Structural organization of human DR antigens and their murine analog, I-E antigens: serologic, genetic, and functional implications.
Explore the source record for details and available documents.
Animals↗
SEARCH · Search PubMed
Results for “functional genetics”
Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
Analysis of thymic subpopulations expressing the activation antigen GL7. Expression, genetics, and function.
Previously, we reported an mAb, GL7, that defines an activation Ag expressed by in vitro-stimulated B and T cells as well as by a subpopulation of thymocytes. The current study analyzes the GL7-expressing populations of adult and fetal thymus and demonstrates that: 1) The majority of GL7+ adult thymocytes are CD4+CD8- cells that are CD3 epsilon high, TCR-alpha beta high, HSAlow, and bimodal for CD69 expression. The 3G11-6C10- subset of CD4+CD8- thymocytes is enriched in GL7-expressing cells. 2) Strain differences exist in the expression of GL7 on adult CD4+CD8- thymocytes; 21.9 +/- 5.9% of BALB/c CD4+CD8- thymocytes are GL7+, whereas 4.4 +/- 1.7% of C57BL/6 CD4+CD8- thymocytes are GL7+. The low GL7 expression phenotype is dominant in CB6F1 thymocytes (7.0 +/- 2.0%), and analysis of BALB/c x CB6F1 mice suggests that low GL7 expression is determined by multiple genes. 3) CD4+CD8- GL7+ thymocytes from BALB/c mice, but not C57BL/6 mice, are skewed toward a high proportion of V beta 8+ cells. 4) Adult GL7+ CD4+CD8- thymocytes can be activated by TCR-specific stimuli to proliferate and to secrete high amounts of IL-4. 5) Fetal thymocytes contain GL7+ cells, which are predominantly CD4-CD8-, HSAlow, CD69-, and bimodal for TCR-gamma delta. Thus, GL7 expression defines a subpopulation of functionally competent TCR-alpha beta+ CD4+CD8- thymocytes as well as TCR-gamma delta+ and TCR- subpopulations of fetal CD4-CD8- thymocytes.
Animals↗
[Cytotoxic factor of Flexner shigella, its biologic function and genetic control].
Explore the source record for details and available documents.
Animals↗
Proceedings of the 10th Goldberg Workshop on Analytical and Quantitative Cardiology: From Genetics to Function. Haifa, Israel, December 2-5, 1996.
Explore the source record for details and available documents.
Animals↗
Recent Advances in the Comprehension of Molecular and Genetic Mechanisms Underlying Yeast Biocontrol Efficacy Against Fungal Pathogens in Agriculture.
Recent advances in biotechnologies have enabled scientists to uncover biological processes across multiple research fields. Still, the molecular and genetic mechanisms underlying the biological control efficacy of yeast biocontrol agents (YBCAs) against fungal plant pathogens remain incompletely elucidated. This review focuses on recent insights into the regulatory bases and molecular interplay underlying successful disease control by YBCAs. It provides a detailed description of core antagonistic molecular mechanisms-nutrient and iron competition, mycoparasitism via cell wall degradation, antifungal compounds production, oxidative stress resistance, biofilm formation and colonization, and induction of the host defense responses-and integrates genomic, transcriptomic, proteomic, and metabolomic evidence to elucidate each mechanism. Further, how genetic engineering-based approaches that leverage omics data and functional genetics can help overcoming obstacles to translate YBCAs efficacy from laboratory conditions to the field are also discussed. Finally, the use of the CRISPR-Cas technology is recommended to better exploit how master transcription factors coordinate multiple mechanisms simultaneously; these factors are crucial for the synergistic antifungal effect, which is critical for developing highly effective YBCAs. Ultimately, the mechanism-based perspective provides a unified conceptual framework for understanding YBCAs efficacy and can guide the rational design of next-generation biocontrol agents for sustainable agriculture.
CRISPR-Cas technology↗
New tools for functional mammalian cancer genetics.
Knowledge of the function of individual genes that encode components of cell-signalling pathways is crucial to our understanding of normal growth control and its deregulation in cancer, but we have functional information for only 15% of human genes at present. Several new technologies have recently become available to identify gene function in mammalian cells using high-throughput genetic screens. These new tools will make it possible to identify new and innovative classes of anticancer drugs, including those that show synthetic lethal interactions with cancer-specific mutations.
Animals↗
Gene clusters and the evolution of the major histocompatibility system.
