Prevalence, predicting factors and impact of internet use by patients with idiopathic pulmonary fibrosis: A cross-sectional observational study

International audienc

Premier épisode de pneumothorax spontané primaire : qui drainer, comment ? [First episode of primary spontaneous pneumothorax: Who and how to treat?]

National audienc

Projet Région LiCorNe: LIMK protein inhibitors, new therapeutic agents for treatment of cognitive disorders associated with type I Neurofibromatosis

National audienc

Milieu d’hébergement domotisé pour la clientèle ayant une déficience cognitive : de l’implantation à l’évaluation

En raison des avancées médicales, davantage de victimes d’un traumatisme craniocérébral (TCC) grave sont sauvées. De plus, leur espérance de vie a augmenté. Ils garderont plusieurs déficiences persistantes, particulièrement des troubles cognitifs. Leurs incapacités multiples entraînent de l’assistance sur une base régulière dans plusieurs habitudes de vie et ils se retrouvent souvent dans des milieux peu adaptés à leurs besoins. Un projet novateur a permis de créer une ressource d’hébergement alternative qui permettra d’optimiser la participation sociale des résidents TCC grâce à différentes technologies d’assistance et de télévigilance développées et introduites progressivement. Suite à une première étude qui a permis de recueillir les attentes et les besoins des résidents, un projet interdisciplinaire a débuté en 2013 en vue de concevoir, implanter et évaluer l’effet d’un assistant culinaire, une aide technologique pour la cognition. Le projet comprend un volet technologique et un volet clinique. Les objectifs sont de 1) développer un assistant-chef pour la préparation de repas (volet technologique), 2) évaluer les effets sur la préparation de repas et l’autonomie des résidents (volet clinique) et 3) évaluer les leviers et les obstacles à son implantation (volet clinique). Cette recherche inclut différentes méthodologies, dont la conception participative (volet technologique) et un devis mixte combinant la recherche-action et une étude de cas uniques multiples (volet clinique). Les retombées anticipées sont de permettre aux résidents de recommencer à cuisiner de façon sécuritaire. Également, nous espérons qu’un tel outil favorisera l’indépendance des personnes avec troubles cognitifs et facilitera le maintien à domicile, qu’il améliorera l’efficience des professionnels de la santé en terme d’intervention cognitive et qu’il diminuera les coûts de santé

Missense variants in DPYSL5 cause a neurodevelopmental disorder with corpus callosum agenesis and cerebellar abnormalities

The collapsin response mediator protein (CRMP) family proteins are intracellular mediators of neurotrophic factors regulating neurite structure/spine formation and are essential for dendrite patterning and directional axonal pathfinding during brain developmental processes. Among this family, CRMP5/DPYSL5 plays a significant role in neuronal migration, axonal guidance, dendrite outgrowth, and synapse formation by interacting with microtubules. Here, we report the identification of missense mutations in DPYSL5 in nine individuals with brain malformations, including corpus callosum agenesis and/or posterior fossa abnormalities, associated with variable degrees of intellectual disability. A recurrent de novo p.Glu41Lys variant was found in eight unrelated patients, and a p.Gly47Arg variant was identified in one individual from the first family reported with Ritscher-Schinzel syndrome. Functional analyses of the two missense mutations revealed impaired dendritic outgrowth processes in young developing hippocampal primary neuronal cultures. We further demonstrated that these mutations, both located in the same loop on the surface of DPYSL5 monomers and oligomers, reduced the interaction of DPYSL5 with neuronal cytoskeleton-associated proteins MAP2 and βIII-tubulin. Our findings collectively indicate that the p.Glu41Lys and p.Gly47Arg variants impair DPYSL5 function on dendritic outgrowth regulation by preventing the formation of the ternary complex with MAP2 and βIII-tubulin, ultimately leading to abnormal brain development. This study adds DPYSL5 to the list of genes implicated in brain malformation and in neurodevelopmental disorders

Missense variants in DPYSL5 cause a neurodevelopmental disorder with corpus callosum agenesis and cerebellar abnormalities

