DLR-ONERA accurate CFD support for the Pre-X project

During the development of Pre-X demonstrator supported by CNES , industrials are in charge of aerodynamic and aerothermodynamic defintion and characterisation of the vehicle. For this preliminary phase of the project, most of the time industrials only used Euler computations associated to boundary layer, so that a lot of parametric analysis can be carried out and the feasibility of the project was globally checked. It is clear that deeper analyses for some critical trajectory points are required to overcome potential infeasibilities. The main objective of the accurate CFD support, provided by DLR and ONERA consists in assessing these high level objectives. Two critical issues are investigated. The heat fluxes level on the windward side of the body, the deflected flap in the hypersonic regime and the aerodynamic static margin at the end of the trajectory in the supersonic regime. Two relevant codes where used: the TAU code from DLR and CELHYO3D from ONERA. * The unstructured TAU code is a finite volume Navier-Stokes solver which is validated in a wide range of sub- trans- and hypersonic cases. Different one and two equation turbulence models are implemented and chemical equilibrium as well as non equilibrium flows can be modelled. Furthermore adaptation of tetrahedral grids on any given output quantity is possible. * The structured CELHYO3D code is a finite volume Navier-Stokes solver with upwind schemes adapted to supersonic and hypersonic flows. Flows of air or CO2 in chemical or thermo-chemical non-equilibrium can be considered. A specific grid management procedure is used in order to provide shock-adapted grids together with information of the grid-convergence of the results. The results of the computations with TAU and CELHYO3D confirm the feasibility of the project with respect to the heat-flux and static-margin issues

NLRP3 leucine-rich repeats control induced and spontaneous inflammasome activation in cryopyrin-associated periodic syndrome.

Cryopyrin-associated periodic syndromes (CAPS) comprise a group of rare autoinflammatory diseases caused by gain-of-function mutations in the NLRP3 gene. NLRP3 contains a leucine-rich repeats (LRR) domain with a highly conserved exonic organization that is subjected to extensive alternative splicing. Aberrant NLRP3 inflammasome assembly in CAPS causes chronic inflammation, however the mechanisms regulating inflammasome function remain unclear. We aimed to elucidate the mechanisms regulating NLRP3 mediated autoinflammation in human disease, characterizing the role of LRR in inflammasome activation. We analyzed sequence read archive data to characterize the patten of NLRP3 splicing in human monocytes and investigated the role of each LRR-coding exon in inflammasome regulation in genetically modified U937 cells representing CAPS and healthy conditions. We show detection of a range of NLRP3 splice variants in human primary cells and monocytic cell lines including two yet undescribed splice variants. We observe that LPS impact the abundancy of certain splice variants suggesting they may regulate NLRP3 activation by affecting alternative splicing. We showed that exons 4,5,7 and 9 are essential for inflammasome function, both in the context of wild type NLRP3 activation by the agonist molecule nigericin and in a model of CAPS-mediated NLRP3 inflammasome assembly. Moreover, the SGT1-NLRP3 interaction is decreased in non-functional variants, suggesting that alternative splicing may regulate the recruitment of proteins that facilitate inflammasome assembly. These findings demonstrate the contribution of LRR domain in inflammasome function and suggest that navigating LRR exon usage within NLRP3 is sufficient to dampen inflammasome assembly in CAPS

Endocytosed soluble cowpox virus protein CPXV012 inhibits antigen cross-presentation in human monocyte-derived dendritic cells

Viruses may interfere with the MHC class I antigen presentation pathway in order to avoid CD8+ T cell-mediated immunity. A key target within this pathway is the peptide transporter TAP. This transporter plays a central role in MHC class I-mediated peptide presentation of endogenous antigens. In addition, TAP plays a role in antigen cross-presentation of exogenously derived antigens by dendritic cells (DCs). In this study, a soluble form of the cowpox virus TAP inhibitor CPXV012 is synthesized for exogenous delivery into the antigen cross-presentation route of human monocyte-derived (mo)DCs. We show that soluble CPXV012 localizes to TAP+ compartments that carry internalized antigen and is a potent inhibitor of antigen cross-presentation. CPXV012 stimulates the prolonged deposition of antigen fragments in storage compartments of moDCs, as a result of reduced endosomal acidification and reduced antigen proteolysis when soluble CPXV012 is present. Thus, a dual function can be proposed for CPXV012: inhibition of TAP-mediated peptide transport and inhibition of endosomal antigen degradation. We propose this second function for soluble CPXV012 can serve to interfere with antigen cross-presentation in a peptide transport-independent manner

Preliminary Evaluation of a Bunyavirus Vector for Cancer Immunotherapy

Replicon particles of Rift Valley fever virus, referred to as nonspreading Rift Valley fever virus (NSR), are intrinsically safe and highly immunogenic. Here, we demonstrate that NSR-infected human dendritic cells can activate CD8+ T cells in vitro and that prophylactic and therapeutic vaccinations of mice with NSR encoding a tumor-associated CD8 peptide can control the outgrowth of lymphoma cells in vivo. These results suggest that the NSR system holds promise for cancer immunotherapy

Preliminary evaluation of a bunyavirus vector for cancer immunotherapy

Replicon particles of Rift Valley fever virus, referred to as nonspreading Rift Valley fever virus (NSR), are intrinsically safe and highly immunogenic. Here, we demonstrate that NSR-infected human dendritic cells can activate CD8+ T cells in vitro and that prophylactic and therapeutic vaccinations of mice with NSR encoding a tumor-associated CD8 peptide can control the outgrowth of lymphoma cells in vivo. These results suggest that the NSR system holds promise for cancer immunotherapy

Natural killer cells facilitate PRAME-specific T-cell reactivity against neuroblastoma

Immunobiology of allogeneic stem cell transplantation and immunotherapy of hematological disease

Natural killer cells facilitate PRAME-specific T-cell reactivity against neuroblastoma

Neuroblastoma is the most common solid tumor in children with an estimated 5-year progression free survival of 20-40% in stage 4 disease. Neuroblastoma actively avoids recognition by natural killer (NK) cells and cytotoxic T lymphocytes (CTLs). Although immunotherapy has gained traction for neuroblastoma treatment, these immune escape mechanisms restrain clinical results. Therefore, we aimed to improve neuroblastoma immunogenicity to further the development of antigen-specific immunotherapy against neuroblastoma. We found that neuroblastoma cells significantly increase surface expression of MHC I upon exposure to active NK cells which thereby readily sensitize neuroblastoma cells for recognition by CTLs. We show that oncoprotein PRAME serves as an immunodominant antigen for neuroblastoma as NK-modulated neuroblastoma cells are recognized by PRAMESLLQHLIGL/A2-specific CTL clones. Furthermore, NK cells induce MHC I upregulation in neuroblastoma through contact-dependent secretion of IFNγ. Our results demonstrate remarkable plasticity in the peptide/MHC I surface expression of neuroblastoma cells, which is reversed when neuroblastoma cells experience innate immune attack by sensitized NK cells. These findings support the exploration of NK cells as adjuvant therapy to enforce neuroblastoma-specific CTL responses

Progress in solving coupled aerothermodynamics issues faced by space vehicles

Communication to : ESA 5th European symposium on aerothermodynamics for space vehicles, Cologne (Germany), 8-11 novembre 2004SIGLEAvailable from INIST (FR), Document Supply Service, under shelf-number : 22419, issue : a.2005 n.2 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc