Showing papers by "French Institute of Health and Medical Research published in 1995"
TL;DR: The inverted duplication of a 500 kb element in normal chromosomes is described and the critical region is narrowed to 140 kb within the telomeric region, suggesting that this gene, termed the survival motor neuron (SMN) gene, is an SMA-determining gene.
3,401 citations
TL;DR: Recently, glutamate has been shown to regulate ion channels and enzymes producing second messengers via specific receptors coupled to G-proteins, and the existence of these receptors is changing views on the functioning of fast excitatory synapses.
2,304 citations
TL;DR: The phosphorylation of the human estrogen receptor (ER) serine residue at position 118 is required for full activity of the ER activation function 1 (AF-1), which is modulated by the phosphorylated Ser118 through the Ras-MAPK cascade of the growth factor signaling pathways.
Abstract: The phosphorylation of the human estrogen receptor (ER) serine residue at position 118 is required for full activity of the ER activation function 1 (AF-1). This Ser118 is phosphorylated by mitogen-activated protein kinase (MAPK) in vitro and in cells treated with epidermal growth factor (EGF) and insulin-like growth factor (IGF) in vivo. Overexpression of MAPK kinase (MAPKK) or of the guanine nucleotide binding protein Ras, both of which activate MAPK, enhanced estrogen-induced and antiestrogen (tamoxifen)-induced transcriptional activity of wild-type ER, but not that of a mutant ER with an alanine in place of Ser118. Thus, the activity of the amino-terminal AF-1 of the ER is modulated by the phosphorylation of Ser118 through the Ras-MAPK cascade of the growth factor signaling pathways.
1,967 citations
TL;DR: The aim of this study was to evaluate the accuracy of a new automatic device to measure it and then to analyze the major determinants of pulse wave velocity by application of this device in a large population.
Abstract: Pulse wave velocity is widely used as an index of arterial distensibility. The aim of this study was to evaluate the accuracy of a new automatic device to measure it and then to analyze the major determinants of pulse wave velocity by application of this device in a large population. We evaluated the accuracy of on-line and computerized measurement of pulse wave velocity using an algorithm based on the time-shifted and repeated linear correlation calculation between the initial rise in pressure waveforms compared with the reference method (manual calculation) in 56 subjects. The results, analyzed according to the recommendations of Bland and Altman, showed a mean difference of -0.20 +/- 0.45 m/s for the mean carotid-femoral pulse wave velocity values (reference method, 11.05 +/- 2.58 m/s; automatic device, 10.85 +/- 2.44 m/s). The interreproducibility and intrareproducibility of measurements by each method were analyzed with the use of the repeatability coefficient according to the British Standards Institution. The interobserver repeatability coefficient was 0.947 for the manual method and 0.890 for the automatic, and intraobserver repeatability coefficients were 0.938 and 0.935, respectively. We evaluated the major determinants of the carotid-femoral pulse wave velocity measured by the automatic method in a separate study performed in 418 subjects of both sexes without any cardiovascular treatment or complication (18 to 77 years of age; 98 to 222 mm Hg systolic and 62 to 130 mm Hg diastolic pressure).(ABSTRACT TRUNCATED AT 250 WORDS)
1,401 citations
TL;DR: In humans, neuropsychological studies of patients with lesions to the parietal lobule confirm that primitive shape characteristics of an object for grasping are analyzed in theParietal lobe, and also demonstrate that this 'pragmatic' analysis of objects is separated from the 'semantic' analysis performed in the temporal lobe.
1,368 citations
TL;DR: Fas expression and function were analyzed in three children (including two siblings) with a lymphoproliferative syndrome, two of whom also had autoimmune disorders as discussed by the authors, showing that a large deletion in the gene encoding Fas and no detectable cell surface expression characterized the most affected patient.
Abstract: Fas (also known as Apo1 and CD95) is a cell surface receptor involved in apoptotic cell death. Fas expression and function were analyzed in three children (including two siblings) with a lymphoproliferative syndrome, two of whom also had autoimmune disorders. A large deletion in the gene encoding Fas and no detectable cell surface expression characterized the most affected patient. Clinical manifestations in the two related patients were less severe: Fas-mediated apoptosis was impaired and a deletion within the intracytoplasmic domain was detected. These findings illustrate the crucial regulatory role of Fas and may provide a molecular basis for some autoimmune diseases in humans.
1,193 citations
TL;DR: Pup behavioral alterations, including trembling, difficulty in righting, and fearfulness were reversed by the serotonin synthesis inhibitor parachlorophenylalanine, and adults manifested a distinct behavioral syndrome, including enhanced aggression in males.
