178 research outputs found
Somatostatin and opioid receptors do not regulate proliferation or apoptosis of the human multiple myeloma U266 cells
International audienc
On the approximation of extreme quantiles with neural networks
National audienceIn this study, we propose a new parametrization for the generator of a Generative adversarial network (GAN) adapted to data from heavy-tailed distributions. We provide an analysis of the uniform error between an extreme quantile and its GAN approximation. Numerical experiments are conducted both on real and simulated data.Dans cette étude nous proposons une nouvelle paramétrisation du générateur d'un réseau antagoniste génératif (GAN) adaptée aux données issues d'une distribution a queue lourde. Nous apportons une analyse de l'erreur d'approximation en norme uniforme d'un quantile extrême par le GAN ainsi construit. Des simulations numériques sont réalisées sur des données réelles et simulées. Mots-clés. Théorie des valeurs extrêmes, réseau de neurones, modèle génératif
A refined Weissman estimator for extreme quantiles
International audienceWeissman extrapolation methodology for estimating extreme quantiles from heavy-tailed distributions is based on two estimators: an order statistic to estimate an intermediate quantile and an estimator of the tail-index. The common practice is to select the same intermediate sequence for both estimators. In this work, we show how an adapted choice of two different intermediate sequences leads to a reduction of the asymptotic bias associated with the resulting refined Weissman estimator. The asymptotic normality of the latter estimator is established and a data-driven method is introduced for the practical selection of the intermediate sequences. Our approach is compared to Weissman estimator and to six bias reduced estimators of extreme quantiles on a large scale simulation study. It appears that the refined Weissman estimator outperforms its competitors in a wide variety of situations, especially in the challenging high bias cases. Finally, an illustration on an actuarial real data set is provided
Why Anti-Energetic Agents Such as Citrate or 3-Bromopyruvate Should be Tested as Anti-Cancer Agents: Experimental In Vitro and In Vivo Studies
Dynamic simulation of the THAI heavy oil recovery process
Toe-to-Heel Air Injection (THAI) is a variant of conventional In-Situ Combustion (ISC) that uses a horizontal production well to recover mobilised partially upgraded heavy oil. It has a number of advantages over other heavy oil recovery techniques such as high recovery potential. However, existing models are unable to predict the effect of the most important operational parameters, such as fuel availability and produced oxygen concentration, which will give rise to unsafe designs. Therefore, we have developed a new model that accurately predicts dynamic conditions in the reservoir and also is easily scalable to investigate different field scenarios. The model used a three component direct conversion cracking kinetics scheme, which does not depend on the stoichiometry of the products and, thus, reduces the extent of uncertainty in the simulation results as the number of unknowns is reduced. The oil production rate and cumulative oil produced were well predicted, with the latter deviating from the experimental value by only 4%. The improved ability of the model to emulate real process dynamics meant it also accurately predicted when the oxygen was first produced, thereby enabling a more accurate assessment to be made of when it would be safe to shut-in the process, prior to oxygen breakthrough occurring. The increasing trend in produced oxygen concentration following a step change in the injected oxygen rate by 33 % was closely replicated by the model. The new simulations have now elucidated the mechanism of oxygen production during the later stages of the experiment. The model has allowed limits to be placed on the air injection rates that ensure stability of operation. Unlike previous models, the new simulations have provided better quantitative prediction of fuel laydown, which is a key phenomenon that determines whether, or not, successful operation of the THAI process can be achieved. The new model has also shown that, for completely stable operation, the combustion zone must be restricted to the upper portion of the sand pack, which can be achieved by using higher producer back pressure
