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Search Results: 1 - 10 of 150431 matches for " Kevin B. Stacey "
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Tyrosine Phosphorylation of the E3 Ubiquitin Ligase TRIM21 Positively Regulates Interaction with IRF3 and Hence TRIM21 Activity
Kevin B. Stacey, Eamon Breen, Caroline A. Jefferies
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0034041
Abstract: Patients suffering from Systemic Lupus Erythematous (SLE) have elevated type I interferon (IFN) levels which correlate with disease activity and severity. TRIM21, an autoantigen associated with SLE, has been identified as an ubiquitin E3 ligase that targets the transcription factor IRF3 in order to turn off and limit type I IFN production following detection of viral and bacterial infection by Toll Like Receptors (TLRs). However, how the activity of TRIM21 is regulated downstream of TLRs is unknown. In this study we demonstrate that TRIM21 is tyrosine phosphorylated following TLR3 and TLR4 stimulation, suggesting that its activity is potentially regulated by tyrosine phosphorylation. Using Netphos, we have identified three key tyrosines that are strongly predicted to be phosphorylated, two of which are conserved between the human and murine forms of TRIM21, at residues 343, 388, and 393, all of which have been mutated from tyrosine to phenylalanine (Y343F, Y388F, and Y393F). We have observed that tyrosine phosphorylation of TRIM21 only occurs in the substrate binding PRY/SPRY domain, and that Y393, and to a lesser extent, Y388 are required for TRIM21 to function as a negative regulator of IFN-β promoter activity. Further studies revealed that mutating Y393 to phenylalanine inhibits the ability of TRIM21 to interact with its substrate, IRF3, thus providing a molecular explanation for the lack of activity of Y393 on the IFN-β promoter. Our data demonstrates a novel role for tyrosine phosphorylation in regulating the activity of TRIM21 downstream of TLR3 and TLR4. Given the pathogenic role of TRIM21 in systemic autoimmunity, these findings have important implications for the development of novel therapeutics.
A Protective Role for Complement C3 Protein during Pandemic 2009 H1N1 and H5N1 Influenza A Virus Infection
Kevin B. O'Brien,Thomas E. Morrison,David Y. Dundore,Mark T. Heise,Stacey Schultz-Cherry
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0017377
Abstract: Highly pathogenic H5N1 influenza infections are associated with enhanced inflammatory and cytokine responses, severe lung damage, and an overall dysregulation of innate immunity. C3, a member of the complement system of serum proteins, is a major component of the innate immune and inflammatory responses. However, the role of this protein in the pathogenesis of H5N1 infection is unknown. Here we demonstrate that H5N1 influenza virus infected mice had increased levels of C5a and C3 activation byproducts as compared to mice infected with either seasonal or pandemic 2009 H1N1 influenza viruses. We hypothesized that the increased complement was associated with the enhanced disease associated with the H5N1 infection. However, studies in knockout mice demonstrated that C3 was required for protection from influenza infection, proper viral clearance, and associated with changes in cellular infiltration. These studies suggest that although the levels of complement activation may differ depending on the influenza virus subtype, complement is an important host defense mechanism.
Transforming Growth Factor-β: Activation by Neuraminidase and Role in Highly Pathogenic H5N1 Influenza Pathogenesis
Christina M. Carlson equal contributor,Elizabeth A. Turpin equal contributor,Lindsey A. Moser,Kevin B. O'Brien,Troy D. Cline,Jeremy C. Jones,Terrence M. Tumpey,Jacqueline M. Katz,Laura A. Kelley,Jack Gauldie,Stacey Schultz-Cherry
PLOS Pathogens , 2010, DOI: 10.1371/journal.ppat.1001136
Abstract: Transforming growth factor-beta (TGF-β), a multifunctional cytokine regulating several immunologic processes, is expressed by virtually all cells as a biologically inactive molecule termed latent TGF-β (LTGF-β). We have previously shown that TGF-β activity increases during influenza virus infection in mice and suggested that the neuraminidase (NA) protein mediates this activation. In the current study, we determined the mechanism of activation of LTGF-β by NA from the influenza virus A/Gray Teal/Australia/2/1979 by mobility shift and enzyme inhibition assays. We also investigated whether exogenous TGF-β administered via a replication-deficient adenovirus vector provides protection from H5N1 influenza pathogenesis and whether depletion of TGF-β during virus infection increases morbidity in mice. We found that both the influenza and bacterial NA activate LTGF-β by removing sialic acid motifs from LTGF-β, each NA being specific for the sialic acid linkages cleaved. Further, NA likely activates LTGF-β primarily via its enzymatic activity, but proteases might also play a role in this process. Several influenza A virus subtypes (H1N1, H1N2, H3N2, H5N9, H6N1, and H7N3) except the highly pathogenic H5N1 strains activated LTGF-β in vitro and in vivo. Addition of exogenous TGF-β to H5N1 influenza virus–infected mice delayed mortality and reduced viral titers whereas neutralization of TGF-β during H5N1 and pandemic 2009 H1N1 infection increased morbidity. Together, these data show that microbe-associated NAs can directly activate LTGF-β and that TGF-β plays a pivotal role protecting the host from influenza pathogenesis.
