Monitoring temporal opacity fluctuations of large structures with muon tomography : a calibration experiment using a water tower tank

Usage of secondary cosmic muons to image the geological structures density distribution significantly developed during the past ten years. Recent applications demonstrate the method interest to monitor magma ascent and volcanic gas movements inside volcanoes. Muon radiography could be used to monitor density variations in aquifers and the critical zone in the near surface. However, the time resolution achievable by muon radiography monitoring remains poorly studied. It is biased by fluctuation sources exterior to the target, and statistically affected by the limited number of particles detected during the experiment. The present study documents these two issues within a simple and well constrained experimental context: a water tower. We use the data to discuss the influence of atmospheric variability that perturbs the signal, and propose correction formulas to extract the muon flux variations related to the water level changes. Statistical developments establish the feasibility domain of muon radiography monitoring as a function of target thickness (i.e. opacity). Objects with a thickness comprised between $\simeq$ 50 $\pm$ 30m water equivalent correspond to the best time resolution. Thinner objects have a degraded time resolution that strongly depends on the zenith angle, whereas thicker objects (like volcanoes) time resolution does not.Comment: 11 pages, 9 figures. Final version published in Scientific Reports, Nature, 14 march 201

Modélisation VHDL/Spectre-HDL et simulation mixte sous Cadence : Conception d’un ASIC de commande de moteur asynchrone

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T315I Mutation INCREASES the GENOMIC Instability and the Mutator Phenotype IN BCR-ABL-Expressing LEUKEMIC CELLS.

Abstract Abstract 3365 Recent data suggest that the occurrence of T315I mutation, due in part to genetic instability induced by BCR-ABL, confers to the hematopoietic cells acquiring this mutation an additional genetic instability. Specific signalling pathways induced by T315I mutation could be at the origin of this phenomenon. As T315I substitution arises as a subclone of BCR-ABL-expressing cells, it is very difficult to study the specific effects of the putative mutational effect in primary CML cells. To determine if an additional genetic instability is induced in the presence of T315I, we have used the human UT7 cell model in which we have stably introduced BCR-ABL and BCR-ABL T315I using retroviral vectors. Western blot analysis showed that BCR-ABL protein levels were equivalent in both cell lines. To determine the global genomic instability phenomenon induced by BCR-ABL we have performed a mutator phenotype assay using the detection of HPRT mutants in the presence of 6-Thioguanine (6-TG) in control, wild-type BCR-ABL and BCR-ABL T315I-expressing UT7 cells in methycellulose assays. 6-TG resistant HPRT mutant colonies were quantified 3–4 weeks after initial seeding. The same cells were also used to quantify the baseline levels of &amp;amp;Ugr;-H2AX phosphorylation, indicative of double strand breaks (DSB). In addition, the same experiments were performed after the co-culture of the cells in the presence of a hematopoietic niche. Results: In the experimental conditions used, 6-TG resistant colonies were identified only in T315I-mutated cells, with a frequency of 7.9 10−6. The individually plucked HPRT mutants grew in liquid cultures in the presence of 6-TG, confirming the presence of a 6-TG resistance. Interestingly, the co-culture in the presence of MS-5 cell line for 3 days, increased the mutator phenotype (12. 10−6). The analysis of baseline g-H2AX levels showed a clear increase of &amp;amp;Ugr;-H2AX phosphorylation in UT7-T315I cells as compared to UT7-BCR-ABL which showed slightly higher levels as compared to control. To determine the long-term influence of Imatinib in the mutator phenotype, we cultured T315I cells in the presence of IM 1 microM for 7, 21 and 36 days followed by a mutator assay. The frequency of mutator phenotype was found to be stable, varying from 4.4 10−6 at day 7 to 5.24 10−6 at day 36 in the presence of IM. To determine the influence of the niche on the genomic instability, we have treated the UT7, UT7-BCR-ABL and UT7-T315I cells with mitomycin C (MMC) for 6 and 18 hours in the absence or in the presence of MS5 cells, followed by quantification of &amp;amp;Ugr;-H2AX levels at day+3. in these conditions, MMC induced '-H2AX levels were higher in T315I-mutated cells as compared to UT7 and the co-culture with MS-5 cells reduced this phenomenon. Thus, T315I mutation confers higher levels of DSB in steady state and increases the mutator phenotype of BCR-ABL-expressing cells. The co-culture in the presence of the niche reduces DSB but further increases the frequency of mutator phenotype, suggesting that the niche is not the major factor of genetic instability but stimulates the self-renewal of T315I-mutation bearing leukemic cells. Disclosures: No relevant conflicts of interest to declare. </jats:sec

Superoxide dismutase 2 (SOD2) contributes to genetic stability of native and T315I-mutated BCR-ABL expressing leukemic cells

International audienceManganese Superoxide dismutase 2 (SOD2) plays a crucial role in antioxidant defense but there are no data suggesting its role in genetic instability in CML. We evaluated the effects of SOD2 silencing in human UT7 cell line expressing either non-mutated or T315I-mutated BCR-ABL. Array-CGH experiments detected in BCR-ABL-expressing cells silenced for SOD2 a major genetic instability within several chromosomal loci, especially in regions carrying the glypican family (duplicated) and β-defensin genes (deleted). In a large cohort of patients with chronic myeloid leukemia (CML), a significant decrease of SOD2 mRNA was observed. This reduction appeared inversely correlated with leukocytosis and Sokal score, high-risk patients showing lower SOD2 levels. The analysis of anti-oxidant gene expression analysis revealed a specific down-regulation of the expression of PRDX2 in UT7-BCR-ABL and UT7-T315I cells silenced for SOD2 expression. Gene set enrichment analysis performed between the two SOD2-dependent classes of CML patients revealed a significant enrichment of Reactive Oxygen Species (ROS) Pathway. Our data provide the first evidence for a link between SOD2 expression and genetic instability in CML. Consequently, SOD2 mRNA levels should be analyzed in prospective studies as patients with low SOD2 expression could be more prone to develop a mutator phenotype under TKI therapies