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PubMed2006

Genetic admixture of burbot (Teleostei: Lota lota) in Lake Constance from two European glacial refugia.

The burbot, Lota lota, is the only freshwater species of the codfish family and has a Holarctic distribution. Pleistocene glaciations caused significant geographical differentiation in the past, but its life history characterized by winter spawning migrations over large distances is likely to homogenize populations by contemporary gene flow. We investigated the population genetic structure of 541 burbots from Lake Constance and adjacent Rhine and Danube tributaries in Europe using the entire mitochondrial DNA (mtDNA) control region and 11 microsatellites. Microsatellites revealed considerable population divergence (F(ST) = 0.26) and evidenced recent bottlenecks in two Central European rivers. In accordance to previous evidence two main phylogeographic lineages (Atlantic and Danubian) were found co-occurring at similar frequencies in Lake Constance, where they currently undergo random mating as indicated by microsatellites. The Danubian lineage contributed only a small proportion to the lake's mtDNA diversity, and probably expanded within the lake shortly after its formation approximately 10,000-15,000 BP. The larger Atlantic haplotype diversity suggested a population expansion older than the lake itself. Levels of admixture at microsatellite loci were less obvious due to their high variability, and coalescence methods were used to estimate past admixture proportions. Our results reinforce a model of a two-step colonization of Europe by burbot from an ancestral Danubian refuge, and confirm the persistence of a secondary Atlantic refuge, as proposed to exist for other freshwater fish. We conclude that the present-day burbot population in Lake Constance bears the genetic signature of both contemporary gene flow and historical separation events.

Animals↗
PubMed2000

Chromosomal instability and p53 inactivation are required for genesis of glioblastoma but not for colorectal cancer in patients with germline mismatch repair gene mutation.

We have previously reported high-frequency microsatellite instability (MSI-H) and germ-line mismatch repair gene mutation in patients with unusually young onset of high-grade glioma. Some of these patients developed metachronous MSI-H colorectal cancer and conformed to the diagnosis of Turcot's syndrome. Frameshift mutation of TGFbetaRII was present in all the colorectal carcinomas but not in brain tumours. We further characterized the genetic pathways of tumour evolution in these metachronous gliomas and colorectal carcinomas. All MSI-H glioblastomas had inactivation of both alleles of the p53 gene and showed over-expression of the p53 protein while none of the colorectal carcinomas had p53 mutation or protein over-expression. Flow cytometry and comparative genomic hybridization revealed that all glioblastomas were chromosomal unstable with aneuploid DNA content, and with a variable number of chromosomal arm aberrations. In contrast, the colorectal carcinomas had diploid or near-diploid DNA content with few chromosomal arm aberrations. The pattern of chromosomal aberrations in the two organs was different. Loss of 9p was consistently observed in all glioblastomas but not in colorectal carcinomas. Epidermal growth factor receptor amplification was absent in all glioblastomas and colorectal carcinomas. Our results suggest that both the frequency of p53 mutation and its effects differ greatly in the two organs. Following loss of mismatch repair function, p53 inactivation and chromosomal instability are not necessary for development of colorectal carcinoma, but are required for genesis of glioblastoma. Oncogene (2000) 19, 4079 - 4083.

Adenocarcinoma↗
PubMed1998

Characterization of an immunosuppressive anti-CD40 ligand monoclonal antibody.

The interaction between CD40 ligand (CD40L) and its counter-receptor CD40 is critically important in T- and B-cell costimulation and generation of the humoral immune response. But several questions still remain unsolved, particularly in the human in vivo system. To clarify the precise function of CD40L and develop an immunosuppressive agent, we have generated a murine monoclonal antibody (MAb), 2B2 specific for human CD40L. The specificity of this MAb for human CD40L was verified by enzyme-linked immunoadsorbent assay (ELISA) and flow cytometry. MAb 2B2 immunoprecipitated proteins of molecular weight 35 and 28 kD on human peripheral blood lymphocytes (PBLs) stimulated with phorbol 12-myristate-13-acetate (PMA) plus ionomycin. Then we have studied the biological effect of MAb 2B2 in severe combined immunodeficiency (SCID) mice reconstituted with human PBLs. The data showed that this MAb strongly suppressed human IgG production of human B cells transplanted in SCID mice, indicating that this MAb 2B2 could be used to regulate unwanted immune responses associated with autoimmune disease. Then we analyzed the sequence of MAb 2B2. The 2B2 heavy chain variable region (VH) and light chain variable region (VL) genes were cloned using PCR. The cloned VH gene coded for 123 amino acid residues and belonged to the subgroup III(D). The VL gene coded for 126 amino acid and belonged to the subgroup V. Collectively, these results will be used to develop an immunosuppressive chimeric or humanized anti-CD40L antibody.

