Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lobular hepatic fibrosis and the presence of myofibroblasts were studied in heroin abusers, by quantitative automatic image analysis. Nineteen addicts (DA) and thirteen patients having stopped consumption (exDA) were compared to a non-addict group (CONTROL). Addicts, all anti-HIV and HBsAg negative, showed increased transaminase levels. Hepatitis C markers were ot available, at the time of biopsy. The surface of the centrolobular fibrosis, measured on picrosirius stained slides, was respectively 1.9 and 3.5 times larger in DA and exDA than in CONTROL (p < 0.0001). Immunolabelling with an alpha-smooth muscle actin antibody (alpha-SMA) revealed stellate cells in a perisinusoidal location, mainly in areas of matrix thickening in the space of Disse. Morphometric analysis of alpha-SMA expression showed significant differences between the three groups of patients, p < 0.0001 (CONTROL: 198.06 +/- 5.59 microns2; DA: 2227.91 +/- 88.02 microns2; exDA: 3469.10 +/- 154.98 microns2). The surface density of collagen and of alpha-SMA reactivity was also significantly different between these groups (p < 0.0001). These data strongly suggest that heroin is responsible for an early and progressive centrolobular liver fibrosis, occurring simultaneously with a myofibroblastic response. It might represent a reparative phenomenon arising from a direct vascular injury, leading to an impairment of blood-hepatocyte exchange.
Cell Mol Biol (Noisy-le-grand) 1997 Jun
PMID:Quantitative studies on liver fibrosis and alpha-smooth muscle actin expression in heroin abusers. 922 Jan 52

Comparison of complete genome sequences for different variants of hepatitis C virus (HCV) reveals several different constraints on sequence change. Synonymous changes are suppressed in coding regions at both 5' and 3' ends of the genome. No evidence was found for the existence of alternative reading frames or for a lower mutation frequency in these regions. Instead, suppression may be due to constraints imposed by RNA secondary structures identified within the core and NS5b genes. Nonsynonymous substitutions are less frequent than synonymous ones except in the hypervariable region of E2 and, to a lesser extent, in E1, NS2, and NS5b. Transitions are more frequent than transversions, particularly at the third position of codons where the bias is 16:1. In addition, nucleotide substitutions may not occur symmetrically since there is a bias toward G or C at the third position of codons, while T left and right arrow C transitions were twice as frequent as A left and right arrow G transitions. These different biases do not affect the phylogenetic analysis of HCV variants but need to be taken into account in interpreting sequence change in longitudinal studies.
J Mol Evol 1997 Sep
PMID:Characteristics of nucleotide substitution in the hepatitis C virus genome: constraints on sequence change in coding regions at both ends of the genome. 930 17

Hepatitis C virus (HCV), a major etiologic agent of transfusion associated hepatitis, is a positive, single-stranded RNA virus and is also known to be implicated in liver cirrhosis and hepatocellular carcinoma. Nonstructural protein 5A (NS5A) of HCV contains acidic and proline-rich amino acids in its carboxy-terminal half. These structural features resemble eukaryotic transcription activators. In this report, we show that NS5A functions as a potent transcriptional activator when fused to the yeast (Saccharomyces cerevisiae) GAL4 DNA-binding domain (1-147). The potential transcriptional activator maps to the C-terminal half of NS5A in the yeast cell. Therefore, our data provides the first evidence that NS5A may modulate host cell function at the transcriptional level.
Mol Cells 1997 Oct 31
PMID:Hepatitis C virus nonstructural protein 5A contains potential transcriptional activator domains. 938 55

Hepatitis C virus (HCV) is the major aetiological agent for blood-borne non-A, non-B hepatitis worldwide. Since its discovery in 1989, at least 28 HCV genotypes have been reported, which differ by > 20% in the nucleotide sequence of the entire genome (approximately 9500 nucleotides) or the sequence of the E1 gene (576 nucleotides). Different HCV genotypes have distinct geographical distributions, and may be associated with variations in viral replication and disease-inducing activity, as well as poor response to interferons in patients with chronic hepatitis C.
Mol Med Today 1995 Apr
PMID:Classifying hepatitis C virus genotypes. 941 33

