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At least 145 records · Page 8Linked to original sources
PubMed2005

Genetic and functional characterization of isolated stromal cell lines from the aorta-gonado-mesonephros region.

The hematopoietic system interacts with a supportive stromal environment allowing maintenance and differentiation of hematopoietic stem cells (HSCs). The aorta-gonado-mesonephros (AGM) region serves as a unique embryonic microenvironment, generating the first adult repopulating HSCs in the mouse embryo. To eludicate factors involved in hematopoietic support and induction of hematopoietic differentiation, we isolated more than 100 stromal cell clones derived from the AGM region of embryonic day (E) 10.5 mouse embryos for functional and genetic analysis. Selected isolated AGM stromal cell lines are highly efficient in supporting maintenance and expansion of mouse and human hematopoietic stem and progenitor cells. In addition, we can demonstrate for the first time that AGM stromal cell lines are also potent inducers of hematopoietic differentiation of murine embryonic stem cells. Stromal gene array analysis has identified genes that could play a role in hematopoietic support.

Animals↗
PubMed2005

Functional and genetic analysis of coronavirus replicase-transcriptase proteins.

The coronavirus replicase-transcriptase complex is an assembly of viral and cellular proteins that mediate the synthesis of genome and subgenome-sized mRNAs in the virus-infected cell. Here, we report a genetic and functional analysis of 19 temperature-sensitive (ts) mutants of Murine hepatitis virus MHV-A59 that are unable to synthesize viral RNA when the infection is initiated and maintained at the non-permissive temperature. Both classical and biochemical complementation analysis leads us to predict that the majority of MHV-A59 ORF1a replicase gene products (non-structural proteins nsp1-nsp11) form a single complementation group (cistron1) while the replicase gene products encoded in ORF1b (non-structural proteins nsp12-nsp16) are able to function in trans and comprise at least three, and possibly five, further complementation groups (cistrons II-VI). Also, we have identified mutations in the non-structural proteins nsp 4, nsp5, nsp10, nsp12, nsp14, and nsp16 that are responsible for the ts phenotype of eight MHV-A59 mutants, which allows us to conclude that these proteins are essential for the assembly of a functional replicase-transcriptase complex. Finally, our analysis of viral RNA synthesis in ts mutant virus-infected cells allows us to discriminate three phenotypes with regard to the inability of specific mutants to synthesize viral RNA at the non-permissive temperature. Mutant LA ts6 appeared to be defective in continuing negative-strand synthesis, mutant Alb ts16 appeared to form negative strands but these were not utilized for positive-strand RNA synthesis, and mutant Alb ts22 was defective in the elongation of both positive- and negative-strand RNA. On the basis of these results, we propose a model that describes a pathway for viral RNA synthesis in MHV-A59-infected cells. Further biochemical analysis of these mutants should allow us to identify intermediates in this pathway and elucidate the precise function(s) of the viral replicase proteins involved.

Coronaviridae↗
PubMed2005

Challenges for identifying functionally important genetic variation: the promise of combining complementary research strategies.

Strategies for the identification of functional genetic variation underlying phenotypic traits of ecological and evolutionary importance have received considerable attention in the literature recently. This paper aims to bring together and compare the relative strengths and limitations of various potentially useful research strategies for dissecting functionally important genetic variation in a wide range of organisms. We briefly explore the relative strengths and limitations of traditional and emerging approaches and evaluate their potential use in free-living populations. While it is likely that much of the progress in functional genetic analyses will rely on progress in traditional model species, it is clear that with prudent choices of methods and appropriate sampling designs, much headway can be also made in a diverse range of species. We suggest that combining research approaches targeting different functional and biological levels can potentially increase understanding the genetic basis of ecological and evolutionary processes both in model and non-model organisms.

Gene Expression Profiling↗
PubMed1999

Genetics of synaptic vesicle function: toward the complete functional anatomy of an organelle.

Synaptic transmission starts with the release of neurotransmitters by exocytosis of synaptic vesicles. As a relatively simple organelle with a limited number of components, synaptic vesicles are in principle accessible to complete structural and functional genetic analysis. At present, the majority of synaptic vesicle proteins has been characterized, and many have been genetically analyzed in mice, Drosophila, and Caenorhabditis elegans. These studies have shown that synaptic vesicles contain proteins with diverse structures and functions. Although the genetic studies are as yet unfinished, they promise to lead to a full description of synaptic vesicles as macromolecular machines involved in all aspects of presynaptic neurotransmitter release.

Animals↗
PubMed1998

Foundations of genetics: genetic structure, function, and therapeutics.

Molecular genetics provides the basis for understanding patterns of health and disease in people and is part of the scientific foundation on which acute and critical care nurses should build their practice. The human genome, defined as all the genetic information in the cells of humans, provides the blueprint for protein production and cellular function in the body. Alterations in protein production may result in illness or organ malfunction that has a genetic derivation. One therapeutic strategy that holds promise to manage genetic diseases is gene therapy. Gene therapy, or human gene transfer, occurs when scientists or physicians modify the genetic material in cells for therapeutic purposes. Genetic structure, function, and therapeutic reflect the science of the present and future and have profound practice implications for acute and critical care nurses.

Genetic Diseases, Inborn↗
PubMed2000

The genetic basis of cardiac function: dissection by zebrafish (Danio rerio) screens.

The vertebrate heart differs from chordate ancestors both structurally and functionally. Genetic units of form, termed 'modules', are identifiable by mutation, both in zebrafish and mouse, and correspond to features recently acquired in evolution, such as the ventricular chamber or endothelial lining of the vessels and heart. Zebrafish (Danio rerio) genetic screens have provided a reasonably inclusive set of such genes. Normal cardiac function may also be disrupted by single-gene mutations in zebrafish. Individual mutations may perturb contractility or rhythm generation. The zebrafish mutations which principally disturb cardiac contractility fall into two broad phenotypic categories, 'dilated' and 'hypertrophic'. Interestingly, these correspond to the two primary types of heart failure in humans. These disorders of early cardiac function provide candidate genes to be examined in complex human heart diseases, including arrhythmias and heart failure.

Animals↗
PubMed2006

Genetic and functional analysis of pyroglutamyl-peptidase I in coeliac disease.

Coeliac disease (CD) is an enteropathy caused by an immune reaction towards wheat gluten and similar proteins from barley and rye. It was shown that some gluten peptides spontaneously form N-terminal L-pyroglutamate. This modification could potentially make gluten more resistant to proteolytic degradation within the intestine. Pyroglutamyl-peptidase I (PGPEPI) is an enzyme that hydrolytically removes the L-pyroglutamyl residues that render the modified proteins and peptides more sensitive to degradation by other proteases. Interestingly, we found that the PGPEP1 gene is located in a CD susceptibility locus. As an impaired enzyme function caused by genetic alterations might increase the amount of immunogenic gluten peptides, we conducted a comprehensive functional genomics analysis of PGPEP1, including DNA sequencing, genetic association testing, and quantifying RNA expression. We also determined the enzymatic activity of PGPEPI in duodenal biopsies. Our results uniformly indicate that PGPEP1 is not involved in the aetiology and pathology of CD.

Adolescent↗
PubMed2005

[Pulmonary hypertension: pathophysiology, genetics and functional genomics].

Novel discoveries of the genetic basis of pulmonary hypertension have recently inspired a whole new area of research in pulmonary medicine. The finding that germ-line mutations in the BMPR2 locus, encoding a transmembrane receptor of the TGF beta superfamily, are the cause for familial and partly idiopathic pulmonary arterial hypertension has provided new clues for our understanding of this complex, yet highly localized disease. The TGF beta superfamily comprises more than 40 different growth and differentiation factors essential in the control of proliferation and differentiation of most cell types. In this review, we summarize the novel genetic and functional genomic findings to provide an outlook for the understanding of this disease.

