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At least 1,243 records · Page 69Linked to original sources
PubMed1996

Genetic control of acquired resistance to Heligmosomoides polygyrus: overcoming genetically determined weak responder status by strategic immunization with ivermectin-abbreviated infections.

The induction of acquired resistance to H. polygyrus, following treatment of mice by a 6 day immunizing infection abbreviated with the anthelmintic drug ivermectin (6d I-AI), was investigated. Four worms were sufficient to elicit > 80% protection against challenge and immunizing infections > 50 worms generated > 95% protection in female NIH mice. A few worms were recovered during the second week from immunized challenged mice but these were rapidly expelled from the gut lumen. Treatment with hydrocortisone from day 10 postinfection, permitted worm burdens to accumulate over the following 2 weeks. The 6d I-AI protocol enabled females of strains previously designated as weak responders to develop potent acquired resistance to challenge (CBA mice showed > 90% protection), although weak responder strain male mice were not significantly protected. Delaying treatment with ivermectin by as little as 24 h resulted in poorer expression of acquired resistance. A positive correlation between the increasing interval from infection to treatment with ivermectin and worm burdens after challenge, and the negative correlation with IgGI antibody responses after challenge indicated that the immunodepressive activities of 7 day and older worms down-regulated local intestinal immune responses. Mice characterized by weak responder phenotype were significantly more sensitive to downregulation than mouse strains showing strong responder phenotype. In consequence, optimal timing of treatment with anthelmintics during exposure to the immunizing infection, intending to minimize exposure to the immunodepressive stages of the parasite, is sufficient to overcome reported genetic constraints on the development of resistance in this system.

Animals↗
PubMed1999

K-ras gene point mutation in neogenetic lesions of subpleural fibrotic lesions: either an early genetic event in lung cancer development or a non-specific genetic change during the inflammatory reparative process.

In the present study, K-ras mutation was investigated in 156 neogenetic epithelia that appeared in the lesion of subpleural fibrosis in order to elucidate the close relationship of lung cancer development with pulmonary interstitial pneumonia. The neogenetic epithelia were histologically subclassified into six types: (i) ciliated bronchial epithelium (CBE); (ii) squamous metaplastic epithelium (SME); (iii) cuboidal immature epithelium (CIE); (iv) stratified immature epithelium (SIE); (v) mucus cell epithelium (MCE); and (vi) intestinal metaplastic epithelium (IME). K-ras mutation was detected in 9.6% of neogenetic epithelia overall; 21% of CIE, 12% of SIE, 16% of SME, but not in other types of neogenetic epithelia. Immunohistochemically, CIE and SIE frequently expressed surfactant apoprotein and SME was characteristic to carcinoembryonic antigen expression. According to Ki-67 immunostain, CIE, SIE and SME are likely to grow faster than other histological types of epithelia. K-ras mutation was seen exclusively in codon 12 with predominant G to A and G to C substitutions without any G to T transversions, results which are somewhat different to previous studies in lung cancers. The present study clearly demonstrated that K-ras mutation appeared in certain histological types of neogenetic epithelia, but raised the question of whether K-ras mutation in neogenetic epithelia during the inflammatory reparative process might be an early genetic event in lung carcinogenesis.

Aged↗
PubMed1986

The ciliate Euplotes raikovi heterozygous at the mat genetic locus coreleases two individual species of mating pheromone: Genetic and biochemical evidence.

Euplotes raikovi of the wild-type strain 13 was found to be heterozygous (mat-1/mat-2) for the genetic locus mat, which is supposed to control the mating-type specificity of freely released mating pheromones ("euplomones"), and capable of yielding the two types of corresponding homozygotes (mat-1/mat-1, mat-2/mat-2). The results of euplomone purification, performed in parallel on Euplotes of the three different genotypes, showed that the heterozygous cells corelease two mat-specific euplomones (namely, euplomone r 1 associated with mat-1 and euplomone r 2 associated with mat-2), while the homozygous cells release either one of the two types according to their genotype. The two euplomones coreleased by the mat heterozygous cells were resolved as separate molecular species present in different relative amounts (euplomone r 1, approximately 70%; euplomone r 2, approximately 30%). A closely similar degree of eccentricity in the euplomone r 1/euplomone r 2 production was again found between the two homozygous cell types. It was concluded that the alleles mat-1 and mat-2 exhibit a relationship of nondominance: the heterozygote apparently behaves as the simple combination of the two corresponding homozygotes. It was inferred that the observed quantitative variations in the production of the different euplomones may be the result of a differential mat gene-type amplification occurring during the development of the cell somatic macronucleus.

