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At least 235 records · Page 13Linked to original sources
PubMed1981

[A simple method for detection of functional and genetics alpha-1-antitrypsin deficiencies of human serum (author's transl)].

Insoluble elastin immobilised in Agar plates was used as substrate to quantitate the elastase inhibitory capacity of human sera. This technique was found valuable to evaluate the genetic deficiency of alpha-1-antitrypsin (Z phenotypes) and also the functional loss of the elastase inhibitory capacity in smokers. A significant decrease of elastase inhibitory capacity was demonstrated in the sera of smokers between 40 and 80 years of age, as compared to non smokers of the same age. This method may be useful for the evaluation of patients suffering from elastic tissue diseases (emphysema, arteriosclerosis).

Elastin↗
PubMed2000

Yeast Eap1p, an eIF4E-associated protein, has a separate function involving genetic stability.

A rate-limiting step during translation initiation in eukaryotic cells involves binding of the initiation factor eIF4E to the 7-methylguanosine-containing cap of mRNAs. Overexpression of eIF4E leads to malignant transformation [1-3], and eIF4E is elevated in many human cancers [4-7]. In mammalian cells, three eIF4E-binding proteins each interact with eIF4E and inhibit its function [8-10]. In yeast, EAP1 encodes a protein that binds eIF4E and inhibits cap-dependent translation in vitro [11]. A point mutation in the canonical eIF4E-binding motif of Eap1p blocks its interaction with eIF4E [11]. Here, we characterized the genetic interactions between EAP1 and NDC1, a gene whose function is required for duplication of the spindle pole body (SPB) [12], the centrosome-equivalent organelle in yeast that functions as the centrosome. We found that the deletion of EAP1 is lethal when combined with the ndc1-1 mutation. Mutations in NDC1 or altered NDC1 gene dosage lead to genetic instability [13,14]. Yeast strains lacking EAP1 also exhibit genetic instability. We tested whether these phenotypes are due to loss of EAP1 function in regulating translation. We found that both the synthetic lethal phenotype and the genetic instability phenotypes are rescued by a mutant allele of EAP1 that is unable to bind eIF4E. Our findings suggest that Eap1p carries out an eIF4E-independent function to maintain genetic stability, most likely involving SPBs.

Eukaryotic Initiation Factor-4E↗
PubMedDate not supplied

Supervised self-organizing maps in drug discovery. 1. Robust behavior with overdetermined data sets.

The utility of the supervised Kohonen self-organizing map was assessed and compared to several statistical methods used in QSAR analysis. The self-organizing map (SOM) describes a family of nonlinear, topology preserving mapping methods with attributes of both vector quantization and clustering that provides visualization options unavailable with other nonlinear methods. In contrast to most chemometric methods, the supervised SOM (sSOM) is shown to be relatively insensitive to noise and feature redundancy. Additionally, sSOMs can make use of descriptors having only nominal linear correlation with the target property. Results herein are contrasted to partial least squares, stepwise multiple linear regression, the genetic functional algorithm, and genetic partial least squares, collectively referred to throughout as the "standard methods". The k-nearest neighbor (kNN) classification method was also performed to provide a direct comparison with a different classification method. The widely studied dihydrofolate reductase (DHFR) inhibition data set of Hansch and Silipo is used to evaluate the ability of sSOMs to classify unknowns as a function of increasing class resolution. The contribution of the sSOM neighborhood kernel to its predictive ability is assessed in two experiments: (1) training with the k-means clustering limit, where the neighborhood radius is zero throughout the training regimen, and (2) training the sSOM until the neighborhood radius is reduced to zero. Results demonstrate that sSOMs provide more accurate predictions than standard linear QSAR methods.

Algorithms↗
PubMedDate not supplied

Estimating genetic covariance functions assuming a parametric correlation structure for environmental effects.

A random regression model for the analysis of "repeated" records in animal breeding is described which combines a random regression approach for additive genetic and other random effects with the assumption of a parametric correlation structure for within animal covariances. Both stationary and non-stationary correlation models involving a small number of parameters are considered. Heterogeneity in within animal variances is modelled through polynomial variance functions. Estimation of parameters describing the dispersion structure of such model by restricted maximum likelihood via an "average information" algorithm is outlined. An application to mature weight records of beef cow is given, and results are contrasted to those from analyses fitting sets of random regression coefficients for permanent environmental effects.

