348 research outputs found
Nonparametric Laguerre estimation in the multiplicative censoring model
International audienceWe study the model where the 's are {\em i.i.d.} with density, , the 's are {\em i.i.d.}, nonnegative with unknown density . The sequences are independent. We aim at estimating on from the observations . We propose projection estimators using a Laguerre basis. A data-driven procedure is described in order to select the dimension of the projection space, which performs automatically the bias variance compromise. Then, we give upper bounds on the -risk on specific Sobolev-Laguerre spaces. Lower bounds matching with the upper bounds within a logarithmic factor are proved. The method is illustrated on simulated data
Sobolev-Hermite versus Sobolev nonparametric density estimation on R
International audienceIn this paper, our aim is to revisit the nonparametric estimation of f assuming that f is square integrable on R, by using projection estimators on a Hermite basis. These estimators are defined and studied from the point of view of their mean integrated squared error on R. A model selection method is described and proved to perform an automatic bias variance compromise. Then, we present another collection of estimators, of deconvolution type, for which we define another model selection strategy. Considering Sobolev and Sobolev-Hermite spaces, the asymptotic rates of these estimators can be computed and compared: they are mainly proved to be equivalent. However, complexity evaluations prove that the Hermite estimators have a much lower computational cost than their deconvolution (or kernel) counterparts. These results are illustrated through a small simulation study
Innate Lymphoid Cells in Autoimmune Diseases.
Innate lymphoid cells (ILC) are a heterogeneous group of immune cells characterized by lymphoid morphology and cytokine profile similar to T cells but which do not express clonally distributed diverse antigen receptors. These particular cells express transcription factors and cytokines reflecting their similarities to T helper (Th)1, Th2, and Th17 cells and are therefore referred to as ILC1, ILC2, and ILC3. Other members of the ILC subsets include lymphoid tissue inducer (LTi) and regulatory ILC (ILCreg). Natural killer (NK) cells share a common progenitor with ILC and also exhibit a lymphoid phenotype without antigen specificity. ILC are found in low numbers in peripheral blood but are much more abundant at barrier sites such as the skin, liver, airways, lymph nodes, and the gastrointestinal tract. They play an important role in innate immunity due to their capacity to respond rapidly to pathogens through the production of cytokines. Recent evidence has shown that ILC also play a key role in autoimmunity, as alterations in their number or function have been identified in systemic lupus erythematosus, systemic sclerosis, and rheumatoid arthritis. Here, we review recent advances in the understanding of the role of ILC in the pathogenesis of autoimmune diseases, with particular emphasis on their role as a potential diagnostic biomarker and as therapeutic targets
Exhaustion of bacteria-specific CD4 T cells and microbial translocation in common variable immunodeficiency disorders.
In the present study, we have investigated the functional profile of CD4 T cells from patients with common variable immunodeficiency (CVID), including production of cytokines and proliferation in response to bacteria and virus-derived antigens. We show that the functional impairment of CD4 T cells, including the reduced capacity to proliferate and to produce IFN-Îł and IL-2, was restricted to bacteria-specific and not virus-specific CD4 T cells. High levels of endotoxins were found in the plasma of patients with CVID, suggesting that CD4 T cell dysfunction might be caused by bacterial translocation. Of note, endotoxemia was associated with significantly higher expression of programmed death 1 (PD-1) on CD4 T cells. The blockade of the PD-1-PD-L1/2 axis in vitro restored CD4 T cell proliferation capacity, thus indicating that PD-1 signaling negatively regulates CD4 T cell functions. Finally, we showed that intravenous immunoglobulin G (IVIG) treatment significantly reduced endotoxemia and the percentage of PD-1(+) CD4 T cells, and restored bacteria-specific CD4 T cell cytokine production and proliferation. In conclusion, the present study demonstrates that the CD4 T cell exhaustion and functional impairment observed in CVID patients is associated with bacterial translocation and that IVIG treatment resolves bacterial translocation and restores CD4 T cell functions
CD160-Associated CD8 T-Cell Functional Impairment Is Independent of PD-1 Expression.