Journal Article↗
PubMed1967

Genetic control of the antibody response. II. Further analysis of the specificity of determinant-specific control, and genetic analysis of the response to (H,G)-A--L in CBA and C57 mice.

CBA and C57 mice were tested for their ability to make an immune response to a related series of branched, multichain synthetic polypeptide antigens in which the antigenic determinants on the amino termini of the branched side chains were systematically varied. Neither strain responded to the polyglutamic acid determinant. Both strains responded well and equally to the poly(phenylalanine, glutamic acid) determinants. CBA mice responded poorly, and C57 mice responded well to two different antigens bearing poly(tyrosine, glutamic acid) determinants. CBA mice responded well, and CS7 mice responded poorly to two different antigens bearing poly(histidine, glutamic acid) determinants. The genetic control of the immune response to (H,G)-A--L appears to be dominant and polygenic, as it has been shown to be for (T,G)-A--L. The related antigens used in this study show extensive cross-reactions with antisera against other members of the related series.

Alanine↗
PubMed1972

Genetic factors controlling anti-sheep erythrocyte antibody response and immunoglobulin synthesis in backcross and F2 progeny of mice genetically selected for "high" or "low" antibody synthesis.

Agglutinin responses to sheep erythrocytes and immunoglobulin heavy chain phenotypes determined in F(1), F(2), and backcross progeny of mice genetically selected for high and low antibody synthesis indicated that an immune response gene for sheep erythrocytes is linked to the immunoglobulin heavy chain allotype. Mice homozygous for the phenotype of the high line had significantly higher titers than mice homozygous for the phenotype of the low line. An association was also observed in some progeny of the backcross of the F(1) generation with the low line. However, the control of the immune response was clearly multigenic since heterozygous mice of the same phenotype (2/3, 5) resulting from the two backcrosses (high and low) had very different immune responses. Immunoglobulin levels in the same progeny showed no linkage to the immunoglobulin allotype but a rather simple pattern of inheritance.

Animals↗
PubMed1998

Graphical interface to the genetic network database GeNet.

UNLABELLED: We designed a Java applet which enables the visualization of genetic networks and can be used as a Web publishing tool by molecular biologists studying the mechanisms of gene interactions. AVAILABILITY: http://www. csa.ru/Inst/gorb_dep/inbios/ genet/Graph/Genes_Graph.html CONTACT: samson@fn.csa.ru

Computational Biology↗
PubMed2003

Evaluating the genetic toxicology of DNA-based products using existing genetic toxicology assays.

Unlike the development of drugs based on small chemical entities there are no conventional regulatory toxicity studies established for DNA-based products. As the potential for insertional mutagenesis is of particular concern for gene therapy, we have investigated the mutagenicity of model non-viral DNA-based products at the HPRT locus in Chinese hamster V79 cells. Cultures were transfected with a pL3112BSKS plasmid in combination with a number of non-viral transfection facilitators: Effectene, Lipofectamine 2000 and ExGen 500. The plasmid contains a green fluorescent protein gene, which was used as a reporter of transfection efficiency. Flow cytometry was used to analyse large numbers of cells. Small scale transient transfection efficiencies (7-90%) were obtained at low cytotoxicity, however, scaling up the process led to decreased transfection and increased cytotoxicity. Stable transfection (chromosomal) was observed, but only at very low levels (<1.5%). Two of the non-viral delivery facilitators (Effectene and ExGen 500) themselves induced mutation at the HPRT locus, although they were considerably less potent than the positive control ethyl methanesulphonate. In transfection experiments, neither of the non-viral delivery facilitators (Effectene and Lipofectamine 2000) had a mutagenic effect, whereas with ExGen 500 there was evidence of a mutagenic effect, consistent with the mutagenicity observed with the non-viral transfection facilitator alone. Moreover, treatment with the plasmid pL3112BSKS itself was able to induce a 3- to 7-fold increase in the mutation frequency at the HPRT locus. Our studies highlight some of the problems associated with using exisiting genetic toxicology testing procedures for the assessment of DNA-based products used in novel gene therapy approaches. However, given the limited level of sophistication of the current approach, the data suggest that non-viral gene therapy may present a detectable mutation risk and more appropriate testing strategies are needed to evaluate the nature of the risk.

Animals↗
PubMed1978

Biochemical genetics of the alpha-keto acid dehydrogenase complexes of Escherichia coli K12: genetic characterization and regulatory properties of deletion mutants.

