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Biomedical subjects

A L Watson

Publications and source records attributed to A L Watson.

17 recordsLinked to original sources
PubMed1995

Life-span, T-cell responses, and incidence of lymphomas in congenic mice.

Survival, T-cell functions, and postmortem histopathology were studied in H-2 congenic strains of mice bearing H-2b, H-2k, and H-2d haplotypes. Males lived longer than females in all homozygous and heterozygous combinations except for H-2d homozygotes, which showed no differences between males and females. Association of heterozygosity with longer survival was observed only with H-2b/H-2b and H-2b/H-2d mice. Analysis using classification and regression trees (CART) showed that both males and females of H-2b homozygous and H-2k/H-2b mice had the shortest life-span of the strains studied. In histopathological analyses, lymphomas were noted to be more frequent in females, while hemangiosarcomas and hepatomas were more frequent in males. Lymphomas appeared earlier than hepatomas or hemangiosarcomas. The incidence of lymphomas was associated with the H-2 haplotype--e.g., H-2b homozygous mice had more lymphomas than did mice of the H-2d haplotype. More vigorous T-cell function was maintained with age (27 months) in H-2d, H-2b/H-2d, and H-2d/H-2k mice as compared with H-2b, H-2k, and H-2b/H-2k mice, which showed a decline of T-cell responses with age.

Animals↗
PubMed1995

Human chorionic gonadotrophin release and tissue viability in placental organ culture.

The use of human chorionic gonadotrophin (HCG) secretion as a measure of viability during the organ culture of human first trimester placental tissue has become a popular practice. It has been suggested that if cultured tissue is releasing large amounts of this protein hormone, there is a high level of viability. We have found, however, that the cytosolic enzyme L-lactate dehydrogenase is released into the culture supernatant in a similar daily pattern as HCG, suggesting that tissue disruption may be occurring, resulting in some of the observed hormone release. In addition, we have shown that the uptake of the fluorescent dye dansyl-L-lysine into the syncytium increases significantly from day 0 to day 4, suggesting a loss of syncytial membrane integrity. Electron micrographs show further evidence of the syncytial degeneration at the ultrastructural level, displaying extensive vacuolation and poor microvillous cover. In contrast to the degenerated state of the syncytiotrophoblast, a high level of bromodeoxyuridine incorporation is observed for cytotrophoblasts and, in particular, stromal cells up to 5 days in culture. Overall, the results suggest that the use of HCG release as a determinant of tissue viability in placental organ culture should be treated with a degree of caution.

Bromodeoxyuridine↗
PubMed1993

In vitro polymerization of oxidized tau into filaments.

Paired helical filaments (PHF) are abnormal neuronal polymers characteristic of Alzheimer's disease (AD). Although tau appears to be a major constituent of PHF, the mechanism for the polymerization of tau or its integration into PHF remains unknown. Here, we show that the oxidation of bovine tau in vitro induces an apparent dimerization of this protein and polymerization into filaments. These observations suggest that the oxidation of tau in vivo may contribute to the development of PHF in individuals with AD.

Actin Cytoskeleton↗
PubMed1992

Traits that influence longevity in mice: a second look.

Analysis of genetic interactions in the F2 of an intercross of (C57BL/6 x DBA/2) F1J revealed influences of genetic factors on life span. Females lived longer than males. Dilute brown females died sooner than females of other colors. H-2b/H-2b males died sooner than H-2b/H-2d or H-2d/H-2d males, except that among dilute brown males those of typeH-2b/H-2d died sooner. Cluster analysis suggested that male and female genotypes each fall into two groups, with female dilute brown mice having shorter lives than other females, and male H-2b/H-2b mice except dilute brown and dilute brown H-2b/H-2d mice having shorter lives than other males. The association of heterozygosity with life span was clearer in females than in males, yet the longest-lived female genotype was homozygous H-2d/H-2d, of dominant Black phenotype at the Brown locus of chromosome 4, and homozygous dd at the Dilute locus of chromosome 9. The shortest-lived females were dilute brown H-2b/H-2b. The longest-lived and shortest-lived male genotypes were dilute brown H-2d/H-2d and dilute brown H-2b/H-2d, respectively. Although histological findings at postmortem differed between the sexes, there was no association of particular disorders with other genetic markers. The importance of H-2 in males was confirmed, but the allelic effects were perturbed, possibly by the absence of Sendai infection in this experiment. Overall our studies suggest that genetic influences on life span involve interactions between loci, and allelic interactions may change with viral infections or other environmental factors.

