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PubMed1991

Human and murine B-cells recognize the HBeAg/beta (or HBe2) epitope as a linear determinant.

The complete amino acid (aa) sequence of the hepatitis B virus (HBV) core protein (HBcAg), deduced from the genome of the HBV ayw subtype, was synthesized as decapeptides with five overlapping aas. The peptides were tested for reactivity with monoclonal antibodies (mAbs) to the beta (or HBe2) epitope of hepatitis B e antigen (HBe/b mAbs; 57/8, 78/3, 141/158 and 141/207). Cross-competition between the mAbs with a mAb to the HBe/alpha epitope (or HBe1) and an anti-HBc mAb showed that all the HBe/b mAbs specifically inhibited human anti-HBe/b binding. Screening the HBc/e peptides showed that all anti-HBe/b mAbs recognized a peptide covering the residues 126-135. Three of the mAbs, 78/3, 141/152 and 141/207, had a less restricted reactivity than the other two, suggesting the recognition of the HBe/b as a discontinuous determinant. Fine mapping of the region aa 126-135 was performed by synthesizing decapeptides with nine overlapping aas, covering residues aa 121-140. All mAbs, except 78/3, reacted with the linear sequence TPPAYR, at residues 128-133. An additional set of peptides was synthesized, where the six aas within the epitope 128-133 were substituted in turn by the other 19 possible aas. By this approach, the essential aas for mAb 57/8 were found to be the sequence of PPA at residues 129-131, and for mAb 141/158 the sequence PP-Y, at residues 129, 130 and 132, respectively. Human recognition of the linear HBe/b epitope was investigated by using a peptide covering residues 121-140 (p 33). Thirty-one sera from chronic carriers of HBsAg, of which seven were positive for HBeAg and the remaining 24 for anti-HBe, were investigated. Of the sera with HBeAg, two had low levels of anti/-HBe/b in the p 33 assay. Out of the sera with anti-HBe, eight were positive in the p 33 EIA. Thus, murine monoclonals and human sera may recognize the HBe/b epitope as a linear determinant residing around aa 130.

Amino Acid Sequence↗

PubMed1995

Molecular cloning and sequencing of the gene encoding a sheep arginine vasopressin type 1a receptor.

The gene for the sheep arginine vasopressin type 1a (V1a) receptor subtype was cloned from a genomic library. The deduced amino acid sequence shows characteristics of a G-protein coupled receptor and high sequence identity to human and rat V1a receptor sequences (81% and 73%, respectively). Reverse transcription-polymerase chain reaction (RT-PCR) analysis showed a tissue distribution consistent with a type V1a receptor. The genomic DNA (7.1 kb) contains a 1586 bp intron between the putative 6th and 7th transmembrane domains.

Amino Acid Sequence↗

PubMed1990

Development and characterization of nucleic acid probes to infectious bursal disease viruses.

Radiolabeled cDNA probes were prepared using both segments of double-stranded genomic infectious bursal disease virus (IBDV) RNA as template. The probes were synthesized and labeled with 32P using random primers and reverse transcriptase. Probes were prepared to the genomic RNA extracted from a pathogenic serotype 1 virus (ST-C) and from an attenuated serotype 1 vaccine virus (D-78) which is commercially available. These probes were determined to range in size from approximately 200 to 1500 nucleotides in length using a 6% denaturing polyacrylamide gel. The probes were used in a dot hybridization assay and detected approximately 10 ng of IBDV RNA. In addition, they detected genomic RNA from five different subtypes of IBDV serotype 1 and from two serotype 2 viruses. The probes appeared to be specific for viral RNA since hybridization to cell culture nucleic acid was not detected.

Animals↗

PubMed2004

Familial subacute sclerosing panencephalitis in two siblings.