Amino Acid Sequence↗
PubMed2006

Phenotypic approaches for understanding patterns of intracemetery biological variation.

This paper reviews studies of phenotypic inheritance and microevolutionary processes in archaeological populations using data on cranial and dental phenotypic variation, often referred to as paleogenetics or biodistance analysis. The estimation of biological distances between populations, or among individuals within populations, is one component of bioarchaeological research on past populations. In this overview, five approaches that focus on morphological variation within cemeteries are summarized: kinship and cemetery structure analysis, postmarital residence analysis, sample aggregate phenotypic variability, temporal microchronology, and age-structured phenotypic variation. Previous research, theoretical justifications, and methods are outlined for each topic. Case studies are presented that illustrate these theoretical and methodological bases, as well as demonstrate the kinds of inferences possible using these approaches. Kinship and cemetery structure analysis seeks to identify the members of family groups within larger cemeteries or determine whether cemeteries were kin-structured. Analysis of sex-specific phenotypic variation allows estimation of postmarital residence practices, which is important for understanding other aspects of prehistoric social organization. Analysis of aggregate phenotypic variability can be used to infer site formation processes or cemetery catchment area. The study of temporal microchronologies can be used to evaluate provisional archaeological chronologies or study microevolutionary processes such as adaptive selection or changing patterns of gene flow. Finally, age-structured phenotypic variation can be reflective of selection processes within populations or it can be used as a measure of morbidity, growth arrest, and early mortality within past populations. Use of phenotypic data as a genotypic proxy is theoretically sound, even at small scales of analysis.

Adolescent↗
PubMed1997

T cell repertoire in patients with multiple myeloma and monoclonal gammopathy of undetermined significance: clonal CD8+ T cell expansions are found preferentially in patients with a low tumor burden.

The T cell receptor (TCR) variable (V) gene repertoire was analyzed in patients with monoclonal gammopathy of undetermined significance (MGUS) (n = 17), multiple myeloma (MM) stage I (n = 16), MM stages II/III (n = 31) and age-matched controls (n = 27) by immunofluorescence and flow cytometry using a panel of mouse monoclonal antibodies (mAb) (n = 10) against TCR V alpha and V beta gene products. T cell expansion was defined as a value > or = thrice the normal median value for each respective TCR V mAb. Fifty-three percent of all patients displayed CD8+ expansion(s) as compared to 30% of age-matched controls (p < 0.001). Within the CD4 subset, 18% of the patients displayed T cell expansion(s) in comparison to 11% of the controls (not significant). Interestingly, the CD8+ expansion(s) were more frequently noted in patients with a low tumor burden (MGUS/MMI) (73%) as compared to those with advanced disease (MM II/III) (32% and control donors (30%) (p < 0.01). Likewise, multiple CD8+ expansions (two or more) were more common in MGUS/MM I patients than in MM II/III and controls (p < 0.01). The T cell expansions were stable over time in patients with a stable disease. A high degree of clonality of the expansions was detected by TCR CDR3 fragment length analysis, determination of J beta gene usage and nucleotide sequencing. The frequent finding of oligoclonal CD8+ T cell expansions in patients with a low tumor mass, but not in patients with advanced disease justifies further work in order to identify the relevance of expanded CD8+ T cells. In one patient with T cell reactivity against the autologous myeloma idiotype, two expansions within the CD8 population (V beta 3 and V beta 5.2 respectively) displayed no reactivity against the idiotype. Instead, idiotype recognition was confined to a CD8 non-expanded V beta 22+ T cell population, with a highly restricted TCR usage (CDR3 fragment length analysis).

Adult↗
PubMed2002

Spatial genetic structure and clonal diversity of island populations of lady's slipper (Cypripedium calceolus) from the Biebrza National Park (northeast Poland).

