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At least 253 records · Page 14Linked to original sources
PubMed1992

Pathogenesis and molecular biology of progressive multifocal leukoencephalopathy, the JC virus-induced demyelinating disease of the human brain.

Studies of the pathogenesis and molecular biology of JC virus infection over the last two decades have significantly changed our understanding of progressive multifocal leukoencephalopathy, which can be described as a subacute viral infection of neuroglial cells that probably follows reactivation of latent infection rather than being the consequence of prolonged JC virus replication in the brain. There is now sufficient evidence to suggest that JC virus latency occurs in kidney and B cells. However, JC virus isolates from brain or kidney differ in the regulatory regions of their viral genomes which are controlled by host cell factors for viral gene expression and replication. DNA sequences of noncoding regions of the viral genome display a certain heterogeneity among isolates from brain and kidney. These data suggest that an archetypal strain of JC virus exists whose sequence is altered during replication in different cell types. The JC virus regulatory region likely plays a significant role in establishing viral latency and must be acted upon for reactivation of the virus. A developing hypothesis is that reactivation takes place from latently infected B lymphocytes that are activated as a result of immune suppression. JC virus enters the brain in the activated B cell. Evidence for this mechanism is the detection of JC virus DNA in peripheral blood lymphocytes and infected B cells in the brains of patients with progressive multifocal leukoencephalopathy. Once virus enters the brain, astrocytes as well as oligodendrocytes support JC virus multiplication. Therefore, JC virus infection of neuroglial cells may impair other neuroglial functions besides the production and maintenance of myelin. Consequently our increased understanding of the pathogenesis of progressive multifocal leukoencephalopathy suggests new ways to intervene in JC virus infection with immunomodulation therapies. Perhaps along with trials of nucleoside analogs or interferon administration, this fatal disease, for which no consensus of antiviral therapy exists, may yield to innovative treatment protocols.

Animals↗
PubMed2000

Simultaneous detection of multiplex-amplified human immunodeficiency virus type 1 RNA, hepatitis C virus RNA, and hepatitis B virus DNA using a flow cytometer microsphere-based hybridization assay.

The feasibility of performing a multiplex assay for the detection of human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus (HCV) RNAs and hepatitis B virus (HBV) DNA is demonstrated. This assay is based (i) on the coamplification of a 142-bp fragment from the gag region of the HIV-1 genome and a 142-bp HIV-1 quantitation standard fragment, a 244-bp fragment from the 5' noncoding region of the HCV genome, and a 104-bp fragment from the pre-C and C gene regions of the HBV genome, using three sets of specific primers; (ii) on the capacity of these four biotinylated PCR products to hybridize to their specific oligonucleotide probe-coated microspheres; and (iii) on the ability of the flow cytometer to discriminate between distinct fluorescent-microsphere categories. Absence of cross-hybridization between the unrelated oligonucleotide probes and PCR products generated by the multiplex reverse transcription-PCR (RT-PCR) and the highly sensitive detection method allowed us to assess unambiguously the HIV-1 viral load and the infectious status of 35 serologically well-established clinical samples and 20 seronegative blood donor plasma samples tested. The results indicate that multiplex RT-PCR and flow cytometer microsphere-based hybridization assays, when combined, provide a rapid, sensitive, and specific method for the quantitation and detection of the major viral agents of infectious diseases in a single plasma sample.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Chronic variant of myocarditis associated with hepatitis C virus infection.