Twenty-eight spontaneous auxotrophic aroP mutants with deletions in the azi--nadC--aroP--aceE--aceF--lpd region of the Escherichia coli K12 chromosome were characterized genetically with respect to various azi, nadC, ace and lpd markers by P1-mediated transduction. One mutant (Kdelta18; aroP--lpddelta) had a deletion which extended through the aceE and aceF genes to end within the lpd gene. The polarity of the ace operon (aceE to aceF) was confirmed. It was concluded that 10 out of 15 deletions generating a strict requirement for acetate terminated in the aceE gene. Of the ten, three mutants (Kdelta22, Cdelta41 and Cdelta41) synthesized detectable dihydrolipoamide acetyltransferase (the aceF gene product) and seven were assumed to possess deletions generating polar effects on aceF gene expression. Five deletions appeared to extend into the aceF gene. A further five deletions, which limited the expression of the ace operon without generating an Ace- phenotype or a complete Ace- phenotype, ended closest to the aroP-proximal aceE markers. The opposite ends of all these deletions appeared to terminate before (10), within (2) or extend beyond (9) the nadC gene. There was no obvious correlation between the deletion end-points and the corresponding lipoamide dehydrogenase activities, which ranged from 30 to 95% of parental levels in different deletion strains. The remaining seven deletions simply extended between the aroP and nadC genes (nad--aroPdelta) without affecting expression of the ace operon. Regulation of the synthesis of the pyruvate and alpha-ketoglutarate dehydrogenase complexes was investigated in some of the parental and deletion strains under different physiological conditions including thiamin-deprivation. The results indicate that the syntheses of the two dehydrogenase complexes are independently regulated. Expression of the lpd gene appears to be coupled to complex synthesis but can be dissociated under some conditions. Mechanisms for regulating lpd gene expression are discussed and an autogenous mechanism involving uncomplexed lipoamide dehydrogenase functioning as a negatively acting repressor at the operator site of an independent lpd gene is proposed as the simplest mechanism which is consistent with all available information.

Chromosome Deletion↗
PubMed1991

Genetic differences shown by HLA typing among Japanese patients with euthyroid Graves' ophthalmopathy, Graves' disease and Hashimoto's thyroiditis: genetic characteristics of euthyroid Graves' ophthalmopathy.

Euthyroid Graves' ophthalmopathy (EO) is an ophthalmic disorder without persistent hyperthyroidism. To elucidate genetic differences among EO, Graves' disease (Gr) and Hashimoto's thyroiditis (H), we analysed HLA-A, B, C, DR, DQ, D and DP types in 23 Japanese EO patients, 88 Gr patients, 46 H patients and 186 control subjects utilizing assays of lymphocyte cytotoxicity and restriction fragment length polymorphism (RFLP). When compared with the control subjects, EO patients showed significant associations with HLA B40 (w61), DR9, DQw3, and Dw15 (P less than 0.01) and with HLA B12 and Cw1 (P less than 0.05). When allowance was made for the number of antigens tested, only DQw3 was significant. Significant differences were found between EO and Gr (DPw2), and between EO and H (Cw1) even after correction of P values. Comparisons between EO and related subgroups of Gr confirmed the heterogeneity of EO again. It is concluded from these results that EO is associated with different HLA types from Gr and H.

Adult↗
PubMed1992

Genetic control of eosinophilia in guinea pig strains inbred for high or low bronchial allergic reactivity. 2. A genetic study of spontaneous and immunization-induced eosinophilia.

In 4 inbred strains of guinea pig the tendency to develop peripheral high-eosinophilia was shown to be genetically controlled. The development of eosinophilia with age and following immunization was examined in high- and low-eosinophilic parental strains, in F1-hybrids and in backcross offspring. The results show that probably only one or a very few segregating genes control eosinophilia, and they also indicate that different genes are involved in the determination of spontaneous (age-related) and immunization-induced eosinophilia.

Animals↗
PubMed1981

Genetic control of the immune response to haemoglobin. I. Demonstration of separate genetic control of the responses to the alpha- and beta-subunits by in vitro lymphocyte proliferation.

These studies were undertaken to analyse the genetic control of the immune response to an oligomeric protein and the role of individual subunits in the regulation of the response. Human adult haemoglobin (Hb) was selected as a model for these studies because it is a well-characterized protein and its antigenic structure is being determined in our laboratories. Mice of various congenic strains were immunized with Hb and the lymph node cells from Hb-primed mice were challenged in vitro with Hb, and its alpha-chain and beta-chains as well as an appropriate control antigen. Lymphocyte proliferation was determined by 3H-thymidine incorporation. The data collected indicated that mice of the H-2b and H-2d haplotypes were high responders while H-2k, H-2s, H-2q and H-2j haplotype mice were low responders to Hb. Studies with H-2 recombinant strains indicated that the immune response to Hb and its subunits is determined by genes in the I-A subregion and the D end of the H-2 complex. The significance of these findings in terms of control and regulation of the overall response to native Hb are discussed.

