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A New Mouse Model for Complete Congenital Stationary Night Blindness Due to Gpr179 Deficiency
No full textInternational audienceMutations in GPR179 lead to autosomal recessive complete congenital stationary night blindness (cCSNB). This condition represents a signal transmission defect from the photoreceptors to the ON-bipolar cells. To confirm the phenotype, better understand the pathogenic mechanism in vivo, and provide a model for therapeutic approaches, a Gpr179 knock-out mouse model was genetically and functionally characterized. We confirmed that the insertion of a neo/lac Z cassette in intron 1 of Gpr179 disrupts the same gene. Spectral domain optical coherence tomography reveals no obvious retinal structure abnormalities. Gpr179 knock-out mice exhibit a so-called no-b-wave (nob) phenotype with severely reduced b-wave amplitudes in the electroretinogram. Optomotor tests reveal decreased optomotor responses under scotopic conditions. Consistent with the genetic disruption of Gpr179, GPR179 is absent at the dendritic tips of ON-bipolar cells. While proteins of the same signal transmission cascade (GRM6, LRIT3, and TRPM1) are correctly localized, other proteins (RGS7, RGS11, and GNB5) known to regulate GRM6 are absent at the dendritic tips of ON-bipolar cells. These results add a new model of cCSNB, which is important to better understand the role of GPR179, its implication in patients with cCSNB, and its use for the development of therapies
C. elegans est-il un bon modèle pour la recherche thérapeutique ?
No full textNational audienceLe choix d’un modèle pour la recherche reflète toujours un équilibre entre sa maniabilité et sa pertinence.Sydney Brenner, pourtant un des pionniers dans l’utilisation du ver nématode Caenorhabditis elegans,est même allé jusqu’à dire, dans son discours Nobel, qu’il n’y a plus besoin d’animaux modèles pour larecherche sur la biologie humaine1 . Il est vrai que grâce aux progrès remarquables des techniquesd’analyse2 , aujourd’hui, de plus en plus, la recherche se fait directement chez l’homme, s’appuyant surl’énorme diversité génétique humaine. Mais on ne peut se permettre d’utiliser l’homme comme modèleexpérimental et il y aura toujours besoin de modèles pour la recherche thérapeutique. Peut-on qualifierC. elegans de bon modèle
Covid-19 : "Appel pour une coordination immédiate entre sciences et société"
No full textSource Agritrop Cirad (https://agritrop.cirad.fr/596067/)International audienc
PHENOTYPIC CHARACTERISTICS OF ROD–CONE DYSTROPHY ASSOCIATED WITH MYO7A MUTATIONS IN A LARGE FRENCH COHORT
No full textInternational audiencePurpose: To document the rod-cone dystrophy phenotype of patients with Usher syndrome type 1 (USH1) harboring MYO7A mutations.Methods: Retrospective cohort study of 53 patients (42 families) with biallelic MYO7A mutations who underwent comprehensive examination, including functional visual tests and multimodal retinal imaging. Genetic analysis was performed either using a multiplex amplicon panel or through direct sequencing. Data were analyzed with IBM SPSS Statistics software v. 21.0.Results: Fifty different genetic variations including 4 novel were identified. Most patients showed a typical rod-cone dystrophy phenotype, with best-corrected visual acuity and central visual field deteriorating linearly with age. At age 29, binocular visual field demonstrated an average preservation of 50 central degrees, constricting by 50% within 5 years. Structural changes based on spectral domain optical coherence tomography, short wavelength autofluorescence, and near-infrared autofluorescence measurements did not however correlate with age. Our study revealed a higher percentage of epiretinal membranes and cystoid macular edema in patients with MYO7A mutations compared with rod-cone dystrophy patients with other mutations. Subgroup analyses did not reveal substantial genotype-phenotype correlations.Conclusion: To the best of our knowledge, this is the largest French cohort of patients with MYO7A mutations reported to date. Functional visual characteristics of this subset of patients followed a linear decline as in other typical rod-cone dystrophy, but structural changes were variable indicating the need for a case-by-case evaluation for prognostic prediction and choice of potential therapies
Identification and characterization of novel TRPM1 autoantibodies from serum of patients with melanoma-associated retinopathy
No full textInternational audienceMelanoma-associated retinopathy (MAR) is a rare paraneoplastic retinal disorder usually occurring in the context of metastatic melanoma. Patients present with night blindness, photopsias and a constriction of the visual field. MAR is an auto-immune disorder characterized by the production of autoantibodies targeting retinal proteins, especially autoantibodies reacting to the cation channel TRPM1 produced in melanocytes and ON-bipolar cells. TRPM1 has at least three different isoforms which vary in the N-terminal region of the protein. In this study, we report the case of three new MAR patients presenting different anti-TRPM1 autoantibodies reacting to the three isoforms of TRPM1 with variable binding affinity. Two sera recognized all isoforms of TRPM1, while one recognized only the two longest isoforms upon immunolocalization studies on overexpressing cells. Similarly, the former two sera reacted with all TRPM1 isoforms on western blot, but an immunoprecipitation enrichment step was necessary to detect all isoforms with the latter serum. In contrast, all sera labelled ON-bipolar cells on Tprm1+/+ but not on Trpm1-/- mouse retina as shown by co-immunolocalization. This confirms that the MAR sera specifically detect TRPM1. Most likely, the anti-TRPM1 autoantibodies of different patients vary in affinity and concentration. In addition, the binding of autoantibodies to TRPM1 may be conformation-dependent, with epitopes being inaccessible in some constructs (truncated polypeptides versus full-length TRPM1) or applications (western blotting versus immunohistochemistry). Therefore, we propose that a combination of different methods should be used to test for the presence of anti-TRPM1 autoantibodies in the sera of MAR patients
On the topology of a real analytic curve in the neighborhood of a singular point
No full textInternational audienceThe purpose of this paper is to describe the topology of real analytic planar curves in the neighborhood of a singular point. Locally, such a curve consists of a number of branches that intersect a small circle centered on the singularity at two points. The local topology is described by a chord diagram: an even number of points on a circle, associated two by two. We show that most chord diagrams do not come from singularities. When this is the case, we call them analytical diagrams. First, we propose a recursive description of analytical diagrams. Then we characterize these analytical diagrams as those that do not contain as subdiagrams those which belong to a collection that we describe explicitly.Le but de cet article est de décrire la topologie des courbes analytiques réelles planes au voisinage d’un point singulier. Localement, une telle courbe est constituée d’un certain nombre de branches qui coupent un petit cercle centré sur la singularité en deux points. La topologie locale est décrite par un diagramme de cordes : un nombre pair de points sur un cercle, associés deux par deux. Nous montrons que la plupart des diagrammes de cordes ne proviennent pas de singularités. Quand c’est le cas nous les qualifions d’analytiques. Nous proposons d’abord une description récursive des diagrammes analytiques. Puis nous caractérisons ces diagrammes analytiques comme étant ceux ne contenant pas comme sous-diagramme ceux qui appartiennent à une famille que nous décrivons explicitemen
Revues de l’American Physical Society :la qualité pour un juste prix !
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Confidence Collapse in a Multi-Household, Self-Reflexive DSGE Model
No full textInternational audienceWe investigate a multi-household DSGE model in which past aggregate consumption impacts the confidence, and therefore consumption propensity, of individual households. We find that such a minimal setup is extremely rich, and leads to a variety of realistic output dynamics: high output with no crises; high output with increased volatility and deep, short lived recessions; alternation of high and low output states where relatively mild drop in economic conditions can lead to a temporary confidence collapse and steep decline in economic activity. The crisis probability depends exponentially on the parameters of the model, which means that markets cannot efficiently price the associated risk premium. We conclude by stressing that within our framework, narratives become an important monetary policy tool, that can help steering the economy back on track