Expression of co-inhibitory molecules is generally associated with T-cell dysfunction in chronic viral infections such as HIV or HCV. However, their relative contribution in the T-cell impairment remains unclear. In the present study, we have evaluated the impact of the expression of co-inhibitory molecules such as 2B4, PD-1 and CD160 on the functions of CD8 T-cells specific to influenza, EBV and CMV. We show that CD8 T-cell populations expressing CD160, but not PD-1, had reduced proliferation capacity and perforin expression, thus indicating that the functional impairment in CD160+ CD8 T cells may be independent of PD-1 expression. The blockade of CD160/CD160-ligand interaction restored CD8 T-cell proliferation capacity, and the extent of restoration directly correlated with the ex vivo proportion of CD160+ CD8 T cells suggesting that CD160 negatively regulates TCR-mediated signaling. Furthermore, CD160 expression was not up-regulated upon T-cell activation or proliferation as compared to PD-1. Taken together, these results provide evidence that CD160-associated CD8 T-cell functional impairment is independent of PD-1 expression
Petits agrĂ©gats molĂ©culaires d'intĂ©rĂȘt astrophysique
Les observations de molĂ©cules complexes dans des environnements trĂšs diffĂ©rents de lâespace, depuis les rĂ©gions de formation dâĂ©toiles aux comĂštes, interrogent quant aux mĂ©canismes qui ont conduit Ă leur formation. Lâutilisation combinĂ©e du dispositif dâirradiation dâagrĂ©gats molĂ©culaires de Lyon et de plusieurs mĂ©thodes thĂ©oriques permet lâĂ©tude statistique des mĂ©canismes de relaxation de dimĂšres molĂ©culaires protonĂ©s suite Ă une excitation sur un temps court (femtoseconde) dâune des deux molĂ©cules de lâagrĂ©gat. Lors dâune collision unique Ă haute vitesse avec un atome, lâagrĂ©gat est placĂ© dans une situation trĂšs Ă©loignĂ©e de lâĂ©quilibre thermique et plusieurs mĂ©canismes de relaxation sont observĂ©s. Les mesures des rapports de branchement et celles de la distribution dâĂ©nergie cinĂ©tique libĂ©rĂ©e pour un canal de relaxation donnĂ© permettent une Ă©tude quantitative de la compĂ©tition entre lâĂ©vaporation dâune molĂ©cule, la fragmentation dâune des deux molĂ©cules, et la formation dâune molĂ©cule plus complexe. Les rĂ©sultats sont comparĂ©s pour diffĂ©rents dimĂšres molĂ©culaires protonĂ©s : le dimĂšre de pyridine, le dimĂšre de mĂ©thanol, le dimĂšre de glycine et un dimĂšre mixte composĂ© dâun dipeptide de glycine et dâune molĂ©cule de glycine. A la diffĂ©rence du dimĂšre de pyridine, les rĂ©sultats obtenus avec le dimĂšre de mĂ©thanol mettent en Ă©vidence la rĂ©action unimolĂ©culaire dâĂ©limination de lâeau par lâagrĂ©gat parent. Les caractĂ©ristiques Ă©nergĂ©tiques de lâĂ©tat fondamental du dimĂšre, des produits de rĂ©action, et des Ă©tats de transitions ont Ă©tĂ© calculĂ©es avec la thĂ©orie de la fonctionnelle de la densitĂ© et utilisĂ©es pour comparer quantitativement les rĂ©sultats expĂ©rimentaux Ă ceux de la thĂ©orie de lâespace de phase. Cela montre, dâune part, que les mesures expĂ©rimentales contraignent quantitativement les modĂšles thĂ©oriques et, dâautre part, que les rĂ©sultats expĂ©rimentaux ne peuvent ĂȘtre interprĂ©tĂ©s quantitativement avec lâhypothĂšse dâune redistribution complĂšte de lâĂ©nergie interne sur tous les modes de lâagrĂ©gat parent avant la dissociation. Cela souligne lâimportance du temps de transfert dâĂ©nergie entre les molĂ©cules dans la compĂ©tition entre les diffĂ©rents canaux de relaxation. Dans le cas de la glycine, la formation du dipeptide et lâallongement de la chaĂźne peptidique ont Ă©tĂ© mis en Ă©vidence dans une rĂ©action unimolĂ©culaire. La mesure de la distribution de vitesse de la molĂ©cule dâeau Ă©liminĂ©e par la rĂ©action de polymĂ©risation montre la prĂ©sence de diffĂ©rents chemins de rĂ©action pour lesquels le rĂŽle du proton a Ă©tĂ© explorĂ© par des calculs de thĂ©orie de la fonctionnelle de la densitĂ©. Lâensemble des rĂ©sultats mettent