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At least 1,423 records · Page 79Linked to original sources
PubMed1974

Alloantiserum-induced inhibition of immune response gene product function. II. Genetic analysis of target antigens.

It has been previously demonstrated that alloantisera can specifically block the activation of T lymphocytes by antigens, the response to which is linked to the presence of histocompatibility (H) types against which the alloantisera are directed. Thus, strain 13 anti-2 serum can inhibit the activation of (2 x 13)F(1) T lymphocytes by a DNP derivative of a copolymer of L-glutamic acid and L-lysine (DNP-GL), an antigen the response to which is controlled by a 2-linked Ir gene. It was proposed that alloantisera can inhibit T-lymphocyte antigen recognition through interference with the activity of immune response (Ir) gene products. In order to further study whether the inhibitory antibodies within the alloantisera are directed against H antigens or against the products of the Ir genes, we have examined whether the anti-2 serum can inhibit the function of an Ir gene (the L-glutamic acid and L-alanine [GA] gene), which is normally linked to strain 2 H genes when this gene occurs in an outbred animal lacking strain 2 H genes. In the majority of cases, the anti-2 serum was capable of inhibiting the in vitro proliferative response to GA of T cells derived from animals that were GA(+)2(+), but the serum had little if any effect on the GA response of T cells from GA(+)2(-) animals. Furthermore, an antiserum prepared in strain 13 animals against the lymphoid cells of a GA(+)2(-) outbred animal was devoid of inhibitory activity on the GA response of cells from a (2 x 13)F(1), while an antiserum prepared in strain 13 animals against the lymphoid cells of a GA(+)2(+) outbred animal was capable of specifically inhibiting the response to GA. It thus appears that the inhibition of the GA response by the anti-2 serum is primarily mediated via antibodies directed toward strain 2 H antigens rather than antibodies specific for the product of the GA Ir gene. The mechanism of alloantiserum induced suppression of Ir gene function would then be by steric interference with the Ir gene product on the cell surface, rather than by direct binding to it. This conclusion implies that the products of both the H genes and the Ir genes are physically related on the cell surface. The implications of such a relationship in terms of the fluid-mosaic model of the lymphocyte surface are discussed.

Antibody Formation↗
PubMed2026

Mitochondrial Function-Related Genes in Sleep Disorders: A Multi-Omics Mendelian Randomization Study.

Mitochondrial dysfunction is linked to sleep disorders in previous report, but the potential roles of specific genes remain unclear. This study aimed to dissect different subtype-specific genetic associations and their underlying mechanisms. A multi-omics Summary-data-based Mendelian Randomization (SMR) approach was performed to identify potential causal links between mitochondrial function-related genes and sleep disorders. We integrated GWAS data from FinnGen database (the discovery set), independent GWAS datasets (covering different sleep-disorder subtypes and used for validation), and cis-QTLs (including mQTLs, eQTLs, and pQTLs) to perform systematic exploration. Specially, we performed targeted validation of tissue-specific effects, leveraging gene expression data from disease-relevant brain regions within the GTEx database. Our SMR analysis identified mitochondrial function-related genes potentially modulating sleep disorders across biological layers, initially identifying 102 genes at the methylation level, 48 at the gene expression level, and 6 at the protein abundance level. Integrative analysis subsequently prioritized DCXR and ACADVL and revealed their distinct, subtype-specific associations. DCXR exhibited a protective role in sleep apnea while ACADVL showed a paradoxical risk conferring role in daytime sleepiness. In addition, the analysis identified an epigenetic regulatory mechanism for DCXR in which its expression and protein levels are modulated by DNA methylation. Finally, validation in brain-hypothalamus tissue confirmed DCXR as a significant potential protective factor (OR = 0.929, 95% CI: 0.887-0.973, P_HEIDI = 0.999, FDR = 0.2449). Our findings implicate key mitochondrial genes, particularly DCXR and ACADVL, in the pathophysiology of specific sleep disorder subtypes, highlighting potential avenues for precision medicine. Clinical trial number: Not applicable.

