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At least 343 records · Page 19Linked to original sources
PubMed1978

Determinant selection and macrophage function in genetic control of the immune response.

The immune response to insulin, in both mouse and guinea pig, is under control of H-linked immune response genes. When immunized with either pork or beef insulin in CFA, both strain 2 and 13 guinea pigs respond by antigen-specific lymphocyte proliferation and synthesis of specific antibody. The specificities of the elicited antibodies and indistinguishable between these inbred strains. By constrast, strain 2 T cells recognized a distinct region of the A chain alpha loop consisting of amino acid residues 8, 9 and 10, while strain 13 T cells see an as yet undefined region of the B chain. H2b (A chain alpha loop responder) and H2d (B chain responder) mice similarly discriminate which areas of the molecule are recognized by their T lymphocytes. The function of the Ir gene in both the guinea pig and mouse appears to be an intramolecular selection of discrete regions within the antigen for recognition by the T cell. The data presented suggest that this function operates at the level of the macrophage.

Animals↗
PubMed2002

Genetic and functional analyses of polymorphisms in the human FSH receptor gene.

To determine the influence of FSH receptor variants Thr307-Asn680 (TN) and Ala307-Ser680 (AS) on ovarian function, we investigated the frequency of these gene polymorphisms by using restriction fragment length polymorphism analysis and observed their effects on clinical manifestations. In a population of 522 Japanese women, the overall frequency of TN/TN (NN), TN/AS (NS), and AS/AS (SS) was 41.0, 46.9 and 12.1% respectively. In polycystic ovary patients, the NS population was significantly larger when compared with the spontaneously ovulating group (66.7 versus 43.5%, P < 0.05). In the SS group, a significantly higher (46%) basal level of serum FSH was observed as compared with that in the NS group (P < 0.05). A higher dose of the exogenous gonadotrophin was required to achieve ovulation induction in the SS group as compared with the NS group (P < 0.05). At the time of hCG administration, estradiol levels per oocyte retrieved for IVF in the SS group were significantly lower as compared with the levels in the NS and NN groups (P < 0.05). There were no significant differences in FSH-stimulated cAMP production and PI turnover as well as ligand-binding affinity between the two receptor isoforms when overexpressed in transfected 293T cells. These results suggest that although FSH receptor polymorphisms have no discernible effect on FSH receptor function in vitro, there are associations between the genotype and some aspects of patient status.

Alleles↗
PubMed2003

Genetics and functional genomics of type 2 diabetes mellitus.

Genome-wide studies of transcription in the skeletal muscle of type 2 diabetic patients have identified coordinated changes in the expression of genes involved in oxidative phosphorylation, and have underlined the central role of the oxidative-phosphorylation regulator, PCG1alpha. These findings help unravel the complex pathogenesis and inheritance of polygenic type 2 diabetes mellitus.

Animals↗
PubMed1999

Future priorities for a successful dental school.

Priorities for success for a dental school of the future are considered. University relations, demographic changes, digital information technology and functional genetic technology are emphasised as important environmental pressures that will influence the priorities. The goal advocated for university relations is creating a culture in which the dental school is viewed as integral and necessary to the University's mission. Financial stability, quality research and scholarship and provision of health care for employees may be important ingredients. Keeping an eye on demographic changes and taking the school's business where the customers are is another key to success in the future. Ethnic diversity, changing approaches with changing disease patterns, flexibility in schedule and collaborations in areas of need are strategies to be considered. The emerging field of functional genetics typifies a new biology with which currency will be needed in a health-sciences field. Necessity for faculty development, adoption of molecular diagnostic technologies, emphasis on risk assessment and preventive counselling, and a shift to a wellness model are likely consequences. Digital information technology will result in increased distance-learning opportunity. Dental schools will also need to make accommodating changes in curriculum structure available. Conversion to electronic imaging and totally electronic patient records are likely to become standard.

Curriculum↗
PubMed2007

Functional and genetic analysis of the Saccharomyces cerevisiae RNC1/TRM2: evidences for its involvement in DNA double-strand break repair.

