Increased production of pro-inflammatory cytokines and enhanced T cell responses after activation of human dendritic cells with IL-1 and CD40 ligand

BACKGROUND: Various microbial, inflammatory and immune signals regulate the activation of dendritic cells (DC), determining their ability to interact with naïve T cells and to produce cytokines that direct T cell development. In particular, CD40L and IL-1 cooperatively activate DC to secrete high levels of IL-12. The immuno-stimulatory capacity of such DC is otherwise not well-defined prompting further characterization of the effects of IL-1 and family members on DC activation in comparison with other pro-inflammatory stimuli. RESULTS: Human DC co-activated in vitro by CD40L and IL-1β expressed numerous cytokine genes including IL-12β, IL-23 p19, IL-1β, IL-1α, IL-1Ra, IL-10, IL-6, IL-18 and IFN-γ. These DC produced high levels of IL-12 protein and appeared capable of producing IFN-γ. Potent CD4(+) and CD8(+) T cell-stimulatory properties were acquired by DC under conditions that also induced IL-12. Notably, these DC induced rapid differentiation of fluMP-specific CD8(+) T cells. Molecules related to IL-1β, like IL-1α, co-induced IL-12 secretion whereas IL-18 did not. Conversely, the inhibitor IL-1Ra, produced endogenously by DC curtailed IL-12 production in response to CD40L. CONCLUSIONS: IL-1 and IL-1Ra play a biologically-relevant role in the positive and negative regulation of DC activation. In conjunction with CD40L, IL-1 sends a powerful activation signal to DC that could be distinguished from other modes of activation. This signal enables the production of pro-inflammatory cytokines by DC, and enhances the differentiation of naïve T cells into effectors of type-1 cellular immune responses

De l'objet à l'expérience dans l'aménagement des lobby d'hôtels de luxe : le cas du Ritz-Carlton Montréal, Canada

Ce mémoire s’appuie sur les éventuels changements survenus dans l’hôtellerie de luxe, secteur en perpétuelle croissance. L’étude porte sur le concept de l’expérience du luxe dans l’aménagement des lobbys pour essayer de répondre à la problématique : qu’est-ce que l’expérience du luxe aujourd’hui en hôtellerie : comment se matérialise-t-elle dès le hall d’entrée et quels sont les éléments de design d’intérieur à considérer pour une meilleure adaptation face à la clientèle de demain ? Le but est d’explorer l’aménagement intérieur d’un lobby, de comprendre le comportement des usagers pour orienter les professionnels de l’aménagement et du design vers des modèles adaptés. La notion de luxe n’est plus seulement une vision d’objets, de marques et d’ostentation mais elle évolue dans une démarche d’expérience associée à des valeurs de bien-être et de plaisir. La clientèle qui séjourne dans ces hôtels de luxe est de plus en plus exigeante, de mieux en mieux informée, présente de jour comme de nuit associée à la notion de temps. Par ailleurs, la mondialisation et la globalisation ont participé à cette transformation avec l’accélération des échanges mondiaux et l’arrivée des technologies provoquant une forme de démocratisation du secteur du luxe. En raison de cette diversité, il peut être intéressant d’étudier aussi la notion d’espace au travers des lobby d’hôtel de luxe, premier contact avec l’établissement. L’étude se situe au Ritz-Carlton Montréal, établissement emblématique datant de 1912. Après une analyse du lieu, une observation avec des tracking est réalisée, ainsi qu’une étude sous forme d’entretiens semi-dirigés afin d’obtenir l’avis du personnel y travaillant. L’aménagement de ces établissements fait appel à une mixité temporelle dans le design qui a su combiner le côté ostentatoire du lieu avec une modernité caractéristique de l’expérience client d’aujourd’hui. Cette étude montre comment l’actuelle répartition des catégories clients révèlerait de nouvelles priorités dans la gestion de l’espace.This thesis draws on potential changes in the perpetually developing luxury hospitality industry. The study is focused on the concept of luxury experience in the development of the lobby to try to answer the problem: how is luxury experienced in the hotel sector today: how does it materialize itself starting in the lobby and what elements of interior design should be considered to better accommodate tomorrow’s clientele? The goal is to explore the interior design of a lobby, to understand the behavior of the users to orient the professionals of planning and design towards adapted models. The notion of luxury is no longer just a vision of objects, brands and ostentation, but evolves in an approach of experience associated with values of well-being and pleasure. Clients of these luxury properties are increasingly demanding, knowledgeable and constantly present day and night, concerned by the notion of time. Furthermore, globalization has participated in this transformation by promoting worldwide exchanges and introducing new technologies that popularized the luxury sector. Because of this diversity, it may be interesting to study the concept of space through luxury hotel lobby, where first contacts occur. The study takes place at the iconic Ritz-Carlton hotel in Montreal, dating back to 1912. Following an analysis of the site, trackings as well as semi-structured interviews with the working personnel were performed. The purpose of this work is to conclude whether luxury hotels have been capable of adapting their interior design to suit their different types of clienteles. The layout of these establishments calls for a design that mixes a variety of time- periods, combining ostentatious history with today’s customer experience-guided modernity. This study shows how the current distribution of customer categories would reveal new priorities in the management of space