Abstract: Deficiency in monoamine oxidase A (MAOA), an enzyme that degrades serotonin and norepinephrine, has recently been shown to be associated with aggressive behavior in men of a Dutch family. A line of transgenic mice was isolated in which transgene integration caused a deletion in the gene encoding MAOA, providing an animal model of MAOA deficiency. In pup brains, serotonin concentrations were increased up to ninefold, and serotonin-like immunoreactivity was present in catecholaminergic neurons. In pup and adult brains, norepinephrine concentrations were increased up to twofold, and cytoarchitectural changes were observed in the somatosensory cortex. Pup behavioral alterations, including trembling, difficulty in righting, and fearfulness were reversed by the serotonin synthesis inhibitor parachlorophenylalanine. Adults manifested a distinct behavioral syndrome, including enhanced aggression in males.
1,165 citations
TL;DR: It is shown that ob gene exhibits diurnal variation, increasing during the night, after rats start eating, which is linked to changes in food intake, as fasting prevented the cyclic variation and decreased ob messenger RNA.
Abstract: Obesity is a disorder of energy balance, indicating a chronic disequilibrium between energy intake and expenditure. Recently, the mouse ob gene, and subsequently its human and rat homologues, have been cloned. The ob gene product, leptin, is expressed exclusively in adipose tissue, and appears to be a signalling factor regulating body-weight homeostasis and energy balance. Because the level of ob gene expression might indicate the size of the adipose depot, we suggest that it is regulated by factors modulating adipose tissue size. Here we show that ob gene exhibits diurnal variation, increasing during the night, after rats start eating. This variation was linked to changes in food intake, as fasting prevented the cyclic variation and decreased ob messenger RNA. Furthermore, refeeding fasted rats restored ob mRNA within 4 hours to levels of fed animals. A single insulin injection in fasted animals increased ob mRNA to levels of fed controls. Experiments to control glucose and insulin independently in animals, and studies in primary adipocytes, showed that insulin regulates ob gene expression directly in rats, regardless of its glucose-lowering effects. Whereas the ob gene product, leptin, has been shown to reduce food intake and increase energy expenditure, our data demonstrate that ob gene expression is increased after food ingestion in rats, perhaps through a direct action of insulin on the adipocyte.
1,126 citations
TL;DR: Induced expression of the cloned protein results in ligand-independent triggering of cytotoxicity, suggesting that it is involved in cell death induction by Fas/APO1.
1,100 citations
TL;DR: Together with some nuclear receptor mutations associated with pathological conditions, knockouts have led to significant advances in the authors' knowledge of the physiological functions of several nuclear receptors, but have also raised unexpected problems.
1,032 citations
TL;DR: An enzymatic rather than a structural protein defect causing a muscular dystrophy is demonstrated, a defect that may have regulatory consequences, perhaps in signal transduction.
TL;DR: IL-2R gamma facilitates mainstream B- and T-cell generation and function and also appears to be essential for NK-cell development in vivo.
Abstract: The interleukin 2 receptor gamma chain (IL-2R gamma) is a component of the receptors for IL-2, IL-4, IL-7, and IL-15. Mutations in IL-2R gamma in man appear responsible for the X chromosome-linked immunodeficiency SCIDX1, characterized by a defect in T-cell and natural killer (NK)-cell differentiation with the presence of poorly functioning B cells. To explore at which level IL-2R gamma affects lymphoid development in vivo, we have analyzed mice derived from embryonic stem (ES) cells with mutant IL-2R gamma loci generated by Cre/loxP-mediated recombination. In the peripheral blood of chimeric animals, lymphoid cells derived from IL-2R gamma- ES cells were not detected, although control ES cells carrying an IL-2R gamma gene with embedded loxP sites gave rise to T-, B-, and NK-cell lineages. Germline IL-2R gamma-deficient male animals, however, developed some mature splenic B and T cells, although the absolute number of lymphocytes was almost 10-fold reduced. In contrast, there was a complete disappearance of NK cells (over 350-fold reduction). Development of gut-associated intraepithelial lymphocytes was also severely diminished, and Peyer's patches were not detected. In vitro mitogenic responses of thymocytes, IL-4-directed immunoglobulin class switch of splenocytes, and NK activity were defective. Thus, IL-2R gamma facilitates mainstream B- and T-cell generation and function and also appears to be essential for NK-cell development.
TL;DR: Increased serum levels of IL-1 beta and IL-6 in severe PPH are demonstrated, and a role for proinflammatory cytokines in PPH is suggested, and it is suggested that COPD-PH patients with pulmonary hypertension secondary to chronic obstructive pulmonary disease should be considered for lung transplantation.
