ALK2 inhibitors display beneficial effects in preclinical models of <i>ACVR1</i> mutant diffuse intrinsic pontine glioma.

Diffuse intrinsic pontine glioma (DIPG) is a lethal childhood brainstem tumour, with a quarter of patients harbouring somatic mutations in ACVR1, encoding the serine/threonine kinase ALK2. Despite being an amenable drug target, little has been done to-date to systematically evaluate the role of ACVR1 in DIPG, nor to screen currently available inhibitors in patient-derived tumour models. Here we show the dependence of DIPG cells on the mutant receptor, and the preclinical efficacy of two distinct chemotypes of ALK2 inhibitor in vitro and in vivo. We demonstrate the pyrazolo[1,5-a]pyrimidine LDN-193189 and the pyridine LDN-214117 to be orally bioavailable and well-tolerated, with good brain penetration. Treatment of immunodeprived mice bearing orthotopic xenografts of H3.3K27M, ACVR1R206H mutant HSJD-DIPG-007 cells with 25 mg/kg LDN-193189 or LDN-214117 for 28 days extended survival compared with vehicle controls. Development of ALK2 inhibitors with improved potency, selectivity and advantageous pharmacokinetic properties may play an important role in therapy for DIPG patients

Effect of Digital Elevation Model Resolution on the Simulation of the Snow Cover Evolution in the High Atlas

International audienceThe snow melt from the High Atlas represents a crucial water resource for crop irrigation in the semiarid regions of Morocco. Recent studies have used assimilation of snow cover area data from high-resolution optical sensors to compute the snow water equivalent and snow melt in other mountain regions. These techniques however require large model ensembles, and therefore it is a challenge to determine the adequate model resolution that yields accurate results with reasonable computation time. Here we study the sensitivity of an energy balance model to the resolution of the model grid for a pilot catchment in the High Atlas. We used a time series of 8-m resolution snow cover area maps with an average revisit time of 7.5 days to evaluate the model results. The digital elevation model was generated from Pléiades stereo images and resampled from 8 to 30, 90, 250, 500, and 1,000 m. The results indicate that the model performs well from 8 to 250 m but the agreement with observations drops at 500 m. This is because significant features of the topography were too smoothed out to properly characterize the spatial variability of meteorological forcing, including solar radiation. We conclude that a resolution of 250 m might be sufficient in this area. This result is consistent with the shape of the semivariogram of the topographic slope, suggesting that this semivariogram analysis could be used to transpose our conclusion to other study regions

Parallel machines scheduling problem subject to transportation delays constraints

International audienc

Resolution of the parallel machines scheduling problem with preemption and transportation delays

International audienc

Performance of temperature and radiation index models for point-scale snow water equivalent (SWE) simulations in the Moroccan High Atlas Mountains

International audienc

Preemptive Scheduling with jobs transportation

International audienc

Linkages between snow cover, temperature and rainfall and the North Atlantic Oscillation over Morocco

Snowpack significantly contributes to water resources in North Africa. The objective of this work was to analyze the impact of the North Atlantic Oscillation (NAO) on rainfall and temperature in Morocco at a sub-seasonal scale and to evaluate, for the first time, linkages between the NAO and snow cover area (SCA) derived from remote sensing observations. For this purpose, we analyzed daily SCA products (2000-2013) from the MODIS sensor, meteorological data from 37 stations (1993-2011), NCEP re-analysis of surface air temperature and rainfall rate, and a monthly NAO index. The linear linkages sought using simple correlation analysis demonstrated that negative (positive) NAO (1) is associated with enhanced (reduced) rainfall in December and February for the northern part of the country; (2) occurs with above-normal (below-normal) temperature and, in contrast with rainfall, the correlation persists far inland and late in the season. These results highlight a possible competing influence of NAO on the snowpack dynamic through rainfall and temperature. Indeed, negative (positive) NAO tends to favor earlier (later) melting and lesser (greater) SCA in spring (April-May) through milder temperatures. Results have direct implications for seasonal forecast of SCA in Morocco

Spatial distribution of the air temperature in mountainous areas using satellite thermal infra-red data

Understanding the spatial distribution of air temperature in mountainous areas is essential in hydrological modelling. In the Moroccan High-Atlas range, the meteorological stations network is sparse. In order to get additional information, we investigated the thermal infrared data supplied by the Enhanced Thematic Mapper (ETM +) sensor onboard the Landsat 7 satellite. The brightness temperature derived from ETM+ images is used as a proxy for air temperature to set up a model that describes its spatial distribution. This model accounts for sun location and topographic characteristics derived from the SRTM digital elevation model. It was evaluated on the Rheraya watershed, a 225-km(2) region located within the semi-arid High-Atlas mountain range, using two different sources of data. The first data set consists in in-situ air temperature collected by meteorological stations installed during the experiment at various altitudes from 1400 to 3200 m. The second data set is satellite estimates of snow-covered areas (SCA) derived from MODIS images over the whole catchment at 500 m spatial resolution