Racial Provocation Induces Cortisol Responses in African-Americans*  [PDF]
Ali A. Weinstein, Angela Termini, Joshua B. Kazman, Stacey A. Zeno, Preetha Abraham, Patricia A. Deuster
Open Journal of Medical Psychology (OJMP) , 2013, DOI: 10.4236/ojmp.2013.24023
Abstract: Purpose: To examine salivary cortisol responses to a racially-charged stimulus in a group of African-American individuals. Methods: A nonrandom sample of 245 (age: 43.8 ± 11.1 years; 64% female) African-American individuals was recruited by advertisements. Specifically, salivary cortisol was assessed prior to and after being exposed to a racially-charged movie clip. In addition, the salivary cortisol was assessed in the morning and evening of the day following exposure to the racially-charged movie clip. Results: A statistically significant increase in cortisol was found (P < 0.005) in the whole sample. High cortisol responders (highest tertile) and low cortisol responders (lowest tertile) were compared. The high cortisol responders had an elevated cortisol level the following morning (P < 0.05) that abated by the evening sample (P > 0.20). In addition, the high cortisol responders who were younger, had lower waist to hip ratios, and experienced less lifetime discrimination than the low cortisol responders (P’s < 0.05). Conclusions: The findings of an increase in cortisol in response to a racial provocation may provide a potential explanatory factor for the increased rates of cardiovascular disease in African-American individuals.
Resource utilization and costs before and after total joint arthroplasty
Kevin J Bozic, Brett Stacey, Ariel Berger, Alesia Sadosky, Gerry Oster
BMC Health Services Research , 2012, DOI: 10.1186/1472-6963-12-73
Abstract: Using a large healthcare claims database, we identified patients over age 39 with hip or knee OA who underwent unilateral primary TJA (hip or knee) between 1/1/2006 and 9/30/2007. Utilization of healthcare services and costs were aggregated into three periods: 12 months "pre-surgery," 91 days "peri-operative," and 3 to 15 month "follow-up," Mean total pre-surgery costs were compared with follow-up costs using Wilcoxon signed-rank test.14,912 patients met inclusion criteria for the study. The mean total number of outpatient visits declined from pre-surgery to follow-up (18.0 visits vs 17.1), while the percentage of patients hospitalized increased (from 7.5% to 9.8%) (both p < 0.01). Mean total costs during the follow-up period were 18% higher than during pre-surgery ($11,043 vs. $9,632, p < 0.01), largely due to an increase in the costs of inpatient care associated with hospital readmissions ($3,300 vs. $1,817, p < 0.01). Pharmacotherapy costs were similar for both periods ($2013 [follow-up] vs. $1922 [pre-surgery], p = 0.33); outpatient care costs were slightly lower in the follow-up period ($4338 vs. $4571, p < 0.01). Mean total costs for the peri-operative period were $36,553.Mean total utilization of outpatient healthcare services declined slightly in the first year following TJA (exclusive of the peri-operative period), while mean total healthcare costs increased during the same time period, largely due to increased costs associated with hospital readmissions. Further study is necessary to determine whether healthcare costs decrease in subsequent years.Advanced osteoarthritis (OA) of the hip and knee is associated with severe pain, limitation in function, and impaired quality of life [1,2]. Patients with advanced OA of the hip or knee incur considerable healthcare costs related to pain medications (both oral and injectable), physical therapy, medical equipment, outpatient visits, and inpatient care [3]. In addition, the indirect or so-called "time costs" associa
The intrinsic value of HFO features as a biomarker of epileptic activity
Stephen V. Gliske,Kevin R. Moon,William C. Stacey,Alfred O. Hero III
Computer Science , 2015,
Abstract: High frequency oscillations (HFOs) are a promising biomarker of epileptic brain tissue and activity. HFOs additionally serve as a prototypical example of challenges in the analysis of discrete events in high-temporal resolution, intracranial EEG data. Two primary challenges are 1) dimensionality reduction, and 2) assessing feasibility of classification. Dimensionality reduction assumes that the data lie on a manifold with dimension less than that of the feature space. However, previous HFO analyses have assumed a linear manifold, global across time, space (i.e. recording electrode/channel), and individual patients. Instead, we assess both a) whether linear methods are appropriate and b) the consistency of the manifold across time, space, and patients. We also estimate bounds on the Bayes classification error to quantify the distinction between two classes of HFOs (those occurring during seizures and those occurring due to other processes). This analysis provides the foundation for future clinical use of HFO features and buides the analysis for other discrete events, such as individual action potentials or multi-unit activity.
