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PubMed2004

Common genetic effects on variation in impulsivity and activity in mice.

Impulsivity is a complex psychological construct that impacts on behavioral predispositions in the normal range and has been shown to have a genetic element through the examination of hereditary patterns of abnormal conditions such as attention deficit/hyperactivity disorder and obsessive compulsive disorder. In this study, we took advantage of the isogenic nature of inbred strains of mice to determine the contribution of genes to impulsive behaviors by examining the performance of four separate mouse strains in a novel murine delayed-reinforcement paradigm, during which the animals had to choose between rewards that were relatively small but available immediately and larger but progressively delayed rewards. To control for maternal effects, all the mice were cross-fostered to a common strain immediately after birth. Under these conditions, we found significant differences between the strains on behaviors indexing impulsive choice and on independent measures of locomotor activity, which subsequent heritability analysis showed could be related, in part, to genetic effects. Moreover, the two aspects of behavior were found to co-vary, with the more active animals also displaying more impulsive behavior. This was not attributable to mundane confounds related to individual task requirements but instead indicated the existence of common genetic factors influencing variation in both impulsivity and locomotor activity. The data are discussed in terms of the coexistence of impulsivity and hyperactivity, interactions between environmental and genetic effects, and possible candidate genes.

Animals↗
PubMed2000

In vivo antitumor activity of ONYX-015 is influenced by p53 status and is augmented by radiotherapy.

The E1B-deleted, replication-competent ONYX-015 (dl1520) adenovirus was originally described as being able to selectively kill p53-deficient cells due to a requirement of p53 inactivation for efficient viral replication. This hypothesis has become controversial because subsequent in vitro studies have demonstrated that the host range specificity of ONYX-015 is independent of p53 gene status. Using a pair of isogenic cell lines that differ only in their p53 status, we demonstrate here that although ONYX-015 can replicate in both p53 wild-type and mutant cells in vitro, the virus demonstrates significantly greater antitumor activity against mutant p53 tumors in vivo. Moreover, ONYX-015 viral therapy can be combined with radiation to improve tumor control beyond that of either monotherapy. The results demonstrate that ONYX-015 can discern in vivo between tumors having a different p53 status and that it may be an effective neoadjuvant to radiation therapy.

Adenoviridae↗
PubMed2002

[Induction of MGE 412 transposition individually by heat and cold shock in spermatogenesis in Drosophila males].

Effects of temperature treatment (heavy heat shock, HHS; heat shock, HS; and cold shock, CS) on the daily productivity of treated males in different spermatogenesis stages have been studied in isogenic line 51 of Drosophila melanogaster. The average productivity was shown to substantially decrease in all cases. The sum of the HS and CS contributions to this decrease was nearly equal to the HHS (the combined HS and CS) contribution, i.e., these contributions were almost additive. The temperature treatments did not kill mature sperm. In the control, mating productivity of day 1 exceeded that of the next day at least by 10-20%. Each day, most sperm in matings was new, i.e., matured during that day. Transposition induction of MGE 412 was studied at four spermatogenesis stages after HS and CS. Both temperature treatments were effective but CS had a more pronounced inducing effect. Most temperature-induced transpositions occurred at stage 3 (meiosis) and 4 (spermiogenesis). The day rates of transpositions at different stages were estimated. After HS at the meiosis stage, lambda = 0.11 events per initial MGE copy per sperm per day of mating, which is approximately equal to the previous estimates after HHS. After CS at the meiosis stage, lambda = 0.51. The transposition hot sites (including the previously known 43B and 97DE as well as a number of new sites) were detected. The lists of transpositions after CS completely included the corresponding lists after HS, which suggests similarity of induction mechanisms underlying CS and HS.

Animals↗
PubMed1977

Regulation of the bacterial microflora of the vagina in cyclic female rats.

The bacterial microflora was examined in the vagina of cyclic female rats kept under normal laboratory conditions. Large variations occurred during the cycle with high numbers of bacteria (10(5)-10(8) per vagina) during proestrus and estrus and low numbers (10(1)-10(4) per vagina) during the diestrus period. Histological analysis of in situ vaginal tissue and transplanted vaginal tissue revealed an association of high bacterial numbers with the presence of large amounts of cellular debris in the vaginal lumen during the period of epithelial keratinization. Absence of phagocytosis in leucocytes at mestestrus suggested that leucocytes did not play an active role in reduction of bacterial numbers between estrus and metestrus. Accurate measurement of the pH in the vaginal lumen failed to reveal differences which could explain the reduction in bacterial numbers between estrus and metestrus. The cyclic changes in the bacterial population-consisting of species which are normally present in the intestinal flora-- seem to be controlled by cyclic changes in the amounts of cellular debris in the vaginal lumen.