65. Long-Term Effects of Hematopoietic Stem Cell Gene Therapy in the Murine Model of Wiskott-Aldrich Syndrome: Persistence of Functional Correction of T Cells and Lack of Malignant Trasformation

Wiskott-Aldrich syndrome (WAS) is a severe X-linked immunodeficiency characterized by recurrent infections, thrombocytopenia, eczema and increased risk of autoimmune disorders and lymphomas. Hematopoietic stem cell (HSC) transplantation from HLA-identical sibling donors is a resolutive treatment, but it is available only for a minority of patients. Transplantation of genetically corrected autologous HSC could represent an alternative treatment, potentially applicable to all patients. In a murine model of WAS (WAS|[minus]|/|[minus]|), we recently demonstrated correction of the T cell defect 4 months after lentiviral vector-mediated gene therapy [Dupr|[eacute]|, Marangoni, et al. Hum Gene Ther. 2006, 17]. The aim of the present study was to investigate the long-term efficacy and safety of our gene therapy approach in WAS|[minus]|/|[minus]| mice

A motif within the N-terminal domain of TSP-1 specifically promotes the proangiogenic activity of endothelial colony-forming cells

Thrombospondin-1 (TSP-1) gives rise to fragments that have both pro- and anti-angiogenic effects in vitro and in vivo. the TSP-HepI peptide (2.3 kDa), located in the N-terminal domain of TSP-1, has proangiogenic effects on endothelial cells. We have previously shown that TSP-1 itself exhibits a dual effect on endothelial colony-forming cells (ECFC) by enhancing their adhesion through its TSP-HepI fragment while reducing their proliferation and differentiation into vascular tubes (tubulogenesis) in vitro. This effect is likely mediated through CD47 binding to the TSP-1 C-terminal domain. Here we investigated the effect of TSP-HepI peptide on the angiogenic properties of ECFC in vitro and in vivo. TSP-HepI peptide potentiated FGF-2-induced neovascularisation by enhancing ECFC chemotaxis and tubulogenesis in a Matrigel plug assay. ECFC exposure to 20 mu g/mL of TSP-HepI peptide for 18 h enhanced cell migration (p < 0.001 versus VEGF exposure), upregulated alpha 6-integrin expression, and enhanced their cell adhesion to activated endothelium under physiological shear stress conditions at levels comparable to those of SDF-1 alpha. the adhesion enhancement appeared to be mediated by the heparan sulfate proteoglycan (HSPG) syndecan-4, as ECFC adhesion was significantly reduced by a syndecan-4-neutralising antibody. ECFC migration and tubulogenesis were stimulated neither by a TSP-HepI peptide with a modified heparin-binding site (S/TSP-HepI) nor when the glycosaminoglycans (GAGS) moieties were removed from the ECFC surface by enzymatic treatment. Ex vivo TSP-HepI priming could potentially serve to enhance the effectiveness of therapeutic neovascularisation with ECFC. (C) 2012 Elsevier Inc. All rights reserved.Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Groupe d'Etude et de Recherches sur l'Hemostase (GEHT)Region Ile-de-France (CORDDIM)Leducq TransAtlantic Network of ExcellenceUniv Estado Rio de Janeiro, Dept Biol Celular, Lab Biol Celula Endotelial & Angiogenese LabAngio, Inst Biol Roberto Alcantara Gomes, BR-20550011 Rio de Janeiro, RJ, BrazilINSERM, U765, Paris, FranceUniv Paris 05, Paris, FranceUniversidade Federal de São Paulo, Escola Paulista Med, Dept Biofis, São Paulo, BrazilUniv Fed Rio de Janeiro, Inst Ciencias Biomed, Rio de Janeiro, RJ, BrazilHop Europeen Georges Pompidou, AP HP, Dept Haematol, Paris, FranceINSERM, Paris Cardiovasc Res Ctr, U970, Paris, FranceUniversidade Federal de São Paulo, Escola Paulista Med, Dept Biofis, São Paulo, BrazilLeducq TransAtlantic Network of Excellence: 04CVD01-LENALeducq TransAtlantic Network of Excellence: 04CVD02 -LINATCNPq: E-26/110.780/2010CAPES: 629/09Web of Scienc

