8 research outputs found
Les enzymes sécrétées par la levure Malassezia en tant que nouvelles cibles thérapeutiques
Les levures du genre Malassezia font partie intĂ©grale de la flore normale de la peau oĂč ils reprĂ©sentent 50-80% du mycobiome total de lâĂ©piderme. Ce champignon se distingue des autres organismes de par son absence de synthase dâacides gras (FAS), ce qui le rend dĂ©pendant Ă une source externe de lipides. De rĂ©cents travaux ont dĂ©montrĂ© la prĂ©sence de cette levure au niveau des organes internes, comme la muqueuse intestinale, oĂč elle pourrait jouer un rĂŽle dans le dĂ©veloppement de la maladie de Crohn. Les circonstances amenant Malassezia Ă passer de commensal Ă pathogĂšne restent, de nos jours, nĂ©buleuses. Afin de mieux comprendre la niche Ă©cologique de Malassezia, nous avons effectuĂ© une caractĂ©risation physiologique de lâassimilation lipidique de diffĂ©rentes espĂšces de Malassezia en contrĂŽlant la source de lipides. Notre analyse a rĂ©vĂ©lĂ© que la prĂ©sence du profil lipidique est hĂ©tĂ©rogĂšne entre les espĂšces ainsi quâentre les souches de la mĂȘme espĂšce. Nos observations sont cohĂ©rentes avec la littĂ©rature, câest-Ă -dire que lâacide palmitique (C16), lâacide stĂ©arique (C18), lâacide olĂ©ique (C18:1) et lâacide linolĂ©ique (C18:2) sont extrĂȘmement importants pour la croissance des diffĂ©rentes espĂšces. Dans lâensemble, notre Ă©tude nous a permis de gĂ©nĂ©rer un nouveau milieu de croissance qui nous a permis de tester diffĂ©rents composĂ©s, seuls et en combinaison, pouvant avoir des propriĂ©tĂ©s antifongiques. La combinaison entre lâitraconazole, la terbinafine et un nouvel inhibiteur de protĂ©ase (BMZ2-134B) sâest avĂ©rĂ©e particuliĂšrement efficace afin dâinhiber Malassezia. Avec le nombre grandissant de donnĂ©es dĂ©montrant un lien Ă©troit entre la dysbiose du microbiote, lâinflammation et les maladies cardiovasculaires, il devient impĂ©ratif de dĂ©velopper de nouvelles stratĂ©gies thĂ©rapeutiques afin de prĂ©venir les maladies cardiovasculaires en tirant profit de nos connaissances sur le mycobiome.Yeasts of the genus Malassezia are an integral part of the normal flora of skin, where they represent 50-80 % of the total epidermis mycobiota. This fungus is distinguishable from other organisms by the fact that it lacks a fatty acid synthase (FAS), making it dependent on an external source of lipids. Recent work has shown the presence of this yeast in internal organs, such as the intestinal mucosa, where it could play a potential role in the development of Crohnâs disease. The circumstances leading Malassezia to switch from commensal to pathogen remain, nowadays, nebulous. In order to better understand the ecological niche of Malassezia, we carried out a physiological characterization of lipid assimilation of different species of Malassezia by controlling the lipid source. Our analysis revealed that the lipid assimilation profile is heterogeneous between species as well as between strains of the same species. Our observations are consistent with the literature, i.e., palmitic acid (C16), stearic acid (C18), oleic acid (C18:1) and linoleum acid (C18:2) are extremely important for the growth of the different species. Overall, our study allowed us to generate a new growth medium where we could test different compounds, alone and in combination, that could have antifungal properties. The combination of itraconazole, terbinafine and a new protease inhibitor proved to be particularly effective in inhibiting Malasseziaâs growth. With the growing evidence demonstrating a strong link between microbiota dysbiosis, inflammation and cardiovascular diseases, it becomes imperative to develop new therapeutic strategies by leveraging our knowledge of the mycobioma
Temporal and spatial evolution of orogens: a guide for geological mapping
International audienceOrogens develop in convergent settings involving twoor more continental and/or oceanic plates. They are tra-ditionally defined as zones of crustal deformation associ-ated with mountain building resulting from either accretionof a terrane and/or an arc, continent-continent collision or rift-inversion. However, this definition does not considerthe genetic link between an oceanic domain and an intra-continental rift, even though extension associated with ascissor-shape opening can be demonstrated in many ocean-floored basins. Consequently, we propose a new conceptof orogenic evolution based on the development of exten-sional margins subsequently subjected to crustal shorten-ing. Thus orogens that develop as a result of the closureof wide basins, are distinguished from mountain belts devel-oped above subduction zones or that result from conti-nental collision and inverted intra-continental rifts. Ourreview of several key orogens identifies similarities anddifferences in geodynamic processes through geologicaltime including prior to the onset of plate tectonics ca. 2.5Ga. We propose that mapping based on comparative tec-tonics is a good way to constrain such an evolution, andthat this can start with a global-scale map of past-to-modernorogens aimed at re-exploring mountain building conceptsspatially and temporarily. This is the primary objective ofIGCP 667 project âWorld Map of Orogensâ
High intraspecific genome diversity in the model arbuscular mycorrhizal symbiont Rhizophagus irregularis
