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At least 757 records · Page 42Linked to original sources
PubMed2002

Distinct rac activation pathways control Caenorhabditis elegans cell migration and axon outgrowth.

Rac GTPases act as molecular switch in various morphogenic events. However, the regulation of their activities during the development of multicellular organisms is not well understood. Caenorhabditis elegans rac genes ced-10 and mig-2 have been shown to act redundantly to control P cell migration and the axon outgrowth of D type motoneurons. We showed that ced-10 and mig-2 also control amphid axon outgrowth and amphid dendrite fasciculation in a redundant fashion. Our biochemical and genetic data indicate that unc-73, which encodes a protein related to Trio-like guanine nucleotide exchange factor, acts as a direct activator of ced-10 and mig-2 during P cell migration and axon outgrowth of D type motoneurons and amphid sensory neurons. Furthermore, rac regulators ced-2/crkII and ced-5/dock180 function genetically upstream of ced-10 and mig-2 during axon outgrowth of D type motoneurons and act upstream of mig-2 but not ced-10 during P cell migration. However, neither ced-2/crkII nor ced-5/dock180 is involved in amphid axon outgrowth. Therefore, distinct rac regulators control ced-10 and mig-2 differentially in various cellular processes.

Animals↗
PubMed1987

Genes in subdivision 1B of the Drosophila melanogaster X-chromosome and their influence on neural development.

Genes within subdivision 1B of the X-chromosome of Drosophila melanogaster are known to affect the development of both the central (CNS) and the peripheral (PNS) embryonic nervous system. In this paper we describe the phenotypes of embryos hemizygous for terminal and interstitial deletions of region 1B1-1B10, and of embryos carrying different mutations in certain genes of this region. A minimum of 6 genetic functions that are involved in neural development can be defined in this region. Three of these genes, mapping to the l'sc(a gene of the achaete-scute complex, ASC),elav and vnd loci, affect major and apparently different aspects of CNS development. Two additional genes of the ASC, ac and sc alpha, also play a role in CNS development, although their participation can only be demonstrated under certain conditions. Finally, in the rightmost part of the region uncovered by the deletion Df(1)260.1, two not yet well separated functions are found to be required for embryonic CNS and compound eye development, respectively. Of these two functions, the embryonic one is similar to the ones of ac and sc alpha, and can therefore be considered as a new element of the ASC.

Animals↗
PubMed1998

Influence of body height on pulsatile arterial hemodynamic data.

OBJECTIVES: This study sought to present evidence that short stature is a hemodynamic liability, which could explain in part the inverse relation between body height and cardiovascular risk. BACKGROUND: Other explanations for the association of short stature with increased cardiovascular risk include advancing age, reduced pulmonary function, genetic factors, poor childhood nutrition and small-caliber coronary arteries. This study adds another factor-the physiologic effects of reduced body height on the arterial tree, which increase left ventricular work and jeopardize myocardial perfusion. METHODS: Four hundred two subjects were studied: 149 with end-stage renal disease and 253 with normal renal function. Measurements included blood pressure, body height, cardiac cycle length, carotid to femoral artery pulse wave velocity, carotid artery pulse waves (by applanation tonometry) and the arrival time of reflected waves. Calculations included the carotid augmentation index, carotid artery compliance and the diastolic to systolic pressure-time ratio (an index of myocardial supply and demand). RESULTS: On linear and stepwise multiple regression, body height correlated with all variables except mean blood pressure. CONCLUSIONS: The early systolic arrival of reflected waves in short people in this group acts to stiffen the aorta and increase the pulsatile effort of the left ventricle, even at the same mean blood pressures. Short stature also induces a faster heart rate, which increases cardiac minute work and shorten diastole. Stiffening lowers the aortic diastolic pressure and, coupled with a shortened diastole, could adversely influence myocardial supply. Although indirect, this evidence supports a physiologic hypothesis for the body height-cardiovascular risk association.

Adolescent↗
PubMed2005

Divergent patterns of linkage disequilibrium and haplotype structure across global populations at the interleukin-13 (IL13) locus.