Animals↗
PubMed1992

Dietary aluminum selectively decreases MAP-2 in brains of developing and adult rats.

Administration of 0.3% aluminum in drinking water elevated serum aluminum concentrations 8-fold in rats. Further, chronic treatment with aluminum for 2-3 mon, in both developing and adult rats, significantly decreased the levels of MAP-2 in brain, as determined by quantitative immunoblot analysis. Aluminum treatment also decreased the level of brain spectrin, but only in the hippocampus of adult rats. These were selective effects, since the levels of tubulin, tau and the three proteins of the neurofilament triplet were unaltered. In the aluminum-treated adult rats MAP-2 levels were significantly decreased in the hippocampus and brainstem to 71% and 56% of control values, respectively. In developing rats, MAP-2 levels were significantly decreased in the cortex and brainstem (65 and 64% of control values, respectively) but not in the hippocampus. In support of these findings, immunohistochemical examination revealed that the intensity of hippocampal MAP-2 immunoreactivity was significantly decreased to 88% of control values with aluminum treatment in adult rats. To determine a possible mechanism by which MAP-2 levels are reduced, the effect of aluminum on calpain-induced proteolysis of MAP-2 was examined in vitro. At the aluminum concentrations tested, there was no apparent effect on calpain-induced proteolysis of MAP-2. In the developing rats, aluminum administration significantly increased the hippocampal cyclic AMP concentration, as reported previously in adult aluminum-treated rats, and decreased the inositol 1,4,5-trisphosphate concentration. These results demonstrate that chronic oral aluminum administration to rats selectively decreases the levels of MAP-2 in specific brain regions independent of calpain proteolysis. This decrease may be associated with increased cyclic AMP and protein phosphorylation, and the impairment of cognition previously observed in this model of aluminum intoxication.

Administration, Oral↗
PubMed1991

Intracellular gastrin in human gastrointestinal tumor cells.

Flow cytometry and immunohistochemical analyses of the human gastric adenocarcinoma cell line MKN45G identified an intracellular peptide recognized by an anti-gastrin-17 (G17) antiserum but not by an anti-cholecystokinin-specific antiserum. Staining was not associated with the parental line MKN45, of which MKN45G is a clonal variant. The MKN45G cell line had elevated in vitro growth in serum-free medium in which the proliferation of MKN45G cells but not MKN45 cells was reduced to 58% of the control value by treatment with a rabbit anti-G17 antiserum. This inhibition of proliferation was reversed by preabsorbing the antiserum with excess G17. Disaggregated primary human gastric and colorectal tumors were screened for gastrin immunoreactivity by flow cytometry, and 6 of 28 colorectal and 8 of 22 gastric tumors had greater than 20% positively staining cells.

Adenocarcinoma↗
PubMed1991

The degradative fate of ubiquitin-protein conjugates in nucleated and enucleated cells.

Covalent ligation of multiple copies of ubiquitin to proteins is known to target intracellular proteins for degradation by large molecular weight cytosolic proteinase(s). Ubiquitin protein conjugates are found in cytosolic cell compartments suggesting that ubiquitination may have multiple roles. We have detected ubiquitinated proteins in the lysosomal apparatus of normal fibroblasts and fibroblasts treated with lysosomal proteinase inhibitors. In contrast rabbit reticulocytes lack lysosomes. We present here direct evidence for ubiquitination of mitochondrial proteins during rabbit reticulocyte maturation. In addition ubiquitination appears to be associated with the terminal differentiation of human keratinocytes. These results suggest that: 1. ubiquitin-protein conjugates may be degraded lysosomally 2. organellar proteins may be degraded by the ubiquitin system 3. ubiquitination is involved in the programmed elimination of proteins and organelles from several cell types during differentiation.

3T3 Cells↗
PubMed1985

Environmental and genetic factors that influence immunity and longevity in mice.