Humans↗
PubMed1997

Angiotensin-converting enzyme gene mutations, blood pressures, and cardiovascular homeostasis.

A common polymorphism of the angiotensin-converting enzyme (ACE) gene (ACE in humans, Ace in mice) is associated with differences in circulating ACE levels that may confer a differential risk for cardiovascular diseases. To study the effects of genetically determined changes in Ace gene function within a defined genetic and environmental background, we have studied mice having one, two, or three functional copies of the Ace gene at its normal chromosomal location. ACE activities in the serum increased progressively from 62% of normal in the one-copy animals to 144% of normal in the three-copy animals (P < 10(-15), n = 132). The blood pressures of the mice having from one to three copies of the Ace gene did not differ significantly, but the heart rates, heart weights, and renal tubulointerstitial volumes decreased significantly with increasing Ace gene copy number. The level of kidney renin mRNA in the one-copy mice was increased to 129 +/- 9% relative to that of the normal two-copy mice (100 +/- 4%, P = .01, n = 16). We conclude that significant homeostatic adaptations successfully normalize the blood pressures of mice that have quantitative changes in Ace gene function. Our results suggest only that quantitative changes in expression of the Ace gene will observably affect blood pressures when accompanied by additional environmental or genetic factors that together with Ace exceed the capacity of the homeostatic mechanisms.

Animals↗
PubMed1999

The Drosophila cinnamon gene is functionally homologous to Arabidopsis cnx1 and has a similar expression pattern to the mammalian gephyrin gene.

Molybdoenzymes are involved in a variety of essential pathways including nitrate assimilation, sulfur and/or purine metabolism and abscisic acid biosynthesis. Most organisms produce several such enzymes requiring a molybdopterin cofactor for catalytic function. Mutations that result in a lack of the molybdopterin cofactor display a pleiotropic loss of molybdoenzyme activities, and this phenotype has been used to identify genes involved in cofactor biosynthesis or utilization. Although several cofactor genes have been analyzed in prokaryotes, much less is known concerning eukaryotic molybdenum cofactor (MoCF) genes. This work is focused on the Drosophila MoCF gene cinnamon (cin) which encodes a multidomain protein, CIN, that shows significant similarity to three proteins encoded by separate prokaryotic MoCF genes. These domains are also present in the product of cnx1, an Arabidopsis MoCF gene, and in GEPHYRIN, a rat protein thought to organize the glycine receptor, GlyR, within the postsynaptic membrane. Since this apparent consolidation of separate prokaryotic genes into a single eukaryotic gene is a feature of other conserved metabolic pathways, we wished to determine whether the protein's function is also conserved. This report shows that the plant gene cnx1 can rescue both enzymatic and physiological defects of Drosophila carrying cin mutations, indicating that the two genes serve similar or identical functions. In addition, we have investigated the relationship between CINNAMON and GEPHYRIN, using immunohistochemical methods to localize the CIN protein in Drosophila embryos. Most of the CIN protein, like GEPHYRIN in the rat CNS, is localized to the cell borders and shows a tissue-specific pattern of expression. In a parallel study, antibody to GEPHYRIN revealed the same tissue-specific expression pattern in fly embryos. Both antibodies show altered staining patterns in cin mutants. Taken together, these results suggest that GEPHYRIN may also carry out a MoCF-related function.

Aldehyde Oxidase↗
PubMed1999

Murine mentors: transgenic and knockout models of surgical disease.

