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61.
62.
In Vivo Pathogenesis of a Human Immunodeficiency Virus Type 1 Reporter Virus 总被引:6,自引:4,他引:2 下载免费PDF全文
Our understanding of human immunodeficiency virus type 1 (HIV-1)-induced pathogenesis is hampered by the inability to detect HIV-1 gene expression in infected viable cells. In this report, we describe two HIV-1 reporter constructs that are replication competent and cytopathic in vivo. These constructs contain DNA regions of two different lengths that bear the cDNA for the murine heat-stable antigen in the vpr region of a CXCR4-tropic virus. We used the SCID-hu mouse model and these reporter viruses to perform detailed kinetic studies of HIV-1 infection of human thymocytes in vivo. We document that the CD4+/CD8+ thymocytes are the first to express virus and that this subset demonstrates the most rapid and extensive HIV-1-induced cell depletion. Following depletion of this subset, subsequent virus expression occurs predominantly in phenotypically CD4− cells, suggesting that CD4 down-regulation occurs in HIV-1-infected thymocytes in vivo. These results demonstrate the utility of these HIV-1 reporter constructs to monitor HIV pathogenesis in vitro and in vivo. 相似文献
63.
Interdomain salt‐bridges in the Ebola virus protein VP40 and their role in domain association and plasma membrane localization 下载免费PDF全文
Jeevan B. GC Kristen A. Johnson Monica L. Husby Cary T. Frick Bernard S. Gerstman Robert V. Stahelin Prem P. Chapagain 《Protein science : a publication of the Protein Society》2016,25(9):1648-1658
The Ebola virus protein VP40 is a transformer protein that possesses an extraordinary ability to accomplish multiple functions by transforming into various oligomeric conformations. The disengagement of the C‐terminal domain (CTD) from the N‐terminal domain (NTD) is a crucial step in the conformational transformations of VP40 from the dimeric form to the hexameric form or octameric ring structure. Here, we use various molecular dynamics (MD) simulations to investigate the dynamics of the VP40 protein and the roles of interdomain interactions that are important for the domain–domain association and dissociation, and report on experimental results of the behavior of mutant variants of VP40. The MD studies find that various salt‐bridge interactions modulate the VP40 domain dynamics by providing conformational specificity through interdomain interactions. The MD simulations reveal a novel salt‐bridge between D45‐K326 when the CTD participates in a latch‐like interaction with the NTD. The D45‐K326 salt‐bridge interaction is proposed to help domain–domain association, whereas the E76‐K291 interaction is important for stabilizing the closed‐form structure. The effects of the removal of important VP40 salt‐bridges on plasma membrane (PM) localization, VP40 oligomerization, and virus like particle (VLP) budding assays were investigated experimentally by live cell imaging using an EGFP‐tagged VP40 system. It is found that the mutations K291E and D45K show enhanced PM localization but D45K significantly reduced VLP formation. 相似文献
64.
Jamieson SE de Roubaix LA Cortina-Borja M Tan HK Mui EJ Cordell HJ Kirisits MJ Miller EN Peacock CS Hargrave AC Coyne JJ Boyer K Bessieres MH Buffolano W Ferret N Franck J Kieffer F Meier P Nowakowska DE Paul M Peyron F Stray-Pedersen B Prusa AR Thulliez P Wallon M Petersen E McLeod R Gilbert RE Blackwell JM 《PloS one》2008,3(6):e2285
65.
Reduced activities of β-galactosidase and β-N-acetylglucosaminidase were found in rat livers following experimentally induced inflammation. The greatest reduction in glycosidase activities were found 24 h after inflammation. The lysosomal fraction accounted for the bulk of both glycosidase activities in experimental and control rats. Kinetic experiments showed that inflammation did not affect Km values, but did result in a significant reduction in Vmax values. One suggestion to explain the results is that inflammation causes a reduction in biosynthesis or activation of the two glycosidases in rat liver. 相似文献
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67.
