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At least 667 records · Page 37Linked to original sources
PubMed2004

Improved analysis of the vascular response to arterial ligation using a multivariate approach.

Ligation of the murine common carotid artery induces a reproducible remodeling response. The contribution of individual genes can be determined by comparison of the phenotypes of genetically modified mice. Although studies have shown the response to carotid artery ligation is influenced by many factors, individual analyses typically only consider a single factor, the presence of a gene of interest. Because of this limitation, measurements of the response to ligation show large variation, making the determination of significant difference between test groups difficult. In this study, we examine the hypothesis that the variation in the response to ligation is due to non-genetic factors in addition to genetic factors. Distance from the ligature, a variable common to all arterial ligation experiments, is an important source of variation and a significant predictor of the remodeling response. We find that the use of statistical regression is an improved analysis technique, as it allows the simultaneous consideration of multiple variables. We demonstrate this by showing improved sensitivity and novel findings in the analysis of the remodeling response in mice genetically mutant for the osteopontin gene. We conclude regression analysis provides a simple way to improve both comparative power and description of vascular remodeling.

Animals↗
PubMed1998

Genetic polymorphisms in carcinogen metabolism and their association to hereditary nonpolyposis colon cancer.

BACKGROUND & AIMS: The phenotype of hereditary nonpolyposis colorectal cancer shows interfamilial and intrafamilial variation even in the presence of identical predisposing mutations, suggesting the existence of additional phenotype determinants. The modifying role of genetic polymorphisms in loci involved in carcinogen metabolism was studied. METHODS: We focused on colon cancers from kindreds sharing one of two predisposing mutations (mutation 1 or 2) in the mismatch repair gene MLH1 (78 and 14 tumors, respectively). Polymorphisms in N-acetyltransferase 1 (NAT1) and glutathione S-transferase (GST) M1 and GSTT1 were investigated. RESULTS: The NAT1 allele 10 was associated with lower median age at diagnosis in both groups. In mutation 1 group, the NAT1 allele 10 was a risk factor for distal tumor location, both alone (P = 0.028) and combined with the GSTT1-positive genotype (P = 0.008). On the other hand, the combined null genotype of GSTM1 and GSTT1 was associated with proximal tumors. Associations with tumor location were not observed in patients with mutation 2, probably reflecting a small sample size. CONCLUSIONS: The results suggest that genetic polymorphisms in carcinogen metabolism modify the age of onset and tumor location in individuals with inherited deficiency of DNA mismatch repair.

Adult↗
PubMed1999

Cloning of the hereditary hemochromatosis gene: implications for pathogenesis, diagnosis, and screening.

Hereditary hemochromatosis (HH) is one of the most common genetic disorders affecting populations of European ancestry. It is characterized by an inappropriately high iron absorption that leads to iron overload preferentially in the parenchymal organs. Although the severity of the phenotype can be modified by a number of factors, it is clear that most homozygotes will eventually become symptomatic. Clinical manifestations are often nonspecific and easily overlooked. Untreated HH can be associated with substantial morbidity and mortality. Diagnosis in the pre-cirrhotic stage, however, results in normal life expectancy. Early diagnosis and the initiation of phlebotomy therapy are therefore keys to preventing complications related to iron overload. The recent isolation of a strong candidate gene for hemochromatosis has the potential to allow for genetic diagnosis and screening in the near future. This exciting finding is likely not only to change clinical practice but also to yield new insights into the poorly understood pathophysiology of the disease.

Cloning, Molecular↗
PubMed1999

Rational design of live-attenuated recombinant vaccine virus for human respiratory syncytial virus by reverse genetics.