OBJECTIVE: Transgenic and knockout technologies have emerged from the "molecular biology revolution" as unprecedented techniques for manipulating gene function in intact mice. The goals of this review are to outline the techniques of creating transgenic and knockout mice, and to demonstrate their use in elucidation of the molecular mechanisms underlying common surgical diseases. SUMMARY BACKGROUND DATA: Gain of gene function is created by transgenic technology, whereas gene function is ablated using gene knockouts. Each technique has distinctive applications and drawbacks. A unique feature of genetically manipulated mice is that combinatorial genetic experiments can be executed that precisely define the functional contribution of a gene to disease progression. Transgenic and knockout mouse models of wound healing, cardiovascular disease, transplant immunology, gut motility and inflammatory bowel disease, and oncology are beginning to illuminate the precise molecular regulation of these diseases. Transgenic technology has also been extended to larger mammals such as pigs, with the goal of using genetic manipulation of the xenogenic immune response to increase the availability of transplant organs. Continual refinements in gene manipulation technology in mice offer the opportunity to turn genes on or off at precise time intervals and in particular tissues, according to the needs of the investigator. Ultimately, investigation of disease development and progression in genetically manipulated mammals may delineate new molecular targets for drug discovery and provide novel platforms for drug efficacy screens. CONCLUSIONS: Emulation of human disease and therapy using genetically manipulated mammals fulfills a promise of molecular medicine: fusion of molecular biochemistry with "classical" biology and physiology. Surgeons have unique skills spanning both worlds that can facilitate their success in this expanding arena.

Animals↗
PubMedDate not supplied

Positional candidate gene approach and functional genomics strategy in atopy gene discovery.

As part of our effort in searching for genetic factors contributing to the susceptibility to atopy and asthma, we have focused on a 'positional candidate' approach in identifying CC chemokine gene polymorphisms and their functional correlates. To date, a single-nucleotide polymorphism was found in the RANTES proximal promoter region, and a high degree of sequence variation was identified in the 3'-untranslated region -of the eotaxin gene. Also, we are pursuing a series of functional genomics' studies designed to identify differentially expressed genes in a panel of allergen-specific human Th2 cells and in antigen-induced hyperreactive murine airways. This is performed using a combination of protocols including suppression-subtractive hybridization and cDNA array hybridizations with 18,363 nonredundant sequences. A data base is being generated from a list of subtracted cDNA sequences and array-positive clones to categorize differentially expressed genes. Sequences are being placed in biologically relevant categories on the basis of function (i.e., receptor, signal transduction pathways, transcription, and translation). With the increasing amount of sequence information compiled by the Human Genome Project, it will be particularly challenging to integrate functional gene-mapping efforts to define and compare aberrant genotypes/phenotypes in atopic diseases.

Chemokine CCL5↗
PubMed2001

Functionally gene-linked polymorphic regions and genetically controlled neurotransmitters metabolism.

In clinical psychopharmacology, the existence of marked inter-individual differences in both outcome and side effects is a common observation. Consequently, pharmacogenetics has also gained an increasing interest in psychiatry. Recent exciting findings seem to suggest that the growing interest in regulatory regions of candidate genes and neurotransmitters metabolism, together with the application of sophisticated molecular approaches, may offer new opportunities in neuropsychopharmacology. Indeed, quantitative variation of gene expression and/or of neurotransmitters metabolism could better explain both psychopathology and clinical response to psychotropic drugs. Three functional polymorphisms, and their possible relationship with clinical variables, are discussed. The first is the 44-bp insertion/deletion reported in the promoter region of the serotonin transporter gene. A functional repeat polymorphism in the promoter region of the gene encoding for the enzyme monoamine oxidase A represents the second example. The last is a functional polymorphism within the coding region of the gene encoding for the enzyme catechol-O-methyltransferase

Animals↗
PubMed1999

Identification and characterisation of a cytochrome P450 gene and processed pseudogene from an arachnid: the cattle tick, Boophilus microplus.