Animals↗
PubMed1986

Selection of patients with Hodgkin's disease and non-Hodgkin's lymphoma for bone marrow transplantation.

Despite substantial progress in curative therapy of malignant lymphomas, some patients fail current treatment and die of refractory disease. Although Although high-dose chemotherapy and supralethal total body irradiation followed by bone marrow transplantation may salvage and cure a proportion of these refractory patients, treatment of such end-stage patients with marrow grafting often fails because of resistant disease or transplant-related complications. Using the analogy of transplantation in the early phases of acute and chronic leukemias, results of marrow transplant in Hodgkin's disease and non-Hodgkin's lymphoma might be improved if performed earlier in the course of the malignancy. The following collaborative report by the Seattle and Stanford groups examines current results of conventional lymphoma therapy to define subgroups of patients with "high-risk" lymphoma for whom early marrow transplant might be offered to control otherwise incurable disease.

Antibodies, Monoclonal↗
PubMed1993

Certain host-donor strain combinations do not reject brain allografts after systemic sensitization.

To investigate the factors related to allogenic brain graft rejection, rat cortex from either LEW-RT1l or BN-RT1n rats was transplanted into brains of several isogenic and allogenic inbred strains: F344-RT1l, LEW-RT1l, BN-RT1n, AO-RT1u, PVG-RT1c, PVG-RT1u, and PVG-RT1l. Each donor and host combination was subsequently subdivided into two subgroups. One group was systematically sensitized twice with donor skin tissue and another group served as a sham-sensitization control. Four weeks after the second sensitization, host brains were examined histologically, and the percentage volume of each graft that showed increased cellularity was estimated. Expression of major histocompatibility complex (MHC) and T cell antigens was also studied immunocytochemically. Almost all grafts in sham-sensitized animals from all groups were accepted with minimal or no reaction. However, two strains (AO-RT1u and F344-RT1l) showed considerable cell infiltration and expression of MHC antigens even without sensitization. After sensitization, almost all allogenic strain combinations showed greater signs of rejection-related responses. The severity of the tissue reaction, however, varied considerably between groups. All grafts from BN-RT1n donors were rejected severely in all host strains. For LEW-RT1l donors, grafts survived well in some host strains (BN-RT1n, AO-RT1u, PVG-RT1c, and PVG-RT1u), even with MHC + non-MHC disparity. Curiously, F344-RT1l hosts rejected LEW-RT1l grafts even though the two strains have the same MHC loci, but different minor histocompatibility (mH) loci. For both donor strains, experimental autoimmune encephalomyelitis-susceptible hosts tended to show more vigorous rejection responses.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗
PubMed1997

MALT-type lymphoma of the stomach is associated with Helicobacter pylori strains expressing the CagA protein.

BACKGROUND & AIMS: Helicobacter pylori is considered to be involved in the pathogenesis of gastric lymphoma of mucosa-associated lymphoid tissue (MALT) type. Strains expressing the CagA protein (CagA+ strains) have been strongly associated with severe gastritis, duodenal ulceration, and gastric adenocarcinoma. The aim of this study was to determine the presence of H. pylori as well as incidence of CagA+ strains in gastric MALT-type lymphoma. METHODS: Sera of 68 patients with gastric MALT-type lymphoma (22 with low grade, 36 with high grade, and 10 with secondary high grade) were obtained, and the serological response to CagA was studied by immunoblotting using a purified recombinant CagA protein, a CagA+ strain, and the corresponding isogenic CagA- mutant. RESULTS: Of the patients with MALT-type lymphoma, 98.5% (67 of 68 patients) were H. pylori seropositive. In the only seronegative patient, the bacterium was detected histologically by Warthin-Starry staining. Of the seropositive patients, 95.5% had serum immunoglobulin G antibodies to CagA compared with 67% of an H. pylori-positive control group (33 of 49 patients; P = 0.000037) with chronic active gastritis. CONCLUSIONS: These results indicate infection of almost all patients with MALT-type lymphoma by CagA+ H. pylori strains. Strains expressing the CagA protein seem to play a crucial role in the pathogenesis of gastric MALT-type lymphoma.

