24 results on '"Suthram S"'
Search Results
2. Additive Process Induced Strain (APIS) Technology for Lg = 30nm Band-Edge High-k/Metal Gate nMOSFET
- Author
-
Hussain, M. M., primary, Rader, K., additional, Smith, C., additional, Young, C., additional, Suthram, S., additional, Park, C., additional, Cruz, M., additional, Kirsch, P. D., additional, and Jammy, R., additional
- Published
- 2008
- Full Text
- View/download PDF
3. Strain additivity in III-V channels for CMOSFETs beyond 22nm technology node
- Author
-
Suthram, S., primary, Sun, Y., additional, Majhi, P., additional, Ok, I., additional, Kim, H., additional, Harris, H. R., additional, Goel, N., additional, Parthasarathy, S., additional, Koehler, A., additional, Acosta, T., additional, Nishida, T., additional, Tseng, H.-H., additional, Tsai, W., additional, Lee, J., additional, Jammy, R., additional, and Thompson, S. E., additional
- Published
- 2008
- Full Text
- View/download PDF
4. High Performance pMOSFETs Using Si/Si1-xGex/Si Quantum Wells with High-k/Metal Gate Stacks and Additive Uniaxial Strain for 22 nm Technology Node
- Author
-
Suthram, S., primary, Majhi, P., additional, Sun, G., additional, Kalra, P., additional, Harris, H. R., additional, Choi, K. J., additional, Heh, D., additional, Oh, J., additional, Kelly, D., additional, Choi, R., additional, Cho, B.J., additional, Hussain, M. M., additional, Smith, C., additional, Banerjee, S., additional, Tsai, W., additional, Thompson, S. E., additional, Tseng, H. H., additional, and Jammy, R., additional
- Published
- 2007
- Full Text
- View/download PDF
5. Piezoresistance Coefficients of (100) Silicon nMOSFETs Measured at Low and High ($\sim$1.5 GPa) Channel Stress
- Author
-
Suthram, S., primary, Ziegert, J. C., additional, Nishida, T., additional, and Thompson, S. E., additional
- Published
- 2007
- Full Text
- View/download PDF
6. Flexible, simplified CMOS on Si(110) with metal gate / high k for HP and LSTP
- Author
-
Harris, H. R., primary, Thompson, S. E., additional, Krishnan, S., additional, Kirsch, P., additional, Majhi, P., additional, Smith, C.E., additional, Hussain, M.M., additional, Sun, G., additional, Adhikari, H., additional, Suthram, S., additional, Lee, B.H., additional, Tseng, H.-H., additional, and Jammy, R., additional
- Published
- 2007
- Full Text
- View/download PDF
7. Future of Strained Si/Semiconductors in Nanoscale MOSFETs
- Author
-
Thompson, S. E., primary, Suthram, S., additional, Sun, Y., additional, Sun, G., additional, Parthasarathy, S., additional, Chu, M., additional, and Nishida, T., additional
- Published
- 2006
- Full Text
- View/download PDF
8. Uncovering Regulatory Pathways with Expression Quantitative Trait Loci.
- Author
-
Beyer, A., Suthram, S., and Ideker, T.
- Published
- 2007
- Full Text
- View/download PDF
9. High Performing pMOSFETs on Si(110) for Application to Hybrid Orientation Technologies -- Comparison of HfO2 and HfSiON.
- Author
-
Krishnan, S.A., Rusty Harris, H., Kirsch, P.D., Krug, C., Quevedo-Lopez, C., Young, C., Byoung Hun Lee, Choi, R., Chowdhury, N., Suthram, S., Thompson, S., Bersuker, G., and Jammy, R.
- Published
- 2006
- Full Text
- View/download PDF
10. Piezoresistance Coefficients of (100) Silicon nMOSFETs Measured at Low and High (~ 1.5 GPa) Channel Stress.
- Author
-
Suthram, S., Ziegert, J. C., Nishida, T., and Thompson, S. E.
