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Search Results: 1 - 10 of 328756 matches for " Gary S. Hayward "
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KSHV RTA Abolishes NFκB Responsive Gene Expression during Lytic Reactivation by Targeting vFLIP for Degradation via the Proteasome
Elana S. Ehrlich, Jennifer C. Chmura, John C. Smith, Nene N. Kalu, Gary S. Hayward
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0091359
Abstract: Kaposi's sarcoma herpesvirus (KSHV) is a gamma-2 herpesvirus present in all cases of Kaposi's sarcoma, primary effusion lymphoma (PEL), and some cases of multicentric Castleman's disease. Viral FLICE inhibitory protein (vFLIP) is a latently expressed gene that has been shown to be essential for survival of latently infected PEL cells by activating the NFκB pathway. Inhibitors of either vFLIP expression or the NF?B pathway result in enhanced lytic reactivation and apoptosis. We have observed a decrease in vFLIP protein levels and of NFκB activation in the presence of the KSHV lytic switch protein RTA. Whereas vFLIP alone induced expression of the NF?B responsive genes ICAM1 and TNFα, inclusion of RTA decreased vFLIP induced ICAM1 and TNFα expression in both co-transfected 293T cells and in doxycycline induced TREx BCBL1 cells. RTA expression resulted in proteasome dependent destabilization of vFLIP. Neither RTA ubiquitin E3 ligase domain mutants nor a dominant-negative RAUL mutant abrogated this effect, while RTA truncation mutants did, suggesting that RTA recruits a novel cellular ubiquitin E3 ligase to target vFLIP for proteasomal degradation, allowing for inhibition of NF?B responsive gene expression early during lytic reactivation.
Recombinant luciferase-expressing human cytomegalovirus (CMV) for evaluation of CMV inhibitors
Ran He, Gordon Sandford, Gary S Hayward, William H Burns, Gary H Posner, Michael Forman, Ravit Arav-Boger
Virology Journal , 2011, DOI: 10.1186/1743-422x-8-40
Abstract: Infection with Cytomegalovirus (CMV) continues to be a major threat in organ transplant recipients and congenitally-infected children [1,2]. Although existing systemic therapies are effective in suppressing virus replication, serious side effects and the emergence of resistant viral strains pose significant treatment dilemmas [3]. The need to identify and develop new anti-CMV compounds coincides with the advancement of rapid, sensitive, and high-throughput methods for screening of lead compounds. While the plaque reduction assay remains the gold-standard for screening of anti-viral compounds, new techniques based on recombinant DNA technology and highly sensitive molecular assays have recently been suggested as alternatives [4-6]. Real-time PCR, the standard of care in the management of CMV disease in high- risk patient populations, may also provide a sensitive tool for drug screening [7-12]In earlier studies, a series of chloramphenicol acetyl transferase (CAT) recombinants expressing CAT under the control of UL54 (DNA polymerase, POL) or UL99 (pp28) promoters were constructed. The expression of CAT in infected cells highly mimicked the expression pattern of the endogenous UL54 and UL99 [4,13]. Thus, these two gene promoters were selected to construct luciferase-recombinant CMV for quatification of CMV replication in a rapid and reproducuble way. We report on the evaluation of two luciferase recombinant viruses (pp28 and POL) and the correlation of the pp28-luciferase system with plaque reduction and real-time PCR in evaluation of CMV inhibition by anti-CMV compounds.Recombinant CMV based on the laboratory-adapted strain, Towne, was constructed by homologous recombination in transfected-infected cells. A β- galactosidase (β -gal)-expressing Towne virus was first constructed using an intergenic insertion site between US9 and US10. Prior studies in which a β-glucuronidase expression cassette was inserted in this intergenic region of the laboratory-adapted AD169 virus
Analysis of Human Cytomegalovirus-Encoded SUMO Targets and Temporal Regulation of SUMOylation of the Immediate-Early Proteins IE1 and IE2 during Infection
Eui Tae Kim, Young-Eui Kim, Ye Ji Kim, Myoung Kyu Lee, Gary S. Hayward, Jin-Hyun Ahn
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0103308
Abstract: Post-translational modification of proteins by members of the small ubiquitin-like modifier (SUMO) is involved in diverse cellular functions. Many viral proteins are SUMO targets and also interact with the cellular SUMOylation system. During human cytomegalovirus (HCMV) infection, the immediate-early (IE) proteins IE1 and IE2 are covalently modified by SUMO. IE2 SUMOylation promotes its transactivation activity, whereas the role of IE1 SUMOylation is not clear. We performed in silico, genome-wide analysis to identify possible SUMOylation sites in HCMV-encoded proteins and evaluated their modification using the E. coli SUMOylation system and in vitro assays. We found that only IE1 and IE2 are substantially modified by SUMO in E. coli, although US34A was also identified as a possible SUMO target in vitro. We also found that SUMOylation of IE1 and IE2 is temporally regulated during viral infection. Levels of SUMO-modified form of IE1 were increased during the early phase of infection, but decreased in the late phase when IE2 and its SUMO-modified forms were expressed at high levels. IE2 expression inhibited IE1 SUMOylation in cotransfection assays. As in IE2 SUMOylation, PIAS1, a SUMO E3 ligase, interacted with IE1 and enhanced IE1 SUMOylation. In in vitro assays, an IE2 fragment that lacked covalent and non-covalent SUMO attachment sites, but was sufficient for PIAS1 binding, effectively inhibited PIAS1-mediated SUMOylation of IE1, indicating that IE2 expression negatively regulates IE1 SUMOylation. We also found that the IE2-mediated downregulation of IE1 SUMOylation correlates with the IE1 activity to repress the promoter containing the interferon stimulated response elements. Taken together, our data demonstrate that IE1 and IE2 are the main viral SUMO targets in HCMV infection and that temporal regulation of their SUMOylation may be important in the progression of this infection.
