Plateforme de calcul parallèle "Design for Demise"

Les risques liés aux débris spatiaux sont à présent considérés comme critiques par les gouvernements et les agences spatiales internationales. Durant la dernière décennie les agences spatiales ont développé des logiciels pour simuler la rentrée atmosphérique des satellites et des stations orbitales afin de déterminer les risques et possibles dommages au sol. Néanmoins les outils actuels fournissent des résultats déterministes alors que les modèles employés utilisent des valeurs de paramètres qui sont mal connues. De plus les résultats obtenus dépendent fortement des hypothèses qui sont faites. Une solution pour obtenir des résultats pertinents et exploitables est de prendre en considération les incertitudes que l'on a sur les différents paramètres de la modélisation afin d'effectuer des analyses de type Monte-Carlo. Mais une telle étude est particulièrement gourmande en temps de calcul à cause du grand espace des paramètres à explorer (ce qui nécessite des centaines de milliers de simulations numériques). Dans le cadre de ces travaux de thèse nous proposons un nouveau logiciel de simulation numérique de rentrée atmosphérique de satellite, permettant de façon native de prendre en considération les incertitudes sur les différents paramètres de modélisations pour effectuer des analyses statistiques. Afin de maitriser les temps de calculs cet outil tire avantage de la méthode de Taguchi pour réduire le nombre de paramètres à étudier et aussi des accélérateurs de calculs de type Graphics Processing Units (GPUs) et Intel Xeon Phi.The risk of space debris is now perceived as primordial by government and international space agencies. Since the last decade, international space agencies have developed tools to simulate the re-entry of satellites and orbital stations in order to assess casualty risk on the ground. Nevertheless , all current tools provide deterministic solutions, though models include various parameters that are not well known. Therefore, the provided results are strongly dependent on the assumptions made. One solution to obtain relevant and exploitable results is to include uncertainties around those parameters in order to perform Monte-Carlo analysis. But such a study is very time consuming due to the large parameter space to explore (that necessitate hundreds of thousands simulations). As part of this thesis work we propose a new satellite atmospheric reentry simulation to perform statistical analysis. To master computing time this tool takes advantage of Taguchi method to restrain the amount of parameter to study and also takes advantage of computing accelerators like Graphic Processing Units (GPUs) and Intel Xeon Phi

Investigating slim disk solutions for HLX-1 in ESO 243-49

The hyper luminous X-ray source HLX-1 in the galaxy ESO 243-49, currently the best intermediate mass black hole candidate, displays spectral transitions similar to those observed in Galactic black hole binaries, but with a luminosity 100-1000 times higher. We investigated the X-ray properties of this unique source fitting multi-epoch data collected by Swift, XMM-Newton & Chandra with a disk model computing spectra for a wide range of sub- and super-Eddington accretion rates assuming a non-spinning black hole and a face-on disk (i = 0 deg). Under these assumptions we find that the black hole in HLX-1 is in the intermediate mass range (~2 x 10^4 M_odot) and the accretion flow is in the sub-Eddington regime. The disk radiation efficiency is eta = 0.11 +/-0.03. We also show that the source does follow the L_X ~ T^4 relation for our mass estimate. At the outburst peaks, the source radiates near the Eddington limit. The accretion rate then stays constant around 4 x 10^(-4) M_odot yr^(-1) for several days and then decreases exponentially. Such "plateaus" in the accretion rate could be evidence that enhanced mass transfer rate is the driving outburst mechanism in HLX-1. We also report on the new outburst observed in August 2011 by the Swift-X-ray Telescope. The time of this new outburst further strengthens the ~1 year recurrence timescale.Comment: 24 pages, 10 figures, accepted for publication in Ap

Metabolic selection of a homologous recombination-mediated gene loss protects Trypanosoma brucei from ROS production by glycosomal fumarate reductase

The genome of trypanosomatids rearranges by using repeated sequences as platforms for amplification or deletion of genomic segments. These stochastic recombination events have a direct impact on gene dosage and foster the selection of adaptive traits in response to environmental pressure. We provide here such an example by showing that the phosphoenolpyruvate carboxykinase (PEPCK) gene knockout (Δpepck) leads to the selection of a deletion event between two tandemly arranged fumarate reductase (FRDg and FRDm2) genes to produce a chimeric FRDg-m2 gene in the Δpepck∗ cell line. FRDg is expressed in peroxisome-related organelles, named glycosomes, expression of FRDm2 has not been detected to date, and FRDg-m2 is nonfunctional and cytosolic. Re-expression of FRDg significantly impaired growth of the Δpepck∗ cells, but FRD enzyme activity was not required for this negative effect. Instead, glycosomal localization as well as the covalent flavinylation motif of FRD is required to confer growth retardation and intracellular accumulation of reactive oxygen species (ROS). The data suggest that FRDg, similar to Escherichia coli FRD, can generate ROS in a flavin-dependent process by transfer of electrons from NADH to molecular oxygen instead of fumarate when the latter is unavailable, as in the Δpepck background. Hence, growth retardation is interpreted as a consequence of increased production of ROS, and rearrangement of the FRD locus liberates Δpepck∗ cells from this obstacle. Interestingly, intracellular production of ROS has been shown to be required to complete the parasitic cycle in the insect vector, suggesting that FRDg may play a role in this proces

Procyclic trypanosomes recycle glucose catabolites and TCA cycle intermediates to stimulate growth in the presence of physiological amounts of proline