en Ă©vidence la rĂ©action unimolĂ©culaire comme une nouvelle voie abiotique pour la formation de molĂ©cules organiques en phase gazeuse, soulignant lâintĂ©rĂȘt des dimĂšres molĂ©culaires protonĂ©s pour la formation de molĂ©cules complexes en conditions astrophysiques.Observations of complex molecules in very different environments in space, from star forming regions to comets, raise questions about the mechanisms that led to their formation. The combined use of the Lyon molecular cluster irradiation device and several theoretical methods allows the statistical study of the relaxation mechanisms of protonated molecular dimers following a short time (femtosecond) excitation of one of the two molecules in the cluster. During a single collision at high velocity with an atom, the cluster is placed in a situation far from thermal equilibrium and several relaxation mechanisms are observed. Measurements of the branching ratios and of the kinetic energy released distribution for a given relaxation channel allow a quantitative study of the competition between the evaporation of a molecule, the fragmentation of one of the two molecules, and the formation of a more complex molecule. The results are compared for different molecular protonated dimers: the pyridine dimer, the methanol dimer, the glycine dimer, and a mixed dimer composed of a glycine dipeptide and a glycine molecule. In contrast to the pyridine dimer, the results obtained with the methanol dimer show the unimolecular reaction with water elimination by the parent cluster. The energy characteristics of the dimer ground state, reaction products, and transition states were calculated with density functional theory and used to compare quantitatively the experimental results with those from phase space theory. This shows, on the one hand, that the experimental measurements quantitatively constrain the theoretical models and, on the other hand, that the experimental results cannot be quantitatively interpreted with the assumption of a complete redistribution of the internal energy over all modes of the parent cluster before dissociation. This highlights the importance of the energy transfer time between molecules on the competition between the different relaxation channels. In the case of glycine, the formation of the dipeptide and the elongation of the peptide chain were demonstrated in a unimolecular reaction. The measurement of the velocity distribution of the water molecule eliminated by the polymerisation reaction shows the presence of different reaction paths for which the role of the proton has been explored by density functional theory calculations. All the results highlight the unimolecular reaction as a new abiotic pathway for the formation of organic molecules in the gas phase, underlining the interest of protonated molecular dimers for the formation of complex molecules under astrophysical conditions
Petits agrĂ©gats molĂ©culaires d'intĂ©rĂȘt astrophysique
Observations of complex molecules in very different environments in space, from star forming regions to comets, raise questions about the mechanisms that led to their formation. The combined use of the Lyon molecular cluster irradiation device and several theoretical methods allows the statistical study of the relaxation mechanisms of protonated molecular dimers following a short time (femtosecond) excitation of one of the two molecules in the cluster. During a single collision at high velocity with an atom, the cluster is placed in a situation far from thermal equilibrium and several relaxation mechanisms are observed. Measurements of the branching ratios and of the kinetic energy released distribution for a given relaxation channel allow a quantitative study of the competition between the evaporation of a molecule, the fragmentation of one of the two molecules, and the formation of a more complex molecule. The results are compared for different molecular protonated dimers: the