Animals↗
PubMed2000

Identification and genetic characterization of Haemophilus influenzae genetic island 1.

The type b capsule of pathogenic Haemophilus influenzae is a critical factor for H. influenzae survival in the blood and the establishment of invasive infections. Other pathogenic factors associated with type b strains may also play a role in invasion and sustained bacteremia, leading to the seeding of deep tissues. The gene encoding haemocin is the only noncapsular gene found to be specific to type b strains until now. Here we report the discovery of an approximately 16-kb genetic locus, HiGI1, that is present primarily in type b strains. Pulsed-field gel electrophoresis and Southern hybridization were used to map this new locus between secG (HI0445) and fruA (HI0446), which are contiguous in Rd, a nonpathogenic derivative of a serotype d strain. It is inserted at the 3' end of tRNA(4)(Leu) and has regions whose G+C content differs from the average genomic G+C content of H. influenzae. An integrase gene, which encodes a CP4-57 like integrase, is located downstream of tRNA(4)(Leu). Hybridization probes based on the sequences within the HiGI1 locus have been used to screen 61 H. influenzae strains (2 type a, 22 type b, 2 type c, 1 type d, 3 type e, 7 type f, and 21 nontypeable H. influenzae [NTHi]) from our collection. This HiGI1 locus exists in all 22 type b strains and two NTHi strains and is likely to have been acquired by an ancestral type b strain.

Bacterial Proteins↗
PubMed2001

Genetic variability and prevalence of Bartonella henselae in cats in Berlin, Germany, and analysis of its genetic relatedness to a strain from Berlin that is pathogenic for humans.

Nineteen Bartonella henselae strains and one Bartonella clarridgeiae strain were isolated from blood samples of 97 pet cats and 96 stray cats from Berlin, Germany, indicating prevalence rates of 1 and 18.7%, respectively, for B. henselae and 0 and 1%, respectively, for B. clarridgeiae. Eighteen of 19 B. henselae isolates corresponded to 16S rRNA type II. Pulsed-field gel electrophoresis (PFGE) analysis revealed seven different PFGE types among the feline B. henselae strains. Interestingly, all feline isolates displayed low genetic relatedness to B. henselae strain Berlin-1, which is pathogenic for humans.

Animals↗
PubMed1980

Genetic and clinical patterns of heritable cerebellar ataxias in adults. I. Genetic analyses.

Family data on 299 probands with spinocerebellar types, 163 with late cortical cerebellar atrophies (LCCA), and 180 with olivopontocerebellar atrophies (OPCA) were analysed. Spinocerebellar types included cases with cerebellar ataxia combined with spasticity. Their family history was not compatible with sex linked inheritance. There were few recessive cases occurring before 24 years of age. The majority of cases were products of non-consanguineous marriages in which one partner was affected. The genetic ratio was 0.5 for each decade at onset between 20 and 59, suggesting that these cases were dominant. The proportion of these familial cases, however, decreased with increasing age at onset, and there were quite a few sporadic cases among the elderly. LCCA and OPCA were considered to represent extremes of a correlated disease spectrum. Although they were weakly familial, single gene heredity was rejected. Sib recurrence rate was 7.5% for LCCA and 9.4% for OPCA. When calculated for different age groups at onset, the rates decreased with increasing age in the two diseases. The rates increased to 25% and 20%, respectively, given two sibs already affected, and to 37.5% and 22.2% when three were affected. These patterns were incompatible with single gene mechanisms and were similar to those in multifactorial diseases with a threshold effect.

Adolescent↗
PubMed1995

Genetic networks controlling the initiation of sporulation and the development of genetic competence in Bacillus subtilis.

Interconnected regulatory networks control the initiation of sporulation and the development of genetic competence in Bacillus subtilis. These two developmental pathways have both common and distinct elements and employ similar regulatory strategies. Activation of the ComK transcription factor serves to integrate many of the physiological signals that control competence development, including cell density signals. The cell density signals for competence are mediated by two different peptide pheromones, the ComX pheromone, a 9 or 10 amino acid peptide with a modified tryptophan residue, and the competence stimulating factor, CSF, which is at least in part a peptide. Activation of the Spo0A transcription factor by phosphorylation serves as a developmental checkpoint and to integrate several physiological signals that control entry into the sporulation pathway. The physiological signals are generated by conditions of nutrient deprivation, high cell density, the Krebs cycle, DNA replication, DNA damage, and some aspect of the chromosome partitioning machinery. Both the ComK and Spo0A transcription factors are part of autogenous regulatory loops that control entry into competence or sporulation.