We previously isolated the RNC1/TRM2 gene and provided evidence that it encodes a protein with a possible role in DNA double strand break repair. RNC1 was independently re-isolated as the TRM2 gene encoding a methyl transferase involved in tRNA maturation. Here we show that Trm2p purified as a fusion protein displayed 5' --> 3' exonuclease activity on double-strand (ds) DNA, and endonuclease activity on single-strand (ss) DNA, properties characteristic of previously isolated endo-exonucleases. A variant of Trm2p, Trm2p(ctDelta76aa) lacking 76 amino acids at the C-terminus retained nuclease activities but not the methyl transferase activity. Both the native and the variant exhibited sensitivity to the endo-exonuclease inhibitor pentamidine. The Saccharomyces cerevisiae trm2(Delta232-1920nt) mutant (containing only the first 231 nucleotides of the TRM2 gene) displayed low sensitivity to methyl methane sulfonate (MMS) and suppressed the MMS sensitivity of rad52 mutants in trm2(Delta232-1920nt)rad52 double mutants. The deletion of KU80, in trm2(Delta232-1920nt) mutant background displayed higher MMS sensitivity supporting the view of the possible role of Trm2p in a competing repair pathway separate from NHEJ. In addition, trm2 exo1 double mutants were synergistically more sensitive to MMS and ionizing radiation than either of the single mutant suggesting that TRM2 and EXO1 can functionally complement each other. However, the C-terminal portion, required for its methyl transferase activity was found not important for DNA repair. These results propose an important role for TRM2 in DNA repair with a potential involvement of its nuclease function in homologous recombination based repair of DNA DSBs.

Antigens, Nuclear↗
PubMed2004

Chronic treatment with fluvastatin improves smooth muscle dilatory function in genetically determined hyperlipoproteinemia.

We hypothesized that the HMG-CoA reductase inhibitor fluvastatin, does not only improve endothelium-dependent vasorelaxation, but that it also increases vascular smooth muscle reactivity in hyperlipoproteinemia. New Zealand White (NZW) rabbits aged 37 weeks (control), Watanabe Heritable Hyperlipidemic rabbits (WHHL) aged 37 weeks, and WHHL aged 35 weeks with fluvastatin treatment of 17 weeks (10 mg/kg/d) were examined. Aortas were isolated for isometric tension recording. Both endothelium-dependent and independent relaxation were impaired in WHHL. Fluvastatin significantly restored impaired endothelium-independent relaxation (WHHL: 57 +/- 12 versus WHHL+ fluvastatin: 150 +/- 22%; P < 0.05) and in tendency endothelium-dependent relaxation (WHHL: 26 +/- 5 versus WHHL+ fluvastatin: 83 +/- 29%; (P = 0.07)). In parallel, fluvastatin restored nitrite plasma level in hyperlipoproteinemic animals (WHHL: 480 (13-3821) versus WHHL+ fluvastatin: 808 (467-1595) nmol; P < 0.05). Thus, chronic treatment with fluvastatin not only improves endothelial but also vascular smooth muscle function in hyperlipoproteinemia, which may contribute to the beneficial clinical effects of statins.

Animals↗
PubMed2004

Genetic and functional characterization of a Bacillus sp. strain excreting surfactin and antifungal metabolites partially identified as iturin-like compounds.

AIMS: A bacterial strain producing antifungal compounds active against the plant pathogenic fungi Fusarium, Rhizoctonia and Sclerotinia has been characterized and shown to control Rhizoctonia root rot of soya bean. METHODS AND RESULTS: The metabolites excreted by Bacillus BNM 122 remained active after autoclaving, were resistant over a wide pH range and to hydrolytic enzymes. By (1)H-NMR and thin-layer chromatography analyses surfactin and iturin-like compounds were partially identified. Moreover, soya bean seeds bacterization with BNM 122 in a compost-based formulation was as effective controlling Rhizoctonia solani as pentachloronitrobenzene. According to its 16S rDNA sequence BNM 122 was closely related to Bacillus amyloliquefaciens and Bacillus subtilis. PCR analysis of the 16S-23S rRNA intergenic spacer region and repetitive sequence-based PCR (rep-PCR) genomic fingerprinting revealed a close genetic relationship to B. amyloliquefaciens. However, by physiological characterization using API tests, this strain resembled more B. subtilis. CONCLUSIONS: This is the first report describing the co-production of surfactin and iturin-like compounds by a putative strain of B. amyloliquefaciens. The synergistic effect of both lipopetides is a remarkable trait for a candidate biocontrol agent. SIGNIFICANCE AND IMPACT OF THE STUDY: This kind of research has relevance in order to minimize the use of synthetic fungicides and surfactants, contributing to the preservation of the environment.

Ascomycota↗
PubMed2005

Genetic and functional characterization of human pemphigus vulgaris monoclonal autoantibodies isolated by phage display.