It has been suggested that prolonged formalin fixation and block storage adversely affect hepatitis C virus (HCV) ribonucleic acid (RNA) detection in tissue by reverse transcriptase-polymerase chain reaction (RT-PCR). We attempted to determine whether short-term perfusion fixation (3-5 days) or prolonged formalin storage adversely affects the detection of HCV RNA in paraffin-embedded tissue in comparison with 24-h fixation. Also, we examined the effects of prolonged storage of paraffin blocks on the sensitivity for HCV detection. We performed RT-PCR in formalin-fixed explanted livers from 20 liver allograft recipients known to be HCV positive (10 with specimens stored for 2-4 years and 10 with specimens stored for > 4 years). We compared the results of perioperative needle liver biopsy specimens fixed overnight with liver sections fixed by perfusion for 3-5 days and bulk liver tissue stored in formalin for years (mean, 6.25 years; range, 2-11 years). HCV RNA was detected in 100%, 85%, and 0% of specimens fixed for 24 h, 3-4 days, and years, respectively. We conclude that HCV can be readily detected in tissue fixed by formalin overnight, sensitivity decreases slightly with intermediate-length fixation, and HCV is rendered undetectable by prolonged fixation. In addition, retention of formalin-fixed tissue in paraffin blocks does not affect the sensitivity of HCV detection.
Diagn Mol Pathol 1997 Oct
PMID:Effects of formalin fixation and prolonged block storage on detection of hepatitis C virus RNA in liver tissue. 945 86

The genetic diversity of hepatitis G virus (HGV) was investigated. By using a RT-PCR procedure, 14% of either HBV (hepatitis B virus)- or HCV (hepatitis C virus)-positive Korean hepatitis patients were proved to be HGV positives. Nucleotide sequences in the E1 region of the eight isolates from Korean patients and the six previously reported isolates were compared. Nucleotide substitutions spread uniformly throughout the E1 region. Sequence homology among the Korean isolates was 84-99% and 88-99% at the nucleotide and amino acid sequences, respectively, whereas those from different geographic areas was slightly lower at both levels. At least two genotypes might exist among the Korean HGV isolates. Compared to the corresponding region of HCV, the E1 sequence from HGV is moderately conserved. In addition, as frameshift mutations were observed in most of the Korean isolates compared to the prototype HGV sequence, the Korean isolates might not use the translational initiation site of the prototype HGV for polyprotein translation. Because a putative signal sequence of E1 for entry into endoplasmic reticulum starts from the N-terminus of the polyprotein, and capsid-like peptides composed of basic amino acids could not be detected from the upstream region of E1, the core protein of HGV is absent, or at least not present, at the region next to 5'-UTR. Therefore, HGV could be clearly distinguished from other genera of Flaviviridae.
Mol Cells 1998 Feb 28
PMID:Analysis of the envelope region of hepatitis G virus isolated from Korean patients. 957 42

The tyrosine phosphatase IA-2 is a molecular target of pancreatic islet autoimmunity in type 1 diabetes. T-cell epitope peptides in autoantigens have potential diagnostic and therapeutic applications, and they may hold clues to environmental agents with similar sequences that could trigger or exacerbate autoimmune disease. We identified 13 epitope peptides in IA-2 by measuring peripheral blood T-cell proliferation to 68 overlapping, synthetic peptides encompassing the intracytoplasmic domain of IA-2 in six at-risk type 1 diabetes relatives selected for HLA susceptibility haplotypes. The dominant epitope, VIVMLTPLVEDGVKQC (aa 805-820), which elicited the highest T-cell responses in all at-risk relatives, has 56% identity and 100% similarity over 9 amino acids (aa) with a sequence in VP7, a major immunogenic protein of human rotavirus. Both peptides bind to HLA-DR4(*0401) and are deduced to present identical aa to the T-cell receptor. The contiguous sequence of VP7 has 75% identity and 92% similarity over 12 aa with a known T-cell epitope in glutamic acid decarboxylase (GAD), another autoantigen in type 1 diabetes. This dominant IA-2 epitope peptide also has 75-45% identity and 88-64% similarity over 8-14 aa to sequences in Dengue, cytomegalovirus, measles, hepatitis C, and canine distemper viruses, and the bacterium Haemophilus influenzae. Three other IA-2 epitope peptides are 71-100% similar over 7-12 aa to herpes, rhino-, hanta- and flaviviruses. Two others are 80-82% similar over 10-11 aa to sequences in milk, wheat, and bean proteins. Further studies should now be carried out to directly test the hypothesis that T-cell activation by rotavirus and possibly other viruses, and dietary proteins, could trigger or exacerbate beta-cell autoimmunity through molecular mimicry with IA-2 and (for rotavirus) GAD.
Mol Med 1998 Apr
PMID:T-cell epitopes in type 1 diabetes autoantigen tyrosine phosphatase IA-2: potential for mimicry with rotavirus and other environmental agents. 960 76