Subacute sclerosing panencephalitis is a form of chronic persistent measles encephalitis in childhood which rarely manifests after wild virus infection. One previous case of familial subacute sclerosing panencephalitis in two siblings and a number of reports of subacute sclerosing panencephalitis in one member of monozygous twins have been reported in the literature. This report describes a second sibling set who both contracted subacute sclerosing panencephalitis after concurrent sporadic measles infection. Two nonimmunized brothers developed neuropsychological decline and progressive myoclonic and complex partial seizures after earlier measles infection. Stereotyped periodic 5- to 8-second complexes in the electroencephalogram suggested the diagnosis of subacute sclerosing panencephalitis, subsequently confirmed by intrathecal and serum measles-specific immunoglobulin G synthesis and the presence of rubeola nucleocapsid protein and ribonucleic acid in the biopsied brain. The viral genome has not been further subtyped in either patient at this point. Although a rare event, subacute sclerosing panencephalitis cases involving familial and singular monozygous twins may shed light on a variety of host susceptibility factors and specific viral genotype features predisposing to this disease.

Child↗

PubMed1999

Interstitial deletion of 8(q13q22) in diffuse large B-cell gastric lymphoma.

An interstitial deletion in the long arm of chromosome 8 as the sole structural anomaly was detected in a primary gastric diffuse large B-cell lymphoma, high-grade mucosa-associated lymphoid tissue (MALT) type, from a 74-year-old man. Low-grade MALT lymphoma was not seen in the sections submitted for examination. Helicobactor pylori organisms were found in a biopsy performed prior to resection of the tumor. The karyotype was described as 45, X,-Y,del(8)(q13q22). No rearrangement between chromosome 8 and others was detected with fluorescence in situ hybridization using a whole chromosome 8 painting probe. Fluorescence in situ hybridization with the C-MYC gene showed its normal location at 8q24 on both chromosomes 8 without rearrangement. Amplification of C-MYC was not detected in interphase cells. Deletion of 8q may represent a unique genomic alteration in this particular subtype of primary gastric lymphoma.

Aged↗

PubMed2003

Genotypes of hepatitis C virus circulating in Tunisia.

Hepatitis C virus (HCV) isolates from 93 patients living in Tunisia, including 16 haemophiliacs, were genotyped by INNO LiPA and partial sequencing of the 5' untranslated region of the viral genome. In non-haemophiliacs, subtype 1b was largely predominant (79%), types 1a, 2a, 2b, 3a and 4a occurred much less frequently at 5, 7, 3, 3 and 1% of cases, respectively. In the group of haemophiliacs, a co-dominance between subtypes 1a and 1b was noticed (38%). Type distribution of HCV in Tunisia differs from that reported in other countries of the Mediterranean and Middle East regions. Genotyping results in respect of clinical status, age, and genotyping methods, are discussed.

Adolescent↗

PubMed2001

Advances in schizophrenia.

Recent studies into the etiology of schizophrenia have yielded both promising leads and disappointing dead ends, indicating the multifactored and complex nature of the disorder. The focus has subsequently shifted back to refining the phenotype and identifying clinical and biological subtypes. Recent technological breakthroughs in genomics and proteomics hold promise for advancing our understanding of the molecular pathophysiology of schizophrenia.

Antipsychotic Agents↗

PubMed2026

Chinese expert consensus on precision testing and molecular diagnosis of pancreatic cancer (2025).