Adult↗
PubMed1997

Histology of rat small bowel transplants: cyclosporine A ameliorates features of rejection including apoptosis and ganglion cell reduction.

The histology of rat small bowel transplants (SBT) was examined in orthotopic isografts and allografts with and without immunosuppression. Lewis to Lewis isografts were examined 7 days after transplant, and LBNF1 to Lewis allografts were examined 2, 4, 7, and 10 days after transplant; one group received cyclosporine A (CyA), and their allografts were examined 7 days after transplant. Compared with similar intestinal segments from unoperated animals, allografts at 4, 7, and 10 days after surgery showed progressive inflammation, cryptitis, villous atrophy, and transmural necrosis. In contrast, SBT in animals given CyA did not significantly differ from normal in any histological parameter. The number of apoptotic structures per 100 crypts in SBT at day 4 (58.25 +/- 32.98) and day 7 (31.86 +/- 27.63) after transplant were significantly increased compared with unoperated bowel (5.23 +/- 13.41) (P < .05); the number in CyA-treated allografts (11.57 +/- 29.56) did not differ significantly from normal. The number of intermyenteric ganglion cells was significantly reduced (P< .05) in allografts 7 and 10 days after transplant (mean and [range] = 31 [18 to 38] and 25 [23 to 27], respectively) but the number in allografts from CyA-treated animals (47 [24 to 72]) did not differ from unoperated bowels (52 [30 to 88]). We conclude that CyA treatment significantly reduces the histological abnormalities associated with transplant rejection including adverse effects on epithelial and ganglion cells; therefore, the absorptive capacity and motility characteristics of the CyA-treated SBT should be preserved compared with untreated allograft controls.

Animals↗
PubMed1989

Specific binding of victorin to a 100-kDa protein from oats.

Susceptibility of oats to victoria blight, caused by the fungus Cochliobolus victoriae, and sensitivity to the host-specific toxin victorin, produced by the fungus, are controlled by the dominant allele at the Vb locus. It has been postulated that the Vb locus encodes a toxin receptor, although direct evidence for such a receptor is not available. Our recent studies on structure-activity relationships of the toxin established a methodology for producing (125)I-labeled victorin. Electrophoretic analysis of proteins from isogenic susceptible and resistant oat genotypes following treatment of leaves with radiolabeled victorin showed that victorin binds in a covalent and a genotype-specific manner to a 100-kDa protein only in susceptible oat leaf slices. This in vivo binding was competitively displaced by reduced victorin, a nontoxic protective compound, and appeared to be correlated with biological activity. In vitro binding to the 100-kDa protein in leaf extracts showed several differences from in vivo binding. Binding was not genotype specific and required a reducing agent that was not required for in vivo binding. Differential centrifugation showed that the 100-kDa victorin binding protein was not a cytosolic protein but was enriched in a high-speed particulate fraction. The data support the hypothesis that the 100-kDa protein is the victorin receptor.

Journal Article↗
PubMed1994

Telomerase activity in human ovarian carcinoma.

Telomeres fulfill the dual function of protecting eukaryotic chromosomes from illegitimate recombination and degradation and may aid in chromosome attachment to the nuclear membrane. We have previously shown that telomerase, the enzyme which synthesizes telomeric DNA, is not detected in normal somatic cells and that telomeres shorten with replicative age. In cells immortalized in vitro, activation of telomerase apparently stabilizes telomere length, preventing a critical destabilization of chromosomes, and cell proliferation continues even when telomeres are short. In vivo, telomeres of most tumors are shorter than telomeres of control tissues, suggesting an analogous role for the enzyme. To assess the relevance of telomerase and telomere stability in the development and progression of tumors, we have measured enzyme activity and telomere length in metastatic cells of epithelial ovarian carcinoma. We report that extremely short telomeres are maintained in these cells and that tumor cells, but not isogenic nonmalignant cells, express telomerase. Our findings suggest that progression of malignancy is ultimately dependent upon activation of telomerase and that telomerase inhibitors may be effective antitumor drugs.