- Subjects
SEMICONDUCTOR wafers ,TENSILE architecture ,BENDING stresses ,STRAINS & stresses (Mechanics) ,SILICON ,MICROELECTRONICS - Abstract
A flexure-based four-point mechanical wafer bending setup is used to apply large uniaxial tensile stress (up to 1.2 GPa) on industrial nMOSFETs with 0 to ∼700 MPa of process-induced stress. This provides the highest uniaxial channel stress to date at ∼1.5 GPa. The stress altered drain-current is measured for long and short (50–140 nm) devices and the extracted π-coefficients are observed to be approximately constant for stresses up to ∼1.5 GPa. For short devices, this trend is seen only after correcting for the significant degradation in the π-coefficients observed due to parasitic source/drain series resistances ( R
s/d ). [ABSTRACT FROM AUTHOR]- Published
- 2007
- Full Text
- View/download PDF
11. Understanding Strain Effects on Double-Gate FinFET Drive-Current Enhancement, Hot-Carrier Reliability and Ring-Oscillator Delay Performance via Uniaxial Wafer Bending Experiments.
- Author
-
Suthram, S., Harris, H.R., Hussain, M.M., Smith, C., Young, C.D., Yang, J.-W., Mathews, K., Freeman, K., Majhi, P., Tseng, H.H.-H., Jammy, R., and Thompson, S.E.
- Published
- 2008
- Full Text
- View/download PDF
12. A direct comparison of protein interaction confidence assignment schemes
- Author
-
Ruppin Eytan, Shlomi Tomer, Suthram Silpa, Sharan Roded, and Ideker Trey
- Subjects
Computer applications to medicine. Medical informatics ,R858-859.7 ,Biology (General) ,QH301-705.5 - Abstract
Abstract Background Recent technological advances have enabled high-throughput measurements of protein-protein interactions in the cell, producing large protein interaction networks for various species at an ever-growing pace. However, common technologies like yeast two-hybrid may experience high rates of false positive detection. To combat false positive discoveries, a number of different methods have been recently developed that associate confidence scores with protein interactions. Here, we perform a rigorous comparative analysis and performance assessment among these different methods. Results We measure the extent to which each set of confidence scores correlates with similarity of the interacting proteins in terms of function, expression, pattern of sequence conservation, and homology to interacting proteins in other species. We also employ a new metric, the Signal-to-Noise Ratio of protein complexes embedded in each network, to assess the power of the different methods. Seven confidence assignment schemes, including those of Bader et al., Deane et al., Deng et al., Sharan et al., and Qi et al., are compared in this work. Conclusion Although the performance of each assignment scheme varies depending on the particular metric used for assessment, we observe that Deng et al. yields the best performance overall (in three out of four viable measures). Importantly, we also find that utilizing any of the probability assignment schemes is always more beneficial than assuming all observed interactions to be true or equally likely.