New evidence of a mitochondrial genetic background paradox: Impact of the J haplogroup on the A3243G mutation
International audienceBackground: The A3243G mutation in the tRNALeu gene (UUR), is one of the most common pathogenic mitochondrial DNA (mtDNA) mutations in France, and is associated with highly variable and heterogeneous disease phenotypes. To define the relationships between the A3243G mutation and mtDNA backgrounds, we determined the haplogroup affiliation of 142 unrelated French patients – diagnosed as carriers of the A3243G mutation – by control-region sequencing and RFLP survey of their mtDNAs. Results: The analysis revealed 111 different haplotypes encompassing all European haplogroups, indicating that the 3243 site might be a mutational hot spot. However, contrary to previous findings, we observed a statistically significant underepresentation of the A3243G mutation on haplogroup J in patients (p = 0.01, OR = 0.26, C.I. 95%: 0.08–0.83), suggesting that might be due to a strong negative selection at the embryo or germ line stages. Conclusion: Thus, our study supports the existence of mutational hotspot on mtDNA and a "haplogroup J paradox," a haplogroup that may increase the expression of mtDNA pathogenic mutations, but also be beneficial in certain environmental contexts
Identification des sites potentiels de phosphorylation impliqués dans la régulation des récepteurs opioïdes delta humains induite par les arrestines
La tolérance aux opioïdes est un processus complexe lié à la désensibilisation des récepteurs opioïdes et à l implication des barrestines. Des travaux du laboratoire ont montré que la barrestine 1 était requise de manière différente dans la désensibilisation du récepteur opioïde delta humain ( -OR) selon les agonistes utilisés (Aguila et al., 2012). Dans une première partie, nous avonss évalué le rôle des barrestines dans la désensibilisation et l internalisation du -OR à court (1h) et long (18h) termes en présence de morphine et d étorphine. Alors que la désensibilisation aiguë ne requière pas la barrestine 1, cette protéine a un rôle majeur dans la désensibilisation induite par la morphine à long terme. Nous n avons pas constaté d effet majeur des barrestines sur l internalisation du -OR en microscopie confocale indiquant l absence de corrélation entre l internalisation et la désensibilisation des récepteurs. Dans une deuxième partie, nous avons étudié les sites potentiels de phosphorylation du -OR pouvant être impliqués dans la désensibilisation et l internalisation ainsi que dans les effets des barrestines. La T161 du -OR intervient dans la désensibilisation induite par l étorphine mais pas pour un autre agoniste, la DPDPE. La désensibilisation barrestine 2 dépendante implique les résidus T161 et S363. Les mutants T161A et Y318A réduisent l internalisation du -OR induite par les deux agonistes alors que la S363 est sélectivement impliquée dans l internalisation induite par l étorphine. En conclusion, les barrestines jouent un rôle important dans la régulation différentielle des récepteurs par différents agonistes ce qui renvoit à la notion d agonisme biaisé.Opioid tolerance is a complex process associated with the desensitization of opioid receptors and the involvement of barrestines. The work of the laboratory have shown that barrestine 1 was required differently in desensitization of human delta opioid receptor ( -OR) according to the agonists used (Aguila et al., 2012). In the first part, we evaluated the role of barrestines in desensitization and internalization of -OR at short (1 hour) and long (18h) time in the presence of morphine and etorphine. While the "acute" desensitization does not require the barrestine 1, this protein has a major role in the desensitization induced by morphine in the long time. We did not observe any major effect of barrestines on -OR internalization by confocal microscopy showing the lack of correlation between internalization and receptor desensitization. In a second part, we studied the potential phosphorylation sites of -OR may be involved in desensitization and internalization as well as the effects of barrestines.T161 of the -OR is involved in the desensitization induced by etorphine but not for another agonist, the DPDPE. barrestine 2-dependent desensitization involves T161 and S363 residues. The mutants T161A and Y318A reduce the internalization of -OR induced by both agonists, while the S363 is selectively involved in etorphine-induced internalization. In conclusion, barrestines play an important role in the differential regulation of the receptors by different agonists which returns to the concept of biased agonism.CAEN-BU Médecine pharmacie (141182102) / SudocSudocFranceF