Interleukin-13 (IL-13) is a cytokine involved in Th2 immune response, which plays a role in susceptibility to infection by extracellular parasites as well as complex diseases of the immune system such as asthma and allergies. To determine the pattern of genetic diversity at the IL13 gene, we sequenced 3950 bp encompassing the IL13 gene and its promoter in 264 chromosomes from individuals originating from East and West Africa, Europe, China and South America. Thirty-one single-nucleotide polymorphisms (SNPs) arranged in 88 haplotypes were indentified, including the nonsynonymous substitution Arg130Gln in exon 4, which differs in frequency across ethnic groups. We show that genetic diversity and linkage disequilibrium (LD) are not evenly distributed across the gene and that sites in the 5' and 3' regions of the gene show strong differentiation among continental groups. We observe a divergent pattern of haplotype variation and LD across geographic regions and we identify a set of htSNPs that will be useful for functional genetic association studies of complex disease. We use several statistical tests to distinguish the effects of natural selection and demographic history on patterns of genetic diversity at the IL13 locus.

Africa↗
PubMed2004

hunchback is required for suppression of abdominal identity, and for proper germband growth and segmentation in the intermediate germband insect Oncopeltus fasciatus.

Insects such as Drosophila melanogaster undergo a derived form of segmentation termed long germband segmentation. In long germband insects, all of the body regions are specified by the blastoderm stage. Thus, the entire body plan is proportionally represented on the blastoderm. This is in contrast to short and intermediate germband insects where only the most anterior body regions are specified by the blastoderm stage. Posterior segments are specified later in embryogenesis during a period of germband elongation. Although we know much about Drosophila segmentation, we still know very little about how the blastoderm of short and intermediate germband insects is allocated into only the anterior segments, and how the remaining posterior segments are produced. In order to gain insight into this type of embryogenesis, we have investigated the expression and function of the homolog of the Drosophila gap gene hunchback in an intermediate germ insect, the milkweed bug, Oncopeltus fasciatus. We find that Oncopeltus hunchback (Of'hb) is expressed in two phases, first in a gap-like domain in the blastoderm and later in the posterior growth zone during germband elongation. In order to determine the genetic function of Of'hb, we have developed a method of parental RNAi in the milkweed bug. Using this technique, we find that Oncopeltus hunchback has two roles in anterior-posterior axis specification. First, Of'hb is required to suppress abdominal identity in the gnathal and thoracic regions. Subsequently, it is then required for proper germband growth and segmentation. In milkweed bug embryos depleted for hunchback, these two effects result in animals in which a relatively normal head is followed by several segments with abdominal identity. This phenotype is reminiscent to that found in Drosophila hunchback mutants, but in Oncopeltus is generated through the combination of the two separate defects.

Abdomen↗
PubMed2004

D1S80 single-locus discrimination among African populations.

The highly polymorphic D1S80 locus has no known genetic function. However, this variable number of tandem repeats (VNTR) locus has been highly valuable in forensic identification. In this study we report the allele and genotype frequencies of five African populations (Benin, Cameroon, Egypt, Kenya, and Rwanda), which can be used as databases to help characterize populations and identify individuals. The allele frequencies were used to infer genetic associations through phylogenetic, principal component, and G test statistical analyses. Compliance with Hardy-Weinberg equilibrium expectations was determined as were F(ST) estimates, theta p values, and power of discrimination assessment for each population. Our analyses of 28 additional populations demonstrate that the D1S80 locus alone can be used to discriminate geographic and ethnic groups. We have generated databases useful for human identification and phylogenetic studies.

Africa↗
PubMed1998

Physical and functional mapping of a tumor suppressor locus for renal cell carcinoma within chromosome 3p12.

Using a functional genetic approach, we previously identified a novel genetic locus, NRC-1 (Nonpapillary Renal Cell Carcinoma 1), that mediated tumor suppression and rapid cell death of renal cell carcinoma (RCC) cells in vivo. For these experiments, a defined subchromosomal fragment of human chromosome 3p was transferred into a sporadic RCC cell line via microcell fusion, and microcell hybrid clones were tested for tumorigenicity in vivo. The results indicated functional evidence for a novel tumor suppressor locus within the 3p14-p12 interval known to contain the most common fragile site of the human genome (FRA3B), the FHIT gene, and the breakpoint region associated with the familial form of RCC. We now report the physical mapping of the NRC-1 critical region by detailed microsatellite analyses of novel microcell hybrid clones containing transferred fragments of chromosome 3p in the RCC cell background that were phenotypically suppressed or unsuppressed for tumorigenicity in vivo. The results limit the region containing the tumor suppressor locus within chromosome 3p12. The FHIT gene, FRA3B, and the familial RCC breakpoint region were excluded from the NRC-1 critical region. Furthermore, the NRC-1 locus falls within a well-characterized homozygous deletion region of 5-7 Mb associated with a small cell lung carcinoma cell line, U2020, suggesting that a more general tumor suppressor gene may reside in this region.