This consensus by the CSCO Pancreatic Cancer Expert Committee establishes evidence-based guidelines for molecular testing in pancreatic ductal adenocarcinoma. It details recommendations for biomarkers (e.g., KRAS, BRCA, MSI), liquid biopsy, and precision imaging to direct targeted therapies and immunotherapy, aiming to standardize diagnosis and optimize individualized patient care. Pancreatic ductal adenocarcinoma (PDAC) is the most common pathological type of primary pancreatic malignancy, accounting for ~95% of cases and generally referred to as pancreatic cancer [1]. Its prognosis is extremely poor and its incidence continues to rise [2]. According to the most recent global cancer statistics, the incidence of pancreatic cancer ranks 12th among all cancers, and its mortality ranks 6th, making it one of the deadliest malignancies worldwide [3]. Approximately 57% of patients have metastatic disease at diagnosis and require systemic therapy, for which chemotherapy remains the standard first-line option [1]. However, the overall response rate to currently available systemic regimens is low, and the 5-year survival rate for patients with metastatic disease remains below 5% [3]. Although most pancreatic cancers harbor canonical driver mutations, they exhibit marked heterogeneity at the molecular level. Whole-genome sequencing (WGS) and integrative genomic analyses have identified molecular subtypes of PDAC with potential clinical relevance [4-9]. With the increasing implementation of precision oncology, the Chinese Society of Clinical Oncology (CSCO) Guidelines for the Diagnosis and Treatment of Pancreatic Cancer give a level 1 recommendation to perform genetic and other molecular testing on tissue or cytologic specimens as part of the pathological diagnostic work-up, in order to guide individualized treatment, including targeted therapy and immunotherapy [10]. To further promote the use of genetic and molecular testing in the precision treatment of pancreatic cancer, the CSCO Pancreatic Cancer Expert Committee convened a multidisciplinary panel to develop the present Chinese Expert Consensus on Precision Testing and Molecular Diagnosis of Pancreatic Cancer (2025), aiming to provide clinicians with an authoritative reference for precision diagnostics and treatment decision-making.

Humans↗

PubMed2001

Presence and chromosomal subtyping of Legionella species in potable water systems in 20 hospitals of Catalonia, Spain.

OBJECTIVE: To investigate the presence and clonal distribution of Legionella species in the water supply of 20 hospitals in Catalonia, Spain. SETTING: 20 hospitals in Catalonia, an area of 32,000 km2, located in northeast Spain. METHODS: Environmental cultures of 186 points of potable water supply and 10 cooling towers were performed for the presence of Legionella species. Following filtration and acid treatment, the samples were seeded in selective MWY (modified Wadowsky Yee)-buffered charcoal yeast extract-alpha agar. All isolates obtained were characterized microbiologically and genotyped by SfiI pulsed-field gel electrophoresis (PFGE). RESULTS: 73 of 196 water samples, representing 17 of the 20 hospitals included in the study, were positive for Legionella pneumophila (serogroups 1, 2-14, or both). The degree of contamination ranged from 200 to 74,250 colony-forming units/L. Twenty-five chromosomal DNA subtypes were detected by PFGE. A single DNA subtype was identified in 10 hospitals, 2 DNA subtypes were observed in 6 hospitals, and 1 hospital exhibited 3 different DNA subtypes. Each hospital had its own Legionella DNA subtype, which was not shared with any other hospitals. CONCLUSIONS: Legionella was present in the water of most of the hospitals studied; each such hospital had a unique, dominant chromosomal DNA subtype. The verification of several genomic DNA restriction profiles in such a small geographic area demonstrates the great genetic diversity of Legionella in the aquatic environment.

Bacterial Typing Techniques↗

PubMed1985

Structural analysis of the gene coding for hepatitis B virus surface antigen and its product.

The entire genome of hepatitis B virus (subtype adr) has been cloned into pBR322. The clones could be classified into at least seven groups by their restriction endonuclease cleavage maps. The nucleotide sequences of the hepatitis B surface antigen (HBsAg)-coding regions for five clones were determined and compared with published sequences of the HBsAg gene including those of adw, ayw, adyw and adr. The 13 available versions of the amino acid sequence of the polypeptide, predicted from the nucleotide sequences, were analysed in terms of the established specificities of the HBsAg, including the four subtypes. The analysis indicated that a relatively hydrophilic region of the HBsAg protein, spanning amino acid residues 110 to 160, specifies the major (w) and (r) subtype system. The (w/r) subtype appears to depend on changes in one or more variable amino acids at positions 47, 110, 113, 126 and 160 of the HBsAg polypeptide.

Amino Acid Sequence↗

PubMed2003

Human cytomegalovirus glycoprotein N (gpUL73-gN) genomic variants: identification of a novel subgroup, geographical distribution and evidence of positive selective pressure.