pyridine dimer, the methanol dimer, the glycine dimer, and a mixed dimer composed of a glycine dipeptide and a glycine molecule. In contrast to the pyridine dimer, the results obtained with the methanol dimer show the unimolecular reaction with water elimination by the parent cluster. The energy characteristics of the dimer ground state, reaction products, and transition states were calculated with density functional theory and used to compare quantitatively the experimental results with those from phase space theory. This shows, on the one hand, that the experimental measurements quantitatively constrain the theoretical models and, on the other hand, that the experimental results cannot be quantitatively interpreted with the assumption of a complete redistribution of the internal energy over all modes of the parent cluster before dissociation. This highlights the importance of the energy transfer time between molecules on the competition between the different relaxation channels. In the case of glycine, the formation of the dipeptide and the elongation of the peptide chain were demonstrated in a unimolecular reaction. The measurement of the velocity distribution of the water molecule eliminated by the polymerisation reaction shows the presence of different reaction paths for which the role of the proton has been explored by density functional theory calculations. All the results highlight the unimolecular reaction as a new abiotic pathway for the formation of organic molecules in the gas phase, underlining the interest of protonated molecular dimers for the formation of complex molecules under astrophysical conditions.Les observations de molĂ©cules complexes dans des environnements trĂšs diffĂ©rents de lâespace, depuis les rĂ©gions de formation dâĂ©toiles aux comĂštes, interrogent quant aux mĂ©canismes qui ont conduit Ă leur formation. Lâutilisation combinĂ©e du dispositif dâirradiation dâagrĂ©gats molĂ©culaires de Lyon et de plusieurs mĂ©thodes thĂ©oriques permet lâĂ©tude statistique des mĂ©canismes de relaxation de dimĂšres molĂ©culaires protonĂ©s suite Ă une excitation sur un temps court (femtoseconde) dâune des deux molĂ©cules de lâagrĂ©gat. Lors dâune collision unique Ă haute vitesse avec un atome, lâagrĂ©gat est placĂ© dans une situation trĂšs Ă©loignĂ©e de lâĂ©quilibre thermique et plusieurs mĂ©canismes de relaxation sont observĂ©s. Les mesures des rapports de branchement et celles de la distribution dâĂ©nergie cinĂ©tique libĂ©rĂ©e pour un canal de relaxation donnĂ© permettent une Ă©tude quantitative de la compĂ©tition entre lâĂ©vaporation dâune molĂ©cule, la fragmentation dâune des deux molĂ©cules, et la formation dâune molĂ©cule plus complexe. Les rĂ©sultats sont comparĂ©s pour diffĂ©rents dimĂšres molĂ©culaires protonĂ©s : le dimĂšre de pyridine, le dimĂšre de mĂ©thanol, le dimĂšre de glycine et un dimĂšre mixte composĂ© dâun dipeptide de glycine et dâune molĂ©cule de glycine. A la diffĂ©rence du dimĂšre de pyridine, les rĂ©sultats obtenus avec le dimĂšre de mĂ©thanol mettent en Ă©vidence la rĂ©action unimolĂ©culaire dâĂ©limination de lâeau par lâagrĂ©gat parent. Les caractĂ©ristiques Ă©nergĂ©tiques de lâĂ©tat fondamental du dimĂšre, des produits de rĂ©action, et des Ă©tats de transitions ont Ă©tĂ© calculĂ©es avec la thĂ©orie de la fonctionnelle de la densitĂ© et utilisĂ©es pour comparer quantitativement les rĂ©sultats expĂ©rimentaux Ă ceux de la thĂ©orie de lâespace de phase. Cela montre, dâune part, que les mesures expĂ©rimentales contraignent quantitativement les modĂšles thĂ©oriques et, dâautre part, que les rĂ©sultats expĂ©rimentaux ne peuvent ĂȘtre interprĂ©tĂ©s quantitativement avec lâhypothĂšse dâune redistribution complĂšte de lâĂ©nergie interne sur tous les modes de lâagrĂ©gat parent avant la dissociation. Cela souligne lâimportance du temps de transfert dâĂ©nergie entre les molĂ©cules dans la compĂ©tition entre les diffĂ©rents canaux de relaxation. Dans le cas de la glycine, la