Age Distribution↗
PubMed1982

Is muscle structure influenced by genetical or functional factors? A study of three forearm muscles.

Relative fibre type composition and weights of 3 forearm muscles; the m. extensor carpi radialis longus (ECRL), m. extensor carpi radialis brevis (ECRB) and the m. brachioradialis (BR) from both the left and right arm were determined. Fibre type 1 muscle weight of the ECRB, which co-contracts posturally during gripping, was significantly greater in the right than the left forearm. Weights of type 2 fibres in this muscle were, however, similar in the left and right arm. Fibre type weights of both ECRL and BR were also similar in both arms. For all these muscles, intra-individual co-variation in relative fibre type occurrence was found. It is proposed that genetic factors may play a role in determining the relative fibre type composition at least as far as the upper extremities are concerned. However, functional demands are also important determining factors for development of muscle structure.

Adult↗
PubMed2003

Social stress in laying hens: differential effect of stress on plasma dopamine concentrations and adrenal function in genetically selected chickens.

Genetic selection for high or low group productivity and survivability (HGPS, LGPS) has created two phenotypically distinct chicken lines. Each line has unique characteristics in behavioral and physiological adaptability to multiple-bird cage system. The present study was designed to examine whether these differences reflect genetic variation in the control of plasma dopamine (DA) concentrations and adrenal function in response to social stress. Chickens from the HGPS and LGPS lines were randomly assigned to single- or 10-bird cages at 17 wk of age. The 10-bird cages were the same as those used in the development of the two lines. Differences in regulation of DA concentrations and adrenal function in response to different social environments were measured between the two lines when the study was conducted at 24 wk of age. In the 10-bird cages, the HGPS line had lower levels of DA (P < 0.05) and heavier adrenal glands (AG, P < 0.05) than those of the LGPS line, but concentrations of corticosterone (CORT) from the two lines were not significantly different. In the single-bird cages, DA levels in both lines were greater than in that of their siblings in the 10-bird cages, but a greater increase was found in the LGPS line (P < 0.01 and P < 0.05, 405% vs. 293%). Likewise, both lines had lower concentrations of CORT (P < 0.05) in the single- vs. 10-bird cages, but the AG were less heavy in the LGPS line but not in HGPS line in the single-bird cages (P < 0.05). The results indicated that the two strains reacted differently in terms of their stress hormone levels in the two different environments. These differences could contribute to the behavioral and physiological differences existing between the two lines.

Adrenal Glands↗
PubMed2005

Dissecting RNA-interference pathway with small molecules.

RNA interference (RNAi) is a process whereby short-interfering RNAs (siRNA) silence gene expression in a sequence-specific manner. We have screened a chemical library of substituted dihydropteridinones and identified a nontoxic, cell permeable, and reversible inhibitor of the RNAi pathway in human cells. Biochemical and fluorescence resonance-energy transfer experiments demonstrated that one of the compounds, named ATPA-18, inhibited siRNA unwinding that occurred within 6 hr of siRNA transfection. Extracts prepared from ATPA-18-treated cells also exhibited a decrease in target RNA cleavage by activated RNA-induced silencing complex (RISC*). Interestingly, when activated RISC*, which harbors unwound antisense siRNA, was treated with ATPA-18 in vitro, target RNA cleavage was not affected, indicating that this compound inhibited siRNA unwinding or steps upstream of unwinding in the RNAi pathway. Our results also establish the timing of siRNA unwinding and show that siRNA helicase activity is required for RNAi. ATPA-18 analogs will therefore provide a new class of small molecules for studying RNAi mechanisms in a variety of model organisms and deciphering in vivo genetic functions through reverse genetics.

Cell Line↗
PubMed2004

A comparison of methods for modeling quantitative structure-activity relationships.