Human cytomegalvirus (HCMV) ORF UL73 is a polymorphic locus, encoding the viral glycoprotein gpUL73-gN, a component of the gC-II envelope complex. The previously identified gN genomic variants, denoted gN-1, gN-2, gN-3 and gN-4, were further investigated in this work by analysing a large panel of HCMV clinical isolates collected from all over the world (223 samples). Sequencing and phylogenetic analysis confirmed the existence of the four gN genotypes, but also allowed the identification of a novel subgroup belonging to the gN-3 genotype, which was designated gN-3b. The number of non-synonymous (d(N)) and synonymous (d(S)) nucleotide substitutions and their ratio (d(N)/d(S)) were estimated among the gN genotypes to evaluate the possibility of positive selection. Results showed that the four variants evolved by neutral (random) selection, but that the gN-3 and gN-4 genotypes are maintained by positive selective pressure. The 223 HCMV clinical isolates were subdivided according to their geographical origin, and four main regions of gN prevalence were identified: Europe, China, Australia and Northern America. The gN variants were found to be widespread and represented within the regions analysed without any significant difference, and no new genotype was detected. Finally, for clinical and epidemiological purposes, a rapid and low-cost method for genetic grouping of the HCMV clinical isolates was developed based on the RFLP revealed by SacI, ScaI and SalI digestion of the PCR-amplified UL73 sequence. This technique enabled us to distinguish all four gN genomic variants and also their subtypes.

Amino Acid Sequence↗

PubMed2006

Anti-apoptotic effects of allopregnanolone on P19 neurons.

Progesterone and its metabolites are potent allosteric modulators of GABA(A) receptor function, through a direct, non-genomic interaction with specific receptor subtypes. In addition, fluctuations in the concentration of progesterone, and allopregnanolone in particular, have been shown to modulate GABA(A) receptor gene expression and activity. In this study, mouse P19 cells were induced to differentiate into post-mitotic neurons which express specific neuronal markers, including GABA(A) and N-methyl-d-aspartate (NMDA) receptors. Apoptotic cell death, induced in the presence of NMDA, was efficiently prevented by allopregnanolone and dehydroepiandrosterone (DHEA) but not DHEA sulfate. Apoptosis was accompanied by cytochrome c release to the cytoplasm and Bax translocation to the mitochondria, while the levels of the anti-apoptotic proteins Bcl-2 and Bcl-xL remained unchanged. In the presence of the most potent neurosteroid, allopregnanolone, DNA fragmentation as well as cytochrome c and Bax translocation were prevented. On the other hand, short-term exposure (1-20 microm, 24 h) of P19-derived neurons to allopregnanolone and DHEA significantly increased the levels of alpha1 and beta2 mRNAs of GABA(A) receptor, while the levels of NR1 mRNA of NMDA receptor were not altered. These results suggest that neurosteroids, interfering with the mitochondrial apoptotic pathway, are able to act as survival factors in neuronal cells, while they contribute to GABA(A) receptor plasticity modulating the expression of its subunits.

Animals↗

PubMed1999

Nucleic acid-based cross-linking assay for detection and quantification of hepatitis B virus DNA.

A nucleic acid photo-cross-linking technology was used to develop a direct assay for the quantification of hepatitis B virus (HBV) DNA levels in serum. Cross-linker-modified DNA probes complementary to the viral genomes of the major HBV subtypes were synthesized and used in an assay that could be completed in less than 6 h. The quantification range of the assay, as determined by testing serial dilutions of Eurohep HBV reference standards and cloned HBV DNA, was 5 x 10(5) to 3 x 10(9) molecules of HBV DNA/ml of serum. Within-run and between-run coefficients of variation (CVs) for the assay were 4. 3 and 4.0%, respectively. The assay was used to determine HBV DNA levels in 302 serum samples, and the results were compared to those obtained after testing the same samples with the Chiron branched-DNA (bDNA) assay for HBV DNA. Of the samples tested, 218 were positive for HBV DNA by both assays and 72 gave results below the cutoff for both assays. Of the remaining 12 samples, 10 were positive for HBV DNA by the cross-linking assay only; the 2 other samples were positive by the bDNA assay only. Twenty-eight samples had to be retested by the bDNA assay (CV, >20% between the results obtained from the testing of each sample in duplicate), whereas only three samples required retesting by the cross-linking assay. The correlation between the HBV DNA levels, as measured by the two tests, was very high (r = 0.902; P = 0.01). We conclude that the cross-linking assay is a sensitive and reproducible method for the detection and quantification of HBV DNA levels in serum.

