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Search Results: 1 - 10 of 401964 matches for " Katrina M. Waters "
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Controlling the Response: Predictive Modeling of a Highly Central, Pathogen-Targeted Core Response Module in Macrophage Activation
Jason E. McDermott,Michelle Archuleta,Brian D. Thrall,Joshua N. Adkins,Katrina M. Waters
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0014673
Abstract: We have investigated macrophage activation using computational analyses of a compendium of transcriptomic data covering responses to agonists of the TLR pathway, Salmonella infection, and manufactured amorphous silica nanoparticle exposure. We inferred regulatory relationship networks using this compendium and discovered that genes with high betweenness centrality, so-called bottlenecks, code for proteins targeted by pathogens. Furthermore, combining a novel set of bioinformatics tools, topological analysis with analysis of differentially expressed genes under the different stimuli, we identified a conserved core response module that is differentially expressed in response to all studied conditions. This module occupies a highly central position in the inferred network and is also enriched in genes preferentially targeted by pathogens. The module includes cytokines, interferon induced genes such as Ifit1 and 2, effectors of inflammation, Cox1 and Oas1 and Oasl2, and transcription factors including AP1, Egr1 and 2 and Mafb. Predictive modeling using a reverse-engineering approach reveals dynamic differences between the responses to each stimulus and predicts the regulatory influences directing this module. We speculate that this module may be an early checkpoint for progression to apoptosis and/or inflammation during macrophage activation.
AHR2 Mutant Reveals Functional Diversity of Aryl Hydrocarbon Receptors in Zebrafish
Britton C. Goodale, Jane K. La Du, William H. Bisson, Derek B. Janszen, Katrina M. Waters, Robert L. Tanguay
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0029346
Abstract: The aryl hydrocarbon receptor (AHR) is well known for mediating the toxic effects of TCDD and has been a subject of intense research for over 30 years. Current investigations continue to uncover its endogenous and regulatory roles in a wide variety of cellular and molecular signaling processes. A zebrafish line with a mutation in ahr2 (ahr2hu3335), encoding the AHR paralogue responsible for mediating TCDD toxicity in zebrafish, was developed via Targeting Induced Local Lesions IN Genomes (TILLING) and predicted to express a non-functional AHR2 protein. We characterized AHR activity in the mutant line using TCDD and leflunomide as toxicological probes to investigate function, ligand binding and CYP1A induction patterns of paralogues AHR2, AHR1A and AHR1B. By evaluating TCDD-induced developmental toxicity, mRNA expression changes and CYP1A protein in the AHR2 mutant line, we determined that ahr2hu3335 zebrafish are functionally null. In silico modeling predicted differential binding of TCDD and leflunomide to the AHR paralogues. AHR1A is considered a non-functional pseudogene as it does not bind TCCD or mediate in vivo TCDD toxicity. Homology modeling, however, predicted a ligand binding conformation of AHR1A with leflunomide. AHR1A-dependent CYP1A immunohistochemical expression in the liver provided in vivo confirmation of the in silico docking studies. The ahr2hu3335 functional knockout line expands the experimental power of zebrafish to unravel the role of the AHR during development, as well as highlights potential activity of the other AHR paralogues in ligand-specific toxicological responses.