formation du dipeptide et lâallongement de la chaĂźne peptidique ont Ă©tĂ© mis en Ă©vidence dans une rĂ©action unimolĂ©culaire. La mesure de la distribution de vitesse de la molĂ©cule dâeau Ă©liminĂ©e par la rĂ©action de polymĂ©risation montre la prĂ©sence de diffĂ©rents chemins de rĂ©action pour lesquels le rĂŽle du proton a Ă©tĂ© explorĂ© par des calculs de thĂ©orie de la fonctionnelle de la densitĂ©. Lâensemble des rĂ©sultats mettent en Ă©vidence la rĂ©action unimolĂ©culaire comme une nouvelle voie abiotique pour la formation de molĂ©cules organiques en phase gazeuse, soulignant lâintĂ©rĂȘt des dimĂšres molĂ©culaires protonĂ©s pour la formation de molĂ©cules complexes en conditions astrophysiques
Petits agrĂ©gats molĂ©culaires d'intĂ©rĂȘt astrophysique
Observations of complex molecules in very different environments in space, from star forming regions to comets, raise questions about the mechanisms that led to their formation. The combined use of the Lyon molecular cluster irradiation device and several theoretical methods allows the statistical study of the relaxation mechanisms of protonated molecular dimers following a short time (femtosecond) excitation of one of the two molecules in the cluster. During a single collision at high velocity with an atom, the cluster is placed in a situation far from thermal equilibrium and several relaxation mechanisms are observed. Measurements of the branching ratios and of the kinetic energy released distribution for a given relaxation channel allow a quantitative study of the competition between the evaporation of a molecule, the fragmentation of one of the two molecules, and the formation of a more complex molecule. The results are compared for different molecular protonated dimers: the pyridine dimer, the methanol dimer, the glycine dimer, and a mixed dimer composed of a glycine dipeptide and a glycine molecule. In contrast to the pyridine dimer, the results obtained with the methanol dimer show the unimolecular reaction with water elimination by the parent cluster. The energy characteristics of the dimer ground state, reaction products, and transition states were calculated with density functional theory and used to compare quantitatively the experimental results with those from phase space theory. This shows, on the one hand, that the experimental measurements quantitatively constrain the theoretical models and, on the other hand, that the experimental results cannot be quantitatively interpreted with the assumption of a complete redistribution of the internal energy over all modes of the parent cluster before dissociation. This highlights the importance of the energy transfer time between molecules on the competition between the different relaxation channels. In the case of glycine, the formation of the dipeptide and the elongation of the peptide chain were demonstrated in a unimolecular reaction. The measurement of the velocity distribution of the water molecule eliminated by the polymerisation reaction shows the presence of different reaction paths for which the role of the proton has been explored by density functional theory calculations. All the results highlight the unimolecular reaction as a new abiotic pathway for the formation of organic molecules in the gas phase, underlining the interest of protonated molecular dimers for the formation of complex molecules under astrophysical conditions.Les observations de molĂ©cules complexes dans des environnements trĂšs diffĂ©rents de lâespace, depuis les rĂ©gions de formation dâĂ©toiles aux comĂštes, interrogent quant aux mĂ©canismes qui ont conduit Ă leur formation. Lâutilisation combinĂ©e du dispositif dâirradiation dâagrĂ©gats molĂ©culaires de Lyon et de plusieurs mĂ©thodes thĂ©oriques permet lâĂ©tude statistique des mĂ©canismes de relaxation de dimĂšres molĂ©culaires protonĂ©s suite Ă une excitation sur un temps court (femtoseconde) dâune des deux molĂ©cules de lâagrĂ©gat. Lors dâune collision