We isolated and sequenced the first known cytochrome P450 gene and pseudogene from an arachnid, the cattle tick, Boophilus microplus. Both the gene and pseudogene belong to the family CYP4, but a new subfamily, CYP4W, had to be created for these genes because they are substantially different to other CYP4 genes. The gene, CYP4W1, has greatest homology with CYP4C1 from a cockroach, Blaberus discoidalis. The predicted molecular weight of the protein encoded by CYP4W1 (63 KDa) is greater than that of the other CYP4 genes. The pseudogene, CYP4W1P, is probably a processed pseudogene derived from the functional gene CYP4W1. This is only the third CYP processed pseudogene to be identified. The pseudogene is 98% identical to the functional gene, CYP4W1, therefore we hypothesise that this pseudogene evolved recently from the functional gene. The CYP4 genes from arthropods have diverged from each other more than those of mammals; consequently the phylogeny of the arthropod genes could not be resolved.

Amino Acid Sequence↗
PubMed2004

Immortalized mouse cell lines that lack a functional Rev3 gene are hypersensitive to UV irradiation and cisplatin treatment.

The catalytic subunit of polymerase zeta is encoded from the Rev3 gene. The enzyme is conserved through eukaryotic evolution and its main function appears to be translesion synthesis (TLS) over damaged bases that stall DNA replication. In non-vertebrate cells, inactivation of polymerase zeta results in a moderate hypersensitivity to DNA damage but no proliferative defect in the absence of exogenous damage. Mouse embryos that lack Rev3 however have a severe growth defect and are aborted at midgestation. This has suggested that polymerase zeta may be involved in vital processes in mammalian cells. Here we describe the establishment of immortalized mouse fibroblast cell lines that lack a functional Rev3 gene. These were established from homozygously Rev3-targeted mouse embryos that were also heterozygously targeted at the p53 locus, but the cell lines lost the wild type p53 allele during transformation. Cell lines in which the Rev3 gene is targeted on both alleles grow more slowly than control lines and the deficiency is also associated with an increased frequency of cells at the G2/M phase of the cell cycle and augmented apoptosis. Targeted cells are hypersensitive to UV irradiation and cisplatin treatment and arrest at the S or G2/M phase of the cell cycle if exposed to these treatments. Thus, although vital for murine embryonic development, polymerase zeta activity is not essential for continuous proliferation of transformed mammalian cells that lack p53. It does, however, appear to play an important role in allowing mammalian cells to tolerate DNA damage.

Animals↗
PubMed1997

Animal models in the study of the biological function of genes on human chromosome 21 and their role in the pathophysiology of Down syndrome.

Human chromosome 21 is the smallest human autosome and many important genetic/familial disorders map to this chromosome, e.g., familial amyotrophic lateral sclerosis (FALS), Down syndrome, Alzheimer's disease and some cases of Ewings sarcoma. Hence, the identification of genes localised to this chromosome and studies on their normal biological function and their role in disease is gaining momentum. The use of animal models to generate gain- and loss-of-function mutations is an important element of these studies on functionality/pathology and has yielded powerful insights. However, no animal model has yet been generated that exactly models any of the disorders associated with this chromosome. The major utility of the animal models has been to illuminate the biological functions of genes and the causation of pathophysiology of diseases associated with genes on this chromosome.

Animals↗
PubMed2001

Zebrafish--an emerging genetic model for the study of cytokines and hematopoiesis in the era of functional genomics.

Now that whole genomes are sequenced, the identification of gene function rather than gene discovery is a major challenge. Saturation mutagenesis and screening for mutant phenotypes are methods that allow sampling of the genome for lesions in genes critical for particular physiological processes. This approach promises to provide new insights into gene function, even for molecularly well-characterized processes such as hematopoiesis and cytokine signaling. Animal models for such genetic approaches have traditionally included Drosophila and the mouse. Recently, the zebrafish (Danio rerio) has emerged as a flexible and informative vertebrate for genetic studies. Zebrafish hematopoiesis has a morphological and molecular complexity closer to that of mammals than does Drosophila, providing scope for recognizing mutant zebrafish phenotypes representing finely tuned lesions in these processes. Compared to mice, zebrafish represent an economical, flexible, and genetically tractable animal model for mutagenesis studies. The structure of the teleost genome creates several phylogenetic issues in assessing zebrafish and piscine orthologues and paralogues of known mammalian genes, here exemplified by a cytokine ligand (interleukin-1beta), kinase receptors (c-kit and c-fins), and a family of intracellular signaling molecules (JAK kinases). Several anemic zebrafish mutants are now genetically characterized, and others present hematopoietic phenotypes that promise novel insights into the regulation of hematopoiesis.