Pemphigus is a life-threatening blistering disorder of the skin and mucous membranes caused by pathogenic autoantibodies to desmosomal adhesion proteins desmoglein 3 (Dsg3) and Dsg1. Mechanisms of antibody pathogenicity are difficult to characterize using polyclonal patient sera. Using antibody phage display, we have isolated repertoires of human anti-Dsg mAbs as single-chain variable-region fragments (scFvs) from a patient with active mucocutaneous pemphigus vulgaris. ScFv mAbs demonstrated binding to Dsg3 or Dsg1 alone, or both Dsg3 and Dsg1. Inhibition ELISA showed that the epitopes defined by these scFvs are blocked by autoantibodies from multiple pemphigus patients. Injection of scFvs into neonatal mice identified 2 pathogenic scFvs that caused blisters histologically similar to those observed in pemphigus patients. Similarly, these 2 scFvs, but not others, induced cell sheet dissociation of cultured human keratinocytes, indicating that both pathogenic and nonpathogenic antibodies were isolated. Genetic analysis of these mAbs showed restricted patterns of heavy and light chain gene usage, which were distinct for scFvs with different desmoglein-binding specificities. Detailed characterization of these pemphigus mAbs should lead to a better understanding of the immunopathogenesis of disease and to more specifically targeted therapeutic approaches.

Amino Acid Sequence↗
PubMedDate not supplied

Experimental evolution and the Krogh principle: generating biological novelty for functional and genetic analyses.

August Krogh counseled the careful selection of the best subject organism on which to undertake mechanistic physiological research. But what if an organism with the desired properties does not exist? It is now within our power to engineer organisms genetically to achieve novel combinations of traits. I propose that it is a logical extension of the Krogh principle that we use biological methodologies to create novel organisms ideally suited for particular physiological studies. Transgenics may first come to mind as the method for such transformations, but here I suggest that an alternative and complementary technique for generating biological novelty is experimental evolution. The latter has several advantages, including modification of multiple characters in one experiment, the production of advantageous traits, the testing of evolutionary hypotheses, and the identification of previously unsuspected factors involved in adaptation. Three experiments are reviewed, each of which examined the evolution of different physiological characters in different environments and organisms: locomotor performance in mice, desiccation tolerance in fruit flies, and high temperature adaptation in bacteria. While diverse in experimental type and subject, all resulted in the successful production of new variants with enhanced function in their new environments. Each experiment successfully tested hypotheses concerning physiological evolution, and in each case, unanticipated results emerged, which suggests previously unsuspected adaptive pathways and mechanisms. In addition, replicate populations in each experiment adjusted to their common environments by several different means, which indicates that physiological evolution may follow diverse stochastic pathways during adaptation. Experimental evolution can be a valuable method to produce and investigate new physiological variants and traits. The choice of experimental subjects, according to the Krogh principle, is no longer limited to currently existing organisms but is open to our imaginations and our ingenuity.

Adaptation, Physiological↗
PubMed1996

Functional and genetic characterization of the oligomerization and DNA binding properties of the Drosophila doublesex proteins.

The doublesex (dsx) gene of Drosophila melanogaster encodes both male-specific (DSXM) and female-specific (DSXF) polypeptides, which are required for normal differentiation of numerous sexually dimorphic somatic traits. The DSX polypeptides are transcription factors and have been shown previously to bind through a zinc finger-like domain to specific sites in an enhancer regulating sex-specific expression of yolk protein genes. We have determined the consensus target sequence for this DNA binding domain to be a palindromic sequence AGNNACTAAATGTNNTC composed of two half-sites around a central (A/T) base pair. As predicted by the symmetric nature of this site, we have found that the DSX proteins exist as dimers in vivo and have mapped two independent dimerization domains by the yeast two-hybrid method; one in the non-sex-specific amino-terminal region of the protein and one that includes the partially sex-specific carboxy-terminal domains of both the male and female polypeptides. We have further identified a missense mutation that eliminates dsx function in female flies, and shown that the same mutation prevents dimerization of DSXF in the yeast two-hybrid system, indicating a critical role for dimerization in dsx function in vivo.

Animals↗
PubMed1985

Genetical and functional organisation of the Escherichia coli haemolysin determinant 2001.