BACKGROUND: Although molecular biological studies suggest a pathogenic link between enterovirus infection and dilated cardiomyopathy (DCM), the frequency of detection of enteroviral RNA is not consistently high in myocardial tissue from patients with DCM. A recent study has suggested that hepatitis C virus (HCV) may also be involved in the development of DCM. METHODS AND RESULTS: We performed genomic analysis for HCV in three patients with chronic active myocarditis. In all three patients, serum aminotransferase activities remained within normal ranges until the terminal stage of heart failure. At necropsy, all three livers showed evidence of tissue damage caused by chronic congestion, and one liver had evidence of chronic hepatitis. Routinely processed, paraffin-embedded tissue blocks of myocardium and liver were analyzed. Renal specimens were also analyzed to exclude the possibility of myocardial contamination with HCV material from the circulating blood. RNA extracted from the heart, liver, and kidney was subjected to strand-specific reverse transcription and amplified by semi-nested polymerase chain reaction. The target nucleotide sequence was a 178-bp fragment of the highly conserved 5'-noncoding region. Both positive- (genomic) and negative-strand RNA (replicative intermediates) were present in myocardial and liver tissue samples from all three patients. However, negative-strand RNA was undetectable in renal tissue from one patient. CONCLUSIONS: These findings suggest that HCV replicated in myocardial tissue of these patients with myocarditis. Thus, HCV infection may contribute to the development of this unusual form of myocarditis.

Chronic Disease↗
PubMed1989

Identification of DNA-protein interactions and enhancer activity at the 5' end of the upstream regulatory region in human papillomavirus type 11.

We have examined the 5' end of the noncoding region of the genome of a human papillomavirus, HPV-11, for regulatory elements using permissive host cells. This region of unknown function in the upstream regulatory region (URR) is known to have unusual DNA structure and frequently contains rearrangements which are associated with some more virulent isolates. This 5' 269-bp fragment was found to exhibit both specific DNA-protein binding using laryngeal papilloma protein extracts and enhancer activity in normal and papillomatous primary laryngeal cells. The viral DNA flanks the L1 open reading frame and does not contain the viral E2 binding site. Three distinct protein binding sites are contained in a 50-bp region of the fragment. This fragment, as a whole, functions as an enhancer in primary laryngeal and papilloma cells when ligated to the SV40 promoter and SV40 T-antigen gene. We conclude that this part of the noncoding region of the papillomaviruses has elements characteristic of regulatory elements in cells permissive for infection by these viruses.

Antigens, Viral, Tumor↗
PubMed1999

Amino acid reiterations in yeast are overrepresented in particular classes of proteins and show evidence of a slippage-like mutational process.

Long amino acid repeats are often observed in eukaryotic proteins. In humans, several neurological disorders are caused by proteins containing abnormally long polyglutamines. However, no systematic analysis has attempted to investigate the relationship between reiterations of particular amino acids and protein function, the possible mechanisms involved in the generation of these regions, or the contribution of selection in restricting their genomic distribution, in a large collection of wild-type proteins. We have used baker's yeast open reading frames to study these questions. The most abundant amino acid repeats found in yeast proteins are repeats of glutamine, asparagine, aspartic acid, glutamic acid, and serine. Different amino acid repeats are concentrated in different classes of proteins. Acidic and polar amino acid repeats are significantly associated with transcription factors and protein kinases, while serine repeats are significantly associated with membrane transporter proteins. In most cases the codon structures encoding the repeats at the gene level show a significant bias toward long tracts of one of the possible codons, suggesting that trinucleotide slippage has played an important role in generating these reiterations. However, many, particularly those encoding serine repeats, do not show evidence of slippage. The distributions of codon repeats within proteins and between coding and noncoding regions of the genome, and of amino acids between proteins with different functions, suggest that repeats of these kinds are subject to strong selection.

Base Sequence↗
PubMed1989

Sequence analysis of the nucleocapsid protein gene of human coronavirus 229E.

Human coronaviruses are important human pathogens and have also been implicated in multiple sclerosis. To further understand the molecular biology of human coronavirus 229E (HCV-229E), molecular cloning and sequence analysis of the viral RNA have been initiated. Following established protocols, the 3'-terminal 1732 nucleotides of the genome were sequenced. A large open reading frame encodes a 389 amino acid protein of 43,366 Da, which is presumably the nucleocapsid protein. The predicted protein is similar in size, chemical properties, and amino acid sequence to the nucleocapsid proteins of other coronaviruses. This is especially evident when the sequence is compared with that of the antigenically related porcine transmissible gastroenteritis virus (TGEV), with which a region of 46% amino acid sequence homology was found. Hydropathy profiles revealed the existence of several conserved domains which could have functional significance. An intergenic consensus sequence precedes the 5'-end of the proposed nucleocapsid protein gene. The consensus sequence is present in other coronaviruses and has been proposed as the site of binding of the leader sequence for mRNA transcriptional start. This region was also examined by primer extension analysis of mRNAs, which identified a 60-nucleotide leader sequence. The 3'-noncoding region of the genome contains an 11-nucleotide sequence, which is relatively conserved throughout the Coronavirus family and lends support to the theory that this region is important for the replication of negative-strand RNA.