Tammy M. Rickabaugh Ruth M. Baxter Mary Sehl Janet S. Sinsheimer Patricia M. Hultin Lance E. Hultin Austin Quach Otoniel Martínez-Maza Steve Horvath Eric Vilain Beth D. Jamieson 《PloS one》2015,10(3)
Patients with treated HIV-1-infection experience earlier occurrence of aging-associated diseases, raising speculation that HIV-1-infection, or antiretroviral treatment, may accelerate aging. We recently described an age-related co-methylation module comprised of hundreds of CpGs; however, it is unknown whether aging and HIV-1-infection exert negative health effects through similar, or disparate, mechanisms. We investigated whether HIV-1-infection would induce age-associated methylation changes. We evaluated DNA methylation levels at >450,000 CpG sites in peripheral blood mononuclear cells (PBMC) of young (20-35) and older (36-56) adults in two separate groups of participants. Each age group for each data set consisted of 12 HIV-1-infected and 12 age-matched HIV-1-uninfected samples for a total of 96 samples. The effects of age and HIV-1 infection on methylation at each CpG revealed a strong correlation of 0.49, p<1 x10-200 and 0.47, p<1x10-200. Weighted gene correlation network analysis (WGCNA) identified 17 co-methylation modules; module 3 (ME3) was significantly correlated with age (cor=0.70) and HIV-1 status (cor=0.31). Older HIV-1+ individuals had a greater number of hypermethylated CpGs across ME3 (p=0.015). In a multivariate model, ME3 was significantly associated with age and HIV status (Data set 1: βage= 0.007088, p=2.08 x 10-9; βHIV= 0.099574, p=0.0011; Data set 2: βage= 0.008762, p=1.27x 10-5; βHIV= 0.128649, p= 0.0001). Using this model, we estimate that HIV-1 infection accelerates age-related methylation by approximately 13.7 years in data set 1 and 14.7 years in data set 2. The genes related to CpGs in ME3 are enriched for polycomb group target genes known to be involved in cell renewal and aging. The overlap between ME3 and an aging methylation module found in solid tissues is also highly significant (Fisher-exact p=5.6 x 10-6, odds ratio=1.91). These data demonstrate that HIV-1 infection is associated with methylation patterns that are similar to age-associated patterns and suggest that general aging and HIV-1 related aging work through some common cellular and molecular mechanisms. These results are an important first step for finding potential therapeutic targets and novel clinical approaches to mitigate the detrimental effects of both HIV-1-infection and aging. 相似文献
68.
Craig Jamieson Robert A. Campbell Iain A. Cumming Kevin J. Gillen Jonathan Gillespie Bert Kazemier Michael Kiczun Yvonne Lamont Amanda J. Lyons John K.F. Maclean Frederic Martin Elizabeth M. Moir John A. Morrow John Pantling Zoran Rankovic Lynn Smith 《Bioorganic & medicinal chemistry letters》2010,20(20):6072-6075
Starting from lead compound 1, we demonstrate how X-ray structural data can be used to understand SAR and expediently optimize bioavailability in a novel series of AMPA receptor modulators, furnishing 5 with improved bioavailability and robust in vivo activity. 相似文献
69.
Lisa C Willcocks Paul A Lyons Andrew J Rees Kenneth GC Smith 《Arthritis research & therapy》2010,12(1):202
The aetiology of anti-neutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis has not been well defined. Here
we review two factors which may play a role in the pathogenesis of the disease: genetics and infection. In particular, we
discuss the role of autoantibodies to LAMP-2, which may arise following infection with Gram-negative bacteria, and may contribute
to the development of ANCA-associated systemic vasculitis in genetically susceptible individuals. 相似文献
70.
Mary A. Jamieson David Knochel Adriana Manrique Timothy R. Seastedt 《Plant Ecology》2012,213(2):185-195
Plant performance is influenced by both top-down (e.g., herbivores) and bottom-up (e.g., soil nutrients) controls. Research
investigating the collective effects of such factors may provide important insight into the success and management of invasive
plants. Through a combination of observational and experimental field studies, we examined top-down and bottom-up effects
on the growth and reproduction of an invasive plant, Linaria dalmatica. First, we assessed attack levels and impacts of an introduced biocontrol agent, the stem-mining weevil Mecinus janthinus, on L. dalmatica plants across multiple years and sites. Then, we conducted a manipulative experiment to examine the effects of weevil attack,
soil nitrogen availability, and interspecific competition on L. dalmatica. We found substantial variations in weevil attack within populations as well as across sites and years. Observational and
experimental data showed that increased weevil attack was associated with a reduction in plant biomass and seed production,
but only at the highest levels of attack. Nitrogen addition had a strong positive effect on plant performance, with a two-fold
increase in biomass and seed production. Clipping neighboring vegetation resulted in no significant effects on L. dalmatica performance, suggesting that plants remained resource limited or continued to experienced belowground competitive effects.
Overall, our research indicates that M. janthinus can exert top-down effects on L. dalmatica; however, weevil densities and attack rates observed in this study have not reached sufficient levels to yield effective
control. Moreover, bottom-up controls, in particular, soil nitrogen availability, may have a large influence on the success
and spread of this invasive plant. 相似文献