- Published
- 2006
- Full Text
- View/download PDF
13. Flt3 agonist enhances immunogenicity of arenavirus vector-based simian immunodeficiency virus vaccine in macaques.
- Author
-
Boopathy AV, Nekkalapudi A, Sung J, Schulha S, Jin D, Sharma B, Ng S, Lu S, Wimmer R, Suthram S, Ahmadi-Erber S, Lauterbach H, Orlinger KK, Hung M, Carr B, Callebaut C, Geleziunas R, Kuhne M, Schmidt S, and Falkard B
- Subjects
- Animals, Simian Acquired Immunodeficiency Syndrome immunology, Simian Acquired Immunodeficiency Syndrome prevention & control, Membrane Proteins immunology, Membrane Proteins genetics, fms-Like Tyrosine Kinase 3 immunology, fms-Like Tyrosine Kinase 3 genetics, Antibodies, Viral immunology, Antibodies, Viral blood, Genetic Vectors, Immunogenicity, Vaccine, CD8-Positive T-Lymphocytes immunology, Macaca mulatta, Simian Immunodeficiency Virus immunology, Dendritic Cells immunology, SAIDS Vaccines immunology
- Abstract
Arenaviral vaccine vectors encoding simian immunodeficiency virus (SIV) immunogens are capable of inducing efficacious humoral and cellular immune responses in nonhuman primates. Several studies have evaluated the use of immune modulators to further enhance vaccine-induced T-cell responses. The hematopoietic growth factor Flt3L drives the expansion of various bone marrow progenitor populations, and administration of Flt3L was shown to promote expansion of dendritic cell populations in spleen and blood, which are targets of arenaviral vectors. Therefore, we evaluated the potential of Flt3 signaling to enhance the immunogenicity of arenaviral vaccines encoding SIV immunogens (SIV
SME543 Gag, Env, and Pol) in rhesus macaques, with a rhesus-specific engineered Flt3L-Fc fusion protein. In healthy animals, administration of Flt3L-Fc led to a 10- to 100-fold increase in type 1 dendritic cells 7 days after dosing, with no antidrug antibody (ADA) generation after repeated dosing. We observed that administration of Flt3L-Fc fusion protein 7 days before arenaviral vaccine increased the frequency and activation of innate immune cells and enhanced T-cell activation with no treatment-related adverse events. Flt3L-Fc administration induced early innate immune activation, leading to a significant enhancement in magnitude, breadth, and polyfunctionality of vaccine-induced T-cell responses. The Flt3L-Fc enhancement in vaccine immunogenicity was comparable to a combination with αCTLA-4 and supports the use of safe and effective variants of Flt3L to augment therapeutic vaccine-induced T-cell responses.IMPORTANCEInduction of a robust human immunodeficiency virus (HIV)-specific CD4+ and CD8+ T-cell response through therapeutic vaccination is considered essential for HIV cure. Arenaviral vaccine vectors encoding simian immunodeficiency virus (SIV) immunogens have demonstrated strong immunogenicity and efficacy in nonhuman primates. Here, we demonstrate that the immunogenicity of arenaviral vectors encoding SIV immunogens can be enhanced by administration of Flt3L-Fc fusion protein 7 days before vaccination. Flt3L-Fc-mediated increase in dendritic cells led to robust improvements in vaccine-induced T- and B-cell responses compared with vaccine alone, and Flt3L-Fc dosing was not associated with any treatment-related adverse events. Importantly, immune modulation by either Flt3L-Fc or αCTLA-4 led to comparable enhancement in vaccine response. These results indicate that the addition of Flt3L-Fc fusion protein before vaccine administration can significantly enhance vaccine immunogenicity. Thus, safe and effective Flt3L variants could be utilized as part of a combination therapy for HIV cure., Competing Interests: A.V.B., J.S., D.J., B.S., S.N., S.L., S. Suthram, M.H., B.C., C.C., R.G., M.K., and B.F. are Gilead employees and shareholders. A.N. is contracted by and works at Gilead. S.A.-E., H.L., K.K.O., R.W., S. Schulha, and S. Schmidt are employees of Hookipa Pharm Inc. and its subsidiary Hookipa Biotech GmbH and shareholders.- Published
- 2024
- Full Text
- View/download PDF
14. Arenavirus-Based Vectors Generate Robust SIV Immunity in Non-Human Primates.
- Author
-
Sharma B, Bekerman E, Truong H, Lee J, Gamez-Guerrero M, Boopathy A, Mital R, Huang KB, Ahmadi-Erber S, Wimmer R, Schulha S, Lauterbach H, Orlinger K, Suthram S, Lewis MG, Blair W, Makadzange T, Geleziunas R, Murry JP, and Schmidt S
- Abstract
Arenavirus-based vectors are being investigated as therapeutic vaccine candidates with the potential to elicit robust CD8 T-cell responses. We compared the immunogenicity of replicating (artPICV and artLCMV) and non-replicating (rPICV and rLCMV) arenavirus-based vectors expressing simian immunodeficiency virus (SIV) Gag and Envelope (Env) immunogens in treatment-naïve non-human primates. Heterologous regimens with non-replicating and replicating vectors elicited more robust SIV IFN-γ responses than a homologous regimen, and replicating vectors elicited significantly higher cellular immunogenicity than non-replicating vectors. The heterologous regimen elicited high anti-Env antibody titers when administered intravenously, with replicating vectors inducing significantly higher titers than non-replicating vectors. Intramuscular immunization resulted in more durable antibody responses than intravenous immunization for both vector platforms, with no difference between the replicating and non-replicating vectors. Overall, both replicating and non-replicating arenavirus vectors generated robust T- and B-cell-mediated immunity to SIV antigens in treatment-naïve non-human primates, supporting further evaluation of these vectors in a clinical setting for HIV therapy.
- Published
- 2024
- Full Text
- View/download PDF
15. Immunogenic arenavirus vector SIV vaccine reduces setpoint viral load in SIV-challenged rhesus monkeys.
- Author
-
Boopathy AV, Sharma B, Nekkalapudi A, Wimmer R, Gamez-Guerrero M, Suthram S, Truong H, Lee J, Li J, Martin R, Blair W, Geleziunas R, Orlinger K, Ahmadi-Erber S, Lauterbach H, Makadzange T, Falkard B, and Schmidt S
- Abstract
HIV affects more than 38 million people worldwide. Although HIV can be effectively treated by lifelong combination antiretroviral therapy, only a handful of patients have been cured. Therapeutic vaccines that induce robust de novo immune responses targeting HIV proteins and latent reservoirs will likely be integral for functional HIV cure. Our study shows that immunization of naïve rhesus macaques with arenavirus-derived vaccine vectors encoding simian immunodeficiency virus (SIV
SME543 Gag, Env, and Pol) immunogens is safe, immunogenic, and efficacious. Immunization induced robust SIV-specific CD8+ and CD4+ T-cell responses with expanded cellular breadth, polyfunctionality, and Env-binding antibodies with antibody-dependent cellular cytotoxicity. Vaccinated animals had significant reductions in median SIV viral load (1.45-log10 copies/mL) after SIVMAC251 challenge compared with placebo. Peak viral control correlated with the breadth of Gag-specific T cells and tier 1 neutralizing antibodies. These results support clinical investigation of arenavirus-based vectors as a central component of therapeutic vaccination for HIV cure., (© 2023. The Author(s).)- Published
- 2023
- Full Text
- View/download PDF
16. Intrahepatic quantification of HBV antigens in chronic hepatitis B reveals heterogeneity and treatment-mediated reductions in HBV core-positive cells.
- Author
-
Aggarwal A, Odorizzi PM, Brodbeck J, van Buuren N, Moon C, Chang S, Adona M, Suthram S, Suri V, Trowe T, Turner S, Marcellin P, Buti M, Gaggar A, Fletcher SP, Diehl L, Feierbach B, and Balsitis S
- Abstract
Background & Aims: Patterns of liver HBV antigen expression have been described but not quantified at single-cell resolution. We applied quantitative techniques to liver biopsies from individuals with chronic hepatitis B and evaluated sampling heterogeneity, effects of disease stage, and nucleos(t)ide (NUC) treatment, and correlations between liver and peripheral viral biomarkers., Methods: Hepatocytes positive for HBV core and HBsAg were quantified using a novel four-plex immunofluorescence assay and image analysis. Biopsies were analysed from HBeAg-positive (n = 39) and HBeAg-negative (n = 75) participants before and after NUC treatment. To evaluate sampling effects, duplicate biopsies collected at the same time point were compared. Serum or plasma samples were evaluated for levels of HBV DNA, HBsAg, hepatitis B core-related antigen (HBcrAg), and HBV RNA., Results: Diffusely distributed individual HBV core+ cells and foci of HBsAg+ cells were the most common staining patterns. Hepatocytes positive for both HBV core and HBsAg were rare. Paired biopsies revealed large local variation in HBV staining within participants, which was confirmed in a large liver resection. NUC treatment was associated with a >100-fold lower median frequency of HBV core+ cells in HBeAg-positive and HBeAg-negative participants, whereas reductions in HBsAg+ cells were not