Acid Anhydride Hydrolases↗
PubMed2003

The functional integrity of the serpin domain of C1-inhibitor depends on the unique N-terminal domain, as revealed by a pathological mutant.

C1-inhibitor (C1-Inh) is a serine protease inhibitor (serpin) with a unique, non-conserved N-terminal domain of unknown function. Genetic deficiency of C1-Inh causes hereditary angioedema. A novel type of mutation (Delta 3) in exon 3 of the C1-Inh gene, resulting in deletion of Asp62-Thr116 in this unique domain, was encountered in a hereditary angioedema pedigree. Because the domain is supposedly not essential for inhibitory activity, the unexpected loss-of-function of this deletion mutant was further investigated. The Delta 3 mutant and three additional mutants starting at Pro76, Gly98, and Ser115, lacking increasing parts of the N-terminal domain, were produced recombinantly. C1-Inh76 and C1-Inh98 retained normal conformation and interaction kinetics with target proteases. In contrast, C1-Inh115 and Delta 3, which both lack the connection between the serpin and the non-serpin domain via two disulfide bridges, were completely non-functional because of a complex-like and multimeric conformation, as demonstrated by several criteria. The Delta 3 mutant also circulated in multimeric form in plasma from affected family members. The C1-Inh mutant reported here is unique in that deletion of an entire amino acid stretch from a domain not shared by other serpins leads to a loss-of-function. The deletion in the unique N-terminal domain results in a "multimerization phenotype" of C1-Inh, because of diminished stability of the central beta-sheet. This phenotype, as well as the location of the disulfide bridges between the serpin and the non-serpin domain of C1-Inh, suggests that the function of the N-terminal region may be similar to one of the effects of heparin in antithrombin III, maintenance of the metastable serpin conformation.

Amino Acid Sequence↗
PubMed1978

The transcription map of mouse mitochondrial DNA.

Nine transcripts complementary to mouse L cell mitochondrial DNA have been detected, sized and mapped to restriction fragments using the method of Berk and Sharp (1977). RNA isolated from L cell mitochondria was hybridized to 32P-labeled, cloned L cell mitochondrial DNA restriction fragments in 70% formamide under conditions 5 degrees C above the melting temperature of the DNA-DNA duplex, but approximately 15 degrees C below the melting temperature of the RNA-DNA duplex. The heteroduplexed material was then treated with the single-strand-specific nuclease S1, whick cleaves the single-stranded DNA not protected by RNA-DNA duplex formation into oligonucleotides and leaves intact 32P-labeled, single-stranded DNA replicas complementary to the transcripts. The single-stranded DNA replicas were then resolved and sized by alkaline agarose gel electrophoresis. Hybridization to strand-separated, 32P-labeled L cell mitochondria DNA restriction fragments under the same conditions showed that all nine transcripts hybridized exclusively to the heavy strand (H strand) of restriction fragments isolated as the dense strand from alkaline CsCl gradients, indicating that all stable transcripts 300 bases or longer detected by this technique originate from genes on the H strand. The two most abundant transcripts homologous to mitochondrial DNA map adjacent to the origin of replication. This result is consistent with map positions assigned to the large and small mitochondrial ribosomal RNAs isolated from Xenopus laevis and HeLa cells. Six of the other seven transcripts map continuously in approximately 40% of the genome. Only one transcript of 950 bases maps in the first quadrant of the genome as defined by the origin and direction of mitochondrial DNA replication, and it does not lie within the D loop region. The genetic function of the remaining 75% of this region of the genome is yet to be determined.

DNA Replication↗
PubMed1990

Structural and functional characterization of tnpI, a recombinase locus in Tn21 and related beta-lactamase transposons.