Osteosarcomagenesis: Modeling Cancer Initiation in the Mouse
Kevin B. Jones
Sarcoma , 2011, DOI: 10.1155/2011/694136
Abstract: Osteosarcoma remains a deadly malignancy afflicting adolescents and young adults. The lack of a precursor and the panoply of genetic aberrations present in identified osteosarcomas makes study of its initiation difficult. A number of candidate hypotheses have been tested in the mouse, a species with a higher background incidence of osteosarcoma. Chemical carcinogens, external beam radiation, and bone-seeking heavy metal radioisotopes have all proven to be osteosarcomagenic in wild-type mice. A number of oncogenes, introduced via integrating viruses or aberrantly activated from heritable genetic loci, participate in and can individually drive osteosarcomagenesis. Germline and conditional gene ablations in the form of some but not all aneuploidy-inducing genes, conventional tumor suppressors, and factors that function normally in mesenchymal differentiation have also proven osteosarcomagenic, especially in combinations that silence the Rb1 and p53 pathways. This paper reviews the rich history of mouse models of osteosarcomagenesis, what they have taught us about the human disease, and what future mouse experiments yet promise to teach.
Population-based epidemiology of intensive care: critical importance of ascertainment of residency status
Kevin B Laupland
Critical Care , 2004, DOI: 10.1186/cc2947
Abstract: A population-based cohort study including all adults admitted to Calgary Health Region (CHR) multidisciplinary and cardiovascular surgical intensive care units (ICUs) between 1 May 1999 and 30 April 2003 was conducted. A comparison of patients resident and nonresident in the base population was then performed.A total of 12,193 adult patients had at least one admission to an ICU; 7767 (63.7%) were CHR residents, for an incidence of 263.7 per 100,000 per year. Male CHR residents were at significant increased risk for ICU admission as compared with females (330.5 per 100,000 versus 198.2 per 100,000; relative risk, 1.67; 95% confidence interval, 1.59–1.74; P < 0.0001), as were CHR residents aged 65 years and older as compared with younger patients (1719.9 per 100,000 versus 238.7 per 100,000; relative risk, 7.21; 95% confidence interval, 6.95–7.47; P < 0.0001). The mortality rate was significantly lower among non-CHR residents (12.7%) as compared with CHR residents (20.0%; P < 0.0001). Logistic regression modeling identified CHR residency as an independent risk factor for death (odds ratio, 1.4; 95% confidence interval, 1.2–1.5; P < 0.0001).This study provides information on the incidence of and demographic risk factors for admission to ICUs in a defined population. Inclusion of patients that are nonresident in base study populations may lead to gross errors in determination of the occurrence and outcomes of critical illness.Knowledge of the occurrence of and determinants of critical illness is important for establishing its burden and the risk factors for acquisition to guide wise allocation of limited healthcare and research resources. Population-based cohort studies that strictly include all episodes of disease occurring in residents of a geographically defined region are commonly accepted as the optimal design for such purposes [1-3]. However, these designs have rarely been used in the critical care medical literature [4-6]. Studies attempting to evaluate the distr
Osteosarcomagenesis: Modeling Cancer Initiation in the Mouse
Kevin B. Jones
Sarcoma , 2011, DOI: 10.1155/2011/694136