statistically significant. The frequency of HBV core+ hepatocytes was lower in HBeAg-negative participants than in HBeAg-positive participants at all time points evaluated. Total HBV+ hepatocyte burden correlated with HBcrAg, HBV DNA, and HBV RNA only in baseline HBeAg-positive samples., Conclusions: Reductions in HBV core+ hepatocytes were associated with HBeAg-negative status and NUC treatment. Variation in HBV positivity within individual livers was extensive. Correlations between the liver and the periphery were found only between biomarkers likely indicative of cccDNA (HBV core+ and HBcrAg, HBV DNA, and RNA)., Impact and Implications: HBV infects liver hepatocyte cells, and its genome can exist in two forms that express different sets of viral proteins: a circular genome called cccDNA that can express all viral proteins, including the HBV core and HBsAg proteins, or a linear fragment that inserts into the host genome typically to express HBsAg, but not HBV core. We used new techniques to determine the percentage of hepatocytes expressing the HBV core and HBsAg proteins in a large set of liver biopsies. We find that abundance and patterns of expression differ across patient groups and even within a single liver and that NUC treatment greatly reduces the number of core-expressing hepatocytes., Competing Interests: At the time this study was conducted, AA, PO, JB, NvB, CM, SC, MVA, VS, TT, ST, AG, SF, LD, BF, and SB were employees and stockholders of Gilead Sciences, Inc. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2022 The Author(s).)
- Published
- 2022
- Full Text
- View/download PDF
17. Novel, Selective Inhibitors of USP7 Uncover Multiple Mechanisms of Antitumor Activity In Vitro and In Vivo .
- Author
-
Ohol YM, Sun MT, Cutler G, Leger PR, Hu DX, Biannic B, Rana P, Cho C, Jacobson S, Wong ST, Sanchez J, Shah N, Pookot D, Abraham B, Young K, Suthram S, Marshall LA, Bradford D, Kozon N, Han X, Okano A, Maung J, Colas C, Schwarz J, Wustrow D, Brockstedt DG, and Kassner PD
- Subjects
- Animals, Cell Culture Techniques, Cell Line, Tumor, Female, Humans, Mice, Models, Molecular, Ubiquitin-Specific Peptidase 7 antagonists & inhibitors
- Abstract
The deubiquitinase USP7 regulates the levels of multiple proteins with roles in cancer progression and immune response. Thus, USP7 inhibition may decrease oncogene function, increase tumor suppressor function, and sensitize tumors to DNA-damaging agents. We have discovered a novel chemical series that potently and selectively inhibits USP7 in biochemical and cellular assays. Our inhibitors reduce the viability of multiple TP53 wild-type cell lines, including several hematologic cancer and MYCN -amplified neuroblastoma cell lines, as well as a subset of TP53 -mutant cell lines in vitro Our work suggests that USP7 inhibitors upregulate transcription of genes normally silenced by the epigenetic repressor complex, polycomb repressive complex 2 (PRC2), and potentiate the activity of PIM and PI3K inhibitors as well as DNA-damaging agents. Furthermore, oral administration of USP7 inhibitors inhibits MM.1S (multiple myeloma; TP53 wild type) and H526 (small cell lung cancer; TP53 mutant) tumor growth in vivo Our work confirms that USP7 is a promising, pharmacologically tractable target for the treatment of cancer., (©2020 American Association for Cancer Research.)