Three populations of the rare and endangered plant species Cypripedium calceolus were included in a study of genetic diversity and spatial genetic structure in the Biebrza National Park, northeast Poland. Analysis of 11 allozyme loci indicate that the populations of this species contained high genetic variability (P = 45.5%, A= 1.73). On the other hand, the genetic differentiation (FST = 0.014, P < 0.05) among C. calceolus populations was very low when compared to other species with similar life history characteristics. The observed high rate of gene flow (Nm = 18) may suggest that the populations studied derived from each other in the recent past. Five polymorphic allozyme markers identified 109 multilocus genotypes in three populations and the majority of them (67%) were population-specific. One of the populations studied, characterized by particularly extensive vegetative reproduction, showed the lowest clonal diversity (G/N = 0.15) and heterozygosity (HO = 0.111) values and the highest FIS(0.380), when compared to other two populations (G/N = 0.26-0.27, HO= 0.166-178, FIS = 0.024-0.055). This may indicate that clonal reproduction has an important influence on the genetic structure of C. calceolus populations. The longevity of genets, the out-crossing breeding system and the presence of recruitment from seeds are factors maintaining genetic diversity in C. calceolus.

Biological Evolution↗
PubMed2003

Single-cell repertoire analysis demonstrates that clonal expansion is a prominent feature of the B cell response in multiple sclerosis cerebrospinal fluid.

Single-cell RT-PCR was used to sample CD19(+) B cell repertoires in cerebrospinal fluid (CSF) of patients with multiple sclerosis (MS) or viral meningitis. Analysis of amplified Ab H and L chain products served to identify the rearranged germline segment and J segment, and to determine the degree of homology for the H and L chain sequence of individual B cells. The B cell repertoire of viral meningitis CSF was predominantly polyclonal, whereas B cell clonal expansion was a prominent feature of the IgG repertoire in three of four MS patients. Two dominant clonal populations in one MS CSF accounted for approximately 70% of the IgG H chain V regions sequenced, while the corresponding IgM repertoires were more heterogeneous. One clonal B cell population revealed multiple L chain rearrangements, raising the possibility of a role for receptor editing in shaping the B cell response in some MS patients. The most immediate implications of identifying rearranged Ig sequences in MS B cells is the potential to accurately recreate recombinant Abs from these overrepresented H and L chains that can be used to discover the relevant Ag(s) in MS.

Acute Disease↗
PubMed2004

Allochronic differentiation among Daphnia species, hybrids and backcrosses: the importance of sexual reproduction for population dynamics and genetic architecture.

Seasonal dynamics of the abundance, sexual reproduction and genetic architecture in a Daphnia hyalina-galeata hybrid complex were studied in the large and deep Lake Constance. We found evidence for the occurrence of first and second order hybridization. Our study revealed strong differences between the parental species not only regarding their seasonal dynamics, genetic architecture and diversity, but also their sexual reproductive behaviour. The overwintering D. hyalina showed low genetic diversity, no genetic differentiation during the season, and reproduced sexually in autumn, whereas D. galeata reached higher levels of genetic diversity, reproduced sexually in early summer, and exhibited changes in genetic structure during the season, but was only present from spring to autumn. However, in both species sexual reproduction was a rare event, and daphnids, including hybrids, reproduced predominantly asexually. This allows long-term persistence of hybrids as well without continuing hybridization events. Within all variables studied, F1 and F2 hybrids showed an intermediate pattern, whereas proposed backcross hybrids were more similar to their respective parentals. These differences in phenotype as well as significant differences in pairwise Fst values between parentals suggest that gene flow seems to be relatively low in the Lake Constance hybrid system. We found evidence for unidirectional introgression by backcrossing from D. galeata to D. hyalina and found a decrease in at least one of the proposed introgressed alleles in the hyalina-backcross while the season progressed. Our findings suggest allochronic differentiation within this hybrid population and different microevolutionary trajectories of the parental species, which will be discussed in the light of the ongoing reoligotrophication process of Lake Constance.

Animals↗
PubMed1989

Evolution of the immunoglobulin heavy chain variable region (Igh-V) locus in the genus Mus.