Detection of a Single Identical Cytomegalovirus (CMV) Strain in Recently Seroconverted Young Women
Suchetha Murthy,Gary S. Hayward,Sarah Wheelan,Michael S. Forman,Jin-Hyun Ahn,Robert F. Pass,Ravit Arav-Boger
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0015949
Abstract: Infection with multiple CMV strains is common in immunocompromised hosts, but its occurrence in normal hosts has not been well-studied.
Quantum Coherence in Two Dimensions
S. W. Hawking,J. D. Hayward
Physics , 1993, DOI: 10.1103/PhysRevD.49.5252
Abstract: The formation and evaporation of two dimensional black holes are discussed. It is shown that if the radiation in minimal scalars has positive energy, there must be a global event horizon or a naked singularity. The former would imply loss of quantum coherence while the latter would lead to an even worse breakdown of predictability. CPT invariance would suggest that there ought to be past horizons as well. A way in which this could happen with wormholes is described.
Determinants of Vessel Targeting in Vasculitis
Gary S. Hoffman
Clinical and Developmental Immunology , 2004, DOI: 10.1080/17402520400001652
Abstract: Studies of autoimmune diseases have not yet elucidated why certain organs or vessels become the objects of injury while others are spared. This paper will explore the hypothesis that important differences exist in regions of the aorta that determine vulnerability to diseases, such as atherosclerosis, aortitis, giant cell arteritis and Takayasu's disease. The reader is invited to reassess; (1) whether the aorta is indeed a single homogeneous structure, and (2) whether the initial stage of aortitis (and indeed other diseases considered “autoimmune”) may be primarily due to acquired alterations of substrate, that influence unique immune profiles, which by themselves may not be pathogenic. Disease susceptibility and patterns are influenced by many factors that are inborn and acquired. Examples include genetic background, gender, ethnicity, aging, prior and concomitant illnesses, habits, diet, toxin and environmental exposures. Studies of vascular diseases must assess how such variables may affect regional differences in endothelial cells, subendothelial matrix, vascular smooth muscle and the response of each to a variety of stimuli.
Evaluation of Two Models for Human Topoisomerase I Interaction with dsDNA and Camptothecin Derivatives
Gary S. Laco
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0024314
Abstract: Human topoisomerase I (Top1) relaxes supercoiled DNA during cell division. Camptothecin stabilizes Top1/dsDNA covalent complexes which ultimately results in cell death, and this makes Top1 an anti-cancer target. There are two current models for how camptothecin and derivatives bind to Top1/dsDNA covalent complexes (Staker, et al., 2002, Proc Natl Acad Sci USA 99: 15387–15392; and Laco, et al., 2004, Bioorg Med Chem 12: 5225–5235). The interaction energies between bound camptothecin, and derivatives, and Top1/dsDNA in the two models were calculated. The published structure-activity-relationships for camptothecin and derivatives correlated with the interaction energies for camptothecin and derivatives in the Laco et al. model, however, this was not the case for several camptothecin derivatives in the Stacker et al. model. By defining the binding orientation of camptothecin and derivatives in the Top1/dsDNA active-site these results allow for the rational design of potentially more efficacious camptothecin derivatives.