Animals↗
PubMed1990

Identification and characterization of a functional nodD gene in Azorhizobium caulinodans ORS571.

Azorhizobium caulinodans ORS571, a bacterium capable of nodulating roots and stems of the tropical legume Sesbania rostrata, has been shown to have no nodD-like gene located immediately upstream from its common nodABC locus. A clone carrying a functional nodD gene of strain ORS571 has now been isolated from a pLAFR1 gene library by screening for naringenin-induced expression of the common nod genes in an Agrobacterium background. Tn5 mutagenesis of the cloned insert DNA delimited the inducing activity to a +/- 0.8-kilobase-pair fragment. One of the Tn5 insertions in the activator locus was homogenotized in the ORS571 genome. This resulted in a mutant strain (ORS571-3) that was unable to induce common nod gene expression in the presence of host plant exudate or the flavanone naringenin and that had lost the capacity to nodulate the roots and stems of S. rostrata. Complementation of both mutant phenotypes was achieved upon introduction of the cloned nodD gene. Sequencing of the nodD locus indicated the presence of a single, 942-base-pair-long open reading frame (ORFD) with significant homology to the nodD gene of (brady)rhizobia. The level of homology, however, is the lowest thus far reported for this kind of gene. ORFD most likely initiates translation with a TTG start codon. Upstream from ORFD, a divergently oriented nod box-like sequence is present, the function of which remains to be determined.

Amino Acid Sequence↗
PubMed1985

How many processed pseudogenes are accumulated in a gene family?

A simple kinetic model is developed that describes the accumulation of processed pseudogenes in a functional gene family. Insertion of new pseudogenes occurs at rate v per gene and is countered by spontaneous deletion (at rate delta per DNA segment) of segments containing processed pseudogenes. If there are k functional genes in a gene family, the equilibrium number of processed pseudogenes is k(v/delta), and the percentage of functional genes in the gene family at equilibrium is 1/[1 + (v/delta)]. v/delta values estimated for five gene families ranged from 1.7 to 15. This fairly narrow range suggests that the rates of formation and deletion of processed pseudogenes may be positively correlated for these families. If delta is sufficiently large relative to the per nucleotide mutation rate mu (delta greater than 20 mu), processed pseudogenes will show high homology with each other, even in the absence of gene conversion between pseudogenes. We argue that formation of processed pseudogenes may share common pathways with transposable elements and retroviruses, creating the potential for correlated responses in the evolution of processed pseudogenes due to direct selection for control of transposable elements and/or retroviruses. Finally, we discuss the nature of the selective forces that may act directly or indirectly to influence the evolution of processed pseudogenes.

Animals↗
PubMed1988

Chromosomal localization and racial distribution of the polymorphic human dihydrofolate reductase pseudogene (DHFRP1).

The human dihydrofolate reductase (DHFR) gene family comprises one functional gene and at least four intronless processed pseudogenes. The functional DHFR gene is on chromosome 5, and DHFRP4 is on chromosome 3. Using in situ hybridization, we have now localized the functional DHFR gene to the region q11.1-q13.3 on chromosome 5. By genomic DNA analysis of a panel of human X rodent somatic-cell hybrids, we determined the chromosomal assignment of the DHFRP1 pseudogene to chromosome 18 and that of the DHFRP2 pseudogene to chromosome 6. The DHFRP1 pseudogene exhibits a novel form of polymorphism in humans in that it is present in the DNA of some individuals and absent in that of others. We investigated the racial distribution of this pseudogene in five racial groups. The allelic frequency as defined by analysis of 180 chromosomes was found to be 94% in Mediterraneans, 77% in Asian Indians, 67% in Chinese, 57% in Southeast Asians, and 32% in American blacks. These data suggest that the transposition of this "perfect" pseudogene occurred prior to the inception of the human racial groups.

