Dominant Role of CD80–CD86 Over CD40 and ICOSL in the Massive Polyclonal B Cell Activation Mediated by LATY136F CD4+ T Cells

Coordinated interactions between T and B cells are crucial for inducing physiological B cell responses. Mutant mice in which tyrosine 136 of linker for activation of T cell (LAT) is replaced by a phenylalanine (LatY136F) exhibit a strong CD4+ T cell proliferation in the absence of intended immunization. The resulting effector T cells produce high amounts of TH2 cytokines and are extremely efficient at inducing polyclonal B cell activation. As a consequence, these LatY136F mutant mice showed massive germinal center formations and hypergammaglobulinemia. Here, we analyzed the involvement of different costimulators and their ligands in such T–B interactions both in vitro and in vivo, using blocking antibodies, knockout mice, and adoptive transfer experiments. Surprisingly, we showed in vitro that although B cell activation required contact with T cells, CD40, and inducible T cell costimulator molecule-ligand (ICOSL) signaling were not necessary for this process. These observations were further confirmed in vivo, where none of these molecules were required for the unfolding of the LAT CD4+ T cell expansion and the subsequent polyclonal B cell activation, although, the absence of CD40 led to a reduction of the follicular B cell response. These results indicate that the crucial functions played by CD40 and ICOSL in germinal center formation and isotype switching in physiological humoral responses are partly overcome in LatY136F mice. By comparison, the absence of CD80–CD86 was found to almost completely block the in vitro B cell activation mediated by LatY136F CD4+ T cells. The role of CD80–CD86 in T–B cooperation in vivo remained elusive due to the upstream implication of these costimulatory molecules in the expansion of LatY136F CD4+ T cells. Together, our data suggest that CD80 and CD86 costimulators play a key role in the polyclonal B cell activation mediated by LatY136F CD4+ T cells even though additional costimulatory molecules or cytokines are likely to be required in this process

Coordination par le biais de l'environnement : une approche biologique

Colloque avec actes et comité de lecture.Cet article décrit un mécanisme de coordination par le biais de l'environnement et illustre sa mise en oeuvre par la simulation de l'activité de construction de toile chez les araignées sociales. Il s'inspire des sociétés d'araignées qui constituent un modèle particulièrement propice à l'étude des caractéristiques individuelles nécessaires à l'apparition de la vie sociale. Nous commençons par exposer les différentes motivations qui nous guident ainsi que l'état de l'art des recherches effectuées dans le domaine des systèmes multi-agents d'inspiration biologique. Nous présentons ensuite un exemple biologique de coordination d'activités par stigmergie dans le cadre de construction de toile par des araignées solitaires et sociales, puis nous détaillons une manière possible de la mettre en oeuvre dans des systèmes d'agents artificiels

Time- and Dose-Related Effects of Di-(2-ethylhexyl) Phthalate and Its Main Metabolites on the Function of the Rat Fetal Testis in Vitro

International audienceBACKGROUND: Endocrine-disrupting effects of phthalates are understood primarily from in utero exposures within the fetal rat testis. Nevertheless, their path of action, dose-response character, and cellular target(s) within the fetal testis are not known. OBJECTIVES: In this study we investigated the effects of di-(2-ethylhexyl) phthalate (DEHP), mono-(2-ethylhexyl) phthalate (MEHP), and several of their metabolites on the development of organo-cultured testes from rat fetus. METHODS: We removed testes from 14.5-day-old rat fetuses and cultured them for 1-3 days with or without DEHP, MEHP, and the metabolites. RESULTS: DEHP (10(-5) M) produced a proandrogenic effect after 3 days of culture, whereas MEHP disrupted testis morphology and function. Leydig cells were the first affected by MEHP, with a number of them being inappropriately located within some seminiferous tubules. Additionally, we found a time- and dose-dependent reduction of testosterone. By 48 hr, gonocyte proliferation had decreased, whereas apoptosis increased. Sertoli cell number was unaffected, although some cells appeared vacuolated, and production of anti-Müllerian hormone decreased in a time- and dose-dependent manner. The derived metabolite mono-(2-ethyl-5-hydroxyhexyl) phthalate was the only one to cause deleterious effects to the rat fetal testis in vitro. CONCLUSION: We hope that this in vitro method will facilitate the study of different phthalate esters and other endocrine disruptors for direct testicular effects

A prototyping method for the re-design of intensive perennial systems: the case of vineyards in France

The results of our re-design and experimentation of grapevine agrosystem, as well as on the other crops (Lançon et al., 2007 and Wery & Langeveld, 2010) show promising perspectives of the prototyping method to achieve high goals for performance and innovation. The complexity of the grapevine agrosystem (ie the number of technical interventions and their potential interactions) requires a strong systemic approach at the interface between the technical and biophysical dimensions of cropping systems (Rapidel et al., 2009). The approach must implement agro-ecological processes to greatly limit inputs. It also required a high innovation and significant changes in the grapevine agrosystem genetics, structure and management. Our results point out the need to re-design grapevine systems from the crop plantation with new varieties, new training systems and with intercrops aiming to improve ecosystem services and maintain a very high level of sustainability criteria

The structure of Staphylococcus aureus epidermolytic toxin A, an atypic serine protease, at 1.7 Å resolution

