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PubMed2003

Colonia Tovar: the history of a semi-isolated Venezuelan population of German ancestry described by HLA class I genes.

The history of Colonia Tovar is very complex, being the home of descendants of only a small fraction of immigrants arriving to the South American continent from a specific region of Germany, with a restricted number of founders, small population size and consanguineous mating, experiencing isolation for 100 years, with later migrations, a low rate of population growth and a high mean number of children per couple. How complex is its genetic structure? Do the highly polymorphic HLA genes reflect its history and confirm the story of this population described by other genes? Several studies have been made in this population, but we describe for the first time the HLA Class I variability in the population of Colonia Tovar using PCR-SSOP. Random genetic drift, founder effect and gene flow could explain the HLA allele and haplotype frequencies observed in this population but alleles at the class I loci were insufficient to identify the German origin of the community established through history. This agrees with findings obtained testing other genetic systems (ACP, AK, ESD, G6PD, GLO, PGM, PGD, ALB, CP, HP, TF), but the HLA-typing results indicate that the original gene pool has been diluted due to gene flow from the surrounding Mestizo population.

Adolescent↗

PubMed2003

Genetic and demographic dynamics of small populations of Silene latifolia.

Small local populations of Silene alba, a short-lived herbaceous plant, were sampled in 1994 and again in 1999. Sampling included estimates of population size and genetic diversity, as measured at six polymorphic allozyme loci. When averaged across populations, there was very little change between samples (about three generations) in population size, measures of within-population genetic diversity such as number of alleles or expected heterozygosity, or in the apportionment of genetic diversity within and among populations as measured by F(st). However, individual populations changed considerably, both in terms of numbers of individuals and genetic composition. Some populations doubled in size between samples, while others shrank by more than 75%. Similarly, expected heterozygosity and allele number increased by more than two-fold in individual populations and decreased by more than three-fold in others. When population-specific change in number and change in measures of genetic diversity were considered together, significant positive correlations were found between the demographic and genetic variables. It is speculated that some populations were released from the demographic consequences of inbreeding depression by gene flow.

Alleles↗

PubMed2000

Genetic variation and population structure in the endangered greater horseshoe bat Rhinolophus ferrumequinum.

Following a dramatic decline last century, the British population of the endangered greater horseshoe bat Rhinolophus ferrumequinum is highly fragmented. To examine the consequences of fragmentation and limited dispersal on patterns of genetic structure and variation, we used microsatellite markers to screen bats from around 50% of the known maternity colonies in Britain, and two areas from continental Europe. Analyses revealed that Welsh and English colonies were genetically isolated. This, and lower variability in Britain than north France, may result from either genetic drift, or the species' colonization history. Gene flow among most neighbouring colonies was not generally restricted, with one exception. These findings have important implications for the ongoing conservation management of this species.

Animals↗

PubMed2001

The clonal analysis of anticardiolipin antibodies in a single patient with primary antiphospholipid syndrome reveals an extreme antibody heterogeneity.

The mechanism underlying the prothrombotic state that characterizes the primary antiphospholipid syndrome proves to be difficult to define mainly because of the variety of the phospholipid and protein targets of antiphospholipid antibodies that have been described. Much of the debate is related to the use of polyclonal antibodies during the different antiphospholipid assays. To better describe the antiphospholipid antibodies, a strategy was designed to analyze the reactivity of each one antibody making up the polyclonal anticardiolipin activity, breaking down this reactivity at the clonal level. This was performed in a single patient with primary antiphospholipid syndrome by combining (1) the antigen-specific selection of single cells sorted by flow cytometry using structurally bilayered labeled anionic phospholipids and (2) the cloning of immunoglobulin (Ig) variable (V) region genes originating from individual IgG anticardiolipin-specific B cells by a single-cell polymerase chain reaction technique. The corresponding V regions were cloned in order to express human recombinant antibodies in insect cells by a baculovirus expression system. The molecular analysis, the fine specificity, and the protein cofactor dependency of the first 5 monoclonal IgG anticardiolipins are reported here. This clonal analysis reveals the extreme heterogeneity of these antibodies, which could account for the difficulties in the previous attempts to define the pathogenic antiphospholipid response. This approach should help to unravel the complex antiphospholipid immune response and the mechanism of the prothrombotic state associated with these antibodies, but it could also shed some light on their possible origins. (Blood. 2001;97:3820-3828)

Adult↗

PubMed1999

Estimates of gene flow among Anopheles maculatus populations in Thailand using microsatellite analysis.