unique Ă haute vitesse avec un atome, lâagrĂ©gat est placĂ© dans une situation trĂšs Ă©loignĂ©e de lâĂ©quilibre thermique et plusieurs mĂ©canismes de relaxation sont observĂ©s. Les mesures des rapports de branchement et celles de la distribution dâĂ©nergie cinĂ©tique libĂ©rĂ©e pour un canal de relaxation donnĂ© permettent une Ă©tude quantitative de la compĂ©tition entre lâĂ©vaporation dâune molĂ©cule, la fragmentation dâune des deux molĂ©cules, et la formation dâune molĂ©cule plus complexe. Les rĂ©sultats sont comparĂ©s pour diffĂ©rents dimĂšres molĂ©culaires protonĂ©s : le dimĂšre de pyridine, le dimĂšre de mĂ©thanol, le dimĂšre de glycine et un dimĂšre mixte composĂ© dâun dipeptide de glycine et dâune molĂ©cule de glycine. A la diffĂ©rence du dimĂšre de pyridine, les rĂ©sultats obtenus avec le dimĂšre de mĂ©thanol mettent en Ă©vidence la rĂ©action unimolĂ©culaire dâĂ©limination de lâeau par lâagrĂ©gat parent. Les caractĂ©ristiques Ă©nergĂ©tiques de lâĂ©tat fondamental du dimĂšre, des produits de rĂ©action, et des Ă©tats de transitions ont Ă©tĂ© calculĂ©es avec la thĂ©orie de la fonctionnelle de la densitĂ© et utilisĂ©es pour comparer quantitativement les rĂ©sultats expĂ©rimentaux Ă ceux de la thĂ©orie de lâespace de phase. Cela montre, dâune part, que les mesures expĂ©rimentales contraignent quantitativement les modĂšles thĂ©oriques et, dâautre part, que les rĂ©sultats expĂ©rimentaux ne peuvent ĂȘtre interprĂ©tĂ©s quantitativement avec lâhypothĂšse dâune redistribution complĂšte de lâĂ©nergie interne sur tous les modes de lâagrĂ©gat parent avant la dissociation. Cela souligne lâimportance du temps de transfert dâĂ©nergie entre les molĂ©cules dans la compĂ©tition entre les diffĂ©rents canaux de relaxation. Dans le cas de la glycine, la formation du dipeptide et lâallongement de la chaĂźne peptidique ont Ă©tĂ© mis en Ă©vidence dans une rĂ©action unimolĂ©culaire. La mesure de la distribution de vitesse de la molĂ©cule dâeau Ă©liminĂ©e par la rĂ©action de polymĂ©risation montre la prĂ©sence de diffĂ©rents chemins de rĂ©action pour lesquels le rĂŽle du proton a Ă©tĂ© explorĂ© par des calculs de thĂ©orie de la fonctionnelle de la densitĂ©. Lâensemble des rĂ©sultats mettent en Ă©vidence la rĂ©action unimolĂ©culaire comme une nouvelle voie abiotique pour la formation de molĂ©cules organiques en phase gazeuse, soulignant lâintĂ©rĂȘt des dimĂšres molĂ©culaires protonĂ©s pour la formation de molĂ©cules complexes en conditions astrophysiques
La scintigraphie myocardique dans le dépistage de l'ischémie myocardique silencieuse chez le diabétique
MONTPELLIER-BU MĂ©decine (341722104) / SudocMONTPELLIER-BU MĂ©decine UPM (341722108) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF
Adverse reactions to biologic agents and their medical management
Biologic agents have substantially advanced the treatment of immunological disorders, including chronic inflammatory and autoimmune diseases. However, these drugs are often associated with adverse events (AEs), including allergic, immunological and other unwanted reactions. AEs can affect almost any organ or system in the body and can occur immediately, within minutes to hours, or with a delay of several days or more after initiation of biologic therapy. Although some AEs are a direct consequence of the functional inhibition of biologic-agent-targeted antigens, the pathogenesis of other AEs results from a drug-induced imbalance of the immune system, intermediary factors and cofactors, a complexity that complicates their prediction. Herein, we review the AEs associated with biologic therapy most relevant to rheumatic and immunological diseases, and discuss their underlying pathogenesis. We also include our recommendations for the medical management of such AEs. Increased understanding and improved risk management of AEs induced by biologic agents will enable better use of these versatile immune-response modifiers
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