RSV is a major cause of pediatric respiratory tract disease worldwide, but a vaccine is not yet available. It is now possible to prepare live infectious RSV completely from cDNA. This provides a method for introducing defined mutations into infectious virus, making possible the rational design of a live-attenuated vaccine virus for intranasal administration. This is particularly important for RSV, for which achieving the appropriate balance between attenuation and immunogenicity by conventional methods has proven elusive. We took advantage of the existence of a panel of biologically derived vaccine candidate viruses that were incompletely attenuated but well characterized biologically. The mutations in these viruses were identified by sequence analysis and characterized by insertion into recombinant virus, thereby providing a menu of known attenuating mutations. These included a series of amino acid point mutations, mostly in the L polymerase, and a nucleotide substitution in a transcription gene-start signal, a cis-acting RNA element. The second source of mutations was from experimental mutational analysis of recombinant virus and involves deletion of the NS1, NS2, or SH gene. We have reconstructed a previously tested, biologically derived attenuated virus, cpts248/404, in recombinant form and are now proceeding to introduce additional mutations from the menu to achieve stepwise increases in attenuation. The ability to modify the attenuation phenotype incrementally in a directed manner should result in an appropriate vaccine virus.

DNA, Complementary↗
PubMed1996

Evidence that lysosomal storage of proteolipids is a cell autonomous process in the motor neuron degeneration (mnd) mouse, a model of neuronal ceroid lipofuscinosis.

The motor neuron degeneration (mnd) mouse has been documented to accumulate proteolipid and thus is a model of neuronal ceroid lipofuscinosis [Dunn, W.A., Raizada, M.K., Vogt, E.S. and Brown, E.A., Int. J. Dev. Neurosci., 12 (1994) 185-196; Faust, J.R., Rodman, J.S., Daniel, P.F., Dice, J.F. and Bronson, R.T., J. Biol. Chem., 269 (1994) 10150-10155]. While accumulation of proteolipid in the hippocampus of chimeric mice composed of mnd and +/+ cells was found to be proportional to the contribution of mnd in the brain, accumulation within individual cells was the same for cells from chimeric and age-matched mnd mice. Bone marrow transplantation was used to altering the milieu of circulating factors to determine whether this might modify the disease phenotype in mnd mice. Transplantation of bone marrow in neonatal or young mice did not reduce the age-associated accumulation of proteolipid within hippocampal neurons. The results of these experiments indicate that mnd results in a cell autonomous defect.

Aging↗
PubMed2000

Cell behaviour of Drosophila fat cadherin mutations in wing development.

We have studied several cell behaviour parameters of mutant alleles of fat (ft) in Drosophila imaginal wing disc development. Mutant imaginal discs continue growing in larvae delayed in pupariation and can reach sizes of several times those of wild-type. Their growth is, however, basically allometric. Homozygous ft cells grow faster than their twin cells in clones and generate larger territories, albeit delimited by normal clonal restrictions. Moreover, ft cells in clones tend to grow towards wing proximal regions. These behaviours can be related with failures in cell adhesiveness and cell recognition. Double mutant combinations with alleles of other genes, e.g. of the Epidermal growth factor receptor (DER) pathway, modify ft clonal phenotypes, indicating that adhesiveness is modulated by intercellular signalling. Mutant ft cells show, in addition, smaller cell sizes during proliferation and abnormal cuticular differentiation, which reflect cell membrane and cytoskeleton anomalies, which are not modulated by the DER pathway.

Alleles↗
PubMed2002

Wing vein formation in Drosophila melanogaster: hairless is involved in the cross-talk between Notch and EGF signaling pathways.

Wing vein development in Drosophila is controlled by different morphogenetic pathways, including Notch. Hairless (H) antagonizes Notch target gene activation by binding to the Notch signal transducer Suppressor of Hairless [Su(H)]. Accordingly, overexpression of H phenocopies reduction of Notch activity. Deletion of the Su(H)-binding domain in H-C2 results in loss of H activity. However, overexpression of H-C2 induces formation of ectopic veins. In a screen for genetic modifiers of this phenotype, we have identified several genes involved in Notch and epidermal growth factor (EGF) signaling. Most notably veinlet, an activator of EGF signaling, acts downstream of H-C2. H-C2 positively regulates veinlet maybe through inhibition of inter-vein determinants in agreement with a model, whereby Notch and EGF signaling pathways cross-regulate vein pre-patterning.