Gene clusters containing one or more sets of duplicated genes with related functions are probably the basic genetic functional units. The major histocompatibility systems, such as HLA and H2, are among the most complex gene clusters so far known and studied, and illustrate many of the features of their structure and evolution. They cover about one thousandth of the mammalian genome and include two major sets of cell surface products with different but related functions in the control of immune interactions, as well as genes for complement components and 21-hydroxylase. Molecular analysis has revealed an extraordinary complexity at the genetic level, reflecting a very long and involved evolutionary history. A description of the organization of the HLA system, especially the HLA-D region, and its function and polymorphism forms the basis for considering the evolution of such complex gene clusters.
Amino Acid Sequence↗
The genetic code-function and evolution.
The genetic code is reviewed from the standpoints of its function and evolution. The code has probably always consisted of 64 units (codons), each containing three bases. Each codon pairs with a three-base anticodon that is part of an adaptor molecule. The adaptors are transfer RNA molecules that are each joined to a specific amino acid. Many departures from the universal code have recently been discovered. These are discussed.
Amino Acids↗
Physiological genomics of antidepressant targets: keeping the periphery in mind.
The plasma membrane transporters that clear extracellular serotonin (5-HT) and norepinephrine (NE), serotonin transporters (SERTs) and NE transporters (NETs), have received considerable attention over the past four decades because of their roles in amine neurotransmitter inactivation. In addition, they interact with many centrally active drugs, including multiple classes of antidepressants such as the serotonin-selective reuptake inhibitors, typified by fluoxetine (Prozac), and the more recently developed norepinephrine-selective transporter antagonists, such as reboxetine. The therapeutic utility of these agents supports biogenic amine theories of affective disorders and raises the question as to whether SERT and NET exhibit a functional genetic variation that could influence risk for behavioral disorders. Although evidence exists that a promoter polymorphism in SERT may influence behavioral states, this contention is not without complexity and its mechanism of action remains poorly understood. The identification of coding variants of NETs and SERTs would offer important opportunities to connect genotype to phenotype. However, given the limited frequency of transporter coding variations evident to date in general population surveys or in psychiatric genetic studies, the identification of informative functional variants of transporters will likely require refined phenotypes. In this regard, NET and SERT play critical roles in cardiovascular and gastrointestinal physiology, respectively. This perspective reviews recent human and mouse studies that suggest how peripheral autonomic phenotypes, linked to genetic disruption of NET and SERT function, can aid in the phenotypic segregation needed for advanced theories of biogenic amine dysfunction and pharmacogenetics.
Antidepressive Agents↗
[Role of family in development of neurophysiological manifestations in children with migraine].
Migraine is a familial disorder. The aim of this study was to compare the relationship between specific neurophysiologic pathogenetic mechanisms of migraine such as abnormal information processing and enhanced cortical excitability on the one hand, and parent-child-interactions and personality traits such as neuroticism and extraversion on the other hand in migraine and healthy families. The correlation and factor analyses demonstrated that the stronger the control over a child and the more intensive the suppression of a child's independence by a parent during a stressful situation in migraine families, the more pronounced the loss of habituation of the contingent negative variation (CNV), and the greater the neuroticism in a migraine child. The CNV amplitude was independent of psychosocial conditions in the family but represented similarities in information processing between parents and their children suffering from migraine. This could be possibly explained by genetic influences on information processing in migraine. In healthy families only the relationship between parameters of parent-child-interaction could be observed. This investigation demonstrates that the neurophysiological disposition to a migraine attack as well as personality traits in migraine could be influenced by psychosocial factors such as parent-child interactions and that different parameters of information processing in headache patients are related to either non-genetic familial conditions (habituation) or functional genetic factors (amplitude).
Arousal↗
Plasmid condensation induced by cationic compounds: hydrophilic polylysine and amphiphilic cationic lipid.
The construction of an efficient carrier for genetic material is a major research objective that needs to be achieved before gene therapy can become a viable pharmacological approach. Artificial aggregates containing nucleic acids are one of the options for the systemic delivery of genetic information. The diversity of functions the aggregate is expected to fulfill necessitates its complex architecture. In order to obtain a complex supramolecular aggregate, formed from elements that are themselves complex molecules, appropriate procedures based on the detailed understanding of processes at the molecular level are required. In this study, we investigated how the various properties of cationic compounds affect nucleic acid condensation. The combination of two condensing agents, differing in their affinity towards water, when mixed with plasmids, resulted in aggregates which are resistant to enzymatic digestion and which form particles with well-defined size distributions. Such uniform and well-defined complexes may subsequently be further modified in order to obtain a fully functional genetic material carrier.
