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PubMed1996

The majority of autologous cytolytic T-lymphocyte clones derived from peripheral blood lymphocytes of a melanoma patient recognize an antigenic peptide derived from gene Pmel17/gp100.

Anti-melanoma cytolytic T-lymphocyte (CTL) clones were derived from peripheral blood lymphocytes of HLA-A2 melanoma patient LB265 after stimulation with the autologous tumor cell line LB265-MEL, which showed high expression of melanocyte-lineage specific genes. Of 55 CTL clones, 46 recognized HLA-A2-restricted antigens. These 46 CTL clones were studied for their ability to specifically release tumor necrosis factor in the presence of COS cells cotransfected with the HLA-A2 gene and the cDNA of either tyrosinase, Melan-A/MART1, Pmel17/gpl00, gp75/TRP1, or MSH receptor. Six CTL clones recognized the Melan-A/MART1 antigen, whereas the remaining 40 CTL clones recognized a Pmel17/gp100 antigen. These 40 anti-PmelI7/gpl00 CTL clones were all able to lyse T2 cells pulsed with the antigenic peptide YLEPGPVTA, as previously reported. The T-cell receptor beta chain hypervariable region was sequenced and found to be identical in the 15 CTL clones analyzed. Taken together, these data show a high frequency of Pmell7/gp100-specific T cells in autologous antitumor CTL clones derived from peripheral blood of a melanoma patient.

Amino Acid Sequence↗
PubMed2002

Time to the most recent common ancestor and divergence times of populations of common chaffinches (Fringilla coelebs) in Europe and North Africa: insights into Pleistocene refugia and current levels of migration.

We analyzed sequences from a 275-bp hypervariable region in the 5' end of the mitochondrial DNA control region in 190 common chaffinches (Fringilla coelebs) from 19 populations in Europe and North Africa, including new samples from Greece and Morocco. Coalescent techniques were applied to estimate the time to the most recent common ancestor (TMRCA) and divergence times of these populations. The first objective of this study was to infer the locations of refugia where chaffinches survived the last glacial episode, and this was achieved by estimating the TMRCA of populations in regions surrounding the Mediterranean that were unglaciated in the late Pleistocene. Although extant populations in Iberia, Corsica, Greece, and North Africa harbor haplotypes that are basal in a phylogenetic tree, this information alone cannot be used to infer that these localities served as refugia, because it is impossible to infer the ages of populations and their divergence times without also considering the population genetic processes of mutation, migration, and drift. Provided we assume the TMRCAs of populations are a reasonable estimate of a population's age, coalescent-based methods place resident populations in Iberia, Corsica, Greece, and North Africa during the time of the last glacial maximum, suggesting these regions served as refugia for the common chaffinch. The second objective was to determine when populations began diverging from each other and to use this as a baseline to estimate current levels of gene flow. Divergence time estimates suggest that European populations began diverging about 60,000 years before present. The relatively recent divergence of populations in North Africa, Italy, and Iberia may explain why classic migration estimates based on equilibrium assumptions are high for these populations. We compare these estimates with nonequilibrium-based estimates and show that the nonequilibrium estimates are consistently lower than the equilibrium estimates.

Africa, Northern↗
PubMed1980

Demonstration and partial characterization of an atypical protein in the urine of a patient with primary amyloidosis.

A paraprotein has been isolated from the urine of a patient with primary amyloidosis. Immunologically it was classified as a free lambda light chain. The molecular weight was 22500 daltons. N-terminal amino acid analysis demonstrated homology with lambda IV variable subgroup in 19 of the first 20 amino acids. Extensive homology with lambda IV chains was demonstrated also in the hypervariable region of the light chain. An antiserum produced against the paraprotein was rendered idiotype-specific by absorption with pooled human light chains. This antiserum stained tissue specimen from the rectum and liver of the patient by the indirect immunofluorescence technique. This strongly indicates that the free lambda light chains that can be isolated from the urine are also deposited in the tissues as amyloid substance.

Amino Acid Sequence↗
PubMed1998

New monoclonal antibodies against a recombinant second envelope protein of Hepatitis C virus.

To study the immunological features of the hepatitis C virus (HCV) envelope protein (E2 protein), new specific monoclonal antibodies (mAbs) were generated. WKA/H rats were immunized with syngeneic cells infected with a vaccinia virus expressing the E2 protein and with soluble E2 protein obtained from Chinese hamster ovary cells with a plasmid-based expression system. By screening hybridoma cells obtained from spleen cells of the immunized rats, three specific mAbs were obtained. One mAb was reactive to a peptide corresponding to the hypervariable region 1 (HVR1) in E2 protein, while the others reacted to regions outside HVR1. The significance of these antibodies for the diagnosis of HCV infection as well as for analysis of the structure of the HCV E2 protein will be discussed.