The Influence of Bioactive Oxylipins from Marine Diatoms on Invertebrate Reproduction and Development
Gary S. Caldwell
Marine Drugs , 2009, DOI: 10.3390/md7030367
Abstract: Diatoms are one of the main primary producers in aquatic ecosystems and occupy a vital link in the transfer of photosynthetically-fixed carbon through aquatic food webs. Diatoms produce an array of biologically-active metabolites, many of which have been attributed as a form of chemical defence and may offer potential as candidate marine drugs. Of considerable interest are molecules belonging to the oxylipin family which are broadly disruptive to reproductive and developmental processes. The range of reproductive impacts includes; oocyte maturation; sperm motility; fertilization; embryogenesis and larval competence. Much of the observed bioactivity may be ascribed to disruption of intracellular calcium signalling, induction of cytoskeletal instability and promotion of apoptotic pathways. From an ecological perspective, the primary interest in diatom-oxylipins is in relation to the potential impact on energy flow in planktonic systems whereby the reproductive success of copepods (the main grazers of diatoms) is compromised. Much data exists providing evidence for and against diatom reproductive effects; however detailed knowledge of the physiological and molecular processes involved remains poor. This paper provides a review of the current state of knowledge of the mechanistic impacts of diatom-oxylipins on marine invertebrate reproduction and development.
'Rac'-ing upstream to treat rheumatoid arthritis
Gary S Firestein
Arthritis Research & Therapy , 2010, DOI: 10.1186/ar2924
Abstract: Protein-based therapeutics for rheumatoid arthritis have limitations despite improved clinical outcomes. In addition to expense and the need for parenteral administration, a significant percentage of patients do not have robust responses. Intracellular signaling molecules, such as members of the Rho family [1], represent an attractive alternative because the compounds are often orally bioavailable and can block numerous proinflammatory mediators simultaneously.Targeting signal transduction, however, has been an exercise in frustration until recently. The p38 mitogen-activated protein kinase saga is emblematic of these problems [2]. Despite abundant preclinical data supporting the utility of p38 inhibitors, benefit has been marginal at best [3]. It is important to recognize that success in biologics also did not come with the first attempt. Numerous failures preceded the advent of TNF blockers, including anti-CD4, anti-CD5 and anti-CD52 antibodies, IL-2-diphtheria toxin fusion protein, IFNγ, IL-2, and several others. Clinical efficacy for JAK and Syk inhibitors demonstrated in recent years crossed the Rubicon for signaling-directed therapeutics [4,5]. The question now is not whether some of these agents can be effective; rather, it is whether the toxicity and side effects will be acceptable in a world where biologics have an advantageous therapeutic index.A distinguishing feature of the encouraging interventions (Syk, JAK, and perhaps c-Kit) compared with p38 inhibitors is that the former targets are proximal in the signaling cascade. Going upstream can be risky, since each enzyme casts a broader penumbra of effects than a downstream target. This increases the potential for both benefit and toxicity. Risk, however, can be managed; lack of efficacy cannot.This lesson is being exploited by going far upstream using therapeutics that inhibit the Rac proteins. These signaling enzymes, unlike the classical protein kinases that phosphorylate various transcription factors, a
Pathogenesis of rheumatoid arthritis: how early is early?
Gary S Firestein
Arthritis Research & Therapy , 2005, DOI: 10.1186/ar1780
Abstract: Development of hypotheses to explain the pathogenesis of chronic rheumatoid arthritis (RA), including the interesting new study by Raza and colleagues [1], has been a wondrous adventure. Virtually every immune cell type and inflammatory mediator has been implicated in the disease process at one time or another. Older, temporarily discarded hypotheses on B cells and immune complexes have enjoyed renewed energy with the advent of anti-B-cell therapies [2]. Now that T-cell-directed approaches, such as CTLA4-Ig [3], demonstrate efficacy, it appears that therapies targeting this cell lineage also are effective in a subpopulation of patients. Hence, chronic rheumatoid synovitis is marked by a complex interplay between multiple cell types, and individual patients display their own distinct hierarchy for the efficacy of therapeutic interventions [4].On the other hand, there is much less information on disease mechanisms in the earliest stages of RA. This is, in part, due to the changing definitions of 'early RA', with a cutoff that has gradually migrated from 2 years of symptoms to as little as 6 weeks. Even in the latter case, a prolonged preclinical period of immune hyper-reactivity and asymptomatic synovitis could exist before the disease becomes fully established. Many investigators believe that an appropriate genetic background in combination with stochastic events, such as activation of innate immunity, can serve as the trigger for RA. Subsequent perpetuation of the disease might involve entirely distinct adaptive immune mechanisms that are independent of the initiating events.Implicit in this assessment, an adaptive T-cell response might be required for full expression of RA. The nature of this response remains poorly defined, and studies of chronic rheumatoid synovitis have generally demonstrated blunted T-cell function and surprisingly limited cytokine production compared with other T-cell-mediated diseases. The lymphocyte cytokine profile in chronic RA synovium an
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