Gene Transfer Techniques↗
Functional significance of genetic abnormalities in multiple myeloma.
Multiple myeloma (MM) is a B-cell neoplasm characterized by infiltration of the bone marrow with malignant plasma cells, synthesizing and secreting monoclonal immunoglobulin fragments. The malignant transformation of this terminally differentiated plasma cell is the result of a multistep transformation process. In spite of recent advances in this field, the cause and the exact molecular genetic basis of MM remain obscure. In this review, an attempt has been made to summarize the genetic alterations having functional significance in the generation and progression of MM, and also the existing relationship between genetic abnormalities and chemosensitivity, as well as the typical genetic alterations in various MM subgroups. Factors known to have a role in the conversion of monoclonal gammopathy of unknown significance (MGUS) to MM are also reviewed.
Cell Transformation, Neoplastic↗
Pharmacogenomics of the OATP and OAT families.
Drug disposition is highly dependent on the interplay between drug metabolism and transport in organs such as the intestine, kidney, and liver. Genetically determined variation in drug transporter function or expression is now increasingly recognized to have a significant role as a determinant of intersubject variability in drug response. Similar to the discoveries of functional genetic variations in drug efflux transporters, such as multi-drug resistance proteins 1 and 2, there have been considerable advances in the identification of single nucleotide polymorphisms in transporters that facilitate cellular drug uptake. Among the uptake transporters, members of the organic anion-transporting polypeptides and organic anion transporters can mediate the cellular uptake of a large number of structurally divergent compounds. Accordingly, functionally relevant polymorphisms in these transporters may contribute to interindividual and interethnic variability in drug disposition and response. In this review, recent progress relating to pharmacogenomics of organic anion transporters will be outlined along with a compilation of currently known genetic polymorphisms.
Animals↗
Reproductive hormonal function in the genetically obese (ob/ob) mouse.
Reproductive function is impaired in the genetically obese (C57 B1/6J) ob/ob mouse. Serum LH, FSH, and testosterone concentrations were assessed in male ob/ob and lean littermates from 39 to 78 days of age. The lean animals demonstrated a three-fold rise in serum LH between 39 and 45 days of age that preceded a steep increase in serum testosterone which peaked at age 70 days. The obese animals did not demonstrate this LH rise; serum testosterone levels were low and had a blunted increase with age that paralleled that of normal animals. Serum FSH was lower than normal at all ages in the obese mice. The ventral prostrate and testes were small in the ob/ob mice. The castration of adult animals resulted in increased serum concentrations of both LH and FSH, with higher levels attained in the lean animals. Fifty-four-day-old castrated lean and obese mice were treated with testosterone for 15 days. Measurements of serum LH and FSH after 8 and 15 days of treatment demonstrated a marked sensitivity in the ob/ob animals to feedback inhibition of gonadotropins. This finding suggested persistent immaturity of the hypothalamic-pituitary axis in obese mice. These studies indicate that the hypogonadism of the ob/ob mouse is the result of altered hypothalamic-pituitary function.
Age Factors↗
Light-induced carotenogenesis in Myxococcus xanthus: genetic analysis of the carR region.
Carotenogenesis is light-inducible in the non-photosynthetic, Gram-negative, bacterium Myxococcus xanthus. We report the characterization of the carR region which controls this phenomenon. Insertion of transposon Tn5 close to the carR region caused a dominant, carotenoid-constitutive mutation because of the presence of a constitutive, outward-reading promoter in the IS50L component of Tn5. In wild-type cells, a powerful, tightly-regulated, light-inducible promoter directs the transcription of two genetic functions. One of these functions is to activate transcription of the genetically unlinked carB gene, which is involved in carotenoid synthesis. The second function (carR) regulates the light-inducible promoter. We also report the mapping of two carotenoid constitutive mutations to the previously characterized carA locus.
Alleles↗
Comparative QSAR modeling of CCR5 receptor binding affinity of substituted 1-(3,3-diphenylpropyl)-piperidinyl amides and ureas.