Bone Morphogenetic Protein Receptors, Type II↗
PubMed1994

Reverse genetics of the mouse central nervous system: targeted genetic analysis of neuropeptide function and reverse genetic screens for genes involved in human neurodegenerative disease.

The development of gene targeting technology in mouse embryonic stem cells allows reverse genetics to be used to investigate the function of any cloned gene in the developing and adult brain. Promoter-trap, replacement and insertion vector strategies can be used to generate defined mutations in the chromosomal copy of a cloned gene in embryonic stem cells. These cells can be used to make chimaeric mice, some of which transmit the in vitro mutation via the germline to transgenic offspring. The phenotype of complete loss-of-function mutations (gene knock-outs) can be studied at molecular, cell biological, neurophysiological and behavioural levels, and allows inferences about gene function to be made. Precise small mutations can also be made using integrative vector or two-step replacement vector strategies, allowing specific questions to be asked about regulation and protein structure-function relationships. Reverse genetics can therefore be used as an alternative or additional approach to pharmacology for the study of molecular functions in the central nervous system. Reverse genetic studies of the involvement of particular molecules in neurological disease syndromes may be superior to pharmacological studies to the extent that the syndrome is determined by genetic predisposition. The general ways in which reverse genetics of the mouse can be used to ask questions about molecules in the central nervous system are illustrated by examples from ongoing work of this laboratory. Neuropeptides are an important class of transmitters in the brain, but only in very few cases have specific CNS functions been assigned to a particular neuropeptide. Targeted mutation of neuropeptide precursor and receptor genes offers a rapid way to learn about neuropeptide function. Complete loss-of-function mutations will provide information on any developmental roles of a neuropeptide and on overall behavioural and physiological effects of loss-of-function. More specific targeted mutations allow dissection of the individual roles of multiple neuropeptides that derive from a common precursor protein, and allow in vivo studies of the functional importance of particular amino acids. Experimental progress towards targeted mutation of the neurotensin receptor is described as an example. Recent technological improvements makes targeted mutation of a number of genes possible. This allows reverse genetic screening to be undertaken for genes involved in particular neurobiological phenomena: genes are identified on the basis of molecular criteria (e.g. expression pattern), and gene-targeting used to check their relevance to a phenotype. Neurodegenerative disease is an important aspect of the human phenotype.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗
PubMed1998

Fitting genetic mapping functions based on sperm typing: results for three chromosomal segments in cattle.

Genetic mapping functions translate the observed recombination rate between two loci into the corresponding map distance in Morgan units. Different mapping functions give different weights to multiple crossing over and therefore lead to different results. This points out that not every function is best suited to fit a data set. The data used in this study originated from 2214 sperm from 37 Norwegian bulls, which were genotyped for 11 markers. The optimal functions for the chromosomes 6, 23 and the sex chromosome of cattle were derived using the maximum likelihood method, the likelihood ratio test and empirical discriminant analysis. It became apparent that for each chromosome a different function fitted the data best. These were the function of Rao et al. (Human Heredity 1977, 27, 99-104) with p = 0.63 for chromosome 6, the function of Goldgar & Fain (American Journal of Human Genetics 1988, 43, 38-45) with C0 = 0.42, C1 = 0.47, C2 = 0.07 and C3 = 0.04 for chromosome 23 and the function of Felsenstein (Genetics 1979, 91, 769-75) with K = 0.23 for the sex chromosome. The well known functions of Haldane (Journal of Genetics 1919, 8, 299-309) and Kosambi (Annals of Eugenics 1944, 12, 172-5) were shown to be suboptimal in most cases. A function is said to be multilocus feasible if the evaluation of the probability of all possible recombination events does not lead to negative values. The optimal function for chromosome 23 turned out to be multilocus feasible, whereas the functions for chromosome 6 and the sex chromosome were not. The choice of the correct mapping function is shown to have a considerable impact in mapping studies, when double recombinations have to be taken into account. Since there is no unique best mapping function, it is argued that it might be useful to use a simple parametric mapping function (like the one of Felsenstein 1979) and to estimate the respective parameter specifically for a given data set.