A large number of methods are available for modeling quantitative structure-activity relationships (QSAR). We examine the predictive accuracy of several methods applied to data sets of inhibitors for angiotensin converting enzyme, acetylcholinesterase, benzodiazepine receptor, cyclooxygenase-2, dihydrofolate reductase, glycogen phosphorylase b, thermolysin, and thrombin. Descriptors calculated with CoMFA, CoMSIA, EVA, HQSAR, and traditional 2D and 2.5D descriptors were used for developing models with partial least squares (PLS). In addition, the genetic function approximation algorithm, genetic PLS, and back-propagation neural networks were used for deriving models from 2.5D descriptors (i.e., 2D descriptors and 3D descriptors calculated from CORINA structures and Gasteiger-Marsili charges). Predictive accuracy was assessed using designed test sets. It was found that HQSAR generally performs as well as CoMFA and CoMSIA; other descriptor sets performed less well. When 2.5D descriptors were used, only neural network ensembles were found to be similarly or more predictive than PLS models. In addition, we show that many cross-validation procedures yield similar estimates of the interpolative accuracy of methods. However, the lack of correspondence between cross-validated and test set predictive accuracy for four sets underscores the benefit of using designed test sets.

Algorithms↗
PubMed2005

The pharmacogenetics of methotrexate in inflammatory bowel disease.

OBJECTIVES: Methotrexate (MTX) is an effective immunosuppressive treatment in inflammatory bowel disease (IBD) but its use is limited by unpredictable toxicity and efficacy. MTX metabolism is complex involving a number of enzymes. An individual's response to MTX may in part be genetically determined by functional genetic variation in genes encoding these enzymes. We report a pharmacogenetic evaluation of MTX therapy in IBD. METHODS: We studied 102 IBD patients treated with MTX, and 202 patients with Crohn's disease (CD), 205 patients with ulcerative colitis (UC) and 189 healthy volunteers served as controls to assess allele frequencies in the disease and healthy populations. All subjects were genotyped for four polymorphisms: G80A in the reduced folate carrier (RFC1) gene, G452T in the gamma-glutamyl hydrolase (GGH) gene and C677T and A1298C in the methylenetetrahydrofolate reductase (MTHFR) gene. Three non-conservative SNPs in the RFC1 and the MTHFR gene could not be detected in our patient cohort. Genotype-phenotype associations were evaluated with respect to efficacy and toxicity of MTX therapy. RESULTS: No significant differences in the allele frequencies between CD, UC and healthy controls were detected. Overall 21% of patients experienced MTX side effects. Patients homozygous for the MTHFR 1298C allele were more likely to experience one or more side effects compared to patients with the wild-type 1298AA genotype (21.0 vs. 6.3%, P < 0.05). None of the genotyped SNPs or haplotypes, either alone or in combination, was associated with short-term efficacy or sustained response. CONCLUSIONS: Side effects of MTX in IBD are associated with a SNP in the MTHFR gene but response cannot be predicted by any of the investigated SNPs.

Adolescent↗
PubMed2026

[Genetic and functional characterization of a novel KIT splicing variant in a Chinese three-generation pedigree with piebaldism].

OBJECTIVES: To investigate the genetic etiology of a three-generation pedigree affected with piebaldism. METHODS: Next-generation sequencing and Sanger sequencing were employed to detect and verify gene variants. Bioinformatics tools were used to predict the effects of candidate variants on splicing and protein function. RT-PCR and Sanger sequencing were further performed to validate the impact of the variant on RNA splicing, and homology modeling was applied to predict its effect on the three-dimensional structure of the KIT protein. The pathogenicity of the variant was then classified according to the guidelines of the American College of Medical Genetics and Genomics (ACMG) and the UK Association for Clinical Genomic Science (ACGS). RESULTS: A heterozygous insertion variant near the splice site, c.1990+8_1990+9insTGCACCATTGGAGGTAAA, was identified in the KIT gene in the proband and was found to co-segregate with the phenotype within the family. RT-PCR and cDNA sequencing revealed that this variant led to aberrant splicing during transcription, resulting in a 21 bp in-frame insertion in the mRNA, which encodes an extra 7 amino acids within the tyrosine kinase domain and may thus affect protein function. In silico predictions, together with the experimental findings, supported classification of this variant as likely pathogenic according to relevant variant interpretation guidelines. CONCLUSIONS: The heterozygous splice-site insertion variant KIT:c.1990+8_1990+9insTGCACCATTGGAGGTAAA is the genetic cause of piebaldism in this pedigree.

