Dynamic stability of a flexible booster subjected to a gimbled, periodically-varying end thrust Technical memorandum no. 104

Dynamic structural behavior of large rocket booster synthesized by two thin-walled cylinders and subjected to periodically varying end thrus

Regulation of major histocompatibility complex class I expression by NF-kB-related proteins in breast cancer cells

Downregulation of MHC Class I antigens has been observed in many cancers and usually results from a decreased gene transcription. A reporter CAT gene dependent on the MHC Class I kB site or on a longer promoter is transactivated by NF-kB complexes contain- ing p65 or RelB. p100 as well as IkB-a are potent inhibitors of this transcription and p100 sequesters RelB and p65 complexes in the cytoplasm of breast cancer cells. However, although p100 is highly expressed in a number of breast cancer cell lines, MHC Class I antigen expression was observed on all the cell lines we analysed and could be further induced by stimulation with the cytokines IFN-g or TNF-a. Stable transfection of a unresponsive mutated IkB-a Ser 32-36 expression vector showed that TNF-a induced MHC Cl I expression in an NF-kB-dependent way while IFN-g did it independently of any NF-kB activation

Direct and Indirect Effects of Cytomegalovirus-Induced γδ T Cells after Kidney Transplantation

Despite effective anti-viral therapies, cytomegalovirus (CMV) is still associated with direct (CMV disease) and indirect effects (rejection and poor graft survival) in kidney transplant recipients. Recently, an unconventional T cell population (collectively designated as Vδ2neg γδ T cells) has been characterized during the anti-CMV immune response in all solid-organ and bone-marrow transplant recipients, neonates, and healthy people. These CMV-induced γδ T cells undergo a dramatic and stable expansion after CMV infection, in a conventional ‘adaptive’ manner. Similarly as CMV-specific CD8+ αβ T cells, they exhibit an effector/memory TEMRA phenotype and cytotoxic effector functions. Activation of Vd2neg gd T cells by CMV-infected cells involves the TCR and still ill-defined co-stimulatory molecules such LFA-1. A multiple of Vd2neg gd TCR ligands are apparently recognized on CMV-infected cells, the first one identified being the MHC-related molecule endothelial protein C receptor (EPCR). A singularity of CMV-induced Vd2neg gd T cells is to acquire CD16 expression and to exert an antibody-dependent cell-mediated inhibition on CMV replication, which is controlled by a specific cytokine microenvironment. Beyond the well-demonstrated direct anti-CMV effect of Vδ2neg γδ T cells, unexpected indirect effects of these cells have been also observed in the context of kidney transplantation. CMV-induced Vδ2neg γδ T cells have been involved in surveillance of malignancy subsequent to long term immunosuppression. Moreover, CMV-induced CD16+ γδ T cells are cell effectors of antibody-mediated rejection of kidney transplants, and represent a new physiopathological contribution to the well-known association between CMV infection and poor graft survival. All these basic and clinical studies paved the road to the development of a future γδ T cell-based immunotherapy. In the meantime, γδ T cell monitoring should prove a valuable immunological biomarker in the management of CMV infection

The antigen presenting potential of Vγ9Vδ2 T-cells during Plasmodium falciparum blood-stage infection.

During Plasmodium falciparum infections, erythrocyte-stage parasites inhibit dendritic cell maturation and function; compromising development of effective anti-malarial adaptive immunity. Human Vγ9Vδ2 T-cells can act in vitro as APCs and induce αβ T-cell activation. However, the relevance of this activity in pathophysiological contexts in vivo has remained elusive. Since Vγ9Vδ2 T-cells are activated during the early immune response against P.falciparum infection, we investigated whether they could contribute to the instruction of adaptive immune responses toward malaria parasites. In P.falciparum-infected patients,Vγ9Vδ2 T-cells presented an increased surface expression of APC-associated markers HLA-DR and CD86. In response to infected red blood cells in vitro, Vγ9Vδ2 T-cells readily up-regulated surface expression of HLA-DR, HLA-ABC, CD40, CD80, CD83 and CD86, induced naive αβ T-cell responses, and cross-presented soluble prototypical protein to antigen-specific CD8+ T-cells. Our findings indicate that P. falciparum parasites induce genuine APC properties in Vγ9Vδ2 T-cells and qualify this subset as an alternative professional APC in malaria patients, which could be harnessed for therapeutic interventions and vaccine design

Editorial: "Recent Advances in Gamma/Delta T Cell Biology: New Ligands, New Functions, and New Translational Perspectives"

Since their discovery in the mid-1980s, interest in the immunological significance of γδ T cells has been subject to oscillations. The initial excitement over the unexpected discovery of a second T cell receptor (TCR) was followed by years of uncertainty as to the biological importance of these ambivalent T cells. Major breakthroughs led to the identification of specific and unique antigens for the γδ TCR and accumulating evidence now shows that γδ T cells play a major role in local immunosurveillance, thereby controlling tumorigenesis. Since 2004, biannual international γδ T cell conferences are held to bring together experts in basic and clinical γδ T cell research. To make accessible and synthesize the body of knowledge that has been put together, to date, we have organized a “Research Topic” on γδ T cells consisting of a collection of original articles and focused reviews written by leading experts in the field. The idea of this Research Focus was to present the current status and “hot topics” as well as clinical perspectives on γδ T cell research

Functional forms of socio-territorial inequities in breast cancer screening – A French cross-sectional study using hierarchical generalised additive models