Animals↗
PubMed2000

The midline glia of Drosophila: a molecular genetic model for the developmental functions of glia.

The Midline Glia of Drosophila are required for nervous system morphogenesis and midline axon guidance during embryogenesis. In origin, gene expression and function, this lineage is analogous to the floorplate of the vertebrate neural tube. The expression or function of over 50 genes, summarised here, has been linked to the Midline Glia. Like the floorplate, the cells which generate the Midline Glia lineage, the mesectoderm, are determined by the interaction of ectoderm and mesoderm during gastrulation. Determination and differentiation of the Midline Glia involves the Drosophila EGF, Notch and segment polarity signaling pathways, as well as twelve identified transcription factors. The Midline Glia lineage has two phases of cell proliferation and of programmed cell death. During embryogenesis, the EGF receptor pathway signaling and Wrapper protein both function to suppress apoptosis only in those MG which are appropriately positioned to separate and ensheath midline axonal commissures. Apoptosis during metamorphosis is regulated by the insect steroid, Ecdysone. The Midline Glia participate in both the attraction of axonal growth cones towards the midline, as well as repulsion of growth cones from the midline. Midline axon guidance requires the Drosophila orthologs of vertebrate genes expressed in the floorplate, which perform the same function. Genetic and molecular evidence of the interaction of attractive (Netrin) and repellent (Slit) signaling is reviewed and summarised in a model. The Midline Glia participate also in the generation of extracellular matrix and in trophic interactions with axons. Genetic evidence for these functions is reviewed.

Animals↗
PubMed2004

Wolcott-Rallison Syndrome: clinical, genetic, and functional study of EIF2AK3 mutations and suggestion of genetic heterogeneity.

Wolcott-Rallison syndrome (WRS) is a rare autosomal-recessive disorder characterized by the association of permanent neonatal or early-infancy insulin-dependent diabetes, multiple epiphyseal dysplasia and growth retardation, and other variable multisystemic clinical manifestations. Based on genetic studies of two inbred families, we previously identified the gene responsible for this disorder as EIF2AK3, the pancreatic eukaryotic initiation factor 2alpha (eIF2alpha) kinase. Here, we have studied 12 families with WRS, totalling 18 cases. With the exception of one case, all patients carried EIF2AK3 mutations resulting in truncated or missense versions of the protein. Exclusion of EIF2AK3 mutations in the one patient case was confirmed by both linkage and sequence data. The activities of missense versions of EIF2AK3 were characterized in vivo and in vitro and found to have a complete lack of activity in four mutant proteins and residual kinase activity in one. Remarkably, the onset of diabetes was relatively late (30 months) in the patient expressing the partially defective EIF2AK3 mutant and in the patient with no EIF2AK3 involvement (18 months) compared with other patients (<6 months). The patient with no EIF2AK3 involvement did not have any of the other variable clinical manifestations associated with WRS, which supports the idea that the genetic heterogeneity between this variant form of WRS and EIF2AK3 WRS correlates with some clinical heterogeneity.

Adolescent↗
PubMed1987

Influence of phlebotomy treatment on abnormal hypothalamic-pituitary function in genetic hemochromatosis.