Topological analysis of protein co-abundance networks identifies novel host targets important for HCV infection and pathogenesis
Jason E McDermott, Deborah L Diamond, Courtney Corley, Angela L Rasmussen, Michael G Katze, Katrina M Waters
BMC Systems Biology , 2012, DOI: 10.1186/1752-0509-6-28
Abstract: We analyzed global proteomics data sets from a cell culture study of HCV infection and from a clinical study of liver biopsies from HCV-positive patients. Using lists of proteins known to be interaction partners with pathogen proteins we show that the most differentially regulated proteins in both data sets are indeed enriched in pathogen interactors. We then use these data sets to generate co-abundance networks that link proteins based on similar abundance patterns in time or across patients. Analysis of these co-abundance networks using a variety of network topology measures revealed that both degree and betweenness could be used to identify pathogen interactors with better accuracy than differential regulation alone, though betweenness provides the best discrimination. We found that though overall differential regulation was not correlated between the cell culture and liver biopsy data, network topology was conserved to an extent. Finally, we identified a set of proteins that has high betweenness topology in both networks including a protein that we have recently shown to be essential for HCV replication in cell culture.The results presented show that the network topology of protein co-abundance networks can be used to identify proteins important for viral replication. These proteins represent targets for further experimental investigation that will provide biological insight and potentially could be exploited for novel therapeutic approaches to combat HCV infection.Recent advances in high-throughput methods for taking global measurements of transcript or protein levels from biological samples have driven the field of systems biology. A common application of such methods is to identify genes or proteins that are likely to be involved in the disease process being studied to direct further experimental investigation. These 'targets' are potential mediators of important aspects of the disease, or may be downstream responses to the disease process. Targets are genera
Network Analysis of Epidermal Growth Factor Signaling Using Integrated Genomic, Proteomic and Phosphorylation Data
Katrina M. Waters, Tao Liu, Ryan D. Quesenberry, Alan R. Willse, Somnath Bandyopadhyay, Loel E. Kathmann, Thomas J. Weber, Richard D. Smith, H. Steven Wiley, Brian D. Thrall
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0034515
Abstract: To understand how integration of multiple data types can help decipher cellular responses at the systems level, we analyzed the mitogenic response of human mammary epithelial cells to epidermal growth factor (EGF) using whole genome microarrays, mass spectrometry-based proteomics and large-scale western blots with over 1000 antibodies. A time course analysis revealed significant differences in the expression of 3172 genes and 596 proteins, including protein phosphorylation changes measured by western blot. Integration of these disparate data types showed that each contributed qualitatively different components to the observed cell response to EGF and that varying degrees of concordance in gene expression and protein abundance measurements could be linked to specific biological processes. Networks inferred from individual data types were relatively limited, whereas networks derived from the integrated data recapitulated the known major cellular responses to EGF and exhibited more highly connected signaling nodes than networks derived from any individual dataset. While cell cycle regulatory pathways were altered as anticipated, we found the most robust response to mitogenic concentrations of EGF was induction of matrix metalloprotease cascades, highlighting the importance of the EGFR system as a regulator of the extracellular environment. These results demonstrate the value of integrating multiple levels of biological information to more accurately reconstruct networks of cellular response.
Conserved host response to highly pathogenic avian influenza virus infection in human cell culture, mouse and macaque model systems
Jason E McDermott, Harish Shankaran, Amie J Eisfeld, Sarah E Belisle, Gabriele Neuman, Chengjun Li, Shannon McWeeney, Carol Sabourin, Yoshihiro Kawaoka, Michael G Katze, Katrina M Waters
BMC Systems Biology , 2011, DOI: 10.1186/1752-0509-5-190