A novel discrete mobile DNA element from Tn21 from the plasmid R100.1 is described, and its mobilization function was confirmed experimentally. In addition, the element behaves as a recombinase-active locus (tnpI) which facilitates insertions of antibiotic resistance genes as modules or cassettes at defined hot spots or integration sites. A similar tnpI sequence was detected by DNA hybridization in a series of beta-lactamase transposons and plasmids and localized on their physical maps. The genetic function of the locus cloned from Tn21 into pACYC184 was tested for conduction and integration into the plasmids R388 and pOX38Km, and the results suggested recombinase-integrase activity and recA independence. DNA sequence analysis of the tnpI locus revealed no inverted or direct terminal repeats or transposition features of class I and class II transposons. The coding capacity revealed three putative open reading frames encoding 131, 134, and 337 amino acids. Orf3 encoded a putative polypeptide product of 337 amino acids that shared highly significant identity with the carboxyl region of integrase proteins. A comparison and an alignment of the tnpI locus from Tn21 and its flanking sequences identified similar sequences in plasmids and in transposons. The alignment revealed discrete nucleotide changes in these tnpI-like loci and a conserved 3' and 5' GTTA/G hot spot as a duplicated target site. Our data confirm the remarkable ubiquity of tnpI associated with antibiotic resistance genes. We present a model of transposon modular evolution into more complex multiresistant units via tnpI and site-specific insertions, deletions, and DNA rearrangements at this locus.

Amino Acid Sequence↗
PubMed1995

Molecular characterization of a deletion-prone region of plasmid pAE1 of Alcaligenes eutrophus H1.

A 93-kb region (D region) of plasmid pAE1 of Alcaligenes eutrophus H1 has been found to have a high rate of spontaneous deletion. In this study, we constructed a restriction endonuclease map and carried out limited sequencing of an approximately 100-kb region from pAE1 which includes the D region (the deleted region) in order to detect and characterize repetitive sequences. Two types of repetitive sequences, the R1 and R2 sequences, were observed to flank the D region; within the D region are three copies of insertion element ISAE1. The R1 and R2 sequences are arranged in direct and inverted orientations, respectively. Molecular analysis of the end product of the deletion is consistent with the hypothesis that the loss of the D-region DNA is the result of recombination between two copies of the R1 sequence. The R1 sequence encodes a 415-amino-acid protein which exhibits substantial sequence similarity to the lambda integrase family of site-specific recombinases. Its genetic function remains to be determined.

Alcaligenes↗
PubMed2006

Geographic patterns of microsatellite variation in Boechera stricta, a close relative of Arabidopsis.

The genus Boechera is a widespread North American group with great potential for studies of ecology and evolution: Boechera is closely related to Arabidopsis and exhibits different ecological and reproductive strategies. Boechera stricta (previously Arabis drummondii) is a morphologically and genetically well-defined, perennial crucifer species. Fifteen natural populations of diploid individuals from the Rocky Mountains were analysed using 21 microsatellite loci. In accordance with our expectation for this predominately inbreeding species, a high F IS value (0.89) was observed. Furthermore, populations of B. stricta were highly differentiated, as indicated by F ST = 0.56. Three clusters were identified using structure- the majority of populations belonged to either the Northern or Southern cluster. Together, the north-south partitioning and evenness of genetic variation across the two clusters suggested multiple refugia for this perennial herb in the Rocky Mountains. Pleistocene glaciation, together with the topographically and climatologically heterogeneous cordillera, has profoundly influenced the genetic architecture of B. stricta. Genetic population structure was also influenced by relatively recent genome admixture at two levels: within species (involving individuals from the Northern and Southern clusters) and between species (with the hybridization of B. stricta and Boechera holboellii). This complexity of population structure at presumably neutral microsatellite loci located throughout the genome in B. stricta provides a baseline against which to test whether functional genetic variation is undergoing local adaptive evolution throughout the natural species range.

Brassicaceae↗
PubMed1994

Anti-IL-2 receptor monoclonal antibody (anti-Tac) treatment of T-cell lymphoma.