Animals↗
PubMed1999

Evolution of Wolbachia pipientis transmission dynamics in insects.

Wolbachia pipientis is an intracellular bacterial parasite of arthropods that enhances its transmission by manipulating host reproduction, most commonly by inducing cytoplasmic incompatibility. The discovery of isolates with modified cytoplasmic incompatibility phenotypes and others with novel virulence properties is an indication of the potential breadth of evolutionary strategies employed by Wolbachia.

Animals↗
PubMed1998

A rational strategy for enhancing the affinity of vancomycin towards depsipeptide ligands.

Glycopeptide antibiotics with enhanced affinity for model depsipeptide ligands may also exhibit enhanced efficacy against bacteria exhibiting the vanA resistance phenotype. To design modified agents with enhanced affinity for these ligands, and better understand why traditional agents have low affinity for depsipeptide ligands, free energy perturbation studies were performed on vancomycin derivatives by means of molecular dynamics simulation. The results suggest that modifications of the asparagine side chain on residue 3 of the antibiotic which enhance its hydrophobicity will enhance the affinity of glycopeptide antibiotics for depsipeptide ligands, and act synergistically with other modifications that enhance the efficacy of these agents against vanA-positive bacteria.

Alanine↗
PubMed2003

Analysis of two additional loci in Neurospora crassa related to Spore killer-2.

Two new loci found in one strain of Neurospora crassa (P2604) collected in Malaya are related to the meiotic drive system Spore killer Sk-2. Sk-2 was found in Neurospora intermedia and introgressed into N. crassa. P2604 showed high resistance to killing when crossed to Sk-2. This resistance was found to be linked to, but not allelic to, resistance locus r(Sk-2) on LGIIIL. Analysis showed that the high resistance phenotype of P2604 requires resistance alleles at two different loci on LGIIIR. Strains carrying a resistance allele at only the proximal or the distal locus, respectively, were obtained and intercrossed. Highly resistant strains were obtained by rejoining the two genes. The proximal locus alone confers a low level of resistance. This locus was named pr(Sk-2) for partial resistance to Sk-2. The distal locus was named mod(pr) because its only known phenotype is to modify pr(Sk-2).

Alleles↗
PubMed2002

Exon-specific RNAi: a tool for dissecting the functional relevance of alternative splicing.

The goal of functional genomics is to determine the function of each protein encoded by an organism. Typically, this is done by inactivating individual genes and, subsequently, analyzing the phenotype of the modified organisms. In higher eukaryotes, where a tremendous amount of alternative splicing occurs, such approaches are not feasible because they have the potential to simultaneously affect multiple proteins that could have quite distinct and important functions. Thus, it is necessary to develop techniques that inactivate only a subset of proteins synthesized from genes encoding alternatively spliced mRNAs. Here we demonstrate that RNA interference (RNAi) can be used to selectively degrade specific alternatively spliced mRNA isoforms in cultured Drosophila cells. This is achieved by treating the cells with double-stranded RNA corresponding to an alternatively spliced exon. This technique may prove to be a powerful tool to assess the function of proteins synthesized from alternatively spliced mRNAs. In addition, these results have implications regarding the mechanism of RNAi in Drosophila.

Alternative Splicing↗
PubMed1996

Site-directed mutagenesis of the CP 47 protein of photosystem II: alteration of conserved charged residues in the domain 364E-444R.