Amino Acid Sequence↗
PubMed1996

Replication of hepatitis C virus in cultured non-neoplastic human hepatocytes.

We established a replication system for hepatitis C virus (HCV) using the PH5CH non-neoplastic human hepatocyte line that had been immortalized with simian virus 40 large T antigen. In cells inoculated with sera derived from two HCV-positive blood donors, positive-stranded HCV RNA was detected up to 30 days postinoculation (p.i.). Semi-quantitative analysis of HCV RNA revealed that HCV multiplied during the period of culture. Sequence analysis of the HCV hypervariable region 1 (HVR1) in both cases indicated that HVR1 populations from the cells at 8 days p.i. were apparently different from those of the original inocula. HVR1 populations in infected cells became homogeneous or just a few species were selected over time. These results suggest that HCV is replicating in the human hepatocyte PH5CH cells. This culture system will be useful for detailed studies of the biological effects of HCV in human hepatocytes.

Amino Acid Sequence↗
PubMed2005

Phylogenetic relationships among Spanish goats breeds.

We partially sequenced the mitochondrial hypervariable region 1 (HVR1) in 60 goats belonging to six Spanish breeds. The analysis of these and previously published sequences reveals a weak phylogeographical structure in the Iberian Peninsula breeds. Individuals from a single breed did not group into a single cluster. Furthermore, individuals from different breeds often shared single phylogenetic tree branches after UPGMA analysis. This could reflect the non-existence of breed isolation because of traditional seasonal pastoralism and annual long-distance migrations. Three goats belonging to the C maternal lineage were found, demonstrating a wider than previously thought distribution for this lineage.

Animals↗
PubMed2006

Phylogenetic analysis of Sicilian goats reveals a new mtDNA lineage.

The mitochondrial hypervariable region 1 (HVR1) sequence of 67 goats belonging to the Girgentana, Maltese and Derivata di Siria breeds was partially sequenced in order to present the first phylogenetic characterization of Sicilian goat breeds. These sequences were compared with published sequences of Indian and Pakistani domestic goats and wild goats. Mitochondrial lineage A was observed in most of the Sicilian goats. However, three Girgentana haplotypes were highly divergent from the Capra hircus clade, indicating that a new mtDNA lineage in domestic goats was found.

Animals↗
PubMed1986

Organization of the zeta-alpha genes in Chinese.

Analysis of alpha and zeta genes in 101 healthy normals and hospitalized patients with non-haematological diseases revealed a 3% incidence of alpha thalassaemia in the local Chinese population of Hong Kong. Triple alpha genes were found in only one person while triple zeta genes were more prevalent, occurring in 13 subjects. Studies of 28 unselected patients with Hb H disease indicated a predominance of the rightward alpha gene deletion. The extent of alpha gene deletion in homozygous alpha thalassaemia 1 was at least 18.1 kb, beginning from the BamH I site 3' to the zeta 1 gene and includes the psi alpha, alpha 2 and alpha 1 genes. Nineteen of the 20 chromosomes bearing the alpha thalassaemia 1 deletion had identical zeta-intergenic hypervariable region suggesting a common origin of this mutation. The co-inheritance of alpha thalassaemia in beta thalassaemia subjects was 8%, but did not ameliorate the clinical features of those with homozygous beta thalassaemia.

China↗
PubMed1988

Characterization of a newly discovered alpha-thalassaemia-1 in two Spanish patients with Hb H disease.

A new deletion of more than 27 kb, removing the psi zeta 1, psi alpha 2, psi alpha 1, alpha 2, alpha 1 and theta 1 globin genes has been found in four members of a Spanish family, including two patients with Hb H disease. The 5' end point of the deletion is located between the zeta and psi zeta genes, and the 3' end of the deletion is downstream of the 3' hypervariable region.

Adolescent↗
PubMed1992

Clonal lymphocytes are detectable in only some cases of MDS.

Clonal analysis of lymphocytes from patients with myelodysplastic syndrome (MDS) has been carried out using X-chromosome inactivation patterns detected by the probe M27 beta, and by polymerase chain reaction amplification of the immunoglobulin heavy chain gene hypervariable region, CDR3. Of 32 female patients heterozygous for M27 beta only seven (22%) demonstrate monoclonality of peripheral blood lymphocytes. 12 (37%) give unequivocal polyclonal results and the remaining cases give patterns of X-inactivation which cannot be interpreted either way. A study of 68 MDS patients showed five (7%) with a population of B-cells with a monoclonal rearrangement of CDR3 compared with none out of 60 normal individuals, none out of 15 with B-non Hodgkin lymphoma (B-NHL) in remission and 19 out of 25 (75%) of cases of B-chronic lymphocytic leukaemia (B-CLL). Monoclonal lymphocytes were found by both techniques in only two females with MDS. We conclude that the presence of polyclonal lymphocytes is a common finding in patients with MDS.

