179 research outputs found
Three inhibitors of type 1 human immunodeficiency virus long terminal repeat-directed gene expression and virus replication.
Low Rate of CMV End-Organ Disease in HIV-Infected Patients Despite Low CD4+ Cell Counts and CMV Viremia: Results of ACTG Protocol A5030
To describe cytomegalovirus (CMV) end-organ disease (EOD) rate in AIDS patients with low CD4+ cell count despite HAART who were enrolled in a randomized, placebo-controlled trial of preemptive valganciclovir (VGCV) to prevent CMV EOD in those with CMV viremia
DNA fragments binding CTCF in vitro and in vivo are capable of blocking enhancer activity
<p>Abstract</p> <p>Background</p> <p>Earlier we identified ten 100-300-bp long CTCF-binding DNA fragments selected earlier from a 1-Mb human chromosome 19 region. Here the positive-negative selection technique was used to check the ability of CTCF-binding human genomic fragments to block enhancer-promoter interaction when inserted into the genome.</p> <p>Results</p> <p>Ten CTCF-binding DNA fragments were inserted between the CMV enhancer and CMV minimal promoter driving the herpes simplex virus thymidine kinase (HSV<it>-tk</it>) gene in a vector expressing also the <it>neo</it><sup>R </sup>gene under a separate promoter. The constructs were then integrated into the genome of CHO cells, and the cells resistant to neomycin and ganciclovir (positive-negative selection) were picked up, and their DNAs were PCR analyzed to confirm the presence of the fragments between the enhancer and promoter in both orientations.</p> <p>Conclusions</p> <p>We demonstrated that all sequences identified by their CTCF binding both <it>in vitro </it>and <it>in vivo </it>had enhancer-blocking activity when inserted between the CMV minimal promoter and enhancer in stably transfected CHO cells.</p
Divergent Effects of Human Cytomegalovirus and Herpes Simplex Virus-1 on Cellular Metabolism
Viruses rely on the metabolic network of the host cell to provide energy and macromolecular precursors to fuel viral replication. Here we used mass spectrometry to examine the impact of two related herpesviruses, human cytomegalovirus (HCMV) and herpes simplex virus type-1 (HSV-1), on the metabolism of fibroblast and epithelial host cells. Each virus triggered strong metabolic changes that were conserved across different host cell types. The metabolic effects of the two viruses were, however, largely distinct. HCMV but not HSV-1 increased glycolytic flux. HCMV profoundly increased TCA compound levels and flow of two carbon units required for TCA cycle turning and fatty acid synthesis. HSV-1 increased anapleurotic influx to the TCA cycle through pyruvate carboxylase, feeding pyrimidine biosynthesis. Thus, these two related herpesviruses drive diverse host cells to execute distinct, virus-specific metabolic programs. Current drugs target nucleotide metabolism for treatment of both viruses. Although our results confirm that this is a robust target for HSV-1, therapeutic interventions at other points in metabolism might prove more effective for treatment of HCMV
Comparative Structural Analysis of Human DEAD-Box RNA Helicases
DEAD-box RNA helicases play various, often critical, roles in all processes where RNAs are involved. Members of this family of proteins are linked to human disease, including cancer and viral infections. DEAD-box proteins contain two conserved domains that both contribute to RNA and ATP binding. Despite recent advances the molecular details of how these enzymes convert chemical energy into RNA remodeling is unknown. We present crystal structures of the isolated DEAD-domains of human DDX2A/eIF4A1, DDX2B/eIF4A2, DDX5, DDX10/DBP4, DDX18/myc-regulated DEAD-box protein, DDX20, DDX47, DDX52/ROK1, and DDX53/CAGE, and of the helicase domains of DDX25 and DDX41. Together with prior knowledge this enables a family-wide comparative structural analysis. We propose a general mechanism for opening of the RNA binding site. This analysis also provides insights into the diversity of DExD/H- proteins, with implications for understanding the functions of individual family members
Developing a predictive modelling capacity for a climate change-vulnerable blanket bog habitat: Assessing 1961-1990 baseline relationships
Aim: Understanding the spatial distribution of high priority habitats and
developing predictive models using climate and environmental variables to
replicate these distributions are desirable conservation goals. The aim of this
study was to model and elucidate the contributions of climate and topography to
the distribution of a priority blanket bog habitat in Ireland, and to examine how
this might inform the development of a climate change predictive capacity for
peat-lands in Ireland.