Many different theoretical approaches may be taken toward understanding the association between aging and immunologic malfunction. The leading theory is based on the natural phenomenon of thymic involution and argues that the T-dependent lymphoid system is genetically programmed to decline in effectiveness, possibly through altered endocrine and central nervous system controls. The "thymic time clock" theory of aging is strongly supported by the consistent finding of defective cellular immunity functions in aged humans and animals and an associated development of the age-related diseases. In several animal models, including autoimmune-prone strains, high spontaneous tumor incidence strains, and normal long-lived strains, it has been possible to forestall the development of the major diseases of aging and extend longevity by restricting diet. The predominant effect of dietary restriction is prolongation of immunologic vigor and retardation of the immunologic dysfunction that normally occurs with age. Studies on environmental factors affecting longevity such as these and others which demonstrate a complex interaction between genes influencing longevity underscore the complexity and challenge of aging research.

Aging↗
PubMed1984

Traits that influence longevity in mice.

Analysis of genetic interactions in the segregating backcross [(C57BL/6 X DBA/2)F1 X DBA/2] mice revealed influences of genetic and environmental factors on life span. Using determinants of coat color (brown locus of chromosome 4 and dilute locus of chromosome 9), serologically determined H-2 antigens (chromosome 17) and sex as genetic markers, we studied the effects of these genes on longevity. The results suggested that genes in the brown locus (b) segment of chromosome 4, genes in a segment of the sex chromosomes and, to a more limited extent, genes in the segment of chromosome 17 which contains the H-2 haplotype all influenced longevity. The coat color (b locus) segment of chromosome 4 was associated with life span predominantly in females, whereas the chromosome 17 (H-2 haplotype) segment was associated with longer life primarily in males. The dilute locus d segment on chromosome 9 did not affect life span. Longevity appears to be influenced by interactions between genes in the chromosomal segment carrying H-2, those in the b segment, gender and the month of birth. Greater heterozygosity at the loci studied was associated with longer life span. Histopathological findings on mice that died at or after 28 months of age were comparable for all genetic combinations except that there was an increased frequency of lymphoma in females and an increased frequency of amyloidosis in males. Our analysis emphasizes the need for comprehensive studies of aging and longevity that would simultaneously determine the effects of several genetic regions and their interactions with the environment with respect to possible causes of death.

Animals↗
PubMed1984

Utilization of murine peripheral blood lymphocytes for H-2 typing.

We adapted the NIH Standard Protocol for HLA-A, B, C typing to perform murine H-2 typing. The assay is direct, measuring the cytotoxicity of the antiserum/cell/complement reaction with a supravital dye. This method is advantageous because it: utilizes peripheral blood lymphocytes (PBL) obtained from the tail vein; uses microliter volumes of antiserum; is practical because the formalin fixed reactions need not be read immediately; involves standard and inexpensive cytotoxicity techniques; is easily interpreted and is readily reproducible.

Animals↗
PubMed1984

Alloantibodies to PHA-activated lymphocytes detect human Qa-like antigens.

Platelet-absorbed sera were obtained from placental clots after delivery by multiparous women. These sera contained antibodies that react with PHA-activated lymphocytes after the latter are separated from peripheral blood and expanded with interleukin 2. These alloantibodies did not react with resting T lymphocytes, but reacted with B lymphocytes, PHA-activated lymphocytes, or both types of cells obtained from some but not all of the T lymphocyte donors. Reactions against B lymphocytes were associated with anti-Ia-like antibodies on the basis of blockage by turkey antibodies against human Ia. Reactions against PHA-activated lymphocytes that were blocked by turkey anti-beta 2m were classified as 'HT'. Several antibodies were found to give reactions to HT determinants in separate panels of lymphocytes from Tel Aviv and Boston. The reproducibility of the cytotoxicity reactions was 89%. Altogether, 23 of 1100 sera were found to contain these reactions when screened by a panel of cells obtained from 30 individuals of known HLA phenotypes. Correlation coefficients were determined for all reactions, determining three clusters of significant reactivities: sera 965 and 1032 defined HT-2; sera SF48 and 1642 defined HT-3; and sera 1136, 1605, 1014, and 1227 defined HT-4. HT-2 was found to be inherited with HLA in 11 siblings from four families. Some of these antibodies react with antigens (non-HLA) containing beta 2m that were expressed on activated lymphocytes, but not on resting T lymphocytes, and did not react with thymocytes from the same donors of the peripheral lymphocytes. Our findings suggest that the HT alloantigens expressed on lectin-activated lymphocytes are class I differentiation antigens of a system analogous to the murine Qa system.

Antigens, Surface↗