We have identified gene products corresponding to hlyC, hlyA and hlyD encoded by the Escherichia coli haemolytic determinant 2001 of human origin cloned into the recombinant plasmid pLG570. The product of hlyC is required for the "activation" of the inactive 107K polypeptide encoded by the hlyA gene. The activated 107K protein constitutes the active haemolysin secreted into the medium. hlyB and hlyD are separate regions defined by complementation studies and encode functions essential for the export of haemolysin with hlyD encoding a 53K protein. Complementation studies using subclones and Tn5 insertions into pLG570 have revealed the presence of two major promoters upstream of hlyC and hlyD which transcribe the four hly genes in the same direction. Finally, we were able to reconstitute the complete haemolysin system from three different plasmids encoding hlyC, hlyA and hlyB + hlyD, respectively.

Cloning, Molecular↗
PubMed2004

Benign summer light eruption and polymorphic light eruption: genetic and functional studies suggest that a revised nomenclature is required.

New research indicates that polymorphic light eruption (PLE) is an autoimmune disease against an ultraviolet radiation-induced cutaneous antigen. PLE may even confer some protection against skin cancer later in life. This new information demands a reassessment of the precise nature and nomenclature of PLE. Benign summer light eruption (BSLE) (lucite estivale bénigne) is the name used in continental Europe, and particularly France, to describe a clinically short-lived, itchy, papular eruption particularly affecting young women after several hours of sunbathing at the beginning of summer or on sunny vacations. Clinically more prolonged forms of solar eruption, starting early in spring and persisting for long periods, have been known in France as polymorphic light eruption (PLE) (lucite polymorphe) ('European PLE'). Investigative studies, however, now suggest that BSLE and some cases of 'European PLE' are part of the same spectrum. In the Anglo-Saxon literature, they are lumped together as PLE ('Anglo-Saxon PLE'). The other cases of 'European PLE', which do not fall within the compass of 'Anglo-Saxon PLE', are, in the Anglo-Saxon literature, classified as either actinic prurigo (AP) (a genetically determined, prolonged, excoriated form of Anglo-Saxon PLE), or chronic actinic dermatitis (CAD) (a sunlight-induced eczema precisely resembling allergic contact dermatitis, apparently to an ultraviolet radiation-induced antigen). It is therefore proposed that: i. the European term BSLE be dropped and that these patients be reclassified within the spectrum of (Anglo-Saxon) PLE, ii. the European use of the term PLE ('European PLE') be discontinued, iii. those previously diagnosed as having 'European PLE' be reclassified as (Anglo-Saxon) PLE, AP or CAD, as appropriate. The benefits of such a change in nomenclature would be twofold, firstly a uniformity of terminology and secondly, and more importantly, terminology would then correlate better with our recently improved understanding of the pathogenesis of these disorders.

Journal Article↗
PubMed1979

[Hemoglobins, XXVIII. Phosphate-protein-interaction, gene expression and function: the genetic and allosteric control of the oxygen affinity of the fetal blood (author's transl)].

This work describes possible molecular mechanisms concerning the control of oxygen affinity in fetal blood of mammalia. There is a genetic control of oxygen affinity through a fetal gene: at constant phosphate concentration (Hb less than P2-glycerate) in humans there is a hemoglobin with only five binding sites to 2,3-bisphosphoglycerate, resulting in an increased oxygen affinity. In several species (sheep, cattle, goat) with Met-Leu as the N-terminal group of the beta-chains, the 2,3-bisphosphoglycerate binding sites are deleted in positions beta 1 and beta 2, so that the regulation is phosphate-independent and thus providing a fetal hemoglobin with an increased oxygen affinity. The allosteric control is observed in pigs. In the postembryonal development "adult" hemoglobin with seven contacts (beta-chains) is demonstrated. The increased oxygen affinity is achieved here by a reduced biosynthesis of 2,3-bisphosphoglycerate (Hb greater than P2-glycerate) (Rapoport-Luebering-cycle). The functional control is discussed with respect to the ontogeny of the hemoglobins.

Allosteric Regulation↗
PubMed1993

[The association of genetic and functional variability of alpha 1-antitrypsin in asbestosis].

The polymorphism and serum levels of alpha 1-antitrypsin (AT) were studied in asbestosis patients, the control and the workers exposed to mineral flax longer or less than ten years. M1S, M3S, M1Z and M2M2 phenotypes had low concentration of this protein. In the course of contact with mineral flax decrease in alpha 1-AT concentration was found. The phenotypes with low protein levels were very rare among workers contacting with asbestos for a long time, and one of them--M1S was more often encountered in asbestosis patients. The standard deviation from the alpha 1-AT concentration was significantly higher in asbestosis patients.

Asbestosis↗
PubMed1994

Abnormal A1 adenosine receptor function in genetic obesity.

