L008 Défaut de différenciation veino-lymphatique embyonnaire par modulation de l’ARN interférence

L’ARN interférence, mécanisme de régulation de l’expression des gènes, est médiée par les siARNs et les microARNs, ARN non-codants de 20 à 22 nucléotides affectant la régulation post-transcriptionnelle d’ARNm cibles avec lesquels ils s’apparient.La RNase DICER est une enzyme centrale de la biosynthèse des siARNs et microARNs. Les souris dont le gène dicer est invalidé ont un phénotype complexe, et meurent très tôt pendant le développement, notamment à cause d’un défaut d’angiogenèse.Afin d’étudier l’ARN interférence au cours de l’angiogenèse embryonnaire, des souris dont le gène dicer est floxé (mutant conditionnel) sont croisées avec des souris exprimant la recombinase Cre, de manière constitutive, sous le contrôle du promoteur du gène tie2, dirigeant ainsi son expression dans les cellules endothéliales (CE) et les cellules hématopiétiques.Nos résultats montrent que l’invalidation de dicer sous le contrôle du promoteur du gène tie2 entraine une mortalité embryonnaire suite à un œdème et des hémorragies au treizième jour du développement (E13,5). L’analyse histologique montre des vaisseaux lymphatiques remplis de sang, suggérant une mauvaise séparation du réseau sanguin et lymphatique. Cette hypothèse est étudiée par marquage des vaisseaux lymphatiques (LYVE-1) et des vaisseaux sanguins (PECAM) sur embryon entier et peaux isolées à différents stades précédant la mort.Ces embryons présentent également un problème de développement du foie, probablement dû à l’activité du promoteur tie2 dans les lignées hématopoiétiques. La mise en culture de ces foies fœtaux à E13,5 révèle une atteinte des précurseurs hématopoétiques.L’étude de ces précurseurs à des stades plus précoces (E8,5) est en cours au laboratoire.Nos résultats démontrent donc un rôle important de l’ARN interférence dans le contrôle épigénétique de l’angiogenèse et de la lymphangiogenèse embryonnaire mais également dans le développement de l’hématopoièse, suggérant son implication dans la différenciation veino-lymphangiogenèse, dont les mécanismes moléculaires seront discutés

Characterising The Atmospheric Dynamics Of HD209458b-like Hot Jupiters Using AI Driven Image Recognition/Categorisation

In-order to understand the results of recent observations of exoplanets, models have become increasingly complex. Unfortunately this increases both the computational cost and output size of said models. We intend to explore if AI-image-recognition can alleviate this burden. We used DYNAMICO to run a series of HD209458-like models with different orbital-radii. Training data for a number of features of interest was selected from the initial outputs of these models. This was used to train a pair of multi-categorisation convolutional-neural-networks (CNN), which we applied to our outer-atmosphere-equilibrated models. The features detected by our CNNs revealed that our models fall into two regimes: models with a shorter orbital-radii exhibit significant global mixing which shapes the entire atmospheres dynamics. Whereas, models with longer orbital-radii exhibit negligible mixing except at mid-pressures. Here, the initial non-detection of any trained features revealed a surprise: a night-side hot-spot. Analysis suggests that this occurs when rotational influence is sufficiently weak that divergent flows from the day-side to the night-side dominate over rotational-driven transport, such as the equatorial jet. We suggest that image-classification may play an important role in future, computational, atmospheric studies. However special care must be paid to the data feed into the model, from the colourmap, to training the CNN on features with enough breadth and complexity that the CNN can learn to detect them. However, by using preliminary-studies and prior-models, this should be more than achievable for future exascale calculations, allowing for a significant reduction in future workloads and computational resources.Comment: Accepted for publication in Ap

Autoradiographic Characterization and Localization of Quisqualate Binding Sites in Rat Brain Using the Antagonist [ 3 H]6-Cyano-7-Nitroquinoxaline-2,3-Dione: Comparison with ( R,S )-[ 3 H]Α-Amino-3-Hydroxy-5-Methyl-4-Isoxazolepropionic Acid Binding Sites