The intrinsic chlorophyll-protein CP 47 is a component of photosystem II in higher plants, green algae and cyanobacteria. We had shown previously by biochemical methods that the domain 364E-440D of CP 47 interacts with the 33 kDa extrinsic protein of photosystem II [Odom, W. R., & Bricker, T. M. (1992) Biochemistry 31, 5616-5620]. In this study, using oligonucleotide-directed mutagenesis in the cyanobacterium Synechocystis 6803, mutations at 17 conserved charged residues were introduced into the domain 364E-444R of the CP 47 protein. Only mutations introduced at positions 384R and 385R led to a modified PS II phenotype. We previously described a mutation at (RR384385GG) which resulted in a mutant with a defective oxygen-evolving complex [Putnam-Evans, C., & Bricker, T. M. (1992) Biochemistry 31, 11482-11488]. An additional set of mutations, 384R to 384G, 385R to 385G, and 384,385RR to 384,385EE has now been introduced at this site yielding the mutants R384G, R385G, and RR384385EE, respectively. Steady state oxygen evolution measurements and quantum yield measurements demonstrated that these mutants exhibited significant alterations in their ability to evolve oxygen. Total fluorescence yield measurements indicated that all of these mutants contained about 85%-90% of the PS II reaction centers found in the control strain. This decrease was insufficient to explain the oxygen evolution results. Analysis of oxygen flash yield parameters indicated that there was little change in the S-state parameters alpha, beta, gamma, or delta. Measurement of the S2 lifetime, however, demonstrated that the S2 lifetime of the mutants was 2-3 times longer than that of the control. Additionally, examination of the risetime of the oxygen signal indicated that there was a significant retardation (6-7-fold) in the rate of oxygen release, suggesting a retarded S3-[S4]-S0 transition. These data reinforce our hypothesis that the positive charge density at positions 384R and 385R in the large extrinsic loop of CP 47 is necessary for its function in water oxidation. We speculate that this positive charge density may be an important factor in establishing the proper interaction between CP 47 and the 33kDa extrinsic protein.

Amino Acid Sequence↗
PubMed2002

Genetics and genomics of asthma and allergic diseases.

Asthma and eczema (atopic dermatitis) are characterized by a number of unexplained phenomena: the familial aggregation of disease, the initiation of disease by apparently trivial exposure to allergens, the preferential transmission of disease from affected mothers and the large increase in prevalence of disease in Westernized societies in the last century. A number of genes and chromosomal regions have been identified that consistently show linkage to asthma and its related phenotypes. Known loci modify the strength of the atopic response, nonspecific inflammation, the ability to respond to particular allergens and nonspecific airway reactivity. Eczema has been shown to be due to a different set of genetic loci that are shared with other skin diseases such as psoriasis and leprosy. Genetic and genomic studies both provide evidence that epithelial surfaces are active in the induction of allergic disease.

Allergens↗
PubMed2001

Adenoviral delivery of TIMP1 or TIMP2 can modify the invasive behavior of pancreatic cancer and can have a significant antitumor effect in vivo.

Pancreatic carcinomas overexpress several matrix metalloproteinases (MMPs), in particular MMP2 and MMP9. These enzymes are involved in the degradation of the extracellular matrix to aid tumor cell invasion. The aim of this study was to investigate the effect of TIMP gene therapy on human pancreatic cancer. Human TIMP1 or TIMP2 has been introduced in pancreatic tumor cells under the control of a constitutive promoter using adenoviral vectors, and the effect on tumor invasion observed. It has been demonstrated in vitro that the TIMP-expressing pancreatic tumor cells were significantly less invasive than those cells transfected with a control vector. In vivo, adenoviral delivery of TIMP1 or TIMP2 to nude mice harboring intraperitoneal human pancreatic cancers resulted in prolonged survival compared with control mice if the gene therapy was given early (P<.009 and P<.0293, respectively). The in vivo experiments demonstrated evidence of gene transfer by adenoviral vectors to tumor cells and murine mesenteric cells. There was no evidence of transgene expression in distant organs. These experiments have proved the hypothesis that TIMP overexpression in pancreatic cancer cells can modify the invasive phenotype. Also, TIMP gene transfer to human tumor cells is possible both in vitro and in vivo.

Adenoviridae↗
PubMed2002

Association between baseline levels of C-reactive protein (CRP) and a dinucleotide repeat polymorphism in the intron of the CRP gene.

