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PubMed2002

HHV-8 subtypes in South Africa: identification of a case suggesting a novel B variant.

Human herpesvirus 8 (HHV-8) has been identified as the causative agent for all forms of Kaposi's sarcoma and is also associated with the development of body cavity-based B-cell lymphomas and multicentric Castleman's disease. HHV-8 genomes are now classified into five major subtypes (A-E) that reflect sequence heterogeneity in the highly variable open reading frame (ORF) K1. To identify HHV-8 subtypes associated with different forms of Kaposi's sarcoma, we compared the ORF 26 and ORF-K1 gene sequences from South African patients with the prototype strains of the major subtypes, as well as published sequences from other African strains. DNA prepared from Kaposi's sarcoma biopsies and/or peripheral blood lymphocytes were available from 14 patients with postrenal transplant (iatrogenic) Kaposi's sarcoma, six patients with the African endemic form, and one patient with AIDS-related body cavity-based B-cell lymphoma. We identified a B2 subtype in six patients, four of whom also had a novel B5 type ORF 26 polymorphism. Two patients had B2 type patterns for both the ORF 26 and ORF-K1 genes. The ORF-K1 subtype A5 was identified in samples from three patients with a B3/C2 type polymorphism in the ORF 26 gene. A novel ORF-K1 B variant strain was identified in a patient with African endemic Kaposi's sarcoma, who also had a B3/C2 class ORF 26 pattern. In 58.3% of iatrogenic Kaposi's sarcoma patients, a B5-type ORF 26 gene sequence pattern was identified. No association was found among particular subtypes, geographical origin of patients, or clinical presentation.

Adult↗

PubMed1997

Neuronal subtype-specific expression directed by the GABA(A) receptor delta subunit gene promoter/upstream region in transgenic mice and in cultured cells.

The promoter of the GABA(A) receptor delta subunit gene was analyzed in transgenic mice and in cultured cells to study sequences involved in neuronal subtype-specific gene expression. A 6.4-kb genomic fragment faithfully directed neuron-specific transcription of a lacZ reporter gene in the central nervous system. The transgene expression pattern in the cerebral cortex, hippocampal formation, thalamus, and brainstem was consistent with the regional and neuronal subtype-specific expression of the endogenous delta subunit protein in both developing and mature brain. In the cerebellum, however, the transgene was ectopically expressed in Purkinje cells and silent in granule cells, where the endogenous delta subunit is abundantly expressed. These mice provide a useful tool for investigating activity-dependent regulation of GABA(A) receptor expression under physiological and pathological conditions. Transfection studies using primary cortical neurons and astroglial cells revealed that the delta subunit gene promoter was selectively active in neurons even when truncated to a 267-bp core fragment. In conclusion, the delta subunit gene promoter/upstream region contains the information for neuronal subtype-specific expression in the entire brain except in the cerebellum and is selectively active in primary cortical neurons in vitro.

Aging↗

PubMed1996

Heterogeneity of hepatitis C virus.

A great deal of information on the molecular heterogeneity of hepatitis C virus (HCV) has been achieved since its discovery in 1989. However, little is known about the clinical significance of these variations. Based on the degree of sequence variation, HCV has been classified into six major groups or types, differing by 31-34% at the nucleotide level over the entire virus genome. Each type is divided into several subtypes that differ by 20-23% in nucleotide sequence. Viruses within the same subtype are up to 10% divergent and, within infected individuals, vary by up to 1.5%. Genotype distributions are not homogeneous around the world and may reflect both historical and recent parenteral routes of transmission. The clinical implication of these genomic variations are not yet fully elucidated: genotype 1b has been associated with end-stage liver disease, including liver cirrhosis and hepatocellular carcinoma, but this finding might rather reflect its earlier introduction to the populations studied. Consistent evidence exists that types 2 and 3 have a higher response rate to interferon treatment than type 1, although the interplay between genotype and viral load in determining the response is still unclear. Immunohistochemical studies indicate a stronger activation of the endogenous interferon system in the liver of patients infected with type 1 compared to those infected with types 2 and 3, explaining, at least in part, its low responsiveness to exogenous interferon treatment. Biological, sequence-dependent variations of genotypes have been poorly investigated to date, but differential efficiency of translation activity of the 5' non-coding region has been reported. The availability of "in vitro" systems for evaluating pathogenetic aspects and neutralization mechanisms will improve the present knowledge on this world-wide infectious disease and on the clinical usefulness of distinguishing between genotypes.

