultures, we confirmed that growth rate governs stress tolerance, with higher growth efficiency at low growth rates liberating the energy for these investments. Cellular functions required for stress tolerance acquisition, independent of the reduction in growth rate, were involved in vesicular transport, the Rpd3 histone deacetylase complex, and the mitotic cell cycle. Stress resistance and acquired stress tolerance in Saccharomyces cerevisiae are governed by a combination of stress-specific and general processes. The reduction of growth rate, irrespective of the cause of this reduction, leads to redistribution of resources toward stress tolerance functions, thus preparing the cells for impending change.

141 citations

Journal ArticleDOI
TL;DR: In this paper, the authors used biochemical and genetic approaches to demonstrate that the third detector senses bacterial DNA and identify it as Aim2, a receptor that has previously been shown to detect viral DNA.
Abstract: Pathogens are detected by pattern recognition receptors that, upon activation, orchestrate an appropriate immune response. The TLRs and the nucleotide-binding oligomerization domain-like receptors (NLRs) are prototypic pattern recognition receptors that detect extracellular and cytosolic pathogens, respectively. Listeria monocytogenes has both extracellular and cytosolic phases and is detected in the cytosol by members of the NLR family. These include two NLR members, NLRC4 and NLRP3, that, upon detection of cytosolic L. monocytogenes, induce the assembly of the inflammasome. Inflammasomes serve as platforms for the activation of the protease caspase 1, which mediates the processing and secretion of pro–IL-1β and pro–IL-18. We previously provided evidence that L. monocytogenes is also detected by a third inflammasome. We now use biochemical and genetic approaches to demonstrate that the third detector senses bacterial DNA and identify it as Aim2, a receptor that has previously been shown to detect viral DNA.

140 citations

Journal ArticleDOI
18 Oct 2012-Nature
TL;DR: The data suggest that the FOXO3–IRF7 regulatory circuit represents a novel mechanism for establishing the requisite set points in the interferon pathway that balances the beneficial effects and deleterious sequelae of the antiviral response.
Abstract: Antiviral responses must be tightly regulated to defend rapidly against infection while minimizing inflammatory damage. Type 1 interferons (IFN-I) are crucial mediators of antiviral responses and their transcription is regulated by a variety of transcription factors; principal among these is the family of interferon regulatory factors (IRFs). The IRF gene regulatory networks are complex and contain multiple feedback loops. The tools of systems biology are well suited to elucidate the complex interactions that give rise to precise coordination of the interferon response. Here we have used an unbiased systems approach to predict that a member of the forkhead family of transcription factors, FOXO3, is a negative regulator of a subset of antiviral genes. This prediction was validated using macrophages isolated from Foxo3-null mice. Genome-wide location analysis combined with gene deletion studies identified the Irf7 gene as a critical target of FOXO3. FOXO3 was identified as a negative regulator of Irf7 transcription and we have further demonstrated that FOXO3, IRF7 and IFN-I form a coherent feed-forward regulatory circuit. Our data suggest that the FOXO3-IRF7 regulatory circuit represents a novel mechanism for establishing the requisite set points in the interferon pathway that balances the beneficial effects and deleterious sequelae of the antiviral response.

140 citations

Journal ArticleDOI
TL;DR: Elevated expression of DKK1, alone or combined with beta-catenin, is a novel prognostic predictor for HCC patients and is a critical event in patients with HCC that indicates poor clinical outcome.

140 citations


Authors

Showing all 1292 results

NameH-indexPapersCitations
Younan Xia216943175757
Ruedi Aebersold182879141881
David Haussler172488224960
Steven P. Gygi172704129173
Nahum Sonenberg167647104053
Leroy Hood158853128452
Mark H. Ellisman11763755289
Wei Zhang112118993641
John Ralph10944239238
Eric H. Davidson10645447058
James R. Heath10342558548
Alan Aderem9924646682
Anne-Claude Gingras9733640714
Trey Ideker9730672276
Michael H. Gelb9450634714
Performance
Metrics
No. of papers from the Institution in previous years
YearPapers
20233
202260
2021216
2020204
2019188
2018168