Bacillus subtilis↗
PubMed2005

Genetic loci for ventricular dilatation in the LEW/Jms rat with fetal-onset hydrocephalus are influenced by gender and genetic background.

BACKGROUND: The LEW/Jms rat strain has inherited hydrocephalus, with more males affected than females and an overall expression rate of 28%. This study aimed to determine chromosomal positions for genetic loci causing the hydrocephalus. METHODS: An F1 backcross was made to the parental LEW/Jms strain from a cross with non-hydrocephalic Fischer 344 rats. BC1 rats were generated for two specific crosses: the first with a male LEW/Jms rat as parent and grandparent, [(F x L) x L], designated B group, and the second with a female LEW/Jms rat as the parent and grandparent [L x (L x F)], designated C group. All hydrocephalic and a similar number of non-hydrocephalic rats from these two groups were genotyped with microsatellite markers and the data was analyzed separately for each sex by MAPMAKER. RESULTS: The frequency of hydrocephalus was not significantly different between the two groups (18.2 and 19.9 %), but there was a significant excess of males in the B group. The mean severity of hydrocephalus, measured as the ventricle-to-brain width ratio, was ranked as B group < C group < LEW/Jms. For the both rat groups, there were several chromosomes that showed possible regions with association between phenotype and genotype significant at the 5% or 1.0% level, but none of these had significant LOD scores. For the C group with a female LEW/Jms parent, there was a fully significant locus on Chr2 with a LOD score of 3.81 that was associated almost exclusively with male rats. Both groups showed possible linkage on Chr17 and the data combined produced a LOD score of 2.71, between suggestive and full significance. This locus was largely associated with male rats with a LEW/Jms male parent. CONCLUSION: Phenotypic expression of hydrocephalus in Lew/Jms, although not X-linked, has a strong male bias. One, and possibly two chromosomal regions are associated with the hydrocephalus.

Journal Article↗
PubMed2001

Genetics University of Toronto Thrombophilia Study in Women (GUTTSI): genetic and other risk factors for venous thromboembolism in women.

BACKGROUND: Women may be at increased risk for venous thromboembolism (VTE) as compared with men. We studied the effects of genetic and biochemical markers of thrombophilia in women, in conjunction with other established risk factors for VTE. METHOD: The present retrospective case-control study was conducted in a thrombosis treatment programme at a large Toronto hospital. The cases were 129 women aged 16-79 years with objectively confirmed VTE. Age-matched control individuals were women who were free of venous thrombosis. Neither cases nor control individuals had known cardiovascular disease. Participants were interviewed regarding personal risk factors for VTE, including smoking, history of malignancy, pregnancy, and oestrogen or oral contraceptive use. Blood specimens were analyzed for common single nucleotide polymorphisms of prothrombin, factor V and methylenetetrahydrofolate reductase (MTHFR; C677T, A1298C and T1317C), and the A66G polymorphism for methionine synthase reductase (MTRR).Fasting plasma homocysteine was also analyzed. RESULTS: Women with VTE were significantly more likely than female control individuals to carry the prothrombin polymorphism and the factor V polymorphism, or to have fasting hyperhomocysteinaemia. Homozygosity for the C677T MTHFR gene was not a significant risk factor for VTE, or were the A1298C or T1317C MTHFR homozygous variants. Also, the A66G MTRR homozygous state did not confer an increased risk for VTE. CONCLUSION: Prothrombin and factor V polymorphisms increased the risk for VTE in women, independent from other established risk factors. Although hyperhomocysteinaemia also heightens this risk, common polymorphisms in two genes that are responsible for homocysteine remethylation do not. These findings are consistent with previous studies that included both men and women.

Journal Article↗
PubMed1987

Rare factor VII variant inherited through genetic variant in proband's mother and another genetic variant in proband's father.

An 11-year-old girl with hereditary factor-VII deficiency and her family have been studied for factor VII coagulation activity (VII:C) and factor VII antigen level (VII:Ag). The proband had 11% VII:C, whereas her VII:Ag was at a level that corresponds to about 50% coagulation activity. Forty-two members of the proband's family were tested. This study disclosed that the proband's factor VII deficiency had been inherited through both her mother and her father. Although her father was dead, testing of her father's family showed a factor VII defect of the type VII+ variant, that is, normal production of VII:Ag but reduced VII:C. The maternal side of her family was found to have reduced but identical levels of VII:C and VII:Ag (variant VIIR). The proband's factor VII deficiency is therefore apparently inherited through two different variants, and that could explain this rare genetic type of factor VII deficiency. To our knowledge no such variant has ever been described.

Antigens↗