Cross-Linking Reagents↗

PubMed1994

Identification of three feline immunodeficiency virus (FIV) env gene subtypes and comparison of the FIV and human immunodeficiency virus type 1 evolutionary patterns.

Feline immunodeficiency virus (FIV) is a lentivirus associated with AIDS-like illnesses in cats. As such, FIV appears to be a feline analog of human immunodeficiency virus (HIV). A hallmark of HIV infection is the large degree of viral genetic diversity that can develop within an infected individual and the even greater and continually increasing level of diversity among virus isolates from different individuals. Our goal in this study was to determine patterns of FIV genetic diversity by focusing on a 684-nucleotide region encompassing variable regions V3, V4, and V5 of the FIV env gene in order to establish parallels and distinctions between FIV and HIV type 1 (HIV-1). Our data demonstrate that, like HIV-1, FIV can be separated into distinct envelope sequence subtypes (three are described here). Similar to that found for HIV-1, the pairwise sequence divergence within an FIV subtype ranged from 2.5 to 15.0%, whereas that between subtypes ranged from 17.8 to 26.2%. However, the high number of synonymous nucleotide changes among FIV V3 to V5 env sequences may also include a significant number of back mutations and suggests that the evolutionary distances among FIV subtypes are underestimated. Although only a few subtype B viruses were available for examination, the pattern of diversity between the FIV A and B subtypes was found to be significantly distinct; subtype B sequences had proportionally fewer mutations that changed amino acids, compared with silent changes, suggesting a more advanced state of adaptation to the host. No similar distinction was evident for HIV-1 subtypes. The diversity of FIV genomes within individual infected cats was found to be as high as 3.7% yet twofold lower than that within HIV-1-infected people over a comparable region of the env gene. Despite these differences, significant parallels between patterns of FIV evolution and HIV-1 evolution exist, indicating that a wide array of potentially divergent virus challenges need to be considered in FIV vaccine and pathogenesis studies.

Adaptation, Biological↗

PubMed2006

Impact of estrogen receptor beta on gene networks regulated by estrogen receptor alpha in breast cancer cells.

Two subtypes of the estrogen receptor (ER), ERalpha and ERbeta, mediate the actions of estrogens, and although 70% of human breast cancers express ERbeta along with ERalpha, little is known about the possible comodulatory effects of these two ERs. To investigate this, we have used adenoviral gene delivery to produce human breast cancer (MCF-7) cells expressing different levels of ERbeta, along with their endogenous ERalpha, and have examined the effects of ERbeta and receptor occupancy, using ER subtype selective ligands, on genome-wide gene expression by microarray and pathway network analysis. ERbeta had diverse effects on gene expression, enhancing or counteracting ERalpha regulation for distinct subsets of estrogen target genes. Strikingly, ERbeta in the absence of estradiol (E2), elicited the stimulation or suppression of many genes that were normally only regulated by ERalpha with E2. In addition, ERbeta plus E2 elicited the expression of a unique group of genes that were not regulated by ERalpha plus E2 alone. The expression of genes in many functional categories were modulated by ERbeta, with the greatest numbers associated with transcription factors and signal transduction pathways. Regulation of multiple components in the TGFbeta and semaphorin pathways, and of genes controlling cell cycle progression and apoptosis, may contribute to the suppression of cell proliferation observed with ERbeta. Our observations suggest that the relative levels of ERbeta and ERalpha in breast cancers are likely to impact cell proliferation and the activities of diverse signaling pathways and their response to ER ligands and endocrine therapies.