Abstract: Osteosarcoma remains a deadly malignancy afflicting adolescents and young adults. The lack of a precursor and the panoply of genetic aberrations present in identified osteosarcomas makes study of its initiation difficult. A number of candidate hypotheses have been tested in the mouse, a species with a higher background incidence of osteosarcoma. Chemical carcinogens, external beam radiation, and bone-seeking heavy metal radioisotopes have all proven to be osteosarcomagenic in wild-type mice. A number of oncogenes, introduced via integrating viruses or aberrantly activated from heritable genetic loci, participate in and can individually drive osteosarcomagenesis. Germline and conditional gene ablations in the form of some but not all aneuploidy-inducing genes, conventional tumor suppressors, and factors that function normally in mesenchymal differentiation have also proven osteosarcomagenic, especially in combinations that silence the Rb1 and p53 pathways. This paper reviews the rich history of mouse models of osteosarcomagenesis, what they have taught us about the human disease, and what future mouse experiments yet promise to teach. 1. Introduction Osteosarcoma is the most common primary bone malignancy and a leading cause of cancer death in adolescents and young adults [1]. Phenotypically, osteosarcoma adheres to a narrowly defined pattern of disease. Most osteosarcomas arise in the 2nd and 3rd decades of life in the metaphyses of long bones, especially near the major growth centers of the distal femur, proximal tibia, and proximal humerus [1, 2]. When osteosarcoma rarely develops in a patient over 40, it is usually secondary to prior radiation exposure or Paget's metabolic disease of bone. The vast majority of osteosarcomas (~95 percent) present as high-grade neoplasms, with microscopic metastatic disease at presentation the expectation in every case [3]. Intermediate and low-grade variants of osteosarcoma are extremely scarce [4]; benign bone-forming neoplasms are also much more rare than conventional osteosarcoma itself. There is no identifiable precursor to osteosarcoma. Despite this narrow clinical phenotype, the genotype of osteosarcoma aligns best with high-grade carcinomas, by its many cytogenetic aberrations and multiple mutations. It is difficult to discern which of these many derangements are causative of, as opposed to resultant from oncogenic transformation. Naturally, when the final state of these cells fails to readily highlight the pathway of transformation that engendered them, and no precursor lesion is known, scientists turn to
Basis for a neuronal version of Grover's quantum algorithm
Kevin B. Clark
Frontiers in Molecular Neuroscience , 2014, DOI: 10.3389/fnmol.2014.00029
Abstract: Grover’s quantum (search) algorithm exploits principles of quantum information theory and computation to surpass the strong Church-Turing limit governing classical computers. The algorithm initializes a search field into superposed N (eigen)states to later execute nonclassical “subroutines” involving unitary phase shifts of measured states and to produce root-rate or quadratic gain in the algorithmic time (O(N^1/2)) needed to find some “target” solution m. Akin to this fast technological search algorithm, single eukaryotic cells, such as differentiated neurons, perform natural quadratic speed-up in the search for appropriate store-operated Ca2+ response regulation of, among other processes, protein and lipid biosynthesis, cell energetics, stress responses, cell fate and death, synaptic plasticity, and immunoprotection. Such speed-up in cellular decision making results from spatiotemporal dynamics of networked intracellular Ca2+-induced Ca2+ release and the search (or signaling) velocity of Ca2+ wave propagation. As chemical processes, such as the duration of Ca2+ mobilization, become rate-limiting over interstore distances, Ca2+ waves quadratically decrease interstore-travel time from slow saltatory to fast continuous gradients proportional to the square-root of the classical Ca2+ diffusion coefficient, D^1/2, matching the computing efficiency of Grover’s quantum algorithm. In this Hypothesis and Theory article, I elaborate on these traits using a fire-diffuse-fire model of store-operated cytosolic Ca2+ signaling valid for glutaminergic neurons. Salient model features corresponding to Grover’s quantum algorithm are parameterized to meet requirements for the Oracle Hadamard transform and Grover’s iteration. A neuronal version of Grover’s quantum algorithm figures to benefit signal coincidence detection and integration, bidirectional synaptic plasticity, and other vital cell functions by rapidly selecting, ordering, and/or counting optional response regulation choices
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