International audienceArbuscular mycorrhizal fungi (AMF) are known to improve plant fitness through the establishment of mycorrhizal symbioses. Genetic and phenotypic variations among closely related AMF isolates can significantly affect plant growth, but the genomic changes underlying this variability are unclear. To address this issue, we improved the genome assembly and gene annotation of the model strain Rhizophagus irregularis DAOM197198, and compared its gene content with five isolates of R. irregularis sampled in the same field. All isolates harbor striking genome variations, with large numbers of isolate-specific genes, gene family expansions, and evidence of interisolate genetic exchange. The observed variability affects all gene ontology terms and PFAM protein domains, as well as putative mycorrhiza-induced small secreted effector-like proteins and other symbiosis differentially expressed genes. High variability is also found in active transposable elements. Overall, these findings indicate a substantial divergence in the functioning capacity of isolates harvested from the same field, and thus their genetic potential for adaptation to biotic and abiotic changes. Our data also provide a first glimpse into the genome diversity that resides within natural populations of these symbionts, and open avenues for future analyses of plant-AMF interactions that link AMF genome variation with plant phenotype and fitness
Crossing the Species Barrier: Genomic Hotspots of Introgression between Two Highly Divergent Ciona intestinalis Species
Can Ketones Help Rescue Brain Fuel Supply in Later Life? Implications for Cognitive Health during Aging and the Treatment of Alzheimerâs Disease
The Multifaceted Role of the Ventromedial Prefrontal Cortex in Emotion, Decision Making, Social Cognition, and Psychopathology
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De Novo Pathogenic Variants in N-cadherin Cause a Syndromic Neurodevelopmental Disorder with Corpus Collosum, Axon, Cardiac, Ocular, and Genital Defects
Cadherins constitute a family of transmembrane proteins that mediate calcium-dependent cell-cell adhesion. The extracellular domain of cadherins consists of extracellular cadherin (EC) domains, separated by calcium binding sites. The EC interacts with other cadherin molecules in cis and in trans to mechanically hold apposing cell surfaces together. CDH2 encodes N-cadherin, whose essential roles in neural development include neuronal migration and axon pathfinding. However, CDH2 has not yet been linked to a Mendelian neurodevelopmental disorder. Here, we report de novo heterozygous pathogenic variants (seven missense, two frameshift) in CDH2 in nine individuals with a syndromic neurodevelopmental disorder characterized by global developmental delay and/or intellectual disability, variable axon pathfinding defects (corpus callosum agenesis or hypoplasia, mirror movements, Duane anomaly), and ocular, cardiac, and genital anomalies. All seven missense variants (c.1057G>A [p.Asp353Asn]; c.1789G>A [p.Asp597Asn]; c.1789G>T [p.Asp597Tyr]; c.1802A>C [p.Asn601Thr]; c.1839C>G [p.Cys613Trp]; c.1880A>G [p.Asp627Gly]; c.2027A>G [p.Tyr676Cys]) result in substitution of highly conserved residues, and six of seven cluster within EC domains 4 and 5. Four of the substitutions affect the calcium-binding site in the EC4-EC5 interdomain. We show that cells expressing these variants in the EC4-EC5 domains have a defect in cell-cell adhesion; this defect includes impaired binding in trans with N-cadherin-WT expressed on apposing cells. The two frameshift variants (c.2563_2564delCT [p.Leu855Valfsâ4]; c.2564_2567dupTGTT [p.Leu856Phefsâ5]) are predicted to lead to a truncated cytoplasmic domain. Our study demonstrates that de novo heterozygous variants in CDH2 impair the adhesive activity of N-cadherin, resulting in a multisystemic developmental disorder, that could be named ACOG syndrome (agenesis of corpus callosum, axon pathfinding, cardiac, ocular, and genital defects)
De Novo Pathogenic Variants in N-cadherin Cause a Syndromic Neurodevelopmental Disorder with Corpus Callosum, Axon, Cardiac, Ocular, and Genital Defects
International audienceCadherins constitute a family of transmembrane proteins that mediate calcium-dependent cell-cell adhesion. The extracellular domain of cadherins consists of extracellular cadherin (EC) domains, separated by calcium binding sites. The EC interacts with other cadherin molecules in cis and in trans to mechanically hold apposing cell surfaces together. CDH2 encodes N-cadherin, whose essential roles in neural development include neuronal migration and axon pathfinding. However, CDH2 has not yet been linked to a Mendelian neurodevelopmental disorder. Here, we report de novo heterozygous pathogenic variants (seven missense, two frameshift) in CDH2 in nine individuals with a syndromic neurodevelopmental disorder characterized by global developmental delay and/or intellectual disability, variable axon pathfinding defects (corpus callosum agenesis or hypoplasia, mirror movements, Duane anomaly), and ocular, cardiac, and genital anomalies. All seven missense variants (c.1057G>A [p.Asp353Asn]; c.1789G>A [p.Asp597Asn]; c.1789G>T [p.Asp597Tyr]; c.1802A>C [p.Asn601Thr]; c.1839C>G [p.Cys613Trp]; c.1880A>G [p.Asp627Gly]; c.2027A>G [p.Tyr676Cys]) result in substitution of highly conserved residues, and six of seven cluster within EC domains 4 and 5. Four of the substitutions affect the calcium-binding site in the EC4-EC5 interdomain. We show that cells expressing these variants in the EC4-EC5 domains have a defect in cell-cell adhesion; this defect includes impaired binding in trans with N-cadherin-WT expressed on apposing cells. The two frameshift variants (c.2563_2564delCT [p.Leu855Valfsâ4]; c.2564_2567dupTGTT [p.Leu856Phefsâ5]) are predicted to lead to a truncated cytoplasmic domain. Our study demonstrates that de novo heterozygous variants in CDH2 impair the adhesive activity of N-cadherin, resulting in a multisystemic developmental disorder, that could be named ACOG syndrome (agenesis of corpus callosum, axon pathfinding, cardiac, ocular, and genital defects)