Adenoviridae↗

PubMed2006

Estrogens and the pathophysiology of the biliary tree.

The scientific framework concerning estrogen effects on different tissues has expanded enormously during the last decades, when estrogen receptor (ER) subtypes were identified. Estrogens are not only essential for the female reproductive system, but they also control fundamental functions in other tissues including the cardiovascular system, bone, brain and liver. Recently, estrogens have been shown to target the biliary tree, where they modulate the proliferative and secretory activities of cholangiocytes, the epithelial cells lining bile ducts. By acting on both estrogen receptors (ER-alpha) and (ER-beta) subtypes, and by activating either genomic or non-genomic pathways, estrogens play a key role in the complex loop of growth factors and cytokines, which modulates the proliferative response of cholangiocytes to damage. Specifically, estrogens activate intracellular signalling cascades [ERK(1/2) (extracellular regulated kinases (1/2), PI3- kinase/AKT (phosphatidylinositol-3' kinase/AKT)] typical of growth factors such as insulin like growth factor (IGF1), nerve growth factor (NGF) and vascular endothelial growth factor (VEGF), thus potentiating their action. In addition, estrogens stimulate the secretion of different growth factors in proliferating cholangiocytes. This review specifically deals with the recent advances related to the role and mechanisms by which estrogens modulate cholangiocyte functions in normal and pathological conditions.

Animals↗

PubMed2002

Heritability, genetics and association findings in anorexia nervosa.

Anorexia nervosa (AN) is a severe psychiatric disorder, characterized by a combination of abnormal eating behavior and weight regulation with disturbances of attitudes toward body weight and shape. Prevalence is estimated at 1/1000, but with a high prevalence of the partial syndrome and a 10% mortality rate. This article reviews the findings concerning the heritability and the contributing genes of the disorder, with a focus on candidate genes. In family studies, a higher frequency of AN and BN was found among relatives of AN probands. The heritability rate was estimated at 0.71, similar to twin studies, which estimate 0.58-0.76. The search for genes responsible for the disorder focuses on the monoaminergic and peptidergic systems that are related to appetite and weight regulation. So far, for serotonin and dopamine there are no consistent findings in association studies of AN. However, in an Israeli study, an association was found between susceptibility for AN and the COMT gene, which is involved in monoamine metabolism. Another Israeli study found a relation between AN and the gene encoding for the potassium channel (hSKCa3), which is involved in regulation of neuronal activity. In the endocrine system an unequivocal finding was described of an association to the gene encoding the receptor for beta-estrogen. In the appetite and weight regulation system an association was described between AN and a marker of the uncoupling protein-2 and -3 chromosomal region, raising the likelihood that the mutation within the gene is close to a positive marker. To conclude, although there is a strong familial component in AN, so far the search for candidate genes has not been fruitful and further large scale prospective and adoption studies are needed to confirm genetic factors. We hope that relative studies using a wide genome scan, as well as subtyping the different types of AN, will bring us closer to understanding of the heritability of AN and enable the development of improved means of prevention and treatment.

Adolescent↗

PubMed2002

Geographical distribution of hepatitis C virus genotypes in India.

HCV isolates from around the world show substantial nucleotide sequence variability throughout the viral genome. Based on the identification of these genome differences various genotypes and subtypes have been described from different geographical regions. They have been tentatively classified into six major genotypes and more than 30 subtypes, but new subtypes are continually being discovered. In recent years, substantial evidence has emerged indicating that typing and subtyping for HCV is clinically important. The present study aims at determining and comparing the prevalence of different genotypes from different parts of India (North, South, East and West). A total of 153 samples representing different regions have been genotyped in our lab. Our studies document a high prevalence of genotype 3 (> 76%) and very low prevalence of genotype 2 (< 2%), as a whole. However, genotype 3a has been found to be the highest (50%) with a decreased frequency of approximately 25% in the case of 3b, approximately 14% in 1b and approximately 10% in 1a, whereas a minimal number (approximately 4%) of genotype 4 has been found only in Southern and Western India.

Genotype↗