Breakup prediction under uncertainty: application to Upper Stage controlled reentries from GTO orbit

More and more human-made space objects re-enter the atmosphere, and yet the risk for human population remains often unknown because predicting their reentry trajectories is formidably complex. While falling back on Earth, the space object absorbs large amounts of thermal energy that affects its structural integrity.It undergoes strong aerodynamic forces that lead to one or several breakups. Breakup events have a critical influence on the rest of the trajectory are extremely challenging to predict and subject to uncertainties. In this work, we present an original model for robustly predicting the breakup of a reentering space object. This model is composed of a set of individual solvers that are coupled together such as each solver resolves a specific aspect of this multiphysics problem. This paper deals with two levels of uncertainties. The first level is the stochastic modelling of the breakup while the second level is the statistical characterization of the model input uncertainties. The framework provides robust estimates of the quantities of interest and quantitative sensitivity analysis. The objective is twofold: first to compute a robust estimate of the breakup distribution and secondly to identify the main uncertainties in the quantities of interest. Due to the significant computational cost, we use an efficient framework par-* Corresponding author. ticularly suited to multiple solver predictions for the uncertainty quantification analysis. Then, we illustrate the breakup model for the controlled reentry of an upper stage deorbited from a Geo Transfer Orbit (GTO), which is a classical Ariane mission

ASPM-associated stem cell proliferation is involved in malignant progression of gliomas and constitutes an attractive therapeutic target

<p>Abstract</p> <p>Background</p> <p>ASPM (<it>Abnormal Spindle-like Microcephaly associated</it>) over-expression was recently implicated in the development of malignant gliomas.</p> <p>Results</p> <p>To better characterize the involvement of ASPM in gliomas, we investigated the mRNA expression in 175 samples, including 8 WHO Grade II, 75 WHO Grade III and 92 WHO Grade IV tumors. <it>Aspm </it>expression was strongly correlated with tumor grade and increased at recurrence when compared to the initial lesion, whatever the initial grade of the primary tumor. ASPM expression also increased over serial passages in gliomaspheres <it>in vitro </it>and in mouse xenografts <it>in vivo</it>. Lentivirus-mediated shRNA silencing of ASPM resulted in dramatic proliferation arrest and cell death in two different gliomasphere models.</p> <p>Conclusion</p> <p>These data suggest that ASPM is involved in the malignant progression of gliomas, possibly through expansion of a cancer stem cell compartment, and is an attractive therapeutic target in glioblastoma multiforme.</p

Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1

Myeloproliferative neoplasms (MPNs) originate from genetically transformed hematopoietic stem cells that retain the capacity for multilineage differentiation and effective myelopoiesis. Beginning in early 2005, a number of novel mutations involving Janus kinase 2 (JAK2), Myeloproliferative Leukemia Virus (MPL), TET oncogene family member 2 (TET2), Additional Sex Combs-Like 1 (ASXL1), Casitas B-lineage lymphoma proto-oncogene (CBL), Isocitrate dehydrogenase (IDH) and IKAROS family zinc finger 1 (IKZF1) have been described in BCR-ABL1-negative MPNs. However, none of these mutations were MPN specific, displayed mutual exclusivity or could be traced back to a common ancestral clone. JAK2 and MPL mutations appear to exert a phenotype-modifying effect and are distinctly associated with polycythemia vera, essential thrombocythemia and primary myelofibrosis; the corresponding mutational frequencies are ∼99, 55 and 65% for JAK2 and 0, 3 and 10% for MPL mutations. The incidence of TET2, ASXL1, CBL, IDH or IKZF1 mutations in these disorders ranges from 0 to 17% these latter mutations are more common in chronic (TET2, ASXL1, CBL) or juvenile (CBL) myelomonocytic leukemias, mastocytosis (TET2), myelodysplastic syndromes (TET2, ASXL1) and secondary acute myeloid leukemia, including blast-phase MPN (IDH, ASXL1, IKZF1). The functional consequences of MPN-associated mutations include unregulated JAK-STAT (Janus kinase/signal transducer and activator of transcription) signaling, epigenetic modulation of transcription and abnormal accumulation of oncoproteins. However, it is not clear as to whether and how these abnormalities contribute to disease initiation, clonal evolution or blastic transformation

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to &lt;90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], &gt;300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of &lt;15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P&lt;0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P&lt;0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Explorer et définir les évènements cellulaires et moléculaires nécessaires à une remyelinisation efficace chez les patients atteints de sclérose en plaques