Trypanosoma brucei, a protist responsible for human African trypanosomiasis (sleeping sickness), is transmitted by the tsetse fly where the procyclic forms of the parasite develop in the proline-rich (1–2 mM) and glucose-depleted digestive tract. Proline is essential for the midgut colonization of the parasite in the insect vector, however other carbon sources could be available and used to feed its central metabolism. Here we show that procyclic trypanosomes can consume and metabolize metabolic intermediates, including those excreted from glucose catabolism (succinate, alanine and pyruvate), with the exception of acetate, which is the ultimate end-product excreted by the parasite. Among the tested metabolites, tricarboxylic acid (TCA) cycle intermediates (succinate, malate and α-ketoglutarate) stimulated growth of the parasite in the presence of 2 mM proline. The pathways used for their metabolism were mapped by proton-NMR metabolic profiling and phenotypic analyses of thirteen RNAi and/or null mutants affecting central carbon metabolism. We showed that (i) malate is converted to succinate by both the reducing and oxidative branches of the TCA cycle, which demonstrates that procyclic trypanosomes can use the full TCA cycle, (ii) the enormous rate of α-ketoglutarate consumption (15-times higher than glucose) is possible thanks to the balanced production and consumption of NADH at the substrate level and (iii) α-ketoglutarate is toxic for trypanosomes if not appropriately metabolized as observed for an α-ketoglutarate dehydrogenase null mutant. In addition, epimastigotes produced from procyclics upon overexpression of RBP6 showed a growth defect in the presence of 2 mM proline, which is rescued by α-ketoglutarate, suggesting that physiological amounts of proline are not sufficient per se for the development of trypanosomes in the fly. In conclusion, these data show that trypanosomes can metabolize multiple metabolites, in addition to proline, which allows them to confront challenging environments in the fly

PLoS Biol

Microorganisms must make the right choice for nutrient consumption to adapt to their changing environment. As a consequence, bacteria and yeasts have developed regulatory mechanisms involving nutrient sensing and signaling, known as "catabolite repression," allowing redirection of cell metabolism to maximize the consumption of an energy-efficient carbon source. Here, we report a new mechanism named "metabolic contest" for regulating the use of carbon sources without nutrient sensing and signaling. Trypanosoma brucei is a unicellular eukaryote transmitted by tsetse flies and causing human African trypanosomiasis, or sleeping sickness. We showed that, in contrast to most microorganisms, the insect stages of this parasite developed a preference for glycerol over glucose, with glucose consumption beginning after the depletion of glycerol present in the medium. This "metabolic contest" depends on the combination of 3 conditions: (i) the sequestration of both metabolic pathways in the same subcellular compartment, here in the peroxisomal-related organelles named glycosomes; (ii) the competition for the same substrate, here ATP, with the first enzymatic step of the glycerol and glucose metabolic pathways both being ATP-dependent (glycerol kinase and hexokinase, respectively); and (iii) an unbalanced activity between the competing enzymes, here the glycerol kinase activity being approximately 80-fold higher than the hexokinase activity. As predicted by our model, an approximately 50-fold down-regulation of the GK expression abolished the preference for glycerol over glucose, with glucose and glycerol being metabolized concomitantly. In theory, a metabolic contest could be found in any organism provided that the 3 conditions listed above are met

Complete In Vitro Life Cycle of Trypanosoma congolense: Development of Genetic Tools

Trypanosoma congolense is a parasite responsible for severe disease of African livestock. Its life cycle is complex and divided into two phases, one in the tsetse fly vector and one in the bloodstream of the mammalian host. Molecular tools for gene function analyses in parasitic organisms are essential. Previous studies described the possibility of completing the entire T. congolense life cycle in vitro. However, the model showed major flaws including the absence of stable long-term culture of the infectious bloodstream forms, a laborious time-consuming period to perform the cycle and a lack of genetic tools. We therefore aimed to develop a standardized model convenient for genetic engineering. We succeeded in producing long-term cultures of all the developmental stages on long-term, to define all the differentiation steps and to finally complete the whole cycle in vitro. This improved model offers the opportunity to conduct phenotype analyses of genetically modified strains throughout the in vitro cycle and also during experimental infections

Human Cytomegalovirus Entry into Dendritic Cells Occurs via a Macropinocytosis-Like Pathway in a pH-Independent and Cholesterol-Dependent Manner

Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus that is able to infect fibroblastic, epithelial, endothelial and hematopoietic cells. Over the past ten years, several groups have provided direct evidence that dendritic cells (DCs) fully support the HCMV lytic cycle. We previously demonstrated that the C-type lectin dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) has a prominent role in the docking of HCMV on monocyte-derived DCs (MDDCs). The DC-SIGN/HCMV interaction was demonstrated to be a crucial and early event that substantially enhanced infection in trans, i.e., from one CMV-bearing cell to another non-infected cell (or trans-infection), and rendered susceptible cells fully permissive to HCMV infection. Nevertheless, nothing is yet known about how HCMV enters MDDCs. In this study, we demonstrated that VHL/E HCMV virions (an endothelio/dendrotropic strain) are first internalized into MDDCs by a macropinocytosis-like process in an actin- and cholesterol-dependent, but pH-independent, manner. We observed the accumulation of virions in large uncoated vesicles with endosomal features, and the virions remained as intact particles that retained infectious potential for several hours. This trans-infection property was specific to MDDCs because monocyte-derived macrophages or monocytes from the same donor were unable to allow the accumulation of and the subsequent transmission of the virus. Together, these data allowed us to delineate the early mechanisms of the internalization and entry of an endothelio/dendrotropic HCMV strain into human MDDCs and to propose that DCs can serve as a "Trojan horse" to convey CMV from entry sites to other locations that may favor the occurrence of either latency or acute infection