Genotype↗

PubMed2001

Sequence analysis of hepatitis B virus genomes from an infant with acute severe hepatitis and a hepatitis B e antigen-positive carrier mother.

It is well known that fulminant hepatitis B can occur in infants born to hepatitis B e antigen (HBeAg)-negative hepatitis B virus (HBV) carrier mothers, whereas fulminant hepatitis and severe hepatitis are uncommon in infants born to HBeAg-positive mothers. We have encountered an infant with severe acute hepatitis B born to a HBeAg-positive mother. The aim of this study was to determine whether HBV variants contribute to the pathogenesis of fulminant hepatitis and severe hepatitis in an infant born to an HBeAg-positive mother. The nucleotide sequence of HBV genomes from the infant and his HBeAg-positive carrier mother was analyzed. All HBV isolated from the infant and his mother were subtype adr. The sequences of the cloned HBV genomes, each including a part of the X and precore/core regions, isolated from the infant were almost identical (homology of 99.1-99.9%) to those from his mother. There was no mutation in any of the 17 clones examined at nucleotides 1762 and 1764 in the core promoter, which is reported to be associated with fulminant hepatitis. A point mutation at nucleotide 1758 in the second AT-rich region of the basic core promoter was present in all clones. None of the clones had a point mutation at nucleotide 1896 of the precore region. In this study, no specific HBV variants contributing to the development of neonatal severe hepatitis were found. There is a possibility that host factors rather than viral factors play an important role in some cases of severe neonatal hepatitis B.

Adult↗

PubMed2000

Relationships within and between genotypes of hepatitis B virus at points across the genome: footprints of recombination in certain isolates.

Hepatitis B virus (HBV) was partitioned into type, subtype and isolate categories and the average evolutionary distances within and between categories was plotted at each of 54 points along the genome. The graphs showed alternating variable and conserved domains within and between HBV subtypes and revealed that some specimens assigned to different groups are more similar across several contiguous intervals than specimens belonging to the same group. Isolates were screened individually to determine their conformation to type and mosaic structure was identified in 14/65 specimens. Two entire clades (six specimens) of genotype B had a B/C sequence switch in the core gene region, whereas six genotype D specimens showed D/A switching in one or more regions of the genome. Genotype E was not separate from genotype D in the X and C subgenomic regions. The nature and distribution of polymorphic sites in mosaic regions was mapped at both the nucleotide and protein levels and the position of the variant fragments was related to mutational hot spots and linear epitopes of HBV. Mosaic structure was demonstrated statistically in 11 isolates using bootstrap resampling and recombination, rather than random change, appeared to be the mechanism responsible. The sequence between and including the two DR regions was represented in all putative recombinants. The distribution of genetic distances over subgenomic regions showed that substitution rates are not constant among the lineages of HBV in the preS regions. Genotype F is the most diverse group. Only genotypes A, C and F partition consistently into subtypes.

Animals↗

PubMed2005

Early growth response gene 1 (EGR1) is deleted in estrogen receptor-negative human breast carcinoma.