- Published
- 2020
- Full Text
- View/download PDF
18. Early role for IL-6 signalling during generation of induced pluripotent stem cells revealed by heterokaryon RNA-Seq.
- Author
-
Brady JJ, Li M, Suthram S, Jiang H, Wong WH, and Blau HM
- Subjects
- Animals, Cellular Reprogramming genetics, Cytokine Receptor gp130 genetics, Cytokine Receptor gp130 metabolism, Embryonic Stem Cells, Fungal Proteins, Gene Expression Profiling, Gene Expression Regulation, Humans, Induced Pluripotent Stem Cells cytology, Induced Pluripotent Stem Cells metabolism, Interleukin-6 genetics, Kruppel-Like Factor 4, Male, Mice, Mitogen-Activated Protein Kinases metabolism, Molecular Sequence Data, Sequence Analysis, RNA, Induced Pluripotent Stem Cells physiology, Interleukin-6 metabolism, Signal Transduction
- Abstract
Molecular insights into somatic cell reprogramming to induced pluripotent stem cells (iPS) would aid regenerative medicine, but are difficult to elucidate in iPS because of their heterogeneity, as relatively few cells undergo reprogramming (0.1-1%; refs , ). To identify early acting regulators, we capitalized on non-dividing heterokaryons (mouse embryonic stem cells fused to human fibroblasts), in which reprogramming towards pluripotency is efficient and rapid, enabling the identification of transient regulators required at the onset. We used bi-species transcriptome-wide RNA-seq to quantify transcriptional changes in the human somatic nucleus during reprogramming towards pluripotency in heterokaryons. During heterokaryon reprogramming, the cytokine interleukin 6 (IL6), which is not detectable at significant levels in embryonic stem cells, was induced 50-fold. A 4-day culture with IL6 at the onset of iPS reprogramming replaced stably transduced oncogenic c-Myc such that transduction of only Oct4, Klf4 and Sox2 was required. IL6 also activated another Jak/Stat target, the serine/threonine kinase gene Pim1, which accounted for the IL6-mediated twofold increase in iPS frequency. In contrast, LIF, another induced GP130 ligand, failed to increase iPS frequency or activate c-Myc or Pim1, thereby revealing a differential role for the two Jak/Stat inducers in iPS generation. These findings demonstrate the power of heterokaryon bi-species global RNA-seq to identify early acting regulators of reprogramming, for example, extrinsic replacements for stably transduced transcription factors such as the potent oncogene c-Myc.
- Published
- 2013
- Full Text
- View/download PDF
19. Network-based elucidation of human disease similarities reveals common functional modules enriched for pluripotent drug targets.
- Author
-
Suthram S, Dudley JT, Chiang AP, Chen R, Hastie TJ, and Butte AJ
- Subjects
- Cluster Analysis, Databases, Genetic, Humans, Linear Models, Oligonucleotide Array Sequence Analysis, Random Allocation, Statistics, Nonparametric, Computational Biology methods, Disease classification, Drug Delivery Systems methods, Gene Expression Profiling methods
- Abstract
Current work in elucidating relationships between diseases has largely been based on pre-existing knowledge of disease genes. Consequently, these studies are limited in their discovery of new and unknown disease relationships. We present the first quantitative framework to compare and contrast diseases by an integrated analysis of disease-related mRNA expression data and the human protein interaction network. We identified 4,620 functional modules in the human protein network and provided a quantitative metric to record their responses in 54 diseases leading to 138 significant similarities between diseases. Fourteen of the significant disease correlations also shared common drugs, supporting the hypothesis that similar diseases can be treated by the same drugs, allowing us to make predictions for new uses of existing drugs. Finally, we also identified 59 modules that were dysregulated in at least half of the diseases, representing a common disease-state "signature". These modules were significantly enriched for genes that are known to be drug targets. Interestingly, drugs known to target these genes/proteins are already known to treat significantly more diseases than drugs targeting other genes/proteins, highlighting the importance of these core modules as prime therapeutic opportunities.