International audienceThe collapsin response mediator protein (CRMP) family proteins are intracellular mediators of neurotrophic factors regulating neurite structure/spine formation and are essential for dendrite patterning and directional axonal pathfinding during brain developmental processes. Among this family, CRMP5/DPYSL5 plays a significant role in neuronal migration, axonal guidance, dendrite outgrowth, and synapse formation by interacting with microtubules. Here, we report the identification of missense mutations in DPYSL5 in nine individuals with brain malformations, including corpus callosum agenesis and/or posterior fossa abnormalities, associated with variable degrees of intellectual disability. A recurrent de novo p.Glu41Lys variant was found in eight unrelated patients, and a p.Gly47Arg variant was identified in one individual from the first family reported with Ritscher-Schinzel syndrome. Functional analyses of the two missense mutations revealed impaired dendritic outgrowth processes in young developing hippocampal primary neuronal cultures. We further demonstrated that these mutations, both located in the same loop on the surface of DPYSL5 monomers and oligomers, reduced the interaction of DPYSL5 with neuronal cytoskeleton-associated proteins MAP2 and βIII-tubulin. Our findings collectively indicate that the p.Glu41Lys and p.Gly47Arg variants impair DPYSL5 function on dendritic outgrowth regulation by preventing the formation of the ternary complex with MAP2 and βIII-tubulin, ultimately leading to abnormal brain development. This study adds DPYSL5 to the list of genes implicated in brain malformation and in neurodevelopmental disorders

Ptchd1 deficiency induces excitatory synaptic and cognitive dysfunctions in mouse

International audienceSynapse development and neuronal activity represent fundamental processes for the establishment of cognitive function. Structural organization as well as signalling pathways from receptor stimulation to gene expression regulation are mediated by synaptic activity and misregulated in neurodevelopmental disorders such as autism spectrum disorder (ASD) and intellectual disability (ID). Deleterious mutations in the PTCHD1 (Patched domain containing 1) gene have been described in male patients with X-linked ID and/or ASD. The structure of PTCHD1 protein is similar to the Patched (PTCH1) receptor; however, the cellular mechanisms and pathways associated with PTCHD1 in the developing brain are poorly determined. Here we show that PTCHD1 displays a C-terminal PDZ-binding motif that binds to the postsynaptic proteins PSD95 and SAP102. We also report that PTCHD1 is unable to rescue the canonical sonic hedgehog (SHH) pathway in cells depleted of PTCH1, suggesting that both proteins are involved in distinct cellular signalling pathways. We find that Ptchd1 deficiency in male mice (Ptchd1-/y) induces global changes in synaptic gene expression, affects the expression of the immediate-early expression genes Egr1 and Npas4 and finally impairs excitatory synaptic structure and neuronal excitatory activity in the hippocampus, leading to cognitive dysfunction, motor disabilities and hyperactivity. Thus our results support that PTCHD1 deficiency induces a neurodevelopmental disorder causing excitatory synaptic dysfunction

Comparison of genomes and proteomes of four whole genome-sequenced <i>Campylobacter jejuni</i> from different phylogenetic backgrounds

<div><p>Whole genome sequencing (WGS) has been used to assess the phylogenetic relationships, virulence and metabolic differences, and the relationship between gene carriage and host or niche differentiation among populations of <i>C</i>. <i>jejuni</i> isolates. We previously characterized the presence and expression of CJIE4 prophage proteins in four <i>C</i>. <i>jejuni</i> isolates using WGS and comparative proteomics analysis, but the isolates were not assessed further. In this study we compare the closed, finished genome sequences of these isolates to the total proteome. Genomes of the four isolates differ in phage content and location, plasmid content, capsular polysaccharide biosynthesis loci, a type VI secretion system, orientation of the ~92 kb invertible element, and allelic differences. Proteins with 99% sequence identity can be differentiated using isobaric tags for relative and absolute quantification (iTRAQ) comparative proteomic methods. GO enrichment analysis and the type of artefacts produced in comparative proteomic analysis depend on whether proteins are encoded in only one isolate or common to all isolates, whether different isolates have different alleles of the proteins analyzed, whether conserved and variable regions are both present in the protein group analyzed, and on how the analysis is done. Several proteins encoded by genes with very high levels of sequence identity in all four isolates exhibited preferentially higher protein expression in only one of the four isolates, suggesting differential regulation among the isolates. It is possible to analyze comparative protein expression in more distantly related isolates in the context of WGS data, though the results are more complex to interpret than when isolates are clonal or very closely related. Comparative proteomic analysis produced log₂ fold expression data suggestive of regulatory differences among isolates, indicating that it may be useful as a hypothesis generation exercise to identify regulated proteins and regulatory pathways for more detailed analysis.</p></div