The evolution of the mouse immunoglobulin heavy chain variable region (Igh-V) locus was investigated by the comprehensive analysis of variable region (Vh) gene family content and restriction fragment polymorphism in the genus Mus. The examination of natural Mus domesticus populations suggests an important role for recombination in the generation of the considerable restriction fragment polymorphism found at the Igh-V locus. Although the sizes of individual Vh gene families vary widely both within and between different Mus species, evolutionary trends of Vh gene family copy number are revealed by the analysis of homologues of mouse Vh gene families in Rattus and Peromyscus. Processes of duplication, deletion, and sequence divergence all contribute to the evolution of Vh gene copy number. Certain Vh gene families have expanded or contracted differently in the various muroid lineages examined. Collectively, these findings suggest that the evolution of individual Vh family size is not driven by strong selective pressure but is relatively neutral, and that gene flow, rather than selection, serves to maintain the high level of restriction fragment polymorphism seen in M. domesticus.

Animals↗
PubMed1996

Prognostic significance of p53 expression, chromosome 17 copy number, and DNA ploidy in non-metastasized colorectal carcinomas (stages IB and II).

BACKGROUND AND METHODS: Paraffin-embedded tumor tissue from 101 non-metastasized colorectal adenocarcinomas (tumor stages IB and II--that is, pT2 and 3, pN0, M0) was investigated for p53 expression by immunohistology (IH) (moab DO1), chromosome 17 (#17) copy number by interphase cytogenetics using non-radioactive in situ hybridization (NISH) with a centromer-specific DNA probe (D17Z1), and DNA ploidy by flow cytometry (FCM). The aims of the study were 1) to test whether numerical #17 aberrations are involved in functional TP53 loss in locally confined colorectal carcinomas; 2) to search for correlations between aberrant p53 expression and #17 aberrations with DNA ploidy and histopathology; and 3) to test the prognostic significance of these factors. RESULTS: Sixty cases (59.4%) showed nuclear p53 expression IH (low-grade p53 accumulation (< 50%), n = 16 (15.8%); high-grade (> or = 50%), n = 44 (43.6%)). Nish showed #17 aneusomy in 46% of the carcinomas (34% deletions, 12% gains). In FCM analysis, 43% of the carcinomas were DNA non-diploid. p53 overexpression correlated statistically significantly with FCM non-diploidy (p = 0.013). Furthermore, #17 aneusomy also correlated with FCM non-diploidy (p = 0.001). However, there was no association between #17 status and p53 expression (IH). CONCLUSIONS: Our data suggest a role for the TP53 gene in the aneuploidization process. Numerical deletions of #17, however, were not associated with p53 immunoreactivity in the analyzed tumors. With regard to prognosis, the most important independent variable in stage IB/II colorectal carcinomas was tumor stage, followed by high-grade p53 expression of tumor cells; #17 aneusomy was an independent risk factor for tumor relapse/progression but not for survival. As alterations of the investigated variables were not found in all carcinomas under study, different pathogenetic pathways seem to exist in colorectal carcinogenesis.

Adenocarcinoma↗
PubMed2004

Optimal operating mode for enantioseparation of SB-553261 racemate based on simulated moving bed technology.

The performance of the simulated moving bed (SMB) technology and its modification, the Varicol process, was optimized using an experimentally verified model for the enantioseparation of SB-553261 racemate. Single and multiobjective optimizations have been carried out for both existing as well as design stage and their efficiencies were compared. The optimization problem involves a relatively large number of decision variables, both continuous variables such as flow rates, switching time and length of the columns, as well as discrete variables like number and distribution of columns. A state-of-the-art new optimization technique based on a genetic algorithm (nondominated sorting genetic algorithm with jumping genes) was utilized which allows handling of these complex optimization problems. The optimization results showed that significant improvement could be made to the chiral drug separation process using both the SMB and the Varicol process. It was found that the performance of a Varicol process is superior to that of a SMB process in terms of treating more feed using less desorbent or increasing productivity while at the same time achieving better product quality. Optimum results were explained using equilibrium theory by locating them in the pure separation region.

Algorithms↗
PubMed1999

Diffuse large B cell lymphoma expressing the natural killer cell marker CD56.