Abstract: In the present study, we employed a multivariate modeling approach to characterize and compare the transcriptional regulatory networks between these three model systems after infection with a highly pathogenic avian influenza virus of the H5N1 subtype. Using this approach we identified functions and pathways that display similar behavior and/or regulation including the well-studied impact on the interferon response and the inflammasome. Our results also suggest a primary response role for airway epithelial cells in initiating hypercytokinemia, which is thought to contribute to the pathogenesis of H5N1 viruses. We further demonstrate that we can use a transcriptional regulatory model from the human cell culture data to make highly accurate predictions about the behavior of important components of the innate immune system in tissues from whole organisms.This is the first demonstration of a global regulatory network modeling conserved host response between in vitro and in vivo models.The 1918 influenza virus pandemic was one of the most devastating in history, and is estimated to have killed over 50 million people worldwide [1]. The continued circulation of highly pathogenic avian H5N1 viruses and the emergence of the 2009 H1N1 pandemic virus has revived concerns about another lethal pandemic [2,3]. Although H5N1 viruses are largely zoonotic, human infections have occurred, with mortality approaching 60% [4], and there have been reports of limited human-to-human transmission [5-8]. Thus, there is a considerable need to understand the processes that drive pathogenicity of influenza, both in terms of viral dynamics and the host response to infection.The selection of the appropriate model to study viral pathogenicity is essential to maintain relevance with human disease. Given their considerable similarity to humans, macaques are an excellent choice for studying the host response to influenza infection [9]. However, they are expensive, genetically diverse, and not amenabl
Phosphoproteomics Profiling of Human Skin Fibroblast Cells Reveals Pathways and Proteins Affected by Low Doses of Ionizing Radiation
Feng Yang,Katrina M. Waters,John H. Miller,Marina A. Gritsenko,Rui Zhao,Xiuxia Du,Eric A. Livesay,Samuel O. Purvine,Matthew E. Monroe,Yingchun Wang,David G. Camp II,Richard D. Smith,David L. Stenoien
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0014152
Abstract: High doses of ionizing radiation result in biological damage; however, the precise relationships between long-term health effects, including cancer, and low-dose exposures remain poorly understood and are currently extrapolated using high-dose exposure data. Identifying the signaling pathways and individual proteins affected at the post-translational level by radiation should shed valuable insight into the molecular mechanisms that regulate dose-dependent responses to radiation.
Temporal Proteome and Lipidome Profiles Reveal Hepatitis C Virus-Associated Reprogramming of Hepatocellular Metabolism and Bioenergetics
Deborah L. Diamond equal contributor ,Andrew J. Syder equal contributor,Jon M. Jacobs,Christina M. Sorensen,Kathie-Anne Walters,Sean C. Proll,Jason E. McDermott,Marina A. Gritsenko,Qibin Zhang,Rui Zhao,Thomas O. Metz,David G. Camp II,Katrina M. Waters,Richard D. Smith,Charles M. Rice,Michael G. Katze
PLOS Pathogens , 2010, DOI: 10.1371/journal.ppat.1000719
Abstract: Proteomic and lipidomic profiling was performed over a time course of acute hepatitis C virus (HCV) infection in cultured Huh-7.5 cells to gain new insights into the intracellular processes influenced by this virus. Our proteomic data suggest that HCV induces early perturbations in glycolysis, the pentose phosphate pathway, and the citric acid cycle, which favor host biosynthetic activities supporting viral replication and propagation. This is followed by a compensatory shift in metabolism aimed at maintaining energy homeostasis and cell viability during elevated viral replication and increasing cellular stress. Complementary lipidomic analyses identified numerous temporal perturbations in select lipid species (e.g. phospholipids and sphingomyelins) predicted to play important roles in viral replication and downstream assembly and secretion events. The elevation of lipotoxic ceramide species suggests a potential link between HCV-associated biochemical alterations and the direct cytopathic effect observed in this in vitro system. Using innovative computational modeling approaches, we further identified mitochondrial fatty acid oxidation enzymes, which are comparably regulated during in vitro infection and in patients with histological evidence of fibrosis, as possible targets through which HCV regulates temporal alterations in cellular metabolic homeostasis.
