Human Tau Expression Does Not Induce Mouse Retina Neurodegeneration, Suggesting Differential Toxicity of Tau in Brain vs. Retinal Neurons

The implication of the microtubule-associated protein (MAP) Tau in the ocular manifestations of Alzheimer’s disease (AD) is elusive due to the lack of relevant animal model. However, signs of AD have been reported in the brain of transgenic mice expressing human Tau (hTau). To assess whether hTau is sufficient to induce AD pathogenesis in the retina as well, in the present study, we compared the retinal structure and function of KO mice deprived of Tau (mTKO) with those of transgenic mice expressing hTau. Our results revealed that hTau is particularly abundant in the inner nuclear layer (INL) cells of the retina. By electroretinogram (ERG) recording, light-induced retinal cell activation was not altered in hTau compared with mTKO littermates. Surprisingly, the ERG response mediated by cone photoreceptor stimulation was even stronger in hTau than in mTKO retinae. Immunofluorescent analysis of retinal sections allowed us to observe thicker inner retina in hTau than in mTKO eyes. By Western Blotting (WB), the upregulation of mTOR that was found in hTau mice may underlie retinal structure and function increases. Taken together, our results not only indicate that hTau expression is not toxic for retinal cells but they also suggest that it may play a positive role in visual physiology. The use of hTau may be envisaged to improve visual recovery in ocular diseases affecting the retinal function such as glaucoma or diabetic retinopathy

Normative Indicators of Language Development in Québec French at 54, 60, and 66 Months of Age: Results of the ELLAN Study

Cet article vise à présenter des indicateurs normatifs du développement du vocabulaire réceptif et expressif, de la phonologie et de la morphosyntaxe expressives chez des enfants québécois unilingues francophones âgés de 54, 60 et 66 mois. Ces indicateurs sont basés sur les résultats obtenus par 99 enfants recrutés à l’âge de 36 mois (± 1 semaine; M = 36,1 mois; É-T = 0,2) et suivis jusqu’à l’âge de 66 mois. Les données ont été recueillies lors de trois visites à domicile réalisées à six mois d’intervalle, à l’aide d’outils fréquemment utilisés par les orthophonistes dans leur pratique clinique et valides sur le plan psychométrique. Une technique statistique de rééchantillonnage utilisant l’intervalle de confiance à 95 % du 10e rang centile a permis de déterminer les scores reflétant la présence de difficultés pour chaque mesure de langage chez les enfants et de former trois regroupements de scores pour identifier les enfants en difficulté, ceux se situant dans une zone d’incertitude et ceux ayant un développement typique. Les résultats confirment une progression significative des habiletés langagières mesurées entre l’âge de 54 et 66 mois. Ils suggèrent également que les mesures utilisées sont suffisamment sensibles pour détecter cette évolution chez les enfants, justifiant ainsi leur pertinence clinique. L’interprétation des normes issues des outils originaux est discutée à la lumière des résultats obtenus. Les données de la présente étude contribuent à l’accroissement du corpus de connaissances sur les indicateurs normatifs du développement du langage en français québécois et, en ce sens, constituent des points de repère indispensables pour le travail clinique en orthophonie et la recherche.The objective of this study is to present normative indicators of the development of receptive and expressive vocabulary as well as phonological and morphosyntactic components of expressive language among unilingual francophone Québec children aged 3 to 4 years. These indicators are based on the results obtained by 99 children recruited at precisely 3 years of age (M = 36.1 months, SD = 0.2). The data were collected during three separate visits conducted 6 months apart, using psychometrically valid tools frequently used by speech-language pathologists in their clinical practice. A statistical resampling technique using the 95% confidence interval of the 10th percentile on each language measure led to the categorization of children into three groups, namely children presenting difficulties, those in a zone of uncertainty, and those presenting typical development. The results for each measure confirm a significant increase in children’s language skills between the ages of 3 and 4 years. They suggest that the measures used are sensitive enough to detect changes in language skills of children aged 36, 42, and 48 months, thus confirming their clinical relevance. Interpretations of the norms of the original tools are discussed in relation to the current indicators. The normative data provided in this study add to a body of knowledge which serve as essential benchmarks for clinical work and research

Indicateurs normatifs du développement du langage en français québécois à 36, 42 et 48 mois : résultats du projet ELLAN