The expression of the natural killer (NK) cell antigen, CD56, in hematological malignancies is rare. However, there are several reports that some hematological malignancies, such as T/NK cell lymphoma, multiple myeloma (MM) and acute myeloid leukemia (AML), express this molecule. In B cell non-Hodgkin's lymphomas (NHL), however, very limited number of cases have been reported to express CD56 molecule. Although one study has recently described that half of microvillous B cell lymphoma (MVL), an uncommon subset of large cell lymphoma, expressed CD56, there have been no reports about most common type of B-NHL, diffuse large B cell lymphoma (DLBL) other than a mention of weak CD56 expression in one of 83 DLBL. We herein presented the first case of diffuse large B cell lymphoma expressing CD56 clearly. The immunophenotype determined by immunostaining and flow cytometric analysis was CD10+, CD19+, CD20+, CD45RO-, CD3- and CD56+. On immunohistochemical study, neither bcl-2 nor TIA-1 was positive for tumor cell. Monoclonal immunoglobulin heavy chain (IgH) gene rearrangement was detected, and the sequence analysis of the variable region of IgH (VH) suggested that this tumor was derived from antigen selected post germinal center B cell. Conventional combination chemotherapy (CHOP) was administered, and the patient has still been in complete remission for 10 months.

Adolescent↗
PubMed2005

Assessing moth migration and population structuring in Helicoverpa armigera (Lepidoptera: Noctuidae) at the regional scale: example from the Darling Downs, Australia.

Analysis of gene flow and migration of Helicoverpa armigera (Hübner) in a major cropping region of Australia identified substantial genetic structuring, migration events, and significant population genotype changes over the 38-mo sample period from November 1999 to January 2003. Five highly variable microsatellite markers were used to analyze 916 individuals from 77 collections across 10 localities in the Darling Downs. The molecular data indicate that in some years (e.g., April 2002-March 2003), low levels of H. armigera migration and high differentiation between populations occurred, whereas in other years (e.g., April 2001-March 2002), there were higher levels of adult moth movement resulting in little local structuring of populations. Analysis of populations in other Australian cropping regions provided insight into the quantity and direction of immigration of H. armigera adults into the Darling Downs growing region of Australia. These data provide evidence adult moth movement differs from season to season, highlighting the importance of studies in groups such as the Lepidoptera extending over consecutive years, because short-term sampling may be misleading when population dynamics and migration change so significantly. This research demonstrates the importance of maintaining a coordinated insecticide resistance management strategy, because in some years H. armigera populations may be independent within a region and thus significantly influenced by local management practices; however, periods with high migration will occur and resistance may rapidly spread.

Animal Migration↗
PubMedDate not supplied

Gene flow and genetic diversity in naturally fragmented metapopulations of deep-sea hydrothermal vent animals.

The ephemeral nature of deep-sea hydrothermal vents is expected to favor species with good colonization abilities, high dispersal rates, and rapid individual growth rates. Studies of gene flow in vent-endemic species provide glimpses into modes and patterns of dispersal. For some species, gene flow occurs without geographical bias (i.e., island model); their dispersal capabilities probably exceed the sampled geographical range. For other species, genetic differentiation increases with geographical distance (isolation-by-distance model) and suggests a stepping-stone mode of dispersal between neighboring vents. Genetic subdivision in a third group of species is associated with geographical offsets between contiguous segments of a ridge axis. These species all possess a free-living larval stage and average rates of gene flow (Nm) exceeding the critical value of one. In contrast, an amphipod that broods its young shows evidence for isolation-by-distance along a ridge axis and nearly complete isolation between distinct ridge axes. Early successional species (i.e., those that rapidly establish populations at nascent vents) also have high levels of genetic variability that probably results from a larger global population size. Bivalve species, which are restricted to a few of the known vent sites, appear at a later successional stage and have lower levels of variability. The relative successional position (early versus late) and overall abundance of a species may play significant roles in determining the retention of genetic diversity in populations inhabiting these ephemeral environments.

Animals↗
PubMed2000

Random amplified polymorphic DNA analysis of southern brown bandicoot (Isoodon obesulus) populations in Western Australia reveals genetic differentiation related to environmental variables.