In this study we have investigated the subcellular localization in transfected COS-1 cells of the two major forms of the hepatitis C virus core protein: the immature protein of 191 residues (p21) and its proteolytically cleaved product of 173 residues (p19). In this study, and unlike previous investigations, we have been able to distinguish separately the localization of p21 from p19. This was achieved by the addition of a C-terminal HSV Tag to the p21 full coding sequence, and exploiting the fact that it is subsequently lost in the p19 product. In order to obtain an accurate localization of both p21 and p19 we used a mouse anti-HSV Tag MAb together with a human anti-core MAb (B12.F8) to perform double immunofluorescence studies. The results have shown that p21 is always localized around the nuclear envelope. On the other hand, p19 can be found diffused in the cytoplasm to different degrees. These in vivo results reinforce the proposed links between the regulated processing of the hepatitis C virus core protein and the possibility that this may contribute towards the regulation of its diverse biological functions.
Cell Mol Biol (Noisy-le-grand) 1998 May
PMID:Localization of the different hepatitis C virus core gene products expressed in COS-1 cells. 962 Apr 47

The PKR protein kinase is a critical component of the cellular antiviral and antiproliferative responses induced by interferons. Recent evidence indicates that the nonstructural 5A (NS5A) protein of hepatitis C virus (HCV) can repress PKR function in vivo, possibly allowing HCV to escape the antiviral effects of interferon. NS5A presents a unique tool by which to study the molecular mechanisms of PKR regulation in that mutations within a region of NS5A, termed the interferon sensitivity-determining region (ISDR), are associated with sensitivity of HCV to the antiviral effects of interferon. In this study, we investigated the mechanisms of NS5A-mediated PKR regulation and the effect of ISDR mutations on this regulatory process. We observed that the NS5A ISDR, though necessary, was not sufficient for PKR interactions; we found that an additional 26 amino acids (aa) carboxyl to the ISDR were required for NS5A-PKR complex formation. Conversely, we localized NS5A binding to within PKR aa 244 to 296, recently recognized as a PKR dimerization domain. Consistent with this observation, we found that NS5A from interferon-resistant HCV genotype 1b disrupted kinase dimerization in vivo. NS5A-mediated disruption of PKR dimerization resulted in repression of PKR function and inhibition of PKR-mediated eIF-2alpha phosphorylation. Introduction of multiple ISDR mutations abrogated the ability of NS5A to bind to PKR in mammalian cells and to inhibit PKR in a yeast functional assay. These results indicate that mutations within the PKR-binding region of NS5A, including those within the ISDR, can disrupt the NS5A-PKR interaction, possibly rendering HCV sensitive to the antiviral effects of interferon. We propose a model of PKR regulation by NS5A which may have implications for therapeutic strategies against HCV.
Mol Cell Biol 1998 Sep
PMID:Control of PKR protein kinase by hepatitis C virus nonstructural 5A protein: molecular mechanisms of kinase regulation. 971 Jun 5

We describe the construction and characterization of a hepatitis C virus (HCV) cDNA expression library displayed as a fusion to the carboxy terminus of the capsid protein D of bacteriophage lambda. cDNA inserts were obtained by tagged random-priming of the HCV genome and cloned into a lambda vector from which chimeric phage bearing both wild-type D protein and D fusion products on the capsid surface were produced. The resulting library was affinity-selected with anti-HCV human monoclonal antibodies recognizing linear or conformational epitopes, and human sera from HCV-infected patients. Selection was monitored by immuno-screening experiments, ELISA, and sequence analysis of positive clones. The performance of this library was compared with two additional HCV cDNA display libraries generated as N-terminal fusions to the III and VIII capsid proteins of filamentous phage M13. The results obtained demonstrate the great potential of the lambda display system for constructing complex cDNA libraries for natural ligand discovery.
J Mol Biol 1998 Sep 11
PMID:Efficient display of an HCV cDNA expression library as C-terminal fusion to the capsid protein D of bacteriophage lambda. 973 45


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