AKT activity orchestrates marginal zone B cell development in mice and humans.

The signals controlling marginal zone (MZ) and follicular (FO) B cell development remain incompletely understood. Here, we show that AKT orchestrates MZ B cell formation in mice and humans. Genetic models that increase AKT signaling in B cells or abolish its impact on FoxO transcription factors highlight the AKT-FoxO axis as an on-off switch for MZ B cell formation in mice. In humans, splenic immunoglobulin (Ig) D <sup>+</sup> CD27 <sup>+</sup> B cells, proposed as an MZ B cell equivalent, display higher AKT signaling than naive IgD <sup>+</sup> CD27 <sup>-</sup> and memory IgD <sup>-</sup> CD27 <sup>+</sup> B cells and develop in an AKT-dependent manner from their precursors in vitro, underlining the conservation of this developmental pathway. Consistently, CD148 is identified as a receptor indicative of the level of AKT signaling in B cells, expressed at a higher level in MZ B cells than FO B cells in mice as well as humans

Differential regulation of myeloid leukemias by the bone marrow microenvironment

Like their normal hematopoietic stem cell counterparts, leukemia stem cells (LSC) in chronic myelogenous leukemia (CML) and acute myeloid leukemia (AML) are presumed to reside in specific niches in the bone marrow microenvironment (BMM)1, and may be the cause of relapse following chemotherapy.2 Targeting the niche is a novel strategy to eliminate persistent and drug-resistant LSC. CD443,4 and IL-65 have been implicated previously in the LSC niche. Transforming growth factor (TGF)-β1 is released during bone remodeling6 and plays a role in maintenance of CML LSCs7, but a role for TGF-β1 from the BMM has not been defined. Here, we show that alteration of the BMM by osteoblastic cell-specific activation of the parathyroid hormone (PTH) receptor8,9 attenuates BCR-ABL1-induced CML-like myeloproliferative neoplasia (MPN)10 but enhances MLL-AF9-induced AML11 in mouse transplantation models, possibly through opposing effects of increased TGF-β1 on the respective LSC. PTH treatment caused a 15-fold decrease in LSCs in wildtype mice with CML-like MPN, and reduced engraftment of immune deficient mice with primary human CML cells. These results demonstrate that LSC niches in chronic and acute myeloid leukemias are distinct, and suggest that modulation of the BMM by PTH may be a feasible strategy to reduce LSC, a prerequisite for the cure of CML

Rapport technique : incidence du comportement d'ancrages superficiels sur la résistance à la neige des serres tunnels

[Notes_IRSTEA]bibl., sch., ph., graph., tabl.Rédigé dans le cadre d'une étude plus générale visant à l'établissement d'une méthode de calcul des arceaux de serres tunnels, ce document est la syntèse des essais d'ancrages réalisés dans le cadre de cette étude la caractérisation des sols dans lesquels les essais ont été réalisé n'est pas incluse dans ce rapport

Evaluation de la résistance d'un arceau de serre tunnel : incidence du modèle de comportement des tubes

The frameworks for tunnel greenhouse structures usually comprise slender arches formed from a thin-walled steel circular hollow section. Previous work has shown that a second-order, elasto-plastic analysis is required to predict the structural behaviour of these slender tubular arches. The first objective of the present study has been to assess the moment-rotation relationship of the cross-section of the tubes in order to characterise their true relational behaviour. The influence of this rhéological behaviour on the accuracy of a structural model developed to predict the global resistance of an arch under various loading distributions is then investigated. The pastification of the tubes under combined axial forces and bending moments is also studied using a non-linear 3-dimensional finite element calculation. The results are discussed and an equivalent simplified model is proposed which is more readily usable in practice. Finally, the significance of these results on the calibration of a monotubular arch analysis against experimental results is evaluated. / La structure d'une serre tunnel comprend généralement un arceau flexible formé à partir d'un tube mince de section quasi-circulaire. Une étude précédente avait montré que pour les arceaux de serres, seule une analyse combinant non-linéarités géométriques et matérielles était correctement corrélée avec les résultats expérimentaux. La présente étude a pour objet de caractériser le comportement rhéologique réel des tubes utilisés dans les serres tunnels. Ce modèle de comportement est alors utilisé dans un code de calcul et permet d'évaluer la résistance globale calculée d'un arceau par le calcul d'un facteur de ruine. La plastification de ces tubes par combinaison d'effort normal et de moment fléchissant est aussi étudiée par un calcul d'éléments finis tridimensionnels non linéaire. Il reste alors à replacer ces résultats dans le contexte normatif et à proposer un "modèle simplifié équivalent" plus utilisable en pratique. La dernière étape de cette étude consiste à évaluer l'incidence de ces résultats sur la calibration du calcul global d'un arc monotubulaire sur des résultats expérimentaux

Opportunistic infections and AIDS malignancies early after initiating combination antiretroviral therapy in high-income countries

Background: There is little information on the incidence of AIDS-defining events which have been reported in the literature to be associated with immune reconstitution inflammatory syndrome (IRIS) after combined antiretroviral therapy (cART) initiation. These events include tuberculosis, mycobacterium avium complex (MAC), cytomegalovirus (CMV) retinitis, progressive multifocal leukoencephalopathy (PML), herpes simplex virus (HSV), Kaposi sarcoma, non-Hodgkin lymphoma (NHL), cryptococcosis and candidiasis. Methods: We identified individuals in the HIV-CAUSAL Collaboration, which includes data from six European countries and the US, who were HIV-positive between 1996 and 2013, antiretroviral therapy naive, aged at least 18 years, hadCD4+ cell count and HIV-RNA measurements and had been AIDS-free for at least 1 month between those measurements and the start of follow-up. For each AIDS-defining event, we estimated the hazard ratio for no cART versus less than 3 and at least 3 months since cART initiation, adjusting for time-varying CD4+ cell count and HIV-RNA via inverse probability weighting. Results: Out of 96 562 eligible individuals (78% men) with median (interquantile range) follow-up of 31 [13,65] months, 55 144 initiated cART. The number of cases varied between 898 for tuberculosis and 113 for PML. Compared with non-cART initiation, the hazard ratio (95% confidence intervals) up to 3 months after cART initiation were 1.21 (0.90-1.63) for tuberculosis, 2.61 (1.05-6.49) for MAC, 1.17 (0.34-4.08) for CMV retinitis, 1.18 (0.62-2.26) for PML, 1.21 (0.83-1.75) for HSV, 1.18 (0.87-1.58) for Kaposi sarcoma, 1.56 (0.82-2.95) for NHL, 1.11 (0.56-2.18) for cryptococcosis and 0.77 (0.40-1.49) for candidiasis. Conclusion: With the potential exception of mycobacterial infections, unmasking IRIS does not appear to be a common complication of cART initiation in high-income countries