Adult↗
PubMed1990

Antibodies to the peptide from the plasmid-coded Yersinia outer membrane protein (YOP1) in patients with ankylosing spondylitis.

Seventy-five Norwegian patients with ankylosing spondylitis (AS) were studied for class-specific antibody response against synthetic peptide, P81, representing the sequence of plasmid-coded outer membrane protein of Yersinia (YOP1) containing four amino acid homology (TDRE) with HLA-B27 sequence. Ten (16.7%), five (8.3%) and seven (11.2%) of 60 male AS patients showed elevated anti-YOP1 P81 antibody of IgA, IgG, and IgM class, respectively, whereas for each isotype only one (4%) of 25 healthy male controls was positive. Differences were not observed between female patients and controls. In all isotypes, antibody-positive patients were more frequently found in patients with active disease. The anti-YOP1 P81 antibody levels of the patients were generally not correlated with the antibody levels against the peptide representing the hypervariable region of HLA-B27 (B27 peptide). However, in one patient the antibody was shown to react with both peptides by cross-inhibition analysis. Overall, it appears that any causal relationship between YOP1 and pathogenesis of AS is not strong. Immunogenicity and cross-reactivity of the YOP1 region encompassing the TDRE sequence particularly at the T cell level require further study.

Adhesins, Bacterial↗
PubMed1997

Modulation of hepatitis C virus quasispecies heterogeneity by interferon-alpha and ribavirin therapy.

To determine the effects of interferon-alpha (IFN-alpha) and ribavirin therapy on hepatitis C virus (HCV) quasispecies heterogeneity, 29 patients with chronic HCV infection treated with either IFN-alpha (n = 15), ribavirin (n = 7) or placebo (n = 7) were studied. HCV quasispecies heterogeneity was determined by single-strand conformational polymorphism (SSCP) analysis of the HCV E2 hypervariable region 1 (HVR1). For patients receiving IFN-alpha, HVR1 was amplified in 14 of 15 patients before, and in six of seven patients after therapy. After controlling the amount of amplicon loaded, a reduction in the number of SSCP bands was observed with IFN-alpha therapy (median number of SSCP bands per patient was eight before therapy and two after therapy). In the seven patients within each of the ribavirin- and placebo-treated groups, there was no significant difference in the viraemia level, number of SSCP bands per patient or the SSCP band pattern, before and after therapy. These findings suggest that at the doses given, IFN-alpha, but not ribavirin, exerts a selective pressure on HCV quasispecies heterogeneity.

Adult↗
PubMed2005

The minimum number of clones necessary to sequence in order to obtain the maximum information about hepatitis C virus quasispecies: a comparison of subjects with and without liver cancer.

Most studies of hepatitis C virus (HCV) quasispecies have reported the results of sequencing only three to five clones per sample. The possibility that sequencing so few clones might not provide a representative picture of the quasispecies present in a sample has never been evaluated. The present study was conducted to evaluate whether sequencing greater numbers of clones results in better information about the HCV quasispecies number and distribution, and to compare the HCV quasispecies in liver cancer cases and controls. RNA was extracted from serial serum samples from six subjects with HCV-associated liver cancer and 11 age- and sex-matched HCV-infected controls without liver cancer. The hypervariable region 1 (HVR1) of the HCV genome was amplified, cloned, and sequenced. For further studies of 12 serum samples from two liver cancer cases and two matched controls, successive groups of 10 additional clones were sequenced up to a total of 50 clones per serum sample. When only 10 clones were sequenced from each specimen, no consistent differences were seen between the number of HCV quasispecies in the six liver cancer cases and the 11 controls. However, sequencing 40 clones from each of 12 samples from two liver cancer cases and two controls revealed a greater number of quasispecies in liver cancer cases than in controls. Testing an additional 10 clones (50 clones per sample) did not significantly increase the number of quasispecies detected.

Genetic Variation↗
PubMed2006

Sensitivity to antiviral therapy may change after liver transplantation in patients with chronic hepatitis C virus infection.

In hepatitis C virus (HCV)-infected patients, it is generally assumed that the pattern of response to antiviral therapy remains unaltered after liver transplantation (LT). However, changes in the circulating HCV quasispecies and in the gene expression profiles of the graft might influence response to treatment after LT. We evaluated 22 HCV-infected patients who received antiviral treatment while awaiting LT and in whom HCV infection recurred. Eleven of these patients underwent a new antiviral treatment course. Our study analyses the early virological response to both treatment courses to assess the influence of the changes in HCV on the response to therapy. Patients were considered early virological responders (EVR) if viral load declined > or = 2 log10 during the first 12 weeks of therapy. The remaining individuals were considered nonresponders (NR). HCV sequences from hypervariable region 1 and nonstructural 5A (NS5A) region before both treatment regimens were compared. Of 11 patients, 8 (73%) showed identical early response to both courses of therapy (group A: five EVR-EVR, three NR-NR). Interestingly, the response changed in three patients (27%) (group B): two NR became EVR after transplantation, whereas one EVR became NR. Fixation of mutations within the NS5A occurred preferentially in group B (100%) compared with group A (37%)(P = 0.12). However, the number of fixed mutations was not significantly different between groups, suggesting that the changes in sensitivity to therapy after LT are not exclusively dependent on variations in HCV strains. In conclusion, in HCV-infected patients undergoing LT, the pattern of response to antiviral treatment may change after transplantation, and this possibility needs to be incorporated in clinical practice.