We report an analysis of seven microsatellite loci in eight populations of Anopheles maculatus mosquitoes dispersed over a distance of approximately 1,100 km in Thailand. A wide spectrum of genetic variability, with mean heterozygosities ranging from 0.738 to 0.847 were found. Based on microsatellite analysis, geographic populations of An. maculatus can be grouped into two clusters; one includes upper and lower northern populations that extend from approximately 11 degrees to 16 degrees north latitude, and the other (southern populations) extends south from about 7 degrees to 6 degrees north latitude. Wright's F(ST) and Slatkins's R(ST) for all seven microsatellite loci indicated low estimates of differentiation among all populations (mean values of F(ST) and R(ST) = 0.0406 and 0.051, respectively, corresponding to the Nm values of 5.91 and 4.65, respectively), and suggested that gene flow occurs among populations. However, there is some restriction of gene flow between the northern and southern populations. Geographic barriers could be limiting factors for greater gene flow between populations.

Alleles↗

PubMed2000

Epitope analysis and primary structures of variable regions of anti-human FcepsilonRI monoclonal antibodies, and expression of the chimeric antibodies fused with human constant regions.

The structural analysis of monoclonal antibodies (mAbs) against the alpha subunit of the high affinity IgE receptor (FcepsilonRIalpha) is an alternative approach to obtaining information for the design of inhibitors that will block complementary interaction between IgE and FcepsilonRIalpha and to analyzing the various biological effects induced by anti-FcepsilonRIalpha autoantibodies in chronic urticaria. In this study, epitopes for mouse anti-human FcepsilonRIalpha mAbs and primary structures of variable regions of the mAbs were analyzed. Three mAbs inhibitory for IgE-binding reacted to the deletion mutants of FcepsilonRIalpha containing the whole second immunoglobulin-like domain as well as IgE did. On the other hand, two uninhibitory mAbs reacted to those containing the whole first immunoglobulin-like domain. The cDNAs for variable regions of the five mAbs were cloned and sequenced. Two inhibitory mouse/human chimeric antibodies were expressed in COS7 cells and bound to Chinese hamster ovary transfectant cells expressing FcepsilonRI (CHO/alphabetagamma), and these inhibited the binding of IgE to CHO/alphabetagamma cells.

Amino Acid Sequence↗

PubMed2000

Programmed cell death signaling via cell-surface expression of a single-chain antibody transgene.

BACKGROUND: The monoclonal antibody, 5H7, is specific for a monomorphic determinant on the a3 domain of human class I MHC (A, B, C). Immobilized 5H7 delivers programmed cell death (PCD) signals to human lymphoid tumor cells as well as peripheral blood mononuclear cells. METHODS: The potential clinical utility of 5H7 was addressed by design of a single-chain variable antibody (scFv), termed 5H7scFv, which was coupled to glycophosphotidylinostitol (GPI), thereby providing membrane expression of the 5H7 idiotype (5H7scFv-GPI). Membrane expression of 5H7scFv-GPI conferred PCD-inducing properties to cells that do not normally have the capability to process and express whole antibody molecules. The initial construction was undertaken in a bacterial expression system, and appropriate protein folding was determined by binding to class I MHC-expressing cells. RESULTS: 5H7scFv-GPI-transfected Chinese hamster ovary cells demonstrated reconstitution of the 5H7 idiotype and binding to soluble HLA-A2. Cross-linking of class I MHC, via membrane expression of the scFv, provided effective PCD signaling in B and T lymphocyte tumor cells. Peripheral blood mononuclear cells were susceptible to 5H7scFv-GPI-induced PCD, and augmentation of PCD signals was noted with anti-CD3 and anti-CD28 preactivation. Responder cells demonstrated typical histologic features of PCD and Annexin V-fluorescein isothiocyanate binding. CONCLUSIONS: Cell surface anchorage of scFv thus provides effective delivery of immune modulatory signals, which may be manipulated for various therapeutic strategies.

Animals↗

PubMed1986

Cytological, flow cytometric, and molecular analysis of the rapid evolution of mammalian chromosomes containing highly amplified DNA sequences.

Transfection of a mouse dihydrofolate reductase (DHFR) cDNA contained in a plasmid "expression vector" into DHFR deficient Chinese hamster cells, followed by progressive selection of cells in increasing concentrations of methotrexate (MTX), leads to marked amplification of the exogenous DHFR sequences in the recipient hamster cells. This gene amplification is evident at the cytological level, in the form of homogeneously staining chromosomal regions (HSRs), at a gene expression level, in the form of fluorescein-methotrexate binding, and at the DNA level. Flow sorting, based on variable fluorescein-MTX binding, or direct cellular cloning, followed by chromosome analysis, revealed intercellular heterogeneity of HSRs in size and distribution. This suggested that there was a rapid evolution of HSRs in MTX-resistant transfectants. Chromosomal analysis of HSR evolution in situ, by examining individual colonies presumably derived from one or a few cells, underscored this impression of chromosome structural fluidity. Rates of HSR change in excess of 0.01 per cell division, increased by low doses of the recombinogen, mitomycin C, were detected. The Chinese hamster DHFR transfectants described should be amenable to detailed, coordinate cytological and molecular characterization. Such an analysis should contribute to an understanding of processes such as homologous recombination in mediating HSR evolution in mammalian chromosomes.