A Network Integration Approach to Predict Conserved Regulators Related to Pathogenicity of Influenza and SARS-CoV Respiratory Viruses
Hugh D. Mitchell, Amie J. Eisfeld, Amy C. Sims, Jason E. McDermott, Melissa M. Matzke, Bobbi-Jo M. Webb-Robertson, Susan C. Tilton, Nicolas Tchitchek, Laurence Josset, Chengjun Li, Amy L. Ellis, Jean H. Chang, Robert A. Heegel, Maria L. Luna, Athena A. Schepmoes, Anil K. Shukla, Thomas O. Metz, Gabriele Neumann, Arndt G. Benecke, Richard D. Smith, Ralph S. Baric, Yoshihiro Kawaoka, Michael G. Katze, Katrina M. Waters
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0069374
Abstract: Respiratory infections stemming from influenza viruses and the Severe Acute Respiratory Syndrome corona virus (SARS-CoV) represent a serious public health threat as emerging pandemics. Despite efforts to identify the critical interactions of these viruses with host machinery, the key regulatory events that lead to disease pathology remain poorly targeted with therapeutics. Here we implement an integrated network interrogation approach, in which proteome and transcriptome datasets from infection of both viruses in human lung epithelial cells are utilized to predict regulatory genes involved in the host response. We take advantage of a novel “crowd-based” approach to identify and combine ranking metrics that isolate genes/proteins likely related to the pathogenicity of SARS-CoV and influenza virus. Subsequently, a multivariate regression model is used to compare predicted lung epithelial regulatory influences with data derived from other respiratory virus infection models. We predicted a small set of regulatory factors with conserved behavior for consideration as important components of viral pathogenesis that might also serve as therapeutic targets for intervention. Our results demonstrate the utility of integrating diverse ‘omic datasets to predict and prioritize regulatory features conserved across multiple pathogen infection models.
Caveats of chronic exogenous corticosterone treatments in adolescent rats and effects on anxiety-like and depressive behavior and hypothalamic-pituitary-adrenal (HPA) axis function
Patti Waters, Cheryl M McCormick
Biology of Mood & Anxiety Disorders , 2011, DOI: 10.1186/2045-5380-1-4
Abstract: In experiment 1, rats were injected with 40 mg/kg corticosterone or vehicle from postnatal days 30 to 45 and compared with no injection controls on behavior in the elevated plus maze (EPM) and the forced swim test (FST). Experiment 2 consisted of three treatments administered to rats from postnatal days 30 to 45 or as adults (days 70 to 85): either corticosterone (400 μg/ml) administered in the drinking water along with 2.5% ethanol, 2.5% ethanol or water only. In addition to testing on EPM, blood samples after the FST were obtained to measure plasma corticosterone. Analysis of variance (ANOVA) and alpha level of P < 0.05 were used to determine statistical significance.In experiment 1, corticosterone treatment of adolescent rats increased anxiety in the EPM and decreased immobility in the FST compared to no injection control rats. However, vehicle injected rats were similar to corticosterone injected rats, suggesting that adolescent rats may be highly vulnerable to stress of injection. In experiment 2, the intake of treated water, and thus doses delivered, differed for adolescents and adults, but there were no effects of treatment on behavior in the EPM or FST. Rats that had ingested corticosterone had reduced corticosterone release after the FST. Ethanol vehicle also affected corticosterone release compared to those ingesting water only, but differently for adolescents than for adults.The results indicate that several challenges must be overcome before the exogenous corticosterone model can be used effectively in adolescents.The World Health Organization has found mood disorders such as anxiety and depression to be a major contributor to disability and loss of years of health in women and in men [1]. Stressful experiences are implicated in the pathogenesis of mood disorders, and dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is a key feature of depression in particular (reviewed in [2-6]). Clinical research indicates that adolescence is a time of in
Predicting Job Satisfaction: Contributions of Individual Gratitude and Institutionalized Gratitude  [PDF]
Lea Waters
Psychology (PSYCH) , 2012, DOI: 10.4236/psych.2012.312A173
Abstract:

This study examined the role that employee perceptions of dispositional gratitude, state gratitude and institutionalized gratitude had upon job satisfaction. Employees (n = 171) completed measures of dispositional, state and institutionalized gratitude together with job satisfaction. Multiple Hierarchical Regression showed that state gratitude and institutional gratitude uniquely predict job satisfaction. The results have implications for the fields of positive organizational scholarship and positive organizational behavior and suggest that workplaces aiming to increase job satisfaction can do so through organizationally-based gratitude interventions and by institutionalizing gratitude into workplace culture.

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