To reduce the breast cancer burden, the French National Organised Breast Cancer Screening Programme (FNOBCSP) was implemented in 2004. The recommended participation rate has never been achieved and socio-territorial inequities in participation have been reported on several occasions. We investigated the functional forms and consistency of the relationships between neighbourhood deprivation, travel time to the nearest accredited radiology centre and screening uptake. We used two-level hierarchical generalised additive models in 8 types of territories classified by socio-demographic and economic factors. The first level was 368,201 women aged 50–72 invited to the 2013–2014 screening campaign in metropolitan France. They were nested in 41 départements, the level of organisation of the FNOBCSP. The effect of travel time showed two main patterns: it was either linear (with participation decreasing as travel time increased) or participation first increased with increasing travel time to a peak around 5–15 min and decreased afterward. In nearly all types and départements, the probability of participation decreased linearly with increasing deprivation. Territorial inequities in participation were more context-dependent and complex than social inequities. Inequities in participation represent a loss of opportunity for individuals who already have the worst cancer outcomes. Evidence-based public health policies are needed to increase the effectiveness and equity of breast cancer screening

Réponse des Lymphocytes T Gamma-Delta à deux Complications de la transplantation rénale (le Cytomégalovirus et les anticorps spécifiques du donneur)

La transplantation rénale est la stratégie de suppléance rénale la plus performante. Le renforcement des thérapeutiques ciblant la réponse cellulaire T (i) a conduit à réévaluer la réponse allogénique humorale et (ii) a souligné deux complications majeures de la pression immunosuppressive : l infection à cytomégalovirus CMV et le risque de cancer. Dans le travail présenté ici, nous analysons d abord l impact histologique de deux de ces facteurs de détérioration de l allogreffon rénal : l infection à CMV avant une biopsie sur indication et la pathogénicité des anticorps anti-HLA dirigés contre le donneur, détectés par des techniques d identification en Single Antigen in situ dans le greffon. Nous montrons ensuite comment les lymphocytes T (LT) g Vd2neg font le lien entre CMV et DSA : induits par le CMV, les LT g Vd2neg participent aux lésions médiées par les DSA par leur capacité à réaliser une lyse dépendante de l anticorps (ADCC) impliquant le CD16. En plus de cette nouvelle fonction allogénique indirecte, les LT g Vd2neg possèdent une double réactivité anti-CMV et anti-tumoral. Nous présentons ici un modèle où les lymphocytes T g V 2neg s activent spécifiquement de façon TCR dépendante par la reconnaissance d un marqueur d intégrité épithéliale (EphA2) : ils détournent le mécanisme d interaction classique d EphA2 avec ses ligands naturels éphrines A1 et A4 pour s en faire un signal de costimulation, en s appuyant sur le contexte de stress pour renforcer son activation. Collectivement, nos résultats contribuent à mieux préciser la bioréactivité et le rôle des LT g V 2neg en transplantation rénale. Nos données suggèrent que chez l'homme, a fortiori lorsqu il est immunodéprimé, les LT g constituent un compartiment de surveillance lymphoide du stress, capable de censurer la dérégulation des cellules infectées ou transformées et de prendre part à la réponse allogénique par un mécanisme d ADCC.Kidney transplant is the most performant strategy for renal replacement therapy. Increasing treatment targetting T cell response has led (i) to reappraise the importance of humoral allogenic response, (ii) to underline two main complications subsequent to immunosuppressive pressure : cytomegalovirus infection and tumorigenesis. Here, we first report the pathological impact of two of these factors on kidney allograft deterioration : CMV infection prior a biopsy for cause and Donor Specific Alloantibodies (DSA) detected within the graft with single antigen flow bead assay. Then we showed that CMV-induced V 2neg g T cells are a new player and a potentially useful clinical biomarker in antibody-mediated lesions of kidney transplants. By engaging DSA on their Fcg-receptor CD16, g T cells participate in allograft lesions mediated by DSA through antibody-dependent cell cytotoxicity (ADCC). In addition to this new indirect allogenic function, CMV-induced V 2neg g T cells displayed a dual anti-CMV and anti-tumor reactivity. Finally, we here identified EphA2 as a new stress-regulated antigen targetting by a non V 2neg g T cell clone, which recognition implies the hijacking of the natural EphA2-ephrin interactions to activation. These data suggest that in humans, a fortiori when immunosuppressed, g T cells compose a lymphoid stress-surveillance compartment, capable of recognizing the dysregulated state of infected or transformed cells and to take part to allogenic response through an ADCC mechanism.BORDEAUX2-Bib. électronique (335229905) / SudocBORDEAUX1-Bib.electronique (335229901) / SudocSudocFranceF

Can an Ecological Index of Deprivation Be Used at the Country Level? The Case of the French Version of the European Deprivation Index (F-EDI)

Most ecological indices of deprivation are constructed from census data at the national level, which raises questions about the relevance of their use, and their comparability across a country. We aimed to determine whether a national index can account for deprivation regardless of location characteristics. In Metropolitan France, 43,853 residential census block groups (IRIS) were divided into eight area types based on quality of life. We calculated score deprivation for each IRIS using the French version of the European Deprivation Index (F-EDI). We decomposed the score by calculating the contribution of each of its components by area type, and we assessed the impact of removing each component and recalculating the weights on the identification of deprived IRIS. The set of components most contributing to the score changed according to the area type, but the identification of deprived IRIS remained stable regardless of the component removed for recalculating the score. Not all components of the F-EDI are markers of deprivation according to location characteristics, but the multidimensional nature of the index ensures its robustness. Further research is needed to examine the limitations of using these indices depending on the purpose of the study, particularly in relation to the geographical grid used to calculate deprivation scores

Fluctuation and fixation of rodenticide resistance alleles in Rattus norvegicus

Berthier, K., Benoit, E., Berny, P., Lasseur, R., Merville, A., Peigneaux, F., Cosson, J.-F