Abstract: Primary pulmonary hypertension (PPH) is characterized by the proliferation of smooth-muscle cells, fibroblasts, and endothelial cells in the walls of small pulmonary arteries. In order to evaluate a role for proinflammatory cytokines in this process, we studied the concentration of interleukin-1 beta (IL-1 beta), IL-6, and tumor necrosis factor-alpha (TNF alpha) in the serum of 29 patients with severe PPH referred to our center for lung transplantation. Results were compared with those obtained in 15 normal controls and nine patients with pulmonary hypertension secondary to chronic obstructive pulmonary disease (COPD-PH). TNF alpha serum levels were within the normal range in each group. This contrasted with increased IL-1 beta serum levels in severe PPH (118 +/- 36 pg/ml, mean +/- SEM) as compared with controls (3 +/- 1 pg/ml, p < 0.001) or COPD-PH patients (3 +/- 1 pg/ml, p < 0.001). IL-6 serum concentrations were also higher in severe PPH (66 +/- 20 pg/ml) than in controls (14 +/- 6 pg/ml, p < 0.01). This study demonstrates increased serum levels of IL-1 beta and IL-6 in severe PPH, and suggests a role for proinflammatory cytokines in PPH.
TL;DR: Modulus in the radial or circumferential direction could not be predicted from modulus inThe S-I direction for cortical bone, but could be predicted for cancellous bone, and specific relationships, depending on the types of bone, that predict elastic modulus from density and CT numbers were suggested.
TL;DR: It is shown that the Duffy antigen/chemokine receptor gene (DARC) is composed of a single exon and that most Duffy–negative blacks carry a silent FY*B allele with a single T to C substitution at nucleotide −46.
Abstract: The mRNA for the Duffy blood group antigen, the erythrocyte receptor for the Plasmodium vivax malaria parasite, has recently been cloned and shown to encode a widely expressed chemokine receptor. Here, we show that the Duffy antigen/chemokine receptor gene (DARC) is composed of a single exon and that most Duffy–negative blacks carry a silent FY*B allele with a single T to C substitution at nucleotide −46. This mutation impairs the promoter activity in erythroid cells by disrupting a binding site for the GATA1 erythroid transcription factor. With the recent characterization of the FY*A and FY*B alleles, these findings provide the molecular basis of the Duffy blood group system and an explanation for the erythroid–speeific repression of the DARC gene in Duffy–negative individuals.
TL;DR: The characterization of a monoclonal antibody is reported that selectively recognizes polyglutamine expansion in the proteins implicated in HD and in spinocerebellar ataxia (SCA) 1 and 3 and detects specific pathological proteins expected to contain such expansion.
Abstract: A POLYGLUTAMINE expansion (encoded by a CAG repeat) in specific proteins causes neurodegeneration in Huntington's disease (HD) and four other disorders1–6, by an unknown mechanism thought to involve gain of function or toxicity of the mutated protein7,8. The pathological threshold is 37–40 glutamines in three of these diseases, whereas the corresponding normal proteins contain polymorphic repeats of up to about 35 glutamines1–3. The age of onset of clinical manifestations is inversely correlated to the length of the polyglutamine expansion. Here we report the characterization of a monoclonal antibody that selectively recognizes polyglutamine expansion in the proteins implicated in HD and in spinocerebellar ataxia (SCA) 1 and 3. The intensity of signal depends on the length of the polyglutamine expansion, and the antibody also detects specific pathological proteins expected to contain such expansion, in SCA2 and in autosomal dominant cere-bellar ataxia with retinal degeneration, whose genes have not yet been identified9–13.
TL;DR: A mutation in the nuclear–encoded flavoprotein (Fp) subunit gene of the succinate dehydrogenase (SDH) is reported in two siblings with complex II deficiency presenting as Leigh syndrome, the first report of a nuclear gene mutation causing a mitochondrial respiratory chain deficiency in humans.
Abstract: We now report a mutation in the nuclear-encoded flavoprotein (Fp) subunit gene of the succinate dehydrogenase (SDH) in two siblings with complex II deficiency presenting as Leigh syndrome. Both patients were homozygous for an Arg554Trp substitution in the Fp subunit. Their parents (first cousins) were heterozygous for the mutation that occurred in a conserved domain of the protein and was absent from 120 controls. The deleterious effect of the Arg to Trp substitution on the catalytic activity of SDH was observed in a SDH- yeast strain transformed with mutant Fp cDNA. The Fp subunit gene is duplicated in the human genome (3q29; 5p15), with only the gene on chromosome 5 expressed in human-hamster somatic cell hybrids. This is the first report of a nuclear gene mutation causing a mitochondrial respiratory chain deficiency in humans.