Obesity is increasingly recognized as an important health problem in developed, industrialized countries. As a large proportion of the variance in individual adiposity is based on genetic factors (1-3), recent efforts have focused on identifying genes involved in regulating the percentage of body fat in a given individual. This effort is helped by the existence of rodent models of genetic obesity. Many strains of mice and at least three rat strains have been identified thus far that exhibit inherited obesity accompanied by a similar set of endocrine abnormalities (4). Although the symptoms of the disease are similar in different strains, different genes appear to be involved in causing the syndrome, as the mutation responsible for the obesity maps to different chromosomal sites in the different strains. Efforts to find the products of the mutated genes over the past 30 years have generally been unsuccessful. However, the available data imply that many obesity mutations may involve genes that code for proteins in a single signal transduction pathway or one particular cascade of covalent modification. Reasonable theories are plentiful about the identity of such a pathway, but current studies in the laboratories of the authors suggest that the A1 adenosine receptor signaling pathway may be involved. Evidence of abnormal A1 receptor function has been obtained from studies of Zucker rats and obese (ob/ob) mice (5-7). These strains are obese because of a single recessive mutation. Measurements of adenylyl cyclase activity and regulation in isolated adipocytes and isolated plasma membranes suggest that the receptor is unusually and tonically active in obese rats. Because signaling from this receptor inhibits lipolysis in white and brown fat, induces insulin resistance in skeletal muscle (8, 9), but increases insulin sensitivity in adipose tissue (10, 11), the possibility arises that the excessive activity of the A1 adenosine receptor may induce obesity. Data from human volunteers are also compatible with the possibility that the activity of the receptor is unusually high in vivo in obese individuals (12).

Adenylyl Cyclases↗
PubMed1994

The genetic and functional basis of HIV-1 resistance to nonnucleoside reverse transcriptase inhibitors.

The nonnucleoside reverse transcriptase (RT) inhibitors are structurally diverse compounds that are specific inhibitors of the human immunodeficiency virus type 1 RT enzyme. The compounds are largely functionally identical and bind to a common site in the enzyme. HIV-1 variants that exhibit reduced susceptibility to these inhibitors have been derived in cell culture and, more recently, from HIV-1-infected patients undergoing experimental therapy. The variants express amino acid substitutions at RT positions that apparently interact directly with the inhibitors. Effects of specific substitutions at these positions vary among the compounds, suggesting subtle differences in how the compounds physically interact with the enzyme.

Antiviral Agents↗
PubMed2004

A large-scale RNAi screen in human cells identifies new components of the p53 pathway.

RNA interference (RNAi) is a powerful new tool with which to perform loss-of-function genetic screens in lower organisms and can greatly facilitate the identification of components of cellular signalling pathways. In mammalian cells, such screens have been hampered by a lack of suitable tools that can be used on a large scale. We and others have recently developed expression vectors to direct the synthesis of short hairpin RNAs (shRNAs) that act as short interfering RNA (siRNA)-like molecules to stably suppress gene expression. Here we report the construction of a set of retroviral vectors encoding 23,742 distinct shRNAs, which target 7,914 different human genes for suppression. We use this RNAi library in human cells to identify one known and five new modulators of p53-dependent proliferation arrest. Suppression of these genes confers resistance to both p53-dependent and p19ARF-dependent proliferation arrest, and abolishes a DNA-damage-induced G1 cell-cycle arrest. Furthermore, we describe siRNA bar-code screens to rapidly identify individual siRNA vectors associated with a specific phenotype. These new tools will greatly facilitate large-scale loss-of-function genetic screens in mammalian cells.

Cell Division↗
PubMed2002

Population genetics and functions of the autoimmune regulator (AIRE).

The autoimmune polyglandular syndrome type 1 (APS1), also known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APS1), is a monogenic autosomal disease with recessive inheritance. It is characterized by chronic mucocutaneous candidiasis, multiple autoimmune endocrinopathies, and ectodermal dystrophies. The defective gene responsible for this disease has been identified and named "autoimmune regulator" (AIRE). The AIRE gene is located on chromosome 21q22.3. At least 45 different disease-causing mutations in AIRE have been discovered. This review summarizes the global distribution of AIRE mutations and the relevance of major mutations to the clinical disorders associated with APS1. We also will review studies on the structure and DNA-binding ability of the AIRE protein and the possible malfunctions of the AIRE protein as a result of major disease-causing mutations.

Binding Sites↗