Modulation de la prolifération cellulaire et de l apoptose des cellules de myélome multiple (MM) par les récepteurs couplés aux protéines G, les arrestines et le peptide OFQ3/Noc III, dérivé de la pronociceptine ([thèse soutenue sur un ensemble de travaux])
L objectif de ce travail porte sur la modulation des voies de signalisation anormalement activées dans les cellules d hémopathies malignes par les récepteurs opioïdes, les récepteurs à la somatostatine et les arrestines. Après avoir caractérisé ces récepteurs dans les lignées de MM, nous avons démontré que l U50 488 (agoniste des récepteurs opioïdes kappa) induit un léger blocage de prolifération et une potentialisation de l apoptose induite par Fas, via un mécanisme indépendant des récepteurs opioïdes dans les cellules LP-1. Dans un second temps, nous avons pu montrer que la somatostatine et l octréotide, agonistes des récepteurs à la somatostatine, seuls ou combinés à la morphine étaient incapables de moduler la prolifération et l apoptose les cellules U266 de MM. Nous avons démontré qu un peptide dérivé de la pronociceptine, l OFQ3/Noc III, est capable d induire l apoptose dans les cellules U266 par un mécanisme caspase-indépendant impliquant la libération d AIF. Enfin, dans un dernier temps, nous avons étudié le rôle des arrestines dans la prolifération et l apoptose des cellules U266. La surexpression de la b arrestine 2-GFP induit une diminution de prolifération et une augmentation de l apoptose caspase-dépendante. Ces effets sont associés à une augmentation d expression protéique de p27 et de l activité de liaison du facteur de transcription NF- B. De plus, la présence d une plus grande quantité de chromosomes dans cette lignée suggère l apparition d une catastrophe mitotique. Ces effets sont également retrouvés mais à un degré moindre avec le mutant constitutivement actif de l arrestine (R169E). En conclusion, ces résultats ouvrent des perspectives vers de nouvelles voies thérapeutiques dans le traitement du myélome multiple.The aim of this work was to discover new pathways to regulate proliferation and to induce apoptosis in malignant haematological cells. We examined the role of opioid and somatostatin receptors, known as G-protein coupled receptors (GPCR), arrestins and a pronociceptin-derived peptide, OFQ3/Noc III. After characterization of those GPCR in multiple myeloma (MM) cells, we demonstrated that U50 488 (a kappa selective opioid agonist) induced a weak blockage of proliferation and a potentiation of Fas-induced apoptosis through a non-opioid receptor mechanism. We proved that somatostatin and octreotide, somatostatin receptor agonists, alone or combined with morphine were not able to modulate apoptosis and proliferation in MM cells. We showed that the pronociceptine-derived peptide OFQ3/Noc III induced caspase-independent apoptosis by activating AIF in U266 MM cells. Finally, by overexpressing b arrestin2-GFP in the U266 cells, we demonstrated its role in proliferation and apoptosis. These effects were coupled with an increase of p27 protein expression and an increase of NF- B binding activity. Apoptosis associated with an increase in chromosome number suggested the occurrence of mitotic catastrophe. Those effects were also observed but to a lesser extent when the dominant negative mutant of arrestin, R169E, was overexpressed. In conclusion, our work shows that new therapeutic strategies could be considered for the treatment of multiple myeloma.CAEN-BU Sciences et STAPS (141182103) / SudocSudocFranceF
Identification d'une nouvelle mutation pathogène de l'ADN mitochondrial dans l'ARNt Asn responsable d'une encéphalomyopathie infantile fatale
CAEN-BU Médecine pharmacie (141182102) / SudocSudocFranceF
Efficacité et tolérance de l'abatacept dans la polyarthrite rhumatoïde (expérience des services de Rhumatologie de l'AP-HM)
AIX-MARSEILLE2-BU Méd/Odontol. (130552103) / SudocSudocFranceF
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