Amino Acid Sequence↗
PubMed2004

Identification of mammalian microRNA host genes and transcription units.

To derive a global perspective on the transcription of microRNAs (miRNAs) in mammals, we annotated the genomic position and context of this class of noncoding RNAs (ncRNAs) in the human and mouse genomes. Of the 232 known mammalian miRNAs, we found that 161 overlap with 123 defined transcription units (TUs). We identified miRNAs within introns of 90 protein-coding genes with a broad spectrum of molecular functions, and in both introns and exons of 66 mRNA-like noncoding RNAs (mlncRNAs). In addition, novel families of miRNAs based on host gene identity were identified. The transcription patterns of all miRNA host genes were curated from a variety of sources illustrating spatial, temporal, and physiological regulation of miRNA expression. These findings strongly suggest that miRNAs are transcribed in parallel with their host transcripts, and that the two different transcription classes of miRNAs ('exonic' and 'intronic') identified here may require slightly different mechanisms of biogenesis.

Base Sequence↗
PubMed1999

Hepatitis C virus genotypes and quasispecies.

Genetic heterogeneity is a hallmark of the hepatitis C virus, as a result largely of the infidelity of viral RNA-dependent RNA polymerase. Random nucleotide substitutions are introduced at a very high rate. The existence of genotypes was confirmed by statistical and mathematical techniques, and the relation of the genotypes to each other has been determined. There are six major genotypes, each with multiple subtypes. Isolates of the same genotype have an average sequence homology of 95%, but different genotypes have sequence similarity of approximately 65% on average. The nucleotide sequence in portions of the hepatitis C viral genome, including the 5' noncoding region, part of the core gene, and other nonstructural proteins, is highly conserved. Genotype analysis typically utilizes these highly conserved regions. There are many techniques for determining viral genotype, and in general, concordance between techniques is good. Methods most commonly used for assigning hepatitis C virus (HCV) genotypes in clinical practice include restriction fragment length polymorphism analysis and the reverse hybridization line probe assay (LiPA; Innogenetics, Ghent, Belgium). The worldwide distribution of HCV genotypes has been determined; some genotypes are highly characteristic of certain areas. The most common subtypes, 1 and 2, are less genetically diverse than the others and are more widely distributed. The impact of genotype on disease course is controversial, but recent data suggest that there is a genotype-dependent differential response to therapy. Quasispecies refers to evolution of a highly related but genetically heterogeneous population of HCV isolates. The pathobiological and clinical implications of HCV quasispecies are poorly understood.

Genome, Viral↗
PubMed2003

A significant fraction of conserved noncoding DNA in human and mouse consists of predicted matrix attachment regions.

Noncoding DNA in the human-mouse orthologous intergenic regions contains "islands" of conserved sequences, the functions of which remain largely unknown. We hypothesized that some of these regions might be matrix-scaffold attachment regions, MARs (or S/MARs). MARs comprise one of the few classes of eukaryotic noncoding DNA with an experimentally characterized function, being involved in the attachment of chromatin to the nuclear matrix, chromatin remodeling and transcription regulation. To test our hypothesis, we analyzed the co-occurrence of predicted MARs with highly conserved noncoding DNA regions in human-mouse genomic alignments. We found that 11% of the conserved noncoding DNA consists of predicted MARs. Conversely, more than half of the predicted MARs co-occur with one or more independently identified conserved sequence blocks. An excess of conserved predicted MARs is seen in intergenic regions preceding 5' ends of genes, suggesting that these MARs are primarily involved in transcriptional control.

Animals↗
PubMed2001

The human genome structure and organization.

Genetic information of human is encoded in two genomes: nuclear and mitochondrial. Both of them reflect molecular evolution of human starting from the beginning of life (about 4.5 billion years ago) until the origin of Homo sapiens species about 100,000 years ago. From this reason human genome contains some features that are common for different groups of organisms and some features that are unique for Homo sapiens. 3.2 x 10(9) base pairs of human nuclear genome are packed into 23 chromosomes of different size. The smallest chromosome - 21st contains 5 x 10(7) base pairs while the biggest one -1st contains 2.63 x 10(8) base pairs. Despite the fact that the nucleotide sequence of all chromosomes is established, the organisation of nuclear genome put still questions: for example: the exact number of genes encoded by the human genome is still unknown giving estimations from 30 to 150 thousand genes. Coding sequences represent a few percent of human nuclear genome. The majority of the genome is represented by repetitiVe sequences (about 50%) and noncoding unique sequences. This part of the genome is frequently wrongly called "junk DNA". The distribution of genes on chromosomes is irregular, DNA fragments containing low percentage of GC pairs code lower number of genes than the fragments of high percentage of GC pairs.

Animals↗
PubMed2001

Genomic and evolutionary characterization of TT virus (TTV) in tupaias and comparison with species-specific TTVs in humans and non-human primates.

TT virus (TTV) was recovered from the sera of tupaias (Tupaia belangeri chinensis) by PCR using primers derived from the noncoding region of the human TTV genome, and its entire genomic sequence was determined. One tupaia TTV isolate (Tbc-TTV14) consisted of only 2199 nucleotides (nt) and had three open reading frames (ORFs), spanning 1506 nt (ORF1), 177 nt (ORF2) and 642 nt (ORF3), which were in the same orientation as the ORFs of the human prototype TTV (TA278). ORF3 was presumed to arise from a splicing of TTV mRNA, similar to reported human TTVs whose spliced mRNAs have been identified, and encoded a joint protein of 214 amino acids with a Ser-, Lys- and Arg-rich sequence at the C terminus. Tbc-TTV14 was less than 50% similar to previously reported TTVs of 3.4-3.9 kb and TTV-like mini viruses (TLMVs) of 2.8-3.0 kb isolated from humans and non-human primates, and known animal circoviruses. Although Tbc-TTV14 has a genomic length similar to animal circoviruses (1.8-2.3 kb), Tbc-TTV14 resembled TTVs and TLMVs with regard to putative genomic organization and transcription profile. Conserved motifs were commonly observed in the coding and noncoding regions of the Tbc-TTV14 genome and in all TTV and TLMV genomes. Phylogenetic analysis revealed that Tbc-TTV14 is the closest to TLMVs, and is closer to TTVs isolated from tamarin and douroucouli than to TTVs isolated from humans and chimpanzees. These results indicate that tupaias are naturally infected with a new TTV species that has not been identified among primates.

Amino Acid Sequence↗
PubMed2006

Constitutive expression of the human peroxiredoxin V gene contributes to protection of the genome from oxidative DNA lesions and to suppression of transcription of noncoding DNA.

Peroxiredoxins belong to a family of antioxidant proteins that neutralize reactive oxygen species. One member of this family, peroxiredoxin I (PRDX1), suppresses DNA oxidation. Peroxiredoxin V (PRDX5) has been cloned as a transcriptional corepressor, as a peroxisomal/mitochondrial antioxidant protein, and as an inhibitor of p53-dependent apoptosis. Promoters of mammalian PRDX5 genes contain clusters of antioxidant response elements, which can bind the transcription factor NRF2. However, we found that expression of the human PRDX5 gene in situ was not stimulated by the oxidative agent menadione. Silencing of the NRF2 gene in the absence of oxidative stress by specific siRNA did not decrease PRDX5 protein concentration. We also constructed clones of human lung epithelial cells A549 with siRNA-mediated knockdown of the PRDX5 gene. This led to a significant increase in 8-oxoguanine formation in cell DNA. In the PRDX5 knockdown clone, an increase in transcripts containing sequences of alpha-satellite and satellite III DNAs was also detected, suggesting that this protein may be required for silencing of heterochromatin. Together, these results suggest that constitutively expressed PRDX5 gene plays an important role in protecting the genome against oxidation and may also be involved in the control of transcription of noncoding DNA.

Base Sequence↗
PubMed2001

Temporal control of DNA replication and the adaptive value of chromatin diminution in copepods.

Chromatin diminution is a precisely controlled, highly repeatable, genome-wide deletion of noncoding heterochromatic segments from the presomatic line. The somatic line is reduced in size and reorganized; the germ line remains unaltered. Little is understood about its mechanistic underpinnings and adaptive significance in the nematodes, copepods, and hagfish in which it occurs. Here, we propose that microcrustacean copepods, whose cytology, development, and evolutionary ecology are well understood from an adaptationist point of view, provide the vehicle to test how chromatin diminution might orchestrate certain cell cycle dynamics, with the consequence of influencing the evolution of nuclear DNA contents, organismal development rates, and body size.

Adaptation, Physiological↗
PubMed1991

Oral poliovirus vaccine in the United States: molecular characterization of Sabin type 3 after replication in the gut of vaccinees.

Derivatives of Sabin 3 shed from recipients of oral poliovirus vaccine in the United States (U.S.) were examined for genetic changes identified in strains excreted by vaccinees in the United Kingdom [U.K.; Evans et al., 1985; Cammack et al., 1988, Macadam et al., 1989]. Among the eight primary vaccinees studied, the duration of excretion and molecular evolution of type 3 strains varied greatly. The period of virus excretion after vaccination ranged from as few as 2 days to as many as 36 days. Nucleotide sequence analysis of viral RNAs extracted from shed virus indicated that only fifty percent of the vaccinees exclusively excreted strains in which the attenuating mutation at nucleotide 472 in the 5' noncoding region of the genome had reverted from uracil (U) to cytosine (C), the nucleotide found in neurovirulent strains. Compared to the wild-type Leon strain, the low activity of stool isolate KW4 in a complete monkey neurovirulence test demonstrated that presence of C at 472 does not render a type 3 strain pathogenic. Conversely, an isolate was identified which efficiently replicated in monkey nervous tissue and maintained the attenuated U at 472. Oligonucleotide fingerprinting and sequence analysis of viral RNAs from stool isolates indicated that one vaccinee (KW) eventually excreted intertypic recombinant strains consistent with those reported in the U.K. studies. Unique to this study, one vaccinee (KS) excreted nonrecombinant virus possessing U at 472 for up to 21 days. The significance of the KS strain profile in relation to differences in the U.S. vaccine compared to the vaccine distributed in the U.K. and other countries is discussed.

Animals↗
PubMed1992

Detection of hepatitis C viraemia in Caucasian patients with hepatocellular carcinoma.

Potential risk factors for the development of hepatocellular carcinoma were analysed in 40 Caucasian patients with this malignancy. A higher proportion (14 of 40; 35%) had evidence of hepatitis C virus (HCV) infection than had evidence of either hepatitis B virus (HBV) carriage (17.5%) or alcohol abuse (30%). In all 14 patients whose sera were reactive by HCV ELISA (Ortho second generation test), the presence of antibodies to HCV were confirmed by recombinant immunoblot assay (Ortho RIBA-2). Furthermore, two independent laboratories detected HCV-RNA in 10 of the 14 (71%) anti-HCV positive sera. Two additional sera were shown to contain HCV-RNA when reanalysed by a modified PCR using oligonucleotide primers designed to amplify a shorter fragment of the 5' noncoding region of the genome. Seven of the anti-HCV positive patients also had evidence of prior HBV infection and 2 admitted to alcohol abuse. HCV infection was the only identifiable risk factor in 6 patients. These data confirm the association between HCV infection and hepatocellular carcinoma and suggest that persistent viral replication accompanies tumour development in the majority of patients whose serum contains anti-HCV.

Aged↗
PubMed1994

Complete nucleotide sequence of a beta-cell tropic variant of coxsackievirus B4.

A mouse pancreas-adapted variant of coxsackievirus B4 (P-CB4) has been shown to replicate in, and cause an excessive release of insulin from, pancreatic beta cells cultured in vitro. The prototype CB4 strain (JVB Benschoten), from which the adapted variant was derived, although able to replicate in cultured islets does not cause a similar release of insulin from the beta cells. The pancreas-adapted virus has also been shown to cause host cell protein synthesis shut-off in beta cells and to inhibit (pro)insulin biosynthesis. These metabolic changes occur in the absence of cytolytic damage [Szopa et al.: Bioscience Reports 5:63-69, 1985 and Cell Biochemistry and Function 4:181-187, 1986]. To investigate the genetic basis for this beta cell tropism, the complete nucleotide sequence of P-CB4 has been determined and compared to that of the previously published sequence of the prototype CB4 strain (JVB Benschoten) [Jenkins et al.: Journal of General Virology 68:1835-1848, 1987]. Twenty-five nucleotide sequence differences were observed. Of these, six occur in the 5' noncoding region of the genome and 19 in the coding region (resulting in seven amino acid changes). The possible significance of these changes in relation to the beta cell tropism of the pancreas-adapted virus is discussed.

Base Sequence↗
PubMed1993

Evidence of natural recombination within the S1 gene of infectious bronchitis virus.

During an outbreak of severe respiratory disease, a field strain of infectious bronchitis virus (IBV), PP14, was isolated from a bird in a Texas flock that had been previously vaccinated with an attenuated Mass serotype virus. After cloning and sequencing the S1 gene from several IBV strains, it was found that the 5' end of the cDNA was 96% identical to the published sequences of Mass41 and 77% identical with Ark99. The following 402 bases which included the hypervariable regions (HVR) of the S1 gene were 94% homologous with Ark99 and only 69% with Mass41. In addition, the HVR in the 3' noncoding region of the genome, which is totally absent in Mass41, was 99% homologous with the Ark99 strain. This abrupt shift in identity of PP14 in the S1 strongly indicated that a recombination event had occurred about 98 bases from the beginning of the S1 gene between an Ark-like and a Mass-like virus. Downstream, 33 bases from the PP14 recombination junction, a second putative "cross-over" site was identified in the S1 of the SE17 strain where the 5'131 bases of the S1 gene of the Ark99 and SE17 were found to be 95% identical and the following 368 base sequence was only 78% homologous. In addition, a second shift in homology in the S1 of SE17 was identified between nucleotide 1112 and 1460 which shared 95% identity with Mass41. The putative recombination junctions which were downstream of the signal sequence and upstream of the S1 HVR may represent a "hot spot," but not an exclusive region, for exchanging genetic material between IBV strains. Genetic shifts are apparently not only common mechanisms for variation in nature, but vaccine strains may actually play a critical role in these events in the evolution of virulent strains of IBV.

Animals↗
PubMed1995

Studies on neurovirulence in poliovirus-sensitive transgenic mice and cynomolgus monkeys for the different temperature-sensitive viruses derived from the Sabin type 3 virus.

We have studied methods for testing the neurovirulence of live poliovaccine viruses by intraspinal inoculation into mice carrying the human poliovirus receptor gene (Tg mice). A comparison of the neurovirulence of Sabin type 3 vaccine virus and related viruses using the 50% paralysis dose determined after intraspinal inoculation into the Tg mice as an index revealed a close correlation between the results of the paralysis dose in Tg mice, the neurovirulence expressed by the histopathological lesions core in monkeys, and the temperature sensitivity of the viruses. The results of experiments in the Tg mice also showed a good correlation with the number of mutations at position 472 from U to C in the 5' noncoding region in the genomes of the viruses tested. These results strongly suggest that the neurovirulence test for oral poliomyelitis vaccine using the Tg mice is an excellent method and may be used in place of the test using monkeys.

Animals↗