TL;DR: This study shows that D2 receptors have a key role in the dopaminergic control of nervous function, using homologous recombination to generate D2-receptor-deficient mice, which have therapeutic potential as a model for investigating and correcting dysfunctions of the dopamine system.
Abstract: Dopaminergic neuronal pathways arise from mesencephalic nuclei and project axons to the striatum, cortex, limbic system and hypothalamus. Through these pathways dopamine affects many physiological functions, such as the control of coordinated movement and hormone secretion. Here we have studied the physiological involvement of the dopamine D2 receptors in dopaminergic transmission, using homologous recombination to generate D2-receptor-deficient mice. Absence of D2 receptors leads to animals that are akinetic and bradykinetic in behavioural tests, and which show significantly reduced spontaneous movements. This phenotype presents analogies with symptoms characteristic of Parkinson's disease. Our study shows that D2 receptors have a key role in the dopaminergic control of nervous function. These mice have therapeutic potential as a model for investigating and correcting dysfunctions of the dopaminergic system.
TL;DR: In this paper, the authors studied 148 subjects belonging to seven families by magnetic resonance imaging and genetic linkage analysis and found that all symptomatic subjects had prominent signal abnormalities on MRI with hyperintense lesions on T2-weighted images in the subcortical white matter and basal ganglia.
TL;DR: It is concluded that native VLPs can induce antibody-mediated, type-specific protection against experimental papillomavirus infection against CRPV challenge.
Abstract: We tested the ability of vaccination with virus-like particles (VLPs) to protect domestic rabbits against papillomas induced by the cottontail rabbit papillomavirus (CRPV). A recombinant baculovirus system that expressed only the L1 major papillomavirus structural protein or L1 plus the minor L2 protein was used in insect cells as the source of VLPs. Groups of 10 rabbits were immunized with native or denatured VLPs from CRPV or type 1 bovine papillomavirus by using Freund's adjuvant. Alum was used as the adjuvant for an additional group immunized with CRPV L1-L2 VLPs. Animals were challenged with 5 x 10(10) and 2 x 10(11) particles on opposing flanks. No protection was seen in rabbits immunized with native or denatured bovine papillomavirus L1-L2 or with denatured CRPV L1-L2. In these groups, the lower and higher challenge doses resulted in 27 of 30 animals with extensive papillomas, with each of the remaining animals having a smaller number of persistent papillomas. Progression to carcinoma developed in 20 rabbits. Animals inoculated with native CRPV VLPs composed of L1 alone or L1-L2 developed many fewer lesions; the lower and higher challenge doses resulted in 17 of 29 and 5 of 29 rabbits, respectively, with no lesions, and the remainder developed only one to eight papillomas, which all regressed except for those on 1 rabbit. None developed cancer within 1 year of infection. Rabbits vaccinated with native CRPV VLPs developed high-titer antibodies in an enzyme-linked immunosorbent assay based on native VLPs, and passive transfer of serum or immunoglobulin G from rabbits immunized with CRPV VLPs protected against CRPV challenge. We conclude that native VLPs can induce antibody-mediated, type-specific protection against experimental papillomavirus infection.
TL;DR: Drugs and some endogenous compounds can sequester coenzyme A and/or inhibit mitochondrial beta-oxidation enzymes, and decrease mitochondrial DNA replication (dideoxynucleoside analogues), while other compounds act through a combination of different mechanisms.
TL;DR: It is shown that ICP47 efficiently inhibits peptide transport across the ER membrane such that nascent class I molecules fail to acquire antigenic peptides.
Abstract: Cytotoxic T lymphocytes lyse target cells after T-cell-receptor-mediated recognition of class I major histocompatibility complex molecules presenting peptides Antigenic peptides are generated in the cytoplasm by proteasomes and translocated into the lumen of the endoplasmic reticulum (ER) by peptide transporters (TAP) Herpes simplex virus (HSV) expresses a cytoplasmic protein, ICP47, which seems to interfere with such immune surveillance by mediating retention of 'empty' class I molecules in the ER By expressing ICP47 in HeLa cells under an inducible promoter, we show that ICP47 efficiently inhibits peptide transport across the ER membrane such that nascent class I molecules fail to acquire antigenic peptides This inhibition was overcome by transfecting murine TAP Further, we demonstrate that ICP47 colocalizes and physically associates with TAP within the cell Inhibition of peptide translocation by a viral protein indicates a previously undocumented potential mechanism for viral immune evasion
TL;DR: This proposition that the development of insulin-dependent diabetes is controlled by the T helper 1 (TH1) versus TH2 phenotype of autoreactive TH cells is tested by establishing cultures of TH1 and TH2 cells that express an identical diabetogenic T cell receptor and comparing their ability to initiate disease in neonatal nonobese diabetic mice.