Ascites↗
PubMed2000

The Pseudomonas aeruginosa phaG gene product is involved in the synthesis of polyhydroxyalkanoic acid consisting of medium-chain-length constituents from non-related carbon sources.

We recently identified the phaG(Pp) gene encoding (R)-3-hydroxydecanoyl-ACP:CoA transacylase in Pseudomonas putida, which directly links the fatty acid de novo biosynthesis and polyhydroxyalkanoate (PHA) biosynthesis. An open reading frame (ORF) of which the deduced amino acid sequence shared about 57% identity with PhaG from P. putida was identified in the P. aeruginosa genome sequence. Its coding region (herein called phaG(Pa)) was amplified by PCR and cloned into the vector pBBR1MCS-2 under lac promoter control. The resulting plasmid pBHR88 mediated PHA synthesis contributing to about 13% of cellular dry weight from non-related carbon sources in the phaG(Pp)-negative mutant P. putida PhaG(N)-21. The PHA was composed of 5 mol% 3-hydroxydodecanoate, 61 mol% 3-hydroxydecanoate, 29 mol% 3-hydroxyoctanoate and 5 mol% 3-hydroxyhexanoate. Furthermore, an isogenic phaG(Pa) knock-out mutant of P. aeruginosa was constructed by gene replacement. The phaG(Pa) mutant did not show any difference in growth rate, but PHA accumulation from gluconate was decreased to about 40% of wild-type level, whereas from fatty acids wild-type level PHA accumulation was obtained. These data suggested that PhaG from P. aeruginosa exhibits 3-hydroxyacyl-ACP:CoA transacylase activity and strongly enhances the metabolic flux from fatty acid de novo synthesis towards PHA(MCL) synthesis. Therefore, a function could be assigned to the ORF present in the P. aeruginosa genome, and a second PhaG is now known.

Acyltransferases↗
PubMed2004

A novel lectin, DltA, is required for expression of a full serum resistance phenotype in Haemophilus ducreyi.

Haemophilus ducreyi, the causative agent of chancroid, is highly resistant to the complement-mediated bactericidal activity of normal human serum (NHS). Previously, we identified DsrA (for ducreyi serum resistance A), a major factor required for expression of the serum resistance phenotype in H. ducreyi. We describe here a second outer membrane protein, DltA (for ducreyi lectin A), which also contributes to serum resistance in H. ducreyi. Isogenic dltA mutants, constructed in 35000HP wild-type and FX517 dsrA backgrounds, were more susceptible to the bactericidal effects of NHS than each respective parent, demonstrating the additive effect of the mutations. Furthermore, expression of dltA in H. influenzae strain Rd rendered this highly susceptible strain partially resistant to 5% NHS compared to a vector-control strain. Although primary basic local alignment search tool analysis of the dltA open reading frame revealed no close bacterial homologue, similarity to the beta-chain of the eukaryotic lectin ricin was noted. DltA shares highly conserved structural motifs with the ricin beta chain, such as cysteines and lectin-binding domains. To determine whether dltA was a lectin, ligand blots and affinity chromatography experiments were performed. DltA was affinity purified on immobilized lactose and N-acetylgalactosamine, and N-glycosylated but not glycosidase-treated model glycoproteins bound DltA. These data indicate that DltA is a lectin with specificity for lactose-related carbohydrates (CHO) and is important for H. ducreyi serum resistance.

Amino Acid Sequence↗
PubMed1982

Mammary tumors in BALB/cfC3H and BALB/cfRIII virgin female mice bearing hypophyseal isografts.

The behavior and morphology of mouse mammary tumors in high cancer strain mice are controlled by the causative murine mammary tumor viruses (MuMTV). However, relationships also exist between mammary tumors and other factors such as host genotype, other etiologic agents (chemicals, X-rays), and hormones. Among the latter, prolactin has been particularly studied. The aim of this investigation was to test whether the mammary tumor morphology controlled by C3H and RIII MuMTVs is in any way influenced by continuous prolactin secretion. A total of 28 BALB/cfC3H and 24 BALB/cfRIII virgin female mice was implanted with 2 hypophyseal isografts under the kidney capsule. Mice were of the same BALB/c genotype and carried respectively C3H and RIII MuMTV infection. The biologic and morphologic characterization of the tumors observed showed that several differences previously reported between mammary tumors in breeding female mice of the 2 strains persisted in virgins bearing hypophyseal isografts. These data confirm that the mammary tumor characters in high cancer strain mice are mainly carried out and controlled by the causative MuMTVs but also suggest that different MuMTVs may show different sensitivity to continuous prolactin secretion.