Inflammation in the central nervous system leads to demyelination and neurodegeneration in patients with multiple sclerosis (MS). MS severity is closely correlated with the efficacy of myelin repair, a process whose effectiveness is very heterogeneous among patients. The reasons of this heterogeneity are largely unknown, mainly because it has never been addressed in a humanized pathological context. To tackle this question, we developed a new model combining focal demyelination in nude mice and graft of MS or healthy donor (HD) lymphocytes (LT). We were able to reproduce partially remyelination heterogeneity. Comparing the secretory profile of patients LT according to their repair capacities, we highlighted an heterogeneous cytokine response leading to a differential microglial (MIG) activation and ultimately an efficient or inefficient maturation of precursor cells during remyelination. To decipher why LT from patients display an heterogeneous response, we hypothesized that the genetic variants known for MS susceptibility could also drive disease severity by influencing LT functions. We found that the interaction of variants associated with genes responsible for T Folicular Helper and naïve Th0 cells functions induce the secretion by patient LT induce a pro-inflammatory activation in MIG, leading to remyelination failure.LT orchestrate MIG activation and are therefore responsible for the success or failure of remyelination. Capitalizing on patients with high repair capacities to understand the cellular and molecular actors leading to successful remyelination in pathological conditions seem to be a key approach to develop therapeutical targets.Chez les patients atteints de sclérose en plaques (SEP), l'inflammation induit une demyélinisation et une mort neuronale. La capacité de remyélinisation, hétérogène chez les patients, est intimement corrélée à la sévérité des symptômes. Les raisons de cette hétérogénéité ne sont pas connues, principalement car ce mécanisme n'a jamais été étudié dans un contexte expérimental approprié. Afin d'y remédier, nous avons développé un nouveau modèle en combinant une démyélinisation focale chez des souris nude à une greffe de lymphocytes (LT) provenant de donneurs sains ou de patients SEP. Cette modèle nous a permis de reproduire l'hétérogénéité de remyélinisation. En comparant le profil de sécrétion des patients selon leur capacité de réparation, nous avons mis en évidence des différences dans celui-ci, qui induisait selon le cas une activation bénéfique ou délétère des microglies ayant pour conséquence une différentiation efficace ou entravée des cellules précurseur d'oligodendrocytes. Cette capacité hétérogène des LT à répondre à une stimulation est partiellement expliqué par le background génétique du patients : les patients porteurs de variants associés à des gènes impliqués dans la fonction des LT folliculaires et des LT CD4+ naïfs induisaient un défaut de remyélinisation lorsque greffés dans une lésion démyélinisée, et ce en dirigeant l'activation microgliale vers un phénotype délétère. En résumé, les LT dirigent l'activation microgliale lors de la remyélinisation et sont donc au moins partiellement responsables de l'échec ou de la réussite de ce mécanisme. La façon dont ils réagissent à la démyélinisation est au moins en partie due au patrimoine génétique du patient

Vésicules polymères biorésorbables et stimulables pour des applications en vectorisation

L’auto-assemblage de copolymères à blocs amphiphiles est un outil puissant de la chimie supramoléculaire pour la conception de nano-objets complexes et fonctionnels. Dans ces travaux de thèse, l’étude approfondie d’un copolymère à blocs « hybride » synthétique-b-peptidique poly(triméthylène carbonate)-b-poly(acide glutamique) pour des applications de vectorisation a été menée. Des morphologies vésiculaires, obtenues par auto-assemblage en voie « co-solvant » et présentant une grande stabilité ainsi qu’un caractère stimulable ont été mises en évidence. Une transition inédite en température, par des phénomènes de fusion et de fission, a pu être observée. L’encapsulation dans ces vésicules polymères d’un principe actif anti-tumoral et de nanoparticules magnétiques, à des taux très élevés, permet d’améliorer le contraste en IRM ainsi que de moduler la libération de la molécule par une variation des paramètres environnementaux (pH, T) ou par un effet d’hyperthermie magnétique.Block copolymer self-assembly is a powerful tool within supramolecular chemistry to design smart and functional nano-objects. In this thesis work, comprehensive study of hybrid poly(trimethylene carbonate)-b-poly(glutamic acid) block copolymers for drug delivery applications has been conducted. Highly stable vesicular morphologies presenting stimuli-responsive behaviour were prepared using a solvent-injection method. In particular, original temperature responsiveness mediated by fusion and fission events has been evidenced. Dual loading of an anticancer drug and superparamagnetic nanoparticles in these vesicles, at very high loading contents, allows enhancing MRI contrast and controlling drug release kinetics by varying environmental conditions (pH, T) or by using a magnetic hyperthermia effect