- Published
- 2010
- Full Text
- View/download PDF
20. Evolutionarily conserved herpesviral protein interaction networks.
- Author
-
Fossum E, Friedel CC, Rajagopala SV, Titz B, Baiker A, Schmidt T, Kraus T, Stellberger T, Rutenberg C, Suthram S, Bandyopadhyay S, Rose D, von Brunn A, Uhlmann M, Zeretzke C, Dong YA, Boulet H, Koegl M, Bailer SM, Koszinowski U, Ideker T, Uetz P, Zimmer R, and Haas J
- Subjects
- Cluster Analysis, Evolution, Molecular, HeLa Cells, Herpesviridae metabolism, Herpesvirus 1, Human genetics, Herpesvirus 3, Human genetics, Herpesvirus 4, Human genetics, Herpesvirus 8, Human genetics, Humans, Immunohistochemistry, Muromegalovirus genetics, Phylogeny, Signal Transduction, Viral Core Proteins genetics, Viral Core Proteins metabolism, Virion metabolism, Herpesviridae genetics, Protein Interaction Mapping methods, Viral Proteins genetics, Viral Proteins metabolism
- Abstract
Herpesviruses constitute a family of large DNA viruses widely spread in vertebrates and causing a variety of different diseases. They possess dsDNA genomes ranging from 120 to 240 kbp encoding between 70 to 170 open reading frames. We previously reported the protein interaction networks of two herpesviruses, varicella-zoster virus (VZV) and Kaposi's sarcoma-associated herpesvirus (KSHV). In this study, we systematically tested three additional herpesvirus species, herpes simplex virus 1 (HSV-1), murine cytomegalovirus and Epstein-Barr virus, for protein interactions in order to be able to perform a comparative analysis of all three herpesvirus subfamilies. We identified 735 interactions by genome-wide yeast-two-hybrid screens (Y2H), and, together with the interactomes of VZV and KSHV, included a total of 1,007 intraviral protein interactions in the analysis. Whereas a large number of interactions have not been reported previously, we were able to identify a core set of highly conserved protein interactions, like the interaction between HSV-1 UL33 with the nuclear egress proteins UL31/UL34. Interactions were conserved between orthologous proteins despite generally low sequence similarity, suggesting that function may be more conserved than sequence. By combining interactomes of different species we were able to systematically address the low coverage of the Y2H system and to extract biologically relevant interactions which were not evident from single species.
- Published
- 2009
- Full Text
- View/download PDF
21. eQED: an efficient method for interpreting eQTL associations using protein networks.
- Author
-
Suthram S, Beyer A, Karp RM, Eldar Y, and Ideker T
- Subjects
- Animals, Fungal Proteins metabolism, Genotype, Humans, Linkage Disequilibrium, Models, Genetic, Models, Statistical, Oligonucleotide Array Sequence Analysis, Phenotype, Protein Interaction Mapping, Reproducibility of Results, Computational Biology methods, Proteins metabolism, Quantitative Trait Loci, Systems Biology methods
- Abstract
Analysis of expression quantitative trait loci (eQTLs) is an emerging technique in which individuals are genotyped across a panel of genetic markers and, simultaneously, phenotyped using DNA microarrays. Because of the spacing of markers and linkage disequilibrium, each marker may be near many genes making it difficult to finely map which of these genes are the causal factors responsible for the observed changes in the downstream expression. To address this challenge, we present an efficient method for prioritizing candidate genes at a locus. This approach, called 'eQTL electrical diagrams' (eQED), integrates eQTLs with protein interaction networks by modeling the two data sets as a wiring diagram of current sources and resistors. eQED achieved a 79% accuracy in recovering a reference set of regulator-target pairs in yeast, which is significantly higher than the performance of three competing methods. eQED also annotates 368 protein-protein interactions with their directionality of information flow with an accuracy of approximately 75%.
- Published
- 2008
- Full Text
- View/download PDF
22. A direct comparison of protein interaction confidence assignment schemes.
- Author
-
Suthram S, Shlomi T, Ruppin E, Sharan R, and Ideker T
- Subjects
- Caenorhabditis elegans Proteins genetics, Caenorhabditis elegans Proteins metabolism, Databases, Protein, Drosophila Proteins genetics, Drosophila Proteins metabolism, Protein Binding, Reproducibility of Results, Saccharomyces cerevisiae Proteins genetics, Sequence Alignment, Sequence Analysis, Protein, Sequence Homology, Amino Acid, Protein Interaction Mapping, Proteomics methods, Saccharomyces cerevisiae Proteins metabolism
- Abstract
Background: Recent technological advances have enabled high-throughput measurements of protein-protein interactions in the cell, producing large protein interaction networks for various species at an ever-growing pace. However, common technologies like yeast two-hybrid may experience high rates of false positive detection. To combat false positive discoveries, a number of different methods have been recently developed that associate confidence scores with protein interactions. Here, we perform a rigorous comparative analysis and performance assessment among these different methods., Results: We measure the extent to which each set of confidence scores correlates with similarity of the interacting proteins in terms of function, expression, pattern of sequence conservation, and homology to interacting proteins in other species. We also employ a new metric, the Signal-to-Noise Ratio of protein complexes embedded in each network, to assess the power of the different methods. Seven confidence assignment schemes, including those of Bader et al., Deane et al., Deng et al., Sharan et al., and Qi et al., are compared in this work., Conclusion: Although the performance of each assignment scheme varies depending on the particular metric used for assessment, we observe that Deng et al. yields the best performance overall (in three out of four viable measures). Importantly, we also find that utilizing any of the probability assignment schemes is always more beneficial than assuming all observed interactions to be true or equally likely.