The abnormal and activated T cells in certain neoplasms of mononuclear cells, select autoimmune disorders, and organ allograft rejection express the IL-2R alpha subunit identified by the anti-Tac monoclonal antibody. In contrast, normal resting cells do not express this inducible receptor. Patients with ATL were treated with different forms of IL-2R-directed therapy to exploit the difference in IL-2R expression between normal and malignant cells. Using the unmodified anti-Tac monoclonal antibody, 7 of 19 patients with ATL treated have undergone a remission (2 cases complete), with no toxicity observed. Unmodified murine monoclonal antibodies are limited by their immunogenicity and poor effector functions. Genetic engineering was used to produce humanized anti-Tac that contains the complementarity-determining regions from the mouse with the remainder of the molecule derived from human IgG1-kappa. This antibody is less immunogenic than the murine version, has improved pharmacokinetics, and, in contrast with the parent antibody, manifests ADCC with human mononuclear cells. To enhance its effector function, anti-Tac was armed with toxins or with alpha- and beta-emitting radionuclides. In a clinical trial with 90Y-anti-Tac at the doses used (5, 10, and 15 microCi), 11 of the 17 patients with ATL underwent a partial or sustained a complete remission. Thus, the clinical application of IL-2R-directed therapy represents a new perspective for the treatment of T-cell lymphomas, including HTLV-I-associated ATL.

ADP Ribose Transferases↗
PubMed2000

A misexpression screen identifies genes that can modulate RAS1 pathway signaling in Drosophila melanogaster.

Differentiation of the R7 photoreceptor cell is dependent on the Sevenless receptor tyrosine kinase, which activates the RAS1/mitogen-activated protein kinase signaling cascade. Kinase suppressor of Ras (KSR) functions genetically downstream of RAS1 in this signal transduction cascade. Expression of dominant-negative KSR (KDN) in the developing eye blocks RAS pathway signaling, prevents R7 cell differentiation, and causes a rough eye phenotype. To identify genes that modulate RAS signaling, we screened for genes that alter RAS1/KSR signaling efficiency when misexpressed. In this screen, we recovered three known genes, Lk6, misshapen, and Akap200. We also identified seven previously undescribed genes; one encodes a novel rel domain member of the NFAT family, and six encode novel proteins. These genes may represent new components of the RAS pathway or components of other signaling pathways that can modulate signaling by RAS. We discuss the utility of gain-of-function screens in identifying new components of signaling pathways in Drosophila.

Amino Acid Sequence↗
PubMedDate not supplied

Intraspecific nucleotide sequence variability surrounding the origin of replication in human mitochondrial DNA.

We have cloned the major noncoding region of human mitochondrial DNA (mtDNA) from 11 human placentas. Partial nucleotide sequences of five of these clones have been determined and they share a maximum of 900 bp around the origin of H-strand replication. Alignment of these sequences with others previously determined has revealed a striking pattern of nucleotide substitutions and insertion/deletion events. The level of sequence divergence significantly exceeds the reported estimates of divergence in coding regions. Two particularly hypervariable regions have also been defined. More than 96% of the base changes are transitions, and length alterations have occurred exclusively by addition or deletion of mono-or dinucleotide segments within serially repeating stretches. This region of the mitochondrial genome, which contains the initiation sites for replication and transcription, is the least conserved among species with respect to both sequence and length (Anderson et al., 1981; Walberg and Clayton, 1981). Despite this overall lack of primary sequence conservation, several consistencies appear among the available mammalian mtDNA sequences within this region. Between species, a conserved linear array of characteristic stretches exists which nonetheless differ in primary sequence. Among humans, several conserved blocks of nucleotides appear within domains deleted from the mtDNA of other species. These observations are consistent with both a species-specificity of nucleotide sequence, and a preservation of the necessary genetic functions among species. This provides a model for the evolution of protein-nucleic acid interactions in mammalian mitochondria.

Amino Acid Sequence↗
PubMedDate not supplied

[HLA-DR antigens: cellular expression and molecular structure].