Genetics diagnosis↗
PubMed2004

Functional and genetic assessment of IFN-gamma receptor in patients with clinical tuberculosis.

OBJECTIVE: The molecular basis of the genetic vulnerability underlying the most common form of clinical tuberculosis (TB) remains largely unknown. We speculated that mild genetic defects in the interferon-gamma (IFN-gamma) signalling pathway caused a subtle functional impairment of IFN-gamma which would explain susceptibility to Mycobacterium tuberculosis in clinical TB. DESIGN: A case-control study. RESULTS: We evaluated functional responsiveness to IFN-gamma in monocytes from patients with clinical TB (n = 10), and analysed the genetic sequences of the IFN-gamma receptor 1 (IFN-gammaR1) and STAT1 genes in patients with disseminated TB (n = 18). IFN-gamma stimulated an increase in the expression of HLA-DR and CD64 on monocytes of both controls and patients; the rate of increase in expression was the same in both groups. Treatment with IFN-gamma before lipopolysaccharide (LPS) stimulation further increased tumour necrosis factor-alpha (TNF-alpha) production as compared to TNF-alpha production with LPS stimulation alone; the rate of increase in TNF-alpha production was the same in both groups. The known mutations in the coding sequences of the IFN-gammaR1 and STAT1 genes were not found in the patients with disseminated tuberculosis. CONCLUSION: These results suggest that impairment of the IFN-gamma signalling pathway did not account for cases of clinical TB in this study.

Adult↗
PubMed2003

Rescue of female infertility from the loss of cyclooxygenase-2 by compensatory up-regulation of cyclooxygenase-1 is a function of genetic makeup.

Cyclooxygenase-2 (COX-2), an inducible rate-limiting enzyme in prostaglandin biosynthesis, is implicated in various physiological and pathological processes including female fertility, renal function, angiogenesis, inflammation, and tumorigenesis. We showed previously that targeted deletion of Ptgs2 encoding COX-2, but not Ptgs1 encoding COX-1, in C57BL/6J/129 mice produces complete female infertility resulting from multiple reproductive failures spanning ovulation, fertilization, and implantation. Here we show that Ptgs2 null mice on a CD1 background have dramatically improved female fertility including ovulation, fertilization, and implantation, giving rise to live births. We provide evidence that this improved fertility in CD1 Ptgs2 null mice is the result of a compensatory up-regulation of Ptgs1 which does not occur in C57BL/6J/129 mice missing Ptgs2. These results clearly demonstrate for the first time that COX-1 can replace specific functions of COX-2 in vivo in the context of genetic disparity. In light of this finding, the therapeutic use and efficacy of COX-2-specific inhibitors among human populations without regard for genetic and ethnic diversities should be revisited.

Animals↗
PubMed1984

Genetic and environmental determinants of level of pulmonary function.

Measurements of level of pulmonary function (one second forced expiratory volume (FEV1) and forced expiratory flow between the 25% and 75% volume points (FEF 25-75)) were obtained on members of 404 nuclear families living in East Boston, Massachusetts in 1974. These families were ascertained through a random sample of children aged 5-9 years. Measurements were obtained on family members on three separate occasions during a 5-year period. These data were subjected to the techniques of path analysis to study the relative contributions of heredity and environment to individual levels of pulmonary function. Genetic heritability was found to be consistent through time (41-47%) and was the same for parents and their children. Common familial environmental effects on level of pulmonary function explained 1-4% of the variability in children and 11-28% in adults. Furthermore, we were able to confirm prior epidemiologic analysis of these data which have demonstrated an effect of maternal smoking on the level of pulmonary function in their children.

Boston↗
PubMed2005

Study of androgen receptor functions by genetic models.