Animals↗

PubMed2004

Fluid flow electrophoresis model.

Molecular delivery via electroporation is typically done via molecular diffusion and tissue perfusion. The inherent variability in those distribution methods limits the efficacy of this medical and laboratory technique. Electrophoresis has been shown to improve the distribution and placement of the molecule [Gene Therapy 9 (2002) 1286]. This paper presents a fluid flow model for electrophoresis in tissues. Parallel plate and four-needle needle array electrodes are the electrodes modeled as the delivery devices. The parallel plate electrode produces a homogeneous distribution of the analyte but the needle array electrode creates a peak where the electric field effects diminish.

Animals↗

PubMedDate not supplied

Genetic study in Panaquire, a Venezuelan population.

Panaquire is a population in Venezuela founded in 1733 by Spaniards from the Canary Islands. In order to define the genetic characteristics of this population the following loci were studied: ABO, RH (Cc, D, Ee), FY, K, JK, HB, ESD, ACP1, HP, TF, CP and ALB. Its sociohistorical features were also investigated. Historic censuses reveal that ethnically Blacks were the most important group in this village during the year 1800 (76%), followed by Amerindians (9%), Mulattoes (5%) and Whites (7%). The results of this analysis show that presently the most important genetic component is of African origin (59%), followed by Amerindian (26%) and Caucasian (15%) contributions. These results suggest that Canarians founded Panaquire, but unfavorable sociopolitical and environmental circumstances, as well as the entrance of former slaves, determined the village's evolution as a Black population. Important gene flow also occurred from Indian settlements, and some admixture with Whites. Our analysis shows once again the importance of handling together genetic and sociocultural variables to have a better interpretation of the evolution of human populations.

Animals↗

PubMed2004

Genetic variability of the narrow endemic tree Antirhea aromatica Castillo-Campos Lorence, (Rubiaceae, Guettardeae) in a tropical forest of Mexico.

BACKGROUND AND AIMS: Genetic structure and variability were examined in the only three extant populations of the narrow-endemic tree Antirhea aromatica (Rubiaceae, Guettardeae), an endangered species of the tropical forest of eastern Mexico. Patterns of genetic diversity within and among populations for adult plants and seedlings were obtained. METHODS: Allozyme electrophoresis of 15 loci was conducted and the data analysed with statistical approximation for obtaining genetic diversity, structure and gene flow. KEY RESULTS: The mean expected heterozygosity (He) in the adult and seedling populations was 0.18 +/- 0.08 and 0.20 +/- 0.09, respectively. The genetic variation explained by differences among populations was 51 and 35 %, for adult and seedling populations, respectively. On average, gene flow between paired adult populations was low (Nm = 0.26 +/- 0.09), compared with other trees from the tropical forest. CONCLUSIONS: The results indicated that the populations evaluated have high genetic variability, compared with other endemic and geographically narrowly distributed plant species, in areas with high levels of environmental heterogeneity (e.g. tropical forests). The conservation implications of the results are discussed, and in this regard it is proposed that A. aromatica should be considered as an indicator species with economic potential. It is suggested that sustainable management practices should be implemented and that the areas where the species is distributed should be declared a natural reserve to ensure the species conservation.

Conservation of Natural Resources↗

PubMed2005

Analysis of clonal immunoglobulin heavy chain rearrangements in ocular lymphoma.