The present QSAR study attempts to explore the structural and physicochemical requirements of substituted 1-(3,3-diphenylpropyl)-piperidinyl amides and ureas for CCR5 binding affinity using linear free energy-related (LFER) model of Hansch. QSAR models have been developed using electronic (Hammett sigma), hydrophobicity (pi), and steric (molar refractivity and STERIMOL L, B1, and B5) parameters of phenyl ring substituents of the compounds along with appropriate dummy variables. Whole molecular descriptor like partition coefficient (logP(calcd)) was also tried as an additional descriptor. Statistical techniques like stepwise regression, multiple linear regression with factor analysis as the data preprocessing step (FA-MLR), partial least squares with factor analysis as the preprocessing step (FA-PLS), principal component regression analysis (PCRA), multiple linear regression with genetic function approximation (GFA-MLR), and genetic partial least squares (G/PLS) were applied to identify the structural and physicochemical requirements for the CCR5 binding affinity. The generated equations were statistically validated using leave-one-out technique. The quality of equations obtained from stepwise regression, FA-MLR, FA-PLS, and PCRA is of acceptable statistical range (explained variance ranging from 71.9% to 80.4%, while predicted variance ranging from 67.4% to 77.0%). The GFA-derived models show high intercorrelation among predictor variables used in the equations while the G/PLS model shows lowest statistical quality among all types of models. The best models were also subjected to leave-25%-out crossvalidation.
Amides↗
Glypican-3 modulates inhibitory Bmp2-Smad signaling to control renal development in vivo.
Renal branching morphogenesis, defined as growth and branching of the ureteric bud (UB), is a tightly regulated process controlled by growth factor-dependent tissue interactions. Previously, using in vitro models of branching morphogenesis, we demonstrated that BMP2 signals via its intracellular effectors, SMAD1 and SMAD4, to control UB cell proliferation and branching in a manner modulated by Glypican-3 (GPC3), a cell surface heparan sulfate proteoglycan. Here, we used loss-of-function genetic mouse models to investigate the functions of Bmp2 and Gpc3-Bmp2 interactions in vivo. Progressively greater increases in UB cell proliferation were observed in Bmp2+/-, Smad4+/-, and Bmp2+/-; Smad4+/- mice compared to Wt. This increased cell proliferation was accompanied by a significant increase in UB branching in Smad4+/- and Bmp2+/-;Smad4+/- mice compared to Wt. Reduction of Gpc3 gene dosage also increased UB cell proliferation, an effect that was enhanced in Gpc3+/-;Bmp2+/- mice to an extent greater than the sum of that observed in Gpc3+/- and Bmp2+/- mice. Reduction of both Gpc3 and Bmp2 gene dosage enhanced cell proliferation in the metanephric mesenchyme compared to Wt, an effect not observed in either Bmp2+/- or Gpc3+/- mice. Phosphorylation of SMAD1, a measure of SMAD1 activation, was progressively decreased in Gpc3+/- and Gpc3+/-;Bmp2+/- mice compared to Wt, suggesting that Gpc3 stimulates Bmp2-dependent SMAD signaling in vivo. These results demonstrate that BMP2-SMAD signaling, modulated by GPC3, inhibits renal branching morphogenesis in vivo.
Animals↗
Endothelin-converting enzyme-1 is expressed in human cerebral cortex and protects against Alzheimer's disease.
Cerebral accumulation of beta-amyloid peptide (A beta) is a central event in the pathogenesis of Alzheimer's disease (AD). Endothelin-converting enzyme-1 (ECE-1) is a candidate A beta-degrading enzyme in brain, but its involvement in AD pathogenesis was never assessed. We first performed brain immunocytochemistry, using a monoclonal anti-ECE-1 antibody, and observed neuronal ECE-1 expression in various cortical regions of nondemented subjects. In the hippocampus, ECE-1 immunoreactivity showed a stereotypical pattern inversely correlated with susceptibility to A beta deposition, further suggesting a physiological role in A beta clearance. In order to undertake a genetic association study, we identified a functional genetic variant (ECE1B C-338A) located in a regulatory region of the ECE1 gene. We showed that the A allele is associated with increased transcriptional activity in promoter-reporter gene assays and with increased ECE-1 mRNA expression in human neocortex. In a case-control study involving 401 patients with late-onset AD and 461 aged controls, we found that homozygous carriers of the A allele had a reduced risk of AD (OR=0.47, 95% CI 0.25-0.88). This finding was strengthened by the analysis of two other genetic variants of the ECE1 gene, which showed that the genetic association is extended over at least 13 kilobases of the gene sequence. Our results suggest that ECE-1 expression in brain may be critical for cortical A beta clearance and offer new potential targets for therapeutic interventions in AD.
Adult↗