To test the hypothesis that deficiencies in hypothalamic-pituitary function in genetic hemochromatosis result from cellular injury by iron deposits, we conducted provocative tests in 11 men with genetic hemochromatosis before and after iron depletion by serial phlebotomy and in 10 control subjects. We gave combination intravenous injections of insulin (0.15 U/kg), luteinizing hormone releasing hormone (LHRH, 100 micrograms), and thyrotropin releasing hormone (400 micrograms) and then measured plasma glucose, growth hormone, corticosteroids, follicle-stimulating hormone, luteinizing hormone, prolactin, and thyroid-stimulating hormone at 30-minute intervals for 90 minutes. Phlebotomy caused a substantial decrease in median values for serum ferritin, deferoxamine-chelatable iron, and hepatic iron concentration. Before phlebotomy, stimulation by hypoglycemia and thyrotropin releasing hormone caused significantly less secretion of growth hormone (P = 0.004) and prolactin (P = 0.03) in patients than in control subjects. No significant improvement was noted, however, in growth hormone or prolactin secretion after phlebotomy. Of the 11 patients, 7 had secondary hypogonadism, and phlebotomy did not improve the serum testosterone, follicle-stimulating hormone, luteinizing hormone, or responses to LHRH in any case. Chlorpromazine injections failed to elevate serum prolactin in all patients, and administration of levodopa caused a partial reduction in serum prolactin; thus, the hypothalamus may be an important locus of endocrine malfunction in these patients. We conclude that abnormal hypothalamic-pituitary function in genetic hemochromatosis is not substantially improved by iron-depletion therapy.

Adult↗
PubMed1982

Genetic control of immune response to myoglobin. Ir gene function in genetic restriction between T and B lymphocytes.

We studied the genetic restrictions on the interaction between T cells, B cells, and antigen-presenting cells (APC) involved in the H-2-linked Ir gene control of the in vitro secondary antibody response to sperm whale myoglobin (Mb) in mice. The B cells in this study were specific for Mb itself, rather than for a hapten unrelated to the Ir gene control, as in many previous studies. Low responder mice immunized in vivo with Mb bound to an immunogenic carrier, fowl gamma globulin (F gamma G), produced B cells competent to secrete anti-Mb antibodies in vitro if they received F gamma G-specific T cell help. However, (high-responder X low responder) F1 T cells from Mb-immune mice did not help these primed low responder (H-2k or H-2b) B cells in vitro, even in the presence of various numbers of F1 APC that were demonstrated to be component to reconstitute the response of spleen cells depleted by APC. Similar results were obtained with B6 leads to B6D2F1 radiation bone marrow chimeras. Genotypic low responder (H-2b) T cells from these mice helped Mb-primed B6D2F1B cells plus APC, but did not help syngeneic chimeric H-2b B cells, even in the presence of F1 APC. In contrast, we could not detect any Ir restriction on APC function during these in vitro secondary responses. Moreover, in the preceding paper, we found that low responder mice neonatally tolerized to higher responder H-2 had competent Mb-specific helper T cells capable of helping high responder but not low responder B cells and APC. Therefore, although function Mb-specific T cells and B cells both exist in low responder mice, the Ir gene defect is a manifestation of the failure of syngeneic collaboration between these two cell types. This genetic restriction on the interaction between T cells and B cells is consistent with the additional new finding that Lyb-5-negative B cells are a major participant in ths vitro secondary response because it is this Lyb-5-negative subpopulation of B cells that have recently been shown to require genetically restricted help. The Ir gene defect behaves operationally as a failure of low responder B cells to receive help from any source of Mb-specific T cells either high responder, low responder, or F1. The possible additional role of T cell-APC interactions, either during primary immunization in vivo or in the secondary culture is discussed.

Animals↗
PubMed1993

In vitro perfusion studies of resistance artery function in genetic hypertension.

To examine the function of resistance-sized arteries in hypertension under in vitro conditions that approximate in vivo conditions as much as possible, we mounted segments of second-order mesenteric resistance arteries from spontaneously hypertensive rats (SHR) and Wistar-Kyoto normotensive control rats aged 12 to 13 weeks in a perfusion myograph and exposed them to conditions of constant flow and pressure. The endothelial integrity was validated both functionally and histologically. Vascular sensitivity to norepinephrine was examined when the hormone was applied either intraluminally or extraluminally and before and after removal of the endothelium. Both endothelium-dependent and -independent dilatation was assessed by the intraluminal application of acetylcholine and sodium nitroprusside, respectively. Sodium nitroprusside was applied to arteries after endothelium removal. Arterial responses were measured by changes in intraluminal diameter recorded with a video camera and imaging system. Vessels from SHR demonstrated depressed endothelium-dependent relaxation but similar endothelium-independent relaxation and greater sensitivity to norepinephrine with both intraluminal and extraluminal application. Removal of the endothelium abolished the differences in sensitivity to norepinephrine between the two strains. The results demonstrate that resistance arteries from SHR when examined under in vitro perfusion display enhanced sensitivity to norepinephrine due to depressed endothelium-dependent dilatation, and the data suggest that functional modifications in the endothelium may play an important role in hypertensive vascular disease.