BACKGROUND: The morphologic diagnosis of primary and metastatic intraocular lymphoma (IOL) was made difficult by the paucicellular specimens with fragile populations of lymphocytes retrieved through pars plana vitrectomy (PPV). The analysis of immunoglobulin heavy chain (IgH) gene rearrangements (AIGHR) was used as an adjunct to cytopathology and flow cytometry in systemic lymphoma. In IOL, the sensitivity and specificity of AIGHR are unknown. METHODS: The authors reviewed the clinical records of patients who underwent PPV for suspicion of IOL at the Immunology and Uveitis Service of the Massachusetts Eye and Ear Infirmary (Boston, MA) between 2000 and 2002. AIGHR was performed as a routine diagnostic test on cell lysates isolated from < 0.5 mL of vitreous fluid. The authors used seminested polymerase chain reaction (PCR) with consensus primers for the VDJ-region of the IgH gene. PCR products were analyzed by polyacrylamide gel electrophoresis. RESULTS: Thirty patients (37 specimens) with chronic vitritis and 17 patients (23 specimens) with IOL were included. The specificity of vitreous fluid cytopathology, flow cytometry, and AIGHR was 1.0, and the sensitivity values were 0.24, 0.36, and 0.64, respectively. AIGHR was negative in two patients for whom cytopathology or flow cytometry revealed the diagnosis of lymphoma. Clonal IGHR was found in four specimens classified as negative for lymphoma based on cytopathology and flow cytometry. CONCLUSIONS: AIGHR supplemented cytopathology and flow cytometry to increase the diagnostic yield in IOL.

Adolescent↗

PubMed1999

SEA-scFv as a bifunctional antibody: construction of a bacterial expression system and its functional analysis.

A SEA-antibody single chain Fv (SEA-scFv) fusion protein was produced by bacterial expression system in this study. SEA-scFv has both staphylococcal enterotoxin A (SEA) effects and antibody activity directed at the epithelial mucin core protein MUC1, a cancer associated antigen. It was expressed mostly in the cytoplasm as an insoluble form. The gene product was solubilized by guanidine hydrochloride, refolded by conventional dilution method, and purified using metal-chelating chromatography. The resulting SEA-scFv fusion protein preparation was found to react with MUC1 and MHC class II antigens and had the ability to enhance cytotoxicity of lymphokine activated killer cells with a T cell phenotype against a human bile duct carcinoma cell line, TFK-1, expressing MUC1. This genetically engineered SEA-scFv fusion protein promises to be an important reagent for cancer immunotherapy.

Antibodies, Bispecific↗

PubMed2003

2-deoxycoformycin in the treatment of T-large granular lymphocyte leukemia.

A 52-year-old woman presented to our clinic for investigation of agranulocytosis and mild lymphocytosis. A diagnosis of T-large granular lymphocyte leukemia was made, based on immunophenotyping findings of the peripheral blood lymphocytes (CD3, CD8, CD16, CD57). Flow cytometric analysis of TCR-Vbeta repertoire showed single Vbeta9 expression on peripheral T-cells. Clonality was also demonstrated with PCR analysis which revealed clonal rearrangement of TCRgamma-chain gene. Granulocyte-macrophage colony-stimulating factor (G-CSF) (G-CSF), cyclosporine, methylprednisolone and oral methotrexate failed to correct the neutropenia. Finally, treatment with 2-deoxycoformycin (DCF) was successful and resulted in complete correction of the neutrophil count. Flow cytometric analysis of TCR-Vbeta repertoire proved to be an effective method to assess the therapeutic response to various treatments and to evaluate residual disease.

Antibiotics, Antineoplastic↗

PubMed2003

Flow-cytometric isolation of human antibodies from a nonimmune Saccharomyces cerevisiae surface display library.

A nonimmune library of 10(9) human antibody scFv fragments has been cloned and expressed on the surface of yeast, and nanomolar-affinity scFvs routinely obtained by magnetic bead screening and flow-cytometric sorting. The yeast library can be amplified 10(10)-fold without measurable loss of clonal diversity, allowing its effectively indefinite expansion. The expression, stability, and antigen-binding properties of >50 isolated scFv clones were assessed directly on the yeast cell surface by immunofluorescent labeling and flow cytometry, obviating separate subcloning, expression, and purification steps and thereby expediting the isolation of novel affinity reagents. The ability to use multiplex library screening demonstrates the usefulness of this approach for high-throughput antibody isolation for proteomics applications.

Cells, Cultured↗

PubMed2002

Radiosensitive SCID patients with Artemis gene mutations show a complete B-cell differentiation arrest at the pre-B-cell receptor checkpoint in bone marrow.