The HLA complex encodes several sets of membrane glycoproteins with extensive genetic, functional and structural polymorphism. The HLA-D region and its products, the HLA-DR antigens, are central in immune phenomena. They control the mixed lymphocyte reaction, the graft versus host reaction in vivo and cell/cell interactions involved in immune responses. Monoclonal anti HLA-DR antigens have been used to investigate the expression and synthesis of human Ia antigens on B and active T lymphocytes and macrophages. They were subsequently used in structural studies of HLA-DR antigens analysed by two-dimensional gel electrophoresis. The HLA-DR antigens are composed of a bimolecular complex of two non-covalently linked subunits: a 34,000 dalton alpha chain and a 29,000 dalton beta chain. Glycosylation steps and molecular maturation include the addition of oligosaccharides and sialic acid residues to the native polypeptide chain. The structural polymorphism which correlates with the serologically defined HLA-DR determinants is localized on the beta chain and is of polypeptidic origin. A third component of the HLA-DR antigen is described: the 31,000-dalton "invariant" chain. Its peptide composition, glycosylation pattern and expression are reported. Homologies of HLA-DR antigens with the mouse Ia antigens are discussed. Structural studies of the human Ia system are important in dissecting the functional role of the different epitopes of the HLA-DR molecules.

Animals↗
PubMed2002

Serotonin promotes G(o)-dependent neuronal migration in Caenorhabditis elegans.

BACKGROUND: The directed migration of neurons during development requires attractive and repulsive cues that control the direction of migration as well as permissive cues that potentiate cell motility and responsiveness to guidance molecules. RESULTS: Here, we show that the neurotransmitter serotonin functions as a permissive signal for embryonic and postembryonic neuronal migration in the nematode C. elegans. In serotonin-deficient mutants, the migrations of the ALM, BDU, SDQR, and AVM neurons were often foreshortened or misdirected, indicating a serotonin requirement for normal migration. Moreover, exogenous serotonin could restore motility to AVM neurons in serotonin-deficient mutants as well as induce AVM-like migrations in the normally nonmotile neuron PVM; this indicates that serotonin was functioning as a permissive cue to enable neuronal motility. The migration defects of serotonin-deficient mutants were mimicked by ablations of serotonergic neuroendocrine cells, implicating humoral release of serotonin in these processes. Mutants defective in G(q) and G(o) signaling, or in N-type voltage-gated calcium channels, showed migration phenotypes similar to serotonin-deficient mutants, and these molecules appeared to genetically function downstream of serotonin in the control of neuronal migration. CONCLUSIONS: Thus, serotonin is important for promoting directed neuronal migration in the developing C. elegans nervous system. We hypothesize that serotonin may promote cell motility through G protein-dependent modulation of voltage-gated calcium channels in the migrating cell.

Animals↗
PubMedDate not supplied

[Absence of an association between the C825T polymorphism of the G-protein beta 3 subunit and salt-sensitivity in essential arterial hypertension].

The genetic functional variant C for T in position 825 of the gene encoding G protein beta 3 subunit, GNB3, has been associated with enhanced G protein activation, cell growth and proliferation. This phenotype is associated with enhanced G protein activation and Na(+)-H+ exchanger activity in cells from hypertensive patients. Salt sensitivity affects approximately 50% of hypertensive patients and constitutes an intermediate phenotype determined in part by genetic factors. An association between enhanced Na(+)-H+ exchanger activity and salt sensitivity has been previously reported. The aim of the present study was to investigate the possible association between the G protein polymorphism and salt sensitivity in patients with essential hypertension. A total of 46 patients were studied and classified according to their blood pressure response to a change in sodium intake from low (20 mmol/day) to high (260 mmol/day) into salt sensitive (SS) (n = 20) and salt resistant (SR) (n = 26). GNB3 polymorphism was determined by PCR of genomic DNA and restriction digestion with BseDI. The genotypes distribution among the SS hypertensives was: 8 CC and 12 CT + TT, whereas in SR was: 10 CC and 16 CT + TT (p = 0,577). 24 h mean blood pressure response to salt in the whole group was not different among the different genotypes: CC 4.1 +/- 5.4 mmHg compared to CT + TT 2.9 +/- 6.3 mmHg (p = 0.51). There were no significant differences in the salt induced changes in plasma renin activity, aldosterone, ANP or noradrenaline among the different genotypes. These results indicate that the GNB3 C825T polymorphism has no major influence on the pressor response to salt in essential hypertension and therefore do not support its usefulness as an early genetic marker of salt sensitivity in this disease.

Adult↗