Adult↗
PubMed2006

Type-IV Indian swine HEV infects rhesus monkeys.

In contrast to countries reporting zoonotic spread of hepatitis E virus (HEV), distinct genotypes circulate in humans (genotype 1) and pigs (genotype 4) from India indicating rarity of such spread. Pigs were refractory to human HEV. As rhesus is an excellent animal model for human HEV, an attempt was made to infect rhesus monkeys with swine HEV. Experimental infection of both the rhesus monkeys with swine-HEV as evidenced by seroconversion to anti-HEV antibodies and presence of viraemia suggests possibility of human infections or differential susceptibility. Comparison of Open Reading Frame-2 and hypervariable regions of HEV genomes showed identity of swine and monkey-derived HEV.

Alanine Transaminase↗
PubMed2006

Bathymetric and geographic population structure in the pan-Atlantic deep-sea bivalve Deminucula atacellana (Schenck, 1939).

The deep-sea soft-sediment environment hosts a diverse and highly endemic fauna of uncertain origin. We know little about how this fauna evolved because geographic patterns of genetic variation, the essential information for inferring patterns of population differentiation and speciation are poorly understood. Using formalin-fixed specimens from archival collections, we quantify patterns of genetic variation in the protobranch bivalve Deminucula atacellana, a species widespread throughout the Atlantic Ocean at bathyal and abyssal depths. Samples were taken from 18 localities in the North American, West European and Argentine basins. A hypervariable region of mitochondrial 16S rDNA was amplified by polymerase chain reaction (PCR) and sequenced from 130 individuals revealing 21 haplotypes. Except for several important exceptions, haplotypes are unique to each basin. Overall gene diversity is high (h = 0.73) with pronounced population structure (Phi(ST) = 0.877) and highly significant geographic associations (P < 0.0001). Sequences cluster into four major clades corresponding to differences in geography and depth. Genetic divergence was much greater among populations at different depths within the same basin, than among those at similar depths but separated by thousands of kilometres. Isolation by distance probably explains much of the interbasin variation. Depth-related divergence may reflect historical patterns of colonization or strong environmental selective gradients. Broadly distributed deep-sea organisms can possess highly genetically divergent populations, despite the lack of any morphological divergence.

Animals↗
PubMed1992

Phylogenetic relationships among the agent of bacillary angiomatosis, Bartonella bacilliformis, and other alpha-proteobacteria.

Bacillary angiomatosis (BA) and chronic bartonellosis are bacterial infections of humans which result in an unusual vascular proliferative tissue response. In order to determine their phylogenetic relationships, we have determined greater than 95% of the 16S rRNA sequences for these two organisms by amplification directly from infected BA tissue and from a Bartonella bacilliformis lyophilized culture. The BA agent and B. bacilliformis are closely related alpha-proteobacteria (98.5%), although the BA agent is more closely related to Rochalimaea quintana (99.1%). Contrary to previous belief, the BA agent is distinct from, and less closely related to, the cat scratch bacillus (Afipia felis) (90.7%). We propose a novel secondary structure in a hypervariable region of the 16S rRNA which is useful for alignment of primary sequences and which may be useful for design of nucleic acid probes.

Bacteria↗
PubMed1976

Structural studies of induced antibodies with defined idiotypic specificities. IV. The heavy chains of anti-streptococcal group A carbohydrate antibodies from Sprague-Dawley rats carrying a cross-reacting idiotype.

The heavy (H) chains of three anti-streptococcal group A carbohydrate antibodies (anti-SACHO) of restricted heterogeneity, elicited in inbred Sprague-Dawley rats, were subjected to 40 cycles of automated Edman degradation. All three antibody H-chain preparations had an identical amino acid sequence and were classified as a variant of the VHIII subgroup of immunoglobulin H chains. A comparison of the H-chain sequence of these antibodies with that of pooled rat gamma chains suggests that a very minor population of H chains (closely related to the VHIII subgroup) has been 'recruited' as a consequence of this immunization. This observation further supports the notion that 'framework' and 'specificity' or 'hypervariable regions' are closely linked.

Amino Acid Sequence↗