Using quantitative autoradiography, we have investigated the binding sites for the potent competitive non- N -methyl-D-aspartate (non-NMDA) glutamate receptor antagonist [ 3 H]6-cyano-7-nitro-quinoxaline-2,3-dione ([ 3 H]-CNQX) in rat brain sections. [ 3 H]CNQX binding was regionally distributed, with the highest levels of binding present in hippocampus in the stratum radiatum of CA1, stratum lucidum of CA3, and molecular layer of dentate gyrus. Scatchard analysis of [ 3 H]CNQX binding in the cerebellar molecular layer revealed an apparent single binding site with a K D = 67 ± 9.0 n M and B max = 3.56 ± 0.34 pmol/mg protein. In displacement studies, quisqualate, L-glutamate, and kainate also appeared to bind to a single class of sites. However, ( R,S )- Α -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) displacement of [ 3 H]CNQX binding revealed two binding sites in the cerebellar molecular layer. Binding of [ 3 H]AMPA to quisqualate receptors in the presence of potassium thiocyanate produced curvilinear Scatchard plots. The curves could be resolved into two binding sites with K D1 = 9.0 ± 3.5 n M , B max = 0.15 ± 0.05 pmol/mg protein, K D2 = 278 ± 50 n M , and B max = 1.54 ± 0.20 pmol/mg protein. The heterogeneous anatomical distribution of [ 3 H]CNQX binding sites correlated to the binding of L-[ 3 H]glutamate to quisqualate receptors and to sites labeled with [ 3 H]AMPA. These results suggest that the non-NMDA glutamate receptor antagonist [ 3 H]CNQX binds with equal affinity to two states of quisqualate receptors which have different affinities for the agonist [ 3 H]AMPA.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65634/1/j.1471-4159.1990.tb01925.x.pd

Partially linear censored quantile regression

Censored regression quantile (CRQ) methods provide a powerful and flexible approach to the analysis of censored survival data when standard linear models are felt to be appropriate. In many cases however, greater flexibility is desired to go beyond the usual multiple regression paradigm. One area of common interest is that of partially linear models: one (or more) of the explanatory covariates are assumed to act on the response through a non-linear function. Here the CRQ approach of Portnoy (J Am Stat Assoc 98:1001–1012, 2003) is extended to this partially linear setting. Basic consistency results are presented. A simulation experiment and unemployment example justify the value of the partially linear approach over methods based on the Cox proportional hazards model and on methods not permitting nonlinearity

Air quality in the mid-21st century for the city of Paris under two climate scenarios; from the regional to local scale

Ozone and PM_2.5 concentrations over the city of Paris are modeled with the CHIMERE air-quality model at 4 km × 4 km horizontal resolution for two future emission scenarios. A high-resolution (1 km × 1 km) emission projection until 2020 for the greater Paris region is developed by local experts (AIRPARIF) and is further extended to year 2050 based on regional-scale emission projections developed by the Global Energy Assessment. Model evaluation is performed based on a 10-year control simulation. Ozone is in very good agreement with measurements while PM_2.5 is underestimated by 20% over the urban area mainly due to a large wet bias in wintertime precipitation. A significant increase of maximum ozone relative to present-day levels over Paris is modeled under the "business-as-usual" scenario (+7 ppb) while a more optimistic "mitigation" scenario leads to a moderate ozone decrease (−3.5 ppb) in year 2050. These results are substantially different to previous regional-scale projections where 2050 ozone is found to decrease under both future scenarios. A sensitivity analysis showed that this difference is due to the fact that ozone formation over Paris at the current urban-scale study is driven by volatile organic compound (VOC)-limited chemistry, whereas at the regional-scale ozone formation occurs under NO_x-sensitive conditions. This explains why the sharp NO_x reductions implemented in the future scenarios have a different effect on ozone projections at different scales. In rural areas, projections at both scales yield similar results showing that the longer timescale processes of emission transport and ozone formation are less sensitive to model resolution. PM_2.5 concentrations decrease by 78% and 89% under business-as-usual and mitigation scenarios, respectively, compared to the present-day period. The reduction is much more prominent over the urban part of the domain due to the effective reductions of road transport and residential emissions resulting in the smoothing of the large urban increment modeled in the control simulation