BACKGROUND: Patients with estrogen receptor (ER)-positive and ER-negative breast carcinomas differ in terms of disease progression, treatment regimens, and prognosis. The mechanism underlying the biologic differences of the two groups is understood poorly. Array comparative genome hybridization (CGH) on breast carcinoma subtypes demonstrated a consistent association between loss in regions of chromosome 5q and ER-negative tumors. It was shown previously that early growth response gene 1 (EGR1) on 5q acts like a tumor-suppressor gene, with its expression repressed in breast carcinomas. METHODS: To test the hypothesis that EGR1 is deleted differentially in ER-negative versus ER-positive breast carcinomas, fluorescence in situ hybridization was employed in this study to determine the EGR1 deletion status in 50 breast carcinoma specimens. Deletion status was measured by the signal ratio of EGR1/chromosome 5. Linear regression was used to assess the results. RESULTS: The mean EGR1/chromosome 5 ratio for the ER-negative group was significantly lower compared with the same ratio for the ER-positive group (P < 0.001). Although grade alone was not significant for predicting the ratio, the interaction between ER status and grade was significant (P < 0.01): For ER-negative specimens, the higher the grade, the lower the EGR1/chromosome 5 ratio. CONCLUSIONS: The EGR1 gene appeared to be deleted in ER-negative human breast carcinomas. Egr-1 may contribute to the pathogenesis of ER-negative breast carcinomas versus ER-positive breast carcinomas.

Breast Neoplasms↗

PubMed2001

Genomic imbalances in human lung adenocarcinomas and squamous cell carcinomas.

Comparative genomic hybridization analysis was performed on 67 non-small-cell lung cancers (NSCLCs), including 32 squamous cell carcinomas (SCCs) and 35 adenocarcinomas (ACs), to identify differences in the patterns of genomic imbalance between these two histologic subtypes. Among the entire tumor set, the chromosome arms most often overrepresented were 1q, 3q, 5p, and 8q, each detected in 50-55% of cases. The most frequently underrepresented arms were 9q, 3p, 8p, and 17p. The number of imbalances was similar in SCCs and ACs (median number/case: 12 and 11, respectively). Moreover, many imbalances, such as gains of 1q, 5p, and 8q, occurred at a high frequency in both histologic subgroups. Several statistically significant differences, however, were found. The most prominent difference was gain of 3q24-qter, seen in 81% of SCCs compared with 31% of ACs (P < 0.0001), with amplification at 3q25-26 being detected in eight of 32 (25%) SCCs but in only two of 35 (6%) ACs. Gain of 20p13 and loss of 4q also were seen at a significantly higher rate in SCCs than in ACs, whereas overrepresentation of 6p was more common in ACs. Gains of 7q and 8q each were associated with higher-stage tumors and either positive nodal involvement or higher tumor grade. These data suggest that genes located in several chromosomal regions, particularly 3q25-26, may be associated with phenotypic properties that differentiate lung SCCs from ACs. Furthermore, certain imbalances, prominent among them gains of 7q and 8q, may be indicative of tumor aggressiveness in NSCLCs.

Adenocarcinoma↗

PubMed1994

Receptor-mediated effects of angiotensin II on neurons.

Aside from its well-known and numerous actions at peripheral tissues, the octapeptide angiotensin II (ANG II) elicits specific receptor-mediated effects within the central nervous system. In this review we focus on the receptor-mediated actions of ANG II on neurons. The distribution of ANG II receptors in the brain and physiological, electrophysiological, and cellular effects mediated by these receptors are discussed. This is extended to a review of the characteristics of ANG II receptor subtypes on cultured neurons and the cellular and genomic actions mediated by these receptors. Finally, we develop this information into speculative models for the cellular effects mediated by each ANG II receptor subtype in neurons.

Angiotensin II↗

PubMed1992

Crystallization and preliminary X-ray analysis of three serotypes of foot-and-mouth disease virus.

Foot-and-mouth disease viruses from serotypes O, A and C have been crystallized. The particular strains studied include O1K, A10(61), A22 Iraq 24/64, A24 Cruzeiro and C-S8c1. In addition, crystals have been grown of G67, a monoclonal antibody neutralization escape mutant derived from O1K, and of virus R100, recovered after the establishment of a persistent infection in baby hamster kidney cells with C-S8c1. Empty particles, capsids which lack the RNA genome, have also been crystallized for subtypes A22 Iraq 24/64 and A10(61). In almost all cases, crystals suitable for high resolution structure determination were obtained from (NH4)2SO4 or mixtures of polyethylene glycol and NH4Cl.

Aphthovirus↗

PubMed2004

Screening and analysis of porcine endogenous retrovirus in Chinese Banna minipig inbred line.

Pigs have been the most likely animal as the source of cells, tissues, and organs for xenotransplantation. But the use of pigs in xenotransplantation is associated with the risk of porcine endogenous retrovirus (PERV) transmission. Previous studies have identified that the proviruses are integrated into the genome of normal pigs and that virus particles released from the porcine cells can infect human cells in vitro. As a unique inbred pig, Banna minipig inbred (BMI) has a huge potential value for xenotransplantation and medical research. It has been the focal experimental animal for pig-to-human xenotransplantation in China, due to its clear genetic background and tiny individual differences. To evaluate whether the potential risk of PERV exists in inbred pigs, a series of screening experiments were performed herein. The results of PCR with primers specific for gag, pol, and env showed that proviruses existed in the genome of BMI, and the PERV subtypes were PERV-A and PERV-B. PERV mRNA was expressed functionally in BMI. Positive results of an RT assay identified that PERV in BMI had potential infectivity, but the concentration of PERV reverse transcriptase in BMI was almost 20 times lower than that of HIV. These results suggested that gag, pol and env genes of PERV were not lost during inbreeding, which created favorable conditions to produce viral particles that could possibly infect human cells in xenotransplantation.

Animals↗

PubMed2006

Extensive cross-reactive neutralizing antibody response in Indian patients with limited genetic diversity of HIV-1.

Genome sequence analysis of HIV-1 subtype C viruses from India shows monophyletic lineage and relatively limited genetic diversity. To understand its immunological implication, cross-reactivity of neutralizing antibody response was investigated. In primary screening, neutralizing antibody response to single heterologous primary HIV-1 subtype C isolate was assessed in plasma samples from 235 HIV-1 infected, anti-retroviral treatment naive individuals from Pune, India. Plasma samples that showed > or =90% neutralization and two randomly selected plasma samples that showed 50-60% neutralization were tested against a panel of primary HIV-1 subtype C isolates obtained from epidemiologically unlinked individuals from India. The neutralizing antibody response showed extensive cross-neutralization, suggesting presence of shared neutralization determinants among circulating HIV-1 subtype C viruses in India.

Antibodies, Viral↗

PubMed2026

Faecalibacterium prausnitzii-derived L-arginine ameliorates insomnia by inhibiting POMC-ACTH-cortisol axis.

Insomnia is associated with gut microbial dysbiosis, but the specific microbial metabolites mediating gut-brain communication remain elusive. Here, we integrate metagenomic sequencing from 171 individuals (primary insomnia, post-COVID insomnia, and controls) with functional pathway analysis and preclinical validation. We identify Faecalibacterium prausnitzii depletion and reduced L-arginine biosynthesis as consistent features in both insomnia subtypes, accompanied by elevated cortisol levels. Genomic and in vitro analyses confirm that F. prausnitzii is a key microbial contributor to L-arginine production. In a chronic mild stress mouse model, administration of either F. prausnitzii or L-arginine restores sleep duration, normalizes corticosterone levels, and reverses stress-induced gut dysbiosis. Mechanistically, L-arginine suppresses POMC gene expression and dampens adrenocorticotropic hormone (ACTH)-stimulated corticosterone release, implicating the POMC-ACTH-cortisol axis as a key target. These findings uncover a gut-brain axis driven by F. prausnitzii-derived L-arginine that modulates sleep through endocrine signaling, positioning this metabolite as a potential therapeutic avenue for insomnia.

Arginine↗

PubMed2002

Site-specific translocation and evidence of postnatal origin of the t(1;19) E2A-PBX1 fusion in childhood acute lymphoblastic leukemia.

The t(1;19) translocation yields a fusion between E2A and PBX1 genes and occurs in 5% of acute lymphoblastic leukemia in children and adults. We used chromosomal translocations and Ig heavy chain (IGH)/T cell antigen receptor (TCR) rearrangements to develop an understanding of the etiology and natural history of this subtype of leukemia. We sequenced the genomic fusion between E2A and PBX1 in 22 preB acute lymphoblastic leukemias and two cell lines. The prenatal origin of the leukemia was assessed in 15 pediatric patients by screening for the clonotypic E2A-PBX1 translocation in neonatal blood spots, or Guthrie cards, obtained from the children at the time of birth. Two patients were determined to be weakly positive for the fusion at the time of birth, in contrast to previously studied childhood leukemia fusions, t(12;21), t(8;21), and t(4;11), which were predominantly prenatal. The presence of extensive N-nucleotides at the point of fusion in the E2A-PBX1 translocation as well as specific characteristics of the IGH/TCR rearrangements provided additional evidence for a postnatal, preB cell origin. Intriguingly, 16 of 24 breakpoints on the 3.2-kb E2A intron 14 were located within 5 bp, providing evidence for a site-specific recombination mechanism. Breakpoints on the 232-kb PBX1 intron 1 were more dispersed but highly clustered proximal to exon 2. In sum, the translocation breakpoints displayed evidence of unique temporal, ontological, and mechanistic formation than the previously analyzed pediatric leukemia translocation breakpoints and emphasize the need to differentiate cytogenetic and molecular subgroups for studies of leukemia causality.

Adolescent↗

PubMed1988

Gene encoding capsid protein VP1 of foot-and-mouth disease virus: a quasispecies model of molecular evolution.

A phylogenetic tree relating the VP1 gene of 15 isolates of foot-and-mouth disease virus (FMDV) of serotypes A, C, and O has been constructed. The most parsimonious tree shows that FMDV subtypes and isolates within subtypes constitute sets of related, nonidentical genomes, in agreement with a quasispecies mode of evolution of this virus. The average number of nucleotide replacements per site for all possible pairs of VP1 coding segments is higher among representatives of serotype A than serotype C or O. In comparing amino acid sequences, the values of dispersion index (variance/mean value) are greater than 1, with the highest values scored when all sequences are considered. This indicates an accumulation of mutations at a limited number of residues, suggesting that distributions of sequences fluctuate around points of high stability. Evolution of FMDV follows a path very distant from that of a star phylogeny, and it has not been possible to derive conclusions on constancy of evolutionary rates with the test applied to the analysis. FMDVs, as other RNA viruses, are of limited genetic complexity and their population sizes are extremely large. Their evolution concerns complex, indeterminate mixtures of genomes rather than a single, determinate species.

Amino Acids↗

PubMed1996

Cannabinoid inhibition of adenylate cyclase-mediated signal transduction and interleukin 2 (IL-2) expression in the murine T-cell line, EL4.IL-2.

Cannabinoid receptors negatively regulate adenylate cyclase through a pertussis toxin-sensitive GTP-binding protein. In the present studies, signaling via the adenylate cyclase/cAMP pathway was investigated in the murine thymoma-derived T-cell line, EL4.IL-2. Northern analysis of EL4.IL-2 cells identified the presence of 4-kilobase CB2 but not CB1 receptor-subtype mRNA transcripts. Southern analysis of genomic DNA digests for the CB2 receptor demonstrated identical banding patterns for EL4.IL-2 cells and mouse-derived DNA, both of which were dissimilar to DNA isolated from rat. Treatment of EL4.IL-2 cells with either cannabinol or Delta9-THC disrupted the adenylate cyclase signaling cascade by inhibiting forskolin-stimulated cAMP accumulation which consequently led to a decrease in protein kinase A activity and the binding of transcription factors to a CRE consensus sequence. Likewise, an inhibition of phorbol 12-myristate 13-acetate (PMA)/ionomycin-induced interleukin 2 (IL-2) protein secretion, which correlated to decreased IL-2 gene transcription, was induced by both cannabinol and Delta9-THC. Further, cannabinoid treatment also decreased PMA/ionomycin-induced nuclear factor binding to the AP-1 proximal site of the IL-2 promoter. Conversely, forskolin enhanced PMA/ionomycin-induced AP-1 binding. These findings suggest that inhibition of signal transduction via the adenylate cyclase/cAMP pathway induces T-cell dysfunction which leads to a diminution in IL-2 gene transcription.

Adenylyl Cyclase Inhibitors↗

PubMed1995

Neutralization of primary HIV-1 isolates by anti-envelope monoclonal antibodies.

OBJECTIVE: To evaluate human monoclonal antibodies (MAb) for neutralizing activity against primary HIV-1 isolates in peripheral blood mononuclear cells. DESIGN: Neutralization activity data were obtained from 11 laboratories on a coded panel consisting of six human MAb to HIV envelope V3, CD4-binding region or gp41. Hyperimmune globulin against HIV-1 and normal human immunoglobulin G were supplied as controls. Each laboratory received pre-titered virus for use in the studies. METHODS: Each laboratory measured neutralization of the MAb against laboratory strain HIVMN, genomic clone HIVJR-CSF, two subtype B and one subtype D primary isolates. RESULTS: The titers of the centrally supplied virus stocks as determined by re-titration or back-titration varied among laboratories and were generally 10-100-fold less than provided. The neutralizing activity of each MAb varied by as much as a 1000-fold among laboratories. These differences may result from varying sensitivity in neutralization assay protocols and the differing susceptibility of primary cells to infection with HIV-1. CONCLUSIONS: To consolidate the data from multiple laboratories, the neutralization titers were compared by classifying antibodies as neutralizing if the antibody concentration for 50% virus inhibition was < or = 10 micrograms/ml. By this criterion, the CD4-binding region and gp41 MAb neutralized all four subtype B viruses and the subtype D isolate in a few of the laboratories. The V3 MAb neutralized only HIVMN and the closely related HIVJR-CSF viruses.

Antibodies, Monoclonal↗

PubMed2005

Comparative genomic hybridisation identifies two variants of smoldering multiple myeloma.

Two variants of smoldering multiple myeloma (SMM) have been recognised: (i) an evolving type, characterised by a progressive increase in the M-protein size and short time to progression to overt multiple myeloma (MM) and (ii) a non-evolving type, with a long-lasting, stable M-protein and longer time to progression. Comparative genomic hybridisation (CGH) analyses in both subtypes of SMM (seven evolving and eight non-evolving SMM) were performed. Evolving SMM showed cytogenetic changes consistent with those found in de novo symptomatic MM (1q gains, chromosome 13 deletions) while the non-evolving variant showed no 1q gains and deletions were uncommon.

Bone Marrow Examination↗

PubMed1986

Novel RNA family structure of hepatitis B virus expressed in human cells, using a helper-free adenovirus vector.

Ad5-HBL is a type 5 adenovirus bearing the large BglII fragment (2.8 kilobases; 87% of the total genome) of hepatitis B virus (HBV), subtype adr. Eight HBV RNAs expressed in HeLa cells infected with Ad5-HBL were mapped by the nuclease S1 technique. Three major RNAs spanning 2.4, 2.0, and 0.7 kilobases of the HBV sequences cover the coding regions of "presurface" plus surface antigen, surface antigen alone, and "X" protein, respectively. The 5' segment of an RNA which could code for core antigen (HBcAg) was also detected. All major HBV RNAs initiate from mutually exclusive 5' ends, terminate at the unique 3' end within the HBcAg coding region (except readthrough species), and have no spliced deletion, forming a novel RNA family structure. No TATA box-like sequences were found near the 5' end of these RNAs, except in the case of the 2.4-kilobase RNA. About two thirds of total HBV RNA does not terminate at the mapped 3'-end position, suggesting the termination signal is functionally inefficient. Since the potential 5' end of HBcAg mRNA was mapped at the same position as the minus-strand nick of HBV DNA previously reported, we propose a model that requires inefficient poly(A) addition to produce an RNA which serves both as HBcAg mRNA and as the putative RNA template of minus-strand DNA synthesis in the HBV life cycle.

Adenoviruses, Human↗