Severe combined immunodeficiency disease (SCID) can be immunologically classified by the absence or presence of T, B, and natural killer (NK) cells. About 30% of T(-)B(-)NK(+) SCID patients carry mutations in the recombination activating genes (RAG). Some T(-)B(-)NK(+) SCID patients without RAG gene mutations are sensitive to ionizing radiation, and several of these radiosensitive (RS) SCID patients were recently shown to have large deletions or truncation mutations in the Artemis gene, implying a role for Artemis in DNA double-strand break (dsb) repair. We identified 5 RS-SCID patients without RAG gene mutations, 4 of them with Artemis gene mutations. One patient had a large genomic deletion, but the other 3 patients carried simple missense mutations in conserved amino acid residues in the SNM1 homology domain of the Artemis protein. Extrachromosomal V(D)J recombination assays showed normal and precise signal joint formation, but inefficient coding joint formation in fibroblasts of these patients, which could be complemented by the wild-type Artemis gene. The cells containing the missense mutations in the SNM1 homology domain had the same recombination phenotype as the cells with the large deletion, indicating that these amino acid residues are indispensable for Artemis function. Immunogenotyping and immunophenotyping of bone marrow samples of 2 RS-SCID patients showed the absence of complete V(H)-J(H) gene rearrangements and consequently a complete B-cell differentiation arrest at the pre-B-cell receptor checkpoint-that is, at the transition from CyIgmu(-) pre-B-I cells to CyIgmu(+) pre-B-II cells. The completeness of this arrest illustrates the importance of Artemis at this stage of lymphoid differentiation.

Alternative Splicing↗

PubMed2002

gammadelta T cell subsets in patients with arthritis and chronic neutropenia.

BACKGROUND: An abnormal distribution of subsets of gammadelta T cells, which are a component of the inflammatory infiltrate in arthritic synovium, has been demonstrated in the peripheral blood (PB) of patients with arthritis and neutropenia. OBJECTIVE: To evaluate whether the clinical manifestations of patients with arthritis and neutropenia are related to the specific gammadelta T cell subset predominant in the PB. METHODS: Flow cytometry of PB lymphocytes in six consecutive patients with chronic neutropenia and arthritis was performed. Variable (V) gamma and delta gene families were analysed by polymerase chain reaction. cDNA was subjected to direct automated sequencing of T cell receptor (TCR) genes. RESULTS: Three patients had non-deforming and non-erosive rheumatoid factor (RF)(+) polyarticular rheumatoid arthritis, RF(+) oligoarticular arthritis, or RF(-) non-deforming oligoarticular psoriatic arthritis with persistent expansions of Vgamma1(+)/Vdelta2(+), Vgamma2(+)/Vdelta2(+), or Vgamma1(+)/Vdelta (undetermined (2- 1-)) T cells, respectively. The other three patients, without persistent expansion of gammadelta T cells, had either non-deforming and non-erosive oligo- or polyarthritis with a balanced distribution of several Vdelta and Vgamma genes, or severe erosive RF(+) arthritis with deficiency of all but Vgamma1(+)/Vdelta1(+) T cells. CONCLUSIONS: gammadelta T cell lymphoproliferations in chronic neutropenia and arthritis use different Vgamma and Vdelta gene families, often forming T cell receptor (TCR) structures that are infrequent in normal adult PB. Arthritis with Vgamma1(+)/Vdelta2(+), Vgamma2(+)/Vdelta2(+), or Vgamma1(+)/Vdelta2(-)/Vdelta1(-) gammadelta T cells in the PB is non-deforming and non-erosive, suggesting a protective effect of these cells, as opposed to a more pathogenic contribution of Vgamma1(+)/Vdelta1(+) cells.

Aged↗

PubMed2004

Breeding system and demography shape population genetic structure across ecological and climatic zones in the African freshwater snail, Bulinus forskalii (Gastropoda, Pulmonata), intermediate host for schistosomes.

The role of breeding system and population bottlenecks in shaping the distribution of neutral genetic variation among populations inhabiting patchily distributed, ephemeral water bodies was examined for the hermaphroditic freshwater snail Bulinus forskalii, intermediate host for the medically important trematode Schistosoma guineensis. Levels of genetic variation at 11 microsatellite loci were assessed for 600 individuals sampled from 19 populations that span three ecological and climatic zones (ecozones) in Cameroon, West Africa. Significant heterozygote deficiencies and linkage disequilibria indicated very high selfing rates in these populations. Despite this and the large genetic differentiation detected between populations, high levels of genetic variation were harboured within these populations. The high level of gene flow inferred from assignment tests may be responsible for this pattern. Indeed, metapopulation dynamics, including high levels of gene flow as well as extinction/contraction and recolonization events, are invoked to account for the observed population structuring, which was not a consequence of isolation-by-distance. Because B. forskalii populations inhabiting the northern, Sahelian area are subject to more pronounced annual cycles of drought and flood than the southern equatorial ones, they were expected to be subject to population bottlenecks of increased frequency and severity and, therefore, show reduced genetic variability and elevated population differentiation. Contrary to predictions, the populations inhabiting the most northerly ecozone exhibited higher genetic diversity and lower genetic differentiation than those in the most southerly one, suggesting that elevated gene flow in this region is counteracting genetic drift.

Africa↗