Random amplified polymorphic DNA (RAPD) markers were used to analyse genetic variation within and between populations of Isoodon obesulus in Western Australia. Genetically controlled geographical variation in body size associated with habitat type and rainfall exists in this species, raising the question of whether local conditions may influence gene flow in I. obesulus. The RAPD markers displayed substantial genetic variation, with all animals possessing unique RAPD phenotypes over 39 polymorphic bands produced by three primers. Significant geographical subdivision was apparent (PhiST = 0.208) with southwest locations being divergent from all others, despite there being no physical barriers to gene flow. The pattern of subdivision was unrelated to physical distance between the locations, but was related to both annual rainfall and habitat type. Therefore, the most reasonable explanation for this pattern of subdivision appears to be that gene flow is restricted by selection against migrants between local populations with substantially different habitat type or rainfall. Restriction of gene flow through selection against migrants is rarely investigated, and the results of this study suggest that the importance of this process in the formation of population structure may be underestimated.

Animals↗
PubMed2004

Gene expression analysis of peripheral T cells in a subgroup of common variable immunodeficiency shows predominance of CCR7(-) effector-memory T cells.

Common variable immunodeficiency (CVID) represents a heterogeneous group of antibody deficiency syndromes, characterized by defective antibody production in which T cell deficiency may play a pathogenic role. A subgroup of CVID patients has impaired in vitro T cell proliferation. Using microarray analyses of T cells from these patients, we found a gene expression pattern different from healthy controls and patients with X-linked agammaglobulinaemia. The profile of the differentially expressed genes suggests enhanced cytotoxic effector functions, antigen experienced or chronically activated T cells and a predominance of CCR7(-) T cells. Further experiments using flow cytometry revealed a striking predominance of CCR7(-) T cells in a subgroup of CVID patients, and an association with impaired T cell proliferation. Our observations indicate that a predominance of CCR7(-) T cells with effector-memory cell features and with reduced proliferative capacity may characterize a subgroup of CVID.

Adult↗
PubMedDate not supplied

Expression of CD44 standard and variant isoforms v5, v6 and v7 in human ovarian cancer cell lines.

The expression of standard CD44 protein (CD44std) and its splice variants v5, v6 and v7 was investigated in 43 human ovarian carcinoma cell lines by flow cytometry and immunocytochemistry using monoclonal antibodies raised against extracellular epitopes. Twenty six (60%) cell lines expressed CD44 std. Variant isoforms of CD44 were expressed in 12 of the 26 CD44 positive cell lines. All 12 cell lines expressed CD44 v5. In addition 6 cell lines expressed CD44 v6 and one of these expressed CD44 v7 simultaneously. No significant differences of CD44 expression were found between cell lines derived from solid tumors or ascites. In ovarian cancer cells splicing of CD44 v5 appears to be a prerequisite for expression of downstream variable exons. New acquisition of variable CD44 exons may be implicated in the tumorigenesis of ovarian cancer. The CD44 gene provides a biological model to study the role of alternative splicing in gynecologic malignancy.

Antigens, CD↗
PubMed1989

Regional hemodynamic effects of calcitonin gene-related peptide.

Cardiovascular responses to infusions of rat alpha-calcitonin gene-related peptide (CGRP; 0.06, 0.6, 6.0 nmol/h) or rat alpha-atrial natriuretic peptide (ANP; 3.7 nmol/h) were measured in conscious rats. During infusion of the low dose of CGRP, when mean arterial pressure (MAP) was little affected, there were reductions in common carotid, renal, mesenteric, and hindquarter vascular resistances (the magnitude of the responses in the same descending order). However, only flow in the common carotid vessels was increased above base line. After infusion, there was a hindquarter vasoconstriction. During infusion of the higher doses of CGRP, there were dose-related decreases in MAP and increases in heart rate associated with (hyperemic) hindquarter vasodilatations and mesenteric vasoconstrictions. The common carotid vasodilatation peaked with the intermediate dose of CGRP; the changes in renal vascular resistance were not dose related. After infusion of the high dose of CGRP there were persistent (at least 60 min) common carotid and hindquarter vasodilatations and mesenteric vasoconstriction, with a transient overshoot in renal vascular resistance. Infusions of CGRP and ANP matched for their effects on MAP had similar influences on mesenteric hemodynamics, but all other variables were affected differently.

Animals↗