Abstract: It has been proposed that the development of insulin-dependent diabetes is controlled by the T helper 1 (TH1) versus TH2 phenotype of autoreactive TH cells: TH1 cells would promote diabetes, whereas TH2 cells would actually protect from disease. This proposition was tested by establishing cultures of TH1 and TH2 cells that express an identical diabetogenic T cell receptor and comparing their ability to initiate disease in neonatal nonobese diabetic mice. TH1-like cells actively promoted diabetes; TH2-like cells invaded the islets but did not provoke disease--neither did they provide substantial protection.
TL;DR: The early endogenous activity in auditory cortex may embody activity that is antecedent to the other patterns in multimodal association cortex, and may embody the cognitive closure that is also reflected in the scalp P3b or late positive component.
TL;DR: The LAMA2 gene was investigated for the presence of disease-causing mutations in laminin α2 chain-deficient CMD families and now report splice site and nonsense mutations in two families leading presumably to a truncated laminIn α2 protein.
Abstract: Congenital muscular dystrophies (CMDs), are heterogeneous autosomal recessive disorders. Their severe manifestations consist of early hypotonia and weakness, markedly delayed motor milestones and contractures, often associated with joint deformities. Histological changes seen in muscle biopsies consist of large variations in muscle fibre size, a few necrotic and regenerating fibres and a marked increase in endomysial collagen tissue. Diagnosis is based on clinical features and on morphological changes. In several CMD cases, we have demonstrated an absence of one of the components of the extracellular matrix around muscle fibres, the merosin M chain, now referred to as the alpha 2 chain of laminin-2 (ref.3). We localized this CMD locus to chromosome 6q2 by homozygosity mapping and linkage analysis. The laminin alpha 2 chain gene (LAMA2) maps to the same region on chromosome 6q22-23 (ref. 5). We therefore investigated LAMA2 for the presence of disease-causing mutations in laminin alpha 2 chain-deficient CMD families and now report splice site and nonsense mutations in two families leading presumably to a truncated laminin alpha 2 protein.
TL;DR: A possible dual role for VEGF which includes a chemotactic and/or a cellular maintenance role forVEGF during vascularization of the mouse embryo is suggested.
Abstract: We report the detailed developmental expression profiles of three endothelial specific receptor tyrosine kinases (RTKs) flk-1, tek, tie, as well as vascular endothelial growth factor (VEGF), the flk-1 ligand. We also examined the expression of the other VEGF receptor, flt-1, during placental development.flk-1, tek, and tie transcripts were detected sequentially at one-half day intervals starting at E7.0, suggesting that each of these RTKs play a unique role during vascularization of the mouse embryo. All three RTKs were expressed in the extraembryonic and embryonic mesoderm in regions that eventually give rise to the vasculature. Except for the expression of tek and flk-1 in the mesoderm of the amnion, the expression of these RTKs from E8.5 onwards was virtually indistinguishable. An abundant amount of flt-1 transcripts was found in the spongiotrophoblast cells of the developing placenta from E8.0 onwards. This cellular compartment is located between the maternal and labyrinthine layers of the placenta, which both express VEGF. VEGF transcripts were detected as early as E7.0 in the endoderm juxtaposed to the flk-1 positive mesoderm, and later in development VEGF expression displayed an expression profile both contiguous with that of flk-;1, and also in tissues found some distance from the flk-1-expressing endothelium. These results suggest a possible dual role for VEGF which includes a chemotactic and/or a cellular maintenance role for VEGF during vascularization of the mouse embryo. ©1995 Wiley-Liss, Inc.
TL;DR: It is acknowledged that much more data from endogenous receptors in whole tissues are needed before further recommendations on somatostatin receptor nomenclature can be made, but a promising approach is discussed.
TL;DR: This translocation fused two genes, tel and AML1, that have previously been described in chromosomal translocations specific for myeloid malignancies, that belong to an increasing number of human genes that are involved in a variety of hematopoietic malignant disorders and can be rearranged with numerous partners.
TL;DR: An early P3a-like activity that polarity inverts over short distances in the medial frontal lobe is demonstrated, and that it has a significantly shorter latency than similar potentials recorded in the temporal and parietal cortices.
TL;DR: It is concluded that upon loss of phospholipid asymmetry, cell-derived microvesicles provide a preferential substrate for sPLA2, and the novel lipid mediator LPA can be generated by this pathway.