Elevation of baseline C-reactive protein (CRP) is associated with increased risk of cardiac disease. This increase might reflect low-grade inflammation, but differences in CRP serum levels might also have a genetic component. To test this possibility, we investigated whether a polymorphic GT-repeat in the intron of the CRP gene contributes to variation in baseline CRP. We found that the polymorphism was associated with differences in baseline CRP in both normal individuals and in patients with the inflammatory disease systemic lupus erythematosus, viz. donors carrying two GT(16) alleles, two GT(21)alleles, or GT(16/21) heterozygotes had two-fold lower serum CRP than those with other genotypes. The frequency of GT(16) and GT(21) was two-fold higher in Caucasians than in African-Americans, but there was no difference in allele distribution between patients and controls. It is not yet known how this genetic polymorphism mediates its effect on CRP expression, and it probably is not a systemic lupus erythematosus susceptibility factor. Rather, the CRP intron polymorphism likely modifies the disease phenotype. On the other hand, the fact that baseline CRP does have a genetic component suggests that in coronary disease, stratification of risk assessment based on CRP levels might be enhanced by consideration of this polymorphism.

Adult↗
PubMed2002

Prevalence of endothelial nitric oxide synthase gene polymorphisms in patients with atopic asthma.

BACKGROUND: Asthma is a common multifactorial disease, the aetiology of which is attributable to both environmental and genetic factors. The endothelial nitric oxide synthase (NOS3) gene has been implicated in asthma pathogenesis. OBJECTIVE: This study investigated associations of 27 base-pair tandem repeat polymorphism in intron 4 and the Glu298Asp (G894T) variant of the NOS3 gene with atopic asthma in a Czech population. METHODS: Polymerase chain reaction was used to determine the NOS3 genotypes in subjects with atopic asthma (n = 163) and random controls (n = 209). RESULTS: The NOS3 allele or genotype distributions did not differ significantly between the control and asthma groups. However, the common genotype (bb) of the NOS3 polymorphism in intron 4 was found to be significantly associated with total IgE levels (P = 0.006), specific IgE levels for feathers (P = 0.0002) and a positive skin prick test for hay (P = 0.004). In one atopic patient, we identified an additional 27-bp repeat in the NOS3 gene (NOS3c), which occurred in heterozygous combination with the NOS3b allele (NOS3b/c genotype). In addition, we describe a new polymorphism (A5495G) in the NOS3 gene, which was in almost complete linkage disequilibrium with the NOS3 repeat polymorphism in intron 4. The Glu298Asp variant was not associated with asthma and/or related atopic phenotypes in our study. CONCLUSION: Neither the NOS3 'b' allele nor the NOS3 'b/b' genotype showed any general association with atopic asthma, but they were associated with atopy-related phenotypes. We conclude that the NOS3 gene polymorphisms may act as disease modifiers in atopic asthma phenotype in our population.

Adolescent↗
PubMed1996

The TraB protein, which mediates the intermycelial transfer of the Streptomyces plasmid pSN22, has functional NTP-binding motifs and is localized to the cytoplasmic membrane.

The traB gene on the Streptomyces conjugative plasmid pSN22 is required for intermycelial plasmid transfer and the mobilization of chromosomal markers (Cma). The predicted amino acid sequence of TraB contains one Walker type-A and two type-B NTP-binding motifs. Site-directed mutagenesis revealed that the type-A motif and one of the type-B motifs, 109 amino acid residues downstream of the type-A motif, were essential for both plasmid transfer and Cma. The second type-B sequence could be changed without any phenotypic effect. A modified traB gene was constructed, resulting in the production of a functional protein with an amino-terminal c-Myc epitope tag for immunological analysis. This protein was associated with the cytoplasmic membrane, suggesting that TraB is a membrane protein that uses energy from ATP hydrolysis to transport DNA between mycelia. The c-Myc tagging of TraB decreased the efficiency of intramycelial plasmid spread, suggesting that TraB is involved in both inter- and intramycelial transfer processes.

Amino Acid Sequence↗