Acetylcholine↗
PubMed2026

Zebrafish relatives as models for functional comparative genetics and genomics.

Closely related species, such as danionin fishes of the Danio, Danionella and Devario genera, often differ in their biology despite their shared evolutionary history, providing a platform for defining the molecular basis for the divergence of phenotypic traits. Such an approach requires the availability of large-scale genomic data, which have been provided by recent reports detailing the genomes of several danionins. Facilitated by the large number of genetic tools that are available for manipulation of the most studied member of this subgroup - the zebrafish, Danio rerio - the danionins have emerged as a useful comparative model system. Here we review their phylogeny and outline the phenotypic traits that are distinct to individual species or genera. We highlight how functional genetic tools such as interspecies hybridization, mutagenesis and transgenesis, as well as the recently reported genome assemblies, have enabled new avenues for hypothesis-driven and technology-driven exploration that collectively establish danionins as important genetic models for understanding a wide range of evolutionary innovations.

Journal Article↗
PubMed2001

Polymorphisms of metabolizing enzymes and transporter proteins involved in the clearance of anticancer agents.

BACKGROUND: The efficacies and toxicities of anticancer agents vary greatly among patients. This is attributable to the activities of drug-metabolizing enzymes and membrane transporters, primarily determined by polymorphisms of the functions of genes encoding these proteins. DESIGN: We reviewed the available literature on drug-metabolizing enzymes and membrane transporters, especially their physiological functions, genetic and functional polymorphisms, and involvement in metabolism, pharmacokinetics and toxicity of anticancer agents. RESULTS: Nine enzymes metabolizing anticancer agents have been shown to have genetic polymorphisms: dihydropyrimidine dehydrogenase, cytochrome P450, NAD(P)H:quinone oxidoreductase 1, N-acetyltransferase 2, thiopurine methyltransferase, glutathione S-transferase, and uridine diphosphate glucuronosyltransferase. Decreased activities of these proteins can cause not only inherited metabolic disorders, but also extraordinarily severe toxicity in cancer patients given chemothearpy. Transporter proteins mediate cellular uptake and secretion of organic anions and cations. These proteins have recently been shown to play critical roles in the clearance of anticancer agents, although relations between patients' genetics backgrounds and the clinical significance of drug actions are poorly understood. CONCLUSIONS: Further studies should be focused on dosing and selection of anticancer agents, based on the type and extent of metabolic variation among individuals, in order to avoid adverse reactions and therapeutic failure.

Antineoplastic Agents↗
PubMed2001

The gastrointestinal ecosystem: a precarious alliance among epithelium, immunity and microbiota.

The gastrointestinal (GI) tract is a complex ecosystem generated by the alliance of GI epithelium, immune cells and resident microbiota. The three components of the GI ecosystem have co-evolved such that each relies on the presence of the other two components to achieve its normal function and activity. Experimental systems such as cell culture, germ-free animal models and intestinal isografts have demonstrated that each member of the GI ecosystem can follow a predetermined developmental pathway, even if isolated from the other components of the ecosystem. However, the presence of all three components is required for full physiological function. Genetic or functional alterations of any one component of this ecosystem can result in a broken alliance and subsequent GI pathology. A more detailed understanding of the interactions among microbiota, GI epithelium and the immune system should provide insight into multiple human disease states.

Animals↗