L’objectif de cette étude est de présenter des indicateurs normatifs du développement du vocabulaire réceptif et expressif ainsi que des composantes phonologique et morphosyntaxique du langage expressif chez des enfants québécois unilingues francophones âgés de 3 à 4 ans. Ces indicateurs sont basés sur les résultats obtenus par 99 enfants recrutés à l’âge de 3 ans précisément (M = 36,1 mois; É-T = 0,2). Les données ont été collectées lors de trois visites distinctes réalisées à six mois d’intervalle, à l’aide d’outils valides sur le plan psychométrique et fréquemment privilégiés par les orthophonistes dans leur pratique clinique. Une technique statistique de rééchantillonage utilisant l’intervalle de confiance à 95% du 10e rang centile aux différentes mesures obtenues a permis de regrouper les enfants en difficulté, ceux se situant dans une zone d’incertitude et ceux ayant un développement typique. Les résultats à chacune des mesures confirment une progression significative des compétences langagières des enfants entre l’âge de 3 et 4 ans. Ils suggèrent que les mesures utilisées sont suffisamment sensibles pour détecter l’évolution des habiletés langagières des enfants âgés de 36, 42 et 48 mois, confirmant ainsi leur pertinence clinique. L’interprétation des normes des outils originaux est discutée à la lumière des scores obtenus. Les données normatives de la présente étude s’ajoutent à un corpus de connaissances qui constitue des points de repères indispensables pour le travail clinique et la recherche

The oncometabolite 2-hydroxyglutarate activates the mTOR signalling pathway

The identification of cancer-associated mutations in the tricarboxylic acid (TCA) cycle enzymes isocitrate dehydrogenases 1 and 2 (IDH1/2) highlights the prevailing notion that aberrant metabolic function can contribute to carcinogenesis. IDH1/2 normally catalyse the oxidative decarboxylation of isocitrate into α-ketoglutarate (αKG). In gliomas and acute myeloid leukaemias, IDH1/2 mutations confer gain-of-function leading to production of the oncometabolite R-2-hydroxyglutarate (2HG) from αKG. Here we show that generation of 2HG by mutated IDH1/2 leads to the activation of mTOR by inhibiting KDM4A, an αKG-dependent enzyme of the Jumonji family of lysine demethylases. Furthermore, KDM4A associates with the DEP domain-containing mTOR-interacting protein (DEPTOR), a negative regulator of mTORC1/2. Depletion of KDM4A decreases DEPTOR protein stability. Our results provide an additional molecular mechanism for the oncogenic activity of mutant IDH1/2 by revealing an unprecedented link between TCA cycle defects and positive modulation of mTOR function downstream of the canonical PI3K/AKT/TSC1-2 pathway

Revisiting double diffusion encoding MRS in the mouse brain at 11.7T: Which microstructural features are we sensitive to?

International audienceBrain metabolites, such as N-acetylaspartate or myo-inositol, are constantly probing their local cellular environment under the effect of diffusion. Diffusion-weighted NMR spectroscopy therefore presents unparalleled potential to yield cell-type specific microstructural information. Double diffusion encoding (DDE) consists in applying two diffusion blocks, where gradient's direction in the second block is varied during the course of the experiment. Unlike single diffusion encoding, DDE measurements at long mixing time display some angular modulation of the signal amplitude which reflects microscopic anisotropy (μA), while requiring relatively low gradient strength. This angular dependence has been formerly used to quantify cell fiber diameter using a model of isotropically oriented infinite cylinders. However, how additional features of the cell microstructure (such as cell body diameter, fiber length and branching) may also influence the DDE signal has been little explored. Here, we used a cryoprobe as well as state-of-the-art post-processing to perform DDE acquisitions with high accuracy and precision in the mouse brain at 11.7 T. We then compared our results to simulated DDE datasets obtained in various 3D cell models in order to pinpoint which features of cell morphology may influence the most the angular dependence of the DDE signal. While the infinite cylinder model poorly fits our experimental data, we show that incorporating branched fiber structure in our model allows more realistic interpretation of the DDE signal. Lastly, data acquired in the short mixing time regime suggest that some sensitivity to cell body diameter might be retrieved, although additional experiments would be required to further support this statement

The (un)coupling method: principle and application on fetuses and infants’ skeletal remains up to three postnatal months

The (un)coupling method is a two-step procedure tool available freely online for fetuses and infants up to three postnatal months. It is a method of (1) detection of a possible developmental anomaly and (2) estimation of age using the best non-biased predictor between the femur length and the maximal length/width of the pars basilaris. This presentation describes the principle of the method and gives some examples of application