Androgens exert most of their biological activities through binding to the androgen receptor (AR). The AR belongs to the nuclear receptor superfamily and acts as a ligand-inducible transcriptional factor. AR dysfunction causes a diverse range of clinical conditions, such as testicular mutation (Tfm) syndrome, prostate cancer, and spinal and bulbar muscular atrophy (SBMA). However, the molecular basis of the AR function underlying these AR-related disorders remains largely unknown due to the lack of stable genetic models. Here we review recent results of our studies into genetic models of the loss of AR function in mice and the gain of AR function in Drosophila.

Animals↗
PubMed2001

Considerations for the evaluation of renal function in genetically engineered mice.

Transgenic and gene-targeting techniques have opened a new era of physiologic investigation: the field of functional genomics. The nearly exclusive use of the mouse in this discipline has necessitated the development and adaptation of sophisticated techniques for evaluating murine physiology at the cellular, tissue, organ and whole animal levels. Although many of the methodologies for exploring cardiorenal function have been successfully adapted from their use in the rat, there are important limitations and considerations that must be recognized when applying them in the mouse. Investigators have been successful in measuring a wide variety of functional variables at the whole kidney and even single nephron levels. Reviewed here are recent advances in the measurement of blood pressure, renal blood flow, whole kidney electrolyte excretion and clearance rates, single-nephron glomerular filtration rate and transport, and tubuloglomerular feedback.

Animals↗
PubMed1992

The suppressor of forked locus in Drosophila melanogaster: genetic and molecular analyses.

The suppressor of forked, su(f) locus is one of a class of loci in Drosophila whose mutant alleles are trans-acting allele-specific modifiers of transposable element-insertion mutations at other loci. Mutations of su(f) suppress gypsy insert alleles of forked and enhance the copia insert allele white apricot. Our investigations of su(f) include genetic and molecular analyses of 19 alleles to determine the numbers and types of genetic functions present at the locus. Our results suggest the su(f) locus contains multiple genetic functions. There are two distinct modifier functions and two vital functions. One modifier function is specific for enhancement and the other for suppression. One vital function is required for normal ecdysterone production in the third larval instar, the other is not. We present a restriction map of the su(f) genomic region and the results of an RFLP analysis of several su(f) alleles.

Alleles↗
PubMed2004

The human complement factor H: functional roles, genetic variations and disease associations.

Factor H is an essential regulatory protein that plays a critical role in the homeostasis of the complement system in plasma and in the protection of bystander host cells and tissues from damage by complement activation. Genetic and structural data generated during recent years have been instrumental to delineate the functional domains responsible for these regulatory activities in factor H, which is helping to understand the molecular basis underlying the different pathologies associated to factor H. This review summarises our current knowledge of the role of factor H in health and disease.

Bacteria↗
PubMed2006

Assessing the pathogenicity of MLH1 missense mutations in patients with suspected hereditary nonpolyposis colorectal cancer: correlation with clinical, genetic and functional features.

Assessing the pathogenicity of missense mutations of MLH1 and MSH2 is critical to counsel patients with suspected hereditary nonpolyposis colorectal cancer (HNPCC). Approximately 32% of all MLH1 mutations and 18% of MSH2 mutations are missense variants which often have an uncertain genetic significance. To assess the pathogenicity of four MLH1 missense mutations which were found in five patients with suspected HNPCC, P648S (CCC --> TCC), L559R (CTG --> CGG), K618A (AAG --> GCG), Y646C (TAT --> TGT), we studied their ability to disrupt MLH1 protein function and their relationship with all those clinical, genetic and pathological features which are typical of this syndrome. Our results indicated that the P648S and L559R mutations were probably pathogenic because they disrupted MLH1 protein interaction with its partner PMS2 in vitro and abolished MLH1 expression in HCT116 cells. In addition these variants were associated with features often found in HNPCC patients: in particular high microsatellite instability, occurrence of high grade tumours and, in one case, strong family history. The pathogenicity of the K618A and Y646C mutations was questionable as their correlation with features typical of HNPCC was low and the outcome of the functional analysis was ambiguous. These observations suggested that a clinically usable assessment of the pathogenicity of MLH missense variants can be achieved through the analysis of multiple mutation characteristics among which loss of protein function, occurrence of microsatellite instability and family history seemed to have a predominant role.

Adaptor Proteins, Signal Transducing↗