Animals↗
PubMed1986

Metabolic and morphologic changes in brown adipose tissue from non-growing mice with an isogeneic sarcoma. Evaluation with respect to development of cachexia.

Brown adipose tissue plays a thermoregulatory role influencing energy balance in experimental animals and possibly also in humans. In the present study we have reevaluated whether brown adipose tissue may contribute to the development of cancer cachexia in non-growing mice bearing an isogeneic tumor. Interscapular brown adipose tissue mass decreased by 20% in freely-fed sarcoma-bearing mice housed at room temperature. Increased mitochondrial density and increased oxidation rate of acetate at low acetate concentrations were found in brown fat from sarcoma-bearing mice, while the oxidation capacity was unchanged compared with that of freely-fed controls. Metabolic and morphologic changes in brown fat from sarcoma-bearing mice were similar to those found in weight-paired controls, which had experienced the same loss of body weight as the tumor-bearing mice. Selective and non-selective B-receptor blockade and surgical removal of interscapular brown fat before tumor implantation did not influence the nutritional state of freely-fed tumor-bearing mice. Injections of noradrenaline caused a proportionately lower increase in oxygen uptake in tumor-bearing animals than in freely-fed controls. Exposure to cold (+5 degrees C) doubled food intake and led to hypertrophy of brown fat in both sarcoma-bearing mice and control animals. Tumor growth was lower although not statistically different in animals housed at +5 degrees C compared with animals housed at +25 degrees C. It is concluded that brown adipose tissue from sarcoma-bearing mice could not account quantitatively for the host wasting in tumor-bearing mice housed at room temperature.

Acetates↗
PubMed2001

Comparison of structural changes of cell surface carbohydrates in the eustachian tube epithelium of chinchillas infected with a Streptococcus pneumoniae neuraminidase-deficient mutant or its isogenic parent strain.

Six different lectin probes were used to examine alterations of the cell surface carbohydrates in the chinchilla eustachian tube (ET) lumen subsequent to the intranasal (i.n.) challenge with the Streptococcus pneumoniae parent strain, D39, or its isogenic derivative, DeltaNA1, which is deficient in neuraminidase NanA. The labelling pattern revealed that the binding of wheat germ agglutinin (WGA), Erythrina cristagalli lectin (ECL), peanut agglutinin (PNA), Bandeiraea simplicifolia lectin II (BSL II) and succinylated wheat germ agglutinin (SWGA) were increased in the lumenal surface of the ET in the D39 inoculated cohort compared to the uninfected control, which indicated that N-acetylglucosamine (GlcNAc) and D-galactose residues were exposed. Concurrently, decreased labelling with Sambucus nigra agglutinin (SNA) indicated that there were few sialic acid residues remaining in the ET epithelium subsequent to i.n. inoculation with D39. The DeltaNA1 neuraminidase deficient mutant, however, did not induce any significant changes in the lectin labelling patterns, and was comparable to that of the control cohort. We propose that products of the nanA gene have a significant impact on the changes of the carbohydrate moieties in the ET epithelium and may be responsible for the previously reported increased ability of the D39 parent to colonize the nasopharynx and invade the middle ear.

Animals↗
PubMed1987

Increased production of a knotted form of plasmid pBR322 DNA in Escherichia coli DNA topoisomerase mutants.

Plasmid pBR322 prepared from Escherichia coli strains carrying deletion of the DNA topoisomerase I gene (delta topA) with a compensatory mutation of the DNA gyrase gene (gyrA or gyrB) and from their TopA+ transductants was analyzed by agarose gel electrophoresis followed by electron microscopy, and compared with that from isogenic wild-type strains. It was found that about 1% of the plasmid DNA molecules was a knotted species in the topA+ gyr+ strains W3110 and DM4100, while strains DM750 (delta topA gyrA224), DM800 (delta topA gyrB225), SD275 (topA+ gyrA224) and SD108 (topA+ gyrB225) produced six to ten times as much knotted DNA as the topA+ gyr+ controls. The results suggest that the increased production of knotted pBR322 DNA is closely related to mutations of the gyrase genes.

DNA Topoisomerases, Type I↗