Animals↗
PubMed1983

Anaerobic cultures of Salmonella typhimurium do not exhibit inducible proteolytic function of the recA gene and recBC function.

In a strict anaerobic environment, lack of expression of bacterial recBC function and recA regulatory functions for the SOS repair system is demonstrated by the use of the carcinogenesis-mutagenesis assay and Salmonella phage P22 mutants requiring these host functions for replication. Therefore, we suggest that error-prone repair (SOS repair) is confined to aerobic environments in facultative anaerobes.

Aerobiosis↗
PubMed2002

Application of physiological genomics to the microcirculation.

Physiological genomics represents a new challenge in the biological sciences-the quest to define the functions of thousands of genes that will emerge from the sequencing of the human genome and the genomes of other model organisms. Because the attention of the scientific community has focused on this task, new tools that will allow high-efficiency identification of gene function are being developed at remarkable speed. Physiological genomic approaches to understanding integrated systems function are now becoming widely used in many areas of biological research. The availability of genomic information across species has now revealed a striking degree of conservation of both gene order and function, allowing researchers to easily move from model organisms to man in the hunt for gene function. Physiological genomics approaches in the cardiovascular system have focused on disease-based models and the behavior of large vessels. In the microcirculation, genomic studies have largely been confined to the use of single gene knockouts or to the study of angiogenesis. This review summarizes the strategies for physiological genomics that are appropriate to the study of the microcirculation and discusses several key discoveries that have been made by using these approaches.

Animals↗
PubMed2005

Get ready to GO! A biologist's guide to the Gene Ontology.

The Gene Ontology (GO) project provides a controlled vocabulary to facilitate high-quality functional gene annotation for all species. Genes in biological databases are linked to GO terms, allowing biologists to ask questions about gene function in a manner independent of species. This tutorial provides an introduction for biologists to the GO resources and covers three of the most common methods of querying GO: by individual gene, by gene function and by using a list of genes. [For the sake of brevity, the term 'gene' is used throughout this paper to refer to genes and their products (proteins and RNAs). GO annotations are always based on the characteristics of gene products, even though it may be the gene that is cited in the annotation.].

Abstracting and Indexing↗
PubMed1994

Skeletal muscle overload upregulates the sarcoplasmic reticulum slow calcium pump gene.

Functional data suggest that the kinetics of force production and relaxation are slowed in hypertrophied skeletal muscle because of chronic overload. The purpose of this study was to determine whether gene expression of the slow/cardiac isoform of the sarcoplasmic reticulum (SR) Ca(2+)-adenosinetriphosphatase (ATPase) pump is upregulated in overloaded fast-twitch plantaris muscles. Increased active muscle loading was induced in rat plantaris muscles bilaterally by surgical removal of gastrocnemius and soleus muscles. Mass of the plantaris muscle was 80% greater 5 wk after surgery than in age-matched unoperated control rats (P < 0.05). Expression of the slow pump mRNA was 135% greater in hypertrophied muscles, as determined from autoradiograms of Northern blots with use of a cDNA probe specific for the slow/cardiac isoform. A monoclonal antibody (7E6) was used to quantify slow Ca2+ pump in SR vesicles with use of Western blot analysis. Densitometry of blots showed that the relative expression of the slow pump protein was 130% greater in hypertrophied plantaris muscles. Expression of the fast SR Ca2+ pump protein isoform, assessed using monoclonal antibody A52, was 25% less in hypertrophied than in control muscles. The Ca2+ uptake rate and ATPase activity of SR vesicles was approximately 15% lower in hypertrophied plantaris muscles (P < 0.05). Differential phospholamban expression could not account for changes in SR Ca2+ handling, because it could not be detected in rat slow- or fast-twitch skeletal muscle.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