- Published
- 2006
- Full Text
- View/download PDF
23. The Plasmodium protein network diverges from those of other eukaryotes.
- Author
-
Suthram S, Sittler T, and Ideker T
- Subjects
- Animals, Caenorhabditis elegans metabolism, Conserved Sequence, Drosophila melanogaster metabolism, Helicobacter pylori metabolism, Phylogeny, Plasmodium falciparum genetics, Protein Binding, Protozoan Proteins genetics, Saccharomyces cerevisiae metabolism, Species Specificity, Two-Hybrid System Techniques, Eukaryotic Cells metabolism, Plasmodium falciparum metabolism, Protozoan Proteins metabolism
- Abstract
Plasmodium falciparum is the pathogen responsible for over 90% of human deaths from malaria. Therefore, it has been the focus of a considerable research initiative, involving the complete DNA sequencing of the genome, large-scale expression analyses, and protein characterization of its life-cycle stages. The Plasmodium genome sequence is relatively distant from those of most other eukaryotes, with more than 60% of the 5,334 encoded proteins lacking any notable sequence similarity to other organisms. To systematically elucidate functional relationships among these proteins, a large two-hybrid study has recently mapped a network of 2,846 interactions involving 1,312 proteins within Plasmodium. This network adds to a growing collection of available interaction maps for a number of different organisms, and raises questions about whether the divergence of Plasmodium at the sequence level is reflected in the configuration of its protein network. Here we examine the degree of conservation between the Plasmodium protein network and those of model organisms. Although we find 29 highly connected protein complexes specific to the network of the pathogen, we find very little conservation with complexes observed in other organisms (three in yeast, none in the others). Overall, the patterns of protein interaction in Plasmodium, like its genome sequence, set it apart from other species.
- Published
- 2005
- Full Text
- View/download PDF
24. Conserved patterns of protein interaction in multiple species.
- Author
-
Sharan R, Suthram S, Kelley RM, Kuhn T, McCuine S, Uetz P, Sittler T, Karp RM, and Ideker T
- Subjects
- Amino Acid Sequence, Animals, Caenorhabditis elegans Proteins genetics, Databases, Nucleic Acid, Drosophila Proteins genetics, Saccharomyces cerevisiae Proteins genetics, Sequence Alignment, Sequence Homology, Nucleic Acid, Two-Hybrid System Techniques, Caenorhabditis elegans Proteins metabolism, Drosophila Proteins metabolism, Saccharomyces cerevisiae Proteins metabolism
- Abstract
To elucidate cellular machinery on a global scale, we performed a multiple comparison of the recently available protein-protein interaction networks of Caenorhabditis elegans, Drosophila melanogaster, and Saccharomyces cerevisiae. This comparison integrated protein interaction and sequence information to reveal 71 network regions that were conserved across all three species and many exclusive to the metazoans. We used this conservation, and found statistically significant support for 4,645 previously undescribed protein functions and 2,609 previously undescribed protein interactions. We tested 60 interaction predictions for yeast by two-hybrid analysis, confirming approximately half of these. Significantly, many of the predicted functions and interactions would not have been identified from sequence similarity alone, demonstrating that network comparisons provide essential biological information beyond what is gleaned from the genome.
- Published
- 2005
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.