Vésicules polymères biorésorbables et stimulables pour des applications en vectorisation

L’auto-assemblage de copolymères à blocs amphiphiles est un outil puissant de la chimie supramoléculaire pour la conception de nano-objets complexes et fonctionnels. Dans ces travaux de thèse, l’étude approfondie d’un copolymère à blocs « hybride » synthétique-b-peptidique poly(triméthylène carbonate)-b-poly(acide glutamique) pour des applications de vectorisation a été menée. Des morphologies vésiculaires, obtenues par auto-assemblage en voie « co-solvant » et présentant une grande stabilité ainsi qu’un caractère stimulable ont été mises en évidence. Une transition inédite en température, par des phénomènes de fusion et de fission, a pu être observée. L’encapsulation dans ces vésicules polymères d’un principe actif anti-tumoral et de nanoparticules magnétiques, à des taux très élevés, permet d’améliorer le contraste en IRM ainsi que de moduler la libération de la molécule par une variation des paramètres environnementaux (pH, T) ou par un effet d’hyperthermie magnétique.Block copolymer self-assembly is a powerful tool within supramolecular chemistry to design smart and functional nano-objects. In this thesis work, comprehensive study of hybrid poly(trimethylene carbonate)-b-poly(glutamic acid) block copolymers for drug delivery applications has been conducted. Highly stable vesicular morphologies presenting stimuli-responsive behaviour were prepared using a solvent-injection method. In particular, original temperature responsiveness mediated by fusion and fission events has been evidenced. Dual loading of an anticancer drug and superparamagnetic nanoparticles in these vesicles, at very high loading contents, allows enhancing MRI contrast and controlling drug release kinetics by varying environmental conditions (pH, T) or by using a magnetic hyperthermia effect

Mémoires pour servir a l'histoire de la révolution française, par Sanson, exècuteur des judgemens criminels pendants la révolution

MÉMOIRES POUR SERVIR A L'HISTOIRE DE LA RÉVOLUTION FRANÇAISE, PAR SANSON, EXÈCUTEUR DES JUDGEMENS CRIMINELS PENDANTS LA RÉVOLUTION Mémoires pour servir a l'histoire de la révolution française, par Sanson, exècuteur des judgemens criminels pendants la révolution ([1]) Text (unvollständig) ([1]

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monografi

Vésicules polymères biorésorbables et stimulables pour des applications en vectorisation

L auto-assemblage de copolymères à blocs amphiphiles est un outil puissant de la chimie supramoléculaire pour la conception de nano-objets complexes et fonctionnels. Dans ces travaux de thèse, l étude approfondie d un copolymère à blocs hybride synthétique-b-peptidique poly(triméthylène carbonate)-b-poly(acide glutamique) pour des applications de vectorisation a été menée. Des morphologies vésiculaires, obtenues par auto-assemblage en voie co-solvant et présentant une grande stabilité ainsi qu un caractère stimulable ont été mises en évidence. Une transition inédite en température, par des phénomènes de fusion et de fission, a pu être observée. L encapsulation dans ces vésicules polymères d un principe actif anti-tumoral et de nanoparticules magnétiques, à des taux très élevés, permet d améliorer le contraste en IRM ainsi que de moduler la libération de la molécule par une variation des paramètres environnementaux (pH, T) ou par un effet d hyperthermie magnétique.Block copolymer self-assembly is a powerful tool within supramolecular chemistry to design smart and functional nano-objects. In this thesis work, comprehensive study of hybrid poly(trimethylene carbonate)-b-poly(glutamic acid) block copolymers for drug delivery applications has been conducted. Highly stable vesicular morphologies presenting stimuli-responsive behaviour were prepared using a solvent-injection method. In particular, original temperature responsiveness mediated by fusion and fission events has been evidenced. Dual loading of an anticancer drug and superparamagnetic nanoparticles in these vesicles, at very high loading contents, allows enhancing MRI contrast and controlling drug release kinetics by varying environmental conditions (pH, T) or by using a magnetic hyperthermia effect.BORDEAUX1-Bib.electronique (335229901) / SudocSudocFranceF