AbstractBackground: Staphylococcal epidermolytic toxins A and B (ETA and ETB) are responsible for the staphylococcal scalded skin syndrome of newborn and young infants; this condition can appear just a few hours after birth. These toxins cause the disorganization and disruption of the region between the stratum spinosum and the stratum granulosum —  two of the three cellular layers constituting the epidermis. The physiological substrate of ETA is not known and, consequently, its mode of action in vivo remains an unanswered question. Determination of the structure of ETA and its comparison with other serine proteases may reveal insights into ETA's catalytic mechanism.Results: The crystal structure of staphylococcal ETA has been determined by multiple isomorphous replacement and refined at 1.7 Å resolution with a crystallographic R factor of 0.184. The structure of ETA reveals it to be a new and unique member of the trypsin-like serine protease family. In contrast to other serine protease folds, ETA can be characterized by ETA-specific surface loops, a lack of cysteine bridges, an oxyanion hole which is not preformed, an S1 specific pocket designed for a negatively charged amino acid and an ETA-specific N-terminal helix which is shown to be crucial for substrate hydrolysis.Conclusions: Despite very low sequence homology between ETA and other trypsin-like serine proteases, the ETA crystal structure, together with biochemical data and site-directed mutagenesis studies, strongly confirms the classification of ETA in the Glu-endopeptidase family. Direct links can be made between the protease architecture of ETA and its biological activity

High-resolution mass spectrometry identifies delayed biomarkers for improved precision in acetaminophen/paracetamol human biomonitoring

Paracetamol/acetaminophen (N-acetyl-p-aminophenol, APAP) is a top selling analgesic used in more than 600 prescription and non-prescription pharmaceuticals. To study efficiently some of the potential undesirable effects associated with increasing APAP consumption (e.g., developmental disorders, drug-induced liver injury), there is a need to improve current APAP biomonitoring methods that are limited by APAP short half-life. Here, we demonstrate using high-resolution mass spectrometry (HRMS) in several human studies that APAP thiomethyl metabolite conjugates (S-methyl-3-thioacetaminophen sulfate and S-methyl-3-thioacetaminophen sulphoxide sulfate) are stable biomarkers with delayed excretion rates compared to conventional APAP metabolites, that could provide a more reliable history of APAP ingestion in epidemiological studies. We also show that these biomarkers could serve as relevant clinical markers to diagnose APAP acute intoxication in overdosed patients, when free APAP have nearly disappeared from blood. Using in vitro liver models (HepaRG cells and primary human hepatocytes), we then confirm that these thiomethyl metabolites are directly linked to the toxic N-acetyl-p-benzoquinone imine (NAPQI) elimination, and produced via an overlooked pathway called the thiomethyl shunt pathway. Further studies will be needed to determine whether the production of the reactive hepatotoxic NAPQI metabolites is currently underestimated in human. Nevertheless, these biomarkers could already serve to improve APAP human biomonitoring, and investigate, for instance, inter-individual variability in NAPQI production to study underlying causes involved in APAP-induced hepatotoxicity. Overall, our findings demonstrate the potential of exposomics-based HRMS approach to advance towards a better precision for human biomonitoring.</p

Multi-state and non-volatile control of graphene conductivity with surface electric fields

Planar electrodes patterned on a ferroelectric substrate are shown to provide lateral control of the conductive state of a two-terminal graphene stripe. A multi-level and on-demand memory control of the graphene resistance state is demonstrated under low sub-coercive electric fields, with a susceptibility exceeding by more than two orders of magnitude those reported in a vertical gating geometry. Our example of reversible and low-power lateral control over 11 memory states in the graphene conductivity illustrates the possibility of multimemory and multifunctional applications, as top and bottom inputs remain accessible. (C) 2015 AIP Publishing LLC

Effect of Lactobacillus rhamnosus CGMCC1.3724 supplementation on weight loss and maintenance in obese men and women

The present study investigated the impact of a Lactobacillus rhamnosus CGMCC1.3724 (LPR) supplementation on weight loss and maintenance in obese men and women over 24 weeks. In a double-blind, placebo-controlled, randomised trial, each subject consumed two capsules per d of either a placebo or a LPR formulation (1·6×108 colony-forming units of LPR/capsule with oligofructose and inulin). Each group was submitted to moderate energy restriction for the first 12 weeks followed by 12 weeks of weight maintenance. Body weight and composition were measured at baseline, at week 12 and at week 24. The intention-to-treat analysis showed that after the first 12 weeks and after 24 weeks, mean weight loss was not significantly different between the LPR and placebo groups when all the subjects were considered. However, a significant treatment×sex interaction was observed. The mean weight loss in women in the LPR group was significantly higher than that in women in the placebo group (P=0·02) after the first 12 weeks, whereas it was similar in men in the two groups (P=0·53). Women in the LPR group continued to lose body weight and fat mass during the weight-maintenance period, whereas opposite changes were observed in the placebo group. Changes in body weight and fat mass during the weight-maintenance period were similar in men in both the groups. LPR-induced weight loss in women was associated not only with significant reductions in fat mass and circulating leptin concentrations but also with the relative abundance of bacteria of the Lachnospiraceae family in faeces. The present study shows that the Lactobacillus rhamnosus CGMCC1.3724 formulation helps obese women to achieve sustainable weight los