Methods: Ten climatic and two topographic variables were recorded for grid
cells with a spatial resolution of 1010 km, covering 87% of the mainland
land surface of Ireland. Presence-absence data were matched to these variables
and generalised linear models (GLMs) fitted to identify the main climatic and
terrain predictor variables for occurrence of the habitat. Candidate predictor
variables were screened for collinearity, and the accuracy of the final fitted GLM
was evaluated using fourfold cross-validation based on the area under the curve
(AUC) derived from a receiver operating characteristic (ROC) plot. The GLM
predicted habitat occurrence probability maps were mapped against the actual
distributions using GIS techniques.
Results: Despite the apparent parsimony of the initial GLM using only climatic
variables, further testing indicated collinearity among temperature and precipitation
variables for example. Subsequent elimination of the collinear variables and
inclusion of elevation data produced an excellent performance based on the AUC
scores of the final GLM. Mean annual temperature and total mean annual
precipitation in combination with elevation range were the most powerful
explanatory variable group among those explored for the presence of blanket
bog habitat.
Main conclusions: The results confirm that this habitat distribution in general
can be modelled well using the non-collinear climatic and terrain variables tested
at the grid resolution used. Mapping the GLM-predicted distribution to the
observed distribution produced useful results in replicating the projected
occurrence of the habitat distribution over an extensive area. The methods
developed will usefully inform future climate change predictive modelling for
Irelan
Human Cytomegalovirus IE1 Protein Elicits a Type II Interferon-Like Host Cell Response That Depends on Activated STAT1 but Not Interferon-γ
Human cytomegalovirus (hCMV) is a highly prevalent pathogen that, upon primary
infection, establishes life-long persistence in all infected individuals. Acute
hCMV infections cause a variety of diseases in humans with developmental or
acquired immune deficits. In addition, persistent hCMV infection may contribute
to various chronic disease conditions even in immunologically normal people. The
pathogenesis of hCMV disease has been frequently linked to inflammatory host
immune responses triggered by virus-infected cells. Moreover, hCMV infection
activates numerous host genes many of which encode pro-inflammatory proteins.
However, little is known about the relative contributions of individual viral
gene products to these changes in cellular transcription. We systematically
analyzed the effects of the hCMV 72-kDa immediate-early 1 (IE1) protein, a major
transcriptional activator and antagonist of type I interferon (IFN) signaling,
on the human transcriptome. Following expression under conditions closely
mimicking the situation during productive infection, IE1 elicits a global type
II IFN-like host cell response. This response is dominated by the selective
up-regulation of immune stimulatory genes normally controlled by IFN-γ and
includes the synthesis and secretion of pro-inflammatory chemokines.
IE1-mediated induction of IFN-stimulated genes strictly depends on
tyrosine-phosphorylated signal transducer and activator of transcription 1
(STAT1) and correlates with the nuclear accumulation and sequence-specific
binding of STAT1 to IFN-γ-responsive promoters. However, neither synthesis
nor secretion of IFN-γ or other IFNs seems to be required for the
IE1-dependent effects on cellular gene expression. Our results demonstrate that
a single hCMV protein can trigger a pro-inflammatory host transcriptional
response via an unexpected STAT1-dependent but IFN-independent mechanism and
identify IE1 as a candidate determinant of hCMV pathogenicity
Evolution of Chilean colonizing populations of Drosophila subobscura: lethal genes and chromosomal arrangements
Effect upon the anti-HIV Activity of 3′-Azido-3′-Deoxythymidine and 3′-Fluoro-3′-Deoxythymidine of Combination with anti-Herpes Nucleoside Analogues
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