Involvement in surface antigen expression by a moonlighting FG-repeat nucleoporin in trypanosomes

Components of the nuclear periphery coordinate a multitude of activities, including macromolecular transport, cell-cycle progression, and chromatin organization. Nuclear pore complexes (NPCs) mediate nucleocytoplasmic transport, mRNA processing, and transcriptional regulation, and NPC components can define regions of high transcriptional activity in some organisms at the nuclear periphery and nucleoplasm. Lineage-specific features underpin several core nuclear functions and in trypanosomatids, which branched very early from other eukaryotes, unique protein components constitute the lamina, kinetochores, and parts of the NPCs. Here we describe a phenylalanine-glycine (FG)-repeat nucleoporin, TbNup53b, that has dual localizations within the nucleoplasm and NPC. In addition to association with nucleoporins, TbNup53b interacts with a known trans-splicing component, TSR1, and has a role in controlling expression of surface proteins including the nucleolar periphery-located, procyclin genes. Significantly, while several nucleoporins are implicated in intranuclear transcriptional regulation in metazoa, TbNup53b appears orthologous to components of the yeast/human Nup49/Nup58 complex, for which no transcriptional functions are known. These data suggest that FG-Nups are frequently co-opted to transcriptional functions during evolution and extend the presence of FG-repeat nucleoporin control of gene expression to trypanosomes, suggesting that this is a widespread and ancient eukaryotic feature, as well as underscoring once more flexibility within nucleoporin function

Enabling planetary science across light-years. Ariel Definition Study Report

Ariel, the Atmospheric Remote-sensing Infrared Exoplanet Large-survey, was adopted as the fourth medium-class mission in ESA's Cosmic Vision programme to be launched in 2029. During its 4-year mission, Ariel will study what exoplanets are made of, how they formed and how they evolve, by surveying a diverse sample of about 1000 extrasolar planets, simultaneously in visible and infrared wavelengths. It is the first mission dedicated to measuring the chemical composition and thermal structures of hundreds of transiting exoplanets, enabling planetary science far beyond the boundaries of the Solar System. The payload consists of an off-axis Cassegrain telescope (primary mirror 1100 mm x 730 mm ellipse) and two separate instruments (FGS and AIRS) covering simultaneously 0.5-7.8 micron spectral range. The satellite is best placed into an L2 orbit to maximise the thermal stability and the field of regard. The payload module is passively cooled via a series of V-Groove radiators; the detectors for the AIRS are the only items that require active cooling via an active Ne JT cooler. The Ariel payload is developed by a consortium of more than 50 institutes from 16 ESA countries, which include the UK, France, Italy, Belgium, Poland, Spain, Austria, Denmark, Ireland, Portugal, Czech Republic, Hungary, the Netherlands, Sweden, Norway, Estonia, and a NASA contribution

Evaluation of diversity indices to estimate clonal dominance in gene therapy studies

In cell and gene therapy, achieving the stable engraftment of an abundant and highly polyclonal population of gene-corrected cells is one of the key factors to ensure the successful and safe treatment of patients. Because integrative vectors have been associated with possible risks of insertional mutagenesis leading to clonal dominance, monitoring the relative abundance of individual vector insertion sites in patients’ blood cells has become an important safety assessment, particularly in hematopoietic stem cell-based therapies. Clinical studies often express clonal diversity using various metrics. One of the most commonly used is the Shannon index of entropy. However, this index aggregates two distinct aspects of diversity, the number of unique species and their relative abundance. This property hampers the comparison of samples with different richness. This prompted us to reanalyze published datasets and to model the properties of various indices as applied to the evaluation of clonal diversity in gene therapy. A normalized version of the Shannon index, such as Pielou’s index, or Simpson’s probability index is robust and useful to compare sample evenness between patients and trials. Clinically meaningful standard values for clonal diversity are herein proposed to facilitate the use of vector insertion site analyses in genomic medicine practice

Le Hellp syndrome (à propos de 65 cas)

TOULOUSE3-BU Santé-Centrale (315552105) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF