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International audience; Interleukin-22 (IL-22) is a member of the IL-10 cytokine family that binds to a heterodimeric receptor consisting of IL-22 receptor 1 (IL-22R1) and IL-10R2. IL-22R expression was initially characterized on epithelial cells, and plays an essential role in a number of inflammato-ry diseases. Recently, a functional receptor was detected on cancer cells such as hepatocarcinoma and lung carcinoma, but its presence was not reported in glioblastoma (GBM). Two GBM cell lines and 10 primary cell lines established from patients undergoing surgery for malignant GBM were used to investigate the expression of IL-22 and IL-22R by using quantitative RT-PCR, western blotting and confocal microscopy studies. The role of IL-22 in proliferation and survival of GBM cell lines was investigated in vitro by BrdU and ELISA cell death assays. We report herein that the two subunits of the IL-22R complex are expressed on human GBM cells. Their activation, depending on exogenous IL-22, induced antiapoptotic effect and cell proliferation. IL-22 treatment of GBM cells resulted in increased levels of phosphorylated Akt, STAT3 signaling protein and its downstream antiapoptotic protein Bcl-xL and decreased level of phosphorylated ERK1/2. In addition, IL-22R subunits were expressed in all the 10 tested primary cell lines established from GBM tumors. Our results showed that IL-22R is expressed on GBM established and primary cell lines. Depending on STAT3, ERK1/2 and PI3K/Akt pathways, IL-22 induced GBM cell survival. These data are consistent with a potential role of IL-22R in tumorigenesis of GBM. Since endoge-nous IL-22 was not detected in all studied GBM cells, we hypothesize that IL-22R could be activated by immune microenvironmental IL-22 producing cells.

This paper presents a new model that accounts, on a local scale, for the coupling between plasticity due to gliding in shear bands and damage occurring when the accumulated plastic strain has reached a threshold value. The irreversible thermodynamics with internal state variables is employed to keep a middle way between extensive description of plastic and damage flow and application of accessibility requirements. Plasticity and damage are governed by their proper complementary rules (yield functions and potentials). At the same time, a coupling occurs between the damage variable and the hardening parameters. A large experimental database relative to the fatigue behavior of a mild steel C36 submitted to different loading modes (tension, torsion, combined proportional tension and torsion) proves the efficiency of such a model. The prediction of Wöhler curves for cyclic complex stress states can be readily done, but the main feature of this approach is to ensure a clear link between mesoscopic parameters like the hardening behavior of individual grains and the subsequent local damage.

This paper aims to propose a new interpretation of several energy-based critical plane high cycle fatigue criteria. More exactly, the meaning of several global energy-based criteria is detailed from the calculation of normal and shear work on a critical plane. This study is limited to multiaxial fatigue under constant amplitude and synchronous loadings (proportional or non-proportional), with or without mean load. After a short review of some energy-based criteria using the critical plane concept or a global approach, the reasons why energy-based critical plane criteria are more and more developed in literature are summarized. It is shown that a direct link exists between critical plane energy parameters and global ones. A critical examination of the famous Findley et al. experiments is proposed and the previous link is illustrated with two mesoscopic criteria developed by Papadopoulos and the global energy-based criterion of Banvillet et al. This leads us to propose an interpretation of fatigue crack initiation from the mesoscopic scale up to the macroscopic scale either with stress and strain quantities or with strain energy parameters.

IL-22 belongs to a family of cytokines structurally related to IL-10, including IL-19, IL-20, IL-24, and IL-26. In contrast to IL-10, IL-22 has proinflammatory activities. IL-22 signals through a class II cytokine receptor composed of an IL-22-binding chain, IL-22RA1, and the IL-10RB subunit, which is shared with the IL-10R. In the present study, we show that short-term cultured human epidermal keratinocytes express a functional IL-22R but no IL-10R. Accordingly, IL-22 but not IL-10 induces STAT3 activation in keratinocytes. Using a cDNA array screening approach, real-time RT-PCR, and Western blot analysis, we demonstrate that IL-22 up-regulates, in a dose-dependent manner, the expression of S100A7, S100A8, S100A9, a group of proinflammatory molecules belonging to the S100 family of calcium-binding proteins, as well as the matrix metalloproteinase 3, the platelet-derived growth factor A, and the CXCL5 chemokine. In addition, IL-22 induces keratinocyte migration in an in vitro injury model and down-regulates the expression of at least seven genes associated with keratinocyte differentiation. Finally, we show that IL-22 strongly induces hyperplasia of reconstituted human epidermis. Taken together, these results suggest that IL-22 plays an important role in skin inflammatory processes and wound healing.

The stress gradient and the size of a component are known to influence the fatigue strength of metallic components. Indeed, in high-cycle fatigue, experiments prove that the stress distribution as well as the size of the loaded specimen can be responsible for changes in the fatigue limit (for instance, the fatigue limits in tension and bending are different, and decrease with the size of the specimen). When dealing with multiaxial load conditions, those effects still act but a relevant criterion must be used to account for the complex state of stress. The weakest-link concept together with a multiaxial endurance criterion based on a microplasticity analysis are then combined to describe the fatigue limit distribution of different metallic materials. Several load conditions are analysed: tension-compression, torsion, rotating bending and plane bending. By means of the proposed model, all the known effects on fatigue strength can be reflected. First, the endurance probability can be adequately predicted for any complex load conditions knowing some reference data from uniaxial fatigue tests. It can be linked to the probability of finding a defect with a critical size. The weakest-link theory also accounts for the decrease of multiaxial fatigue limit with the stressed volume. For the same load condition (i.e. for the same stress distribution in the volume), the probability of finding a critical defect increases with the component size and then according to the weakest-link theory the fatigue strength drops. A second model, based only on the damage developed at the surface, is also proposed. While the original Weibull theory makes no distinction between potential initiation sites at the free surface and in the volume and can lead to unsatisfactory predictions when applied to materials containing defects such as nodular cast iron, the new surface approach distinguishes between surface and volume effects.

Introduction Un reseau cytokinique complexe a ete decrit dans les lesions cutanees psoriasiques et illustre le role central des cytokines pro-inflammatoires telles que l’IL-23, l’IL-22, l’IL-17, l’IL-1, l’oncostatine M et le TNFα, produites par les cellules immunitaires infiltrees. Recemment, nous avons montre que l’association d’IL-1α, IL-17A, IL-22, OSM et TNFα agit de facon synergique sur les keratinocytes en augmentant l’expression de molecules liees a l’immunite innee et a l’inflammation, telles que des chimiokines et des peptides antimicrobiens, et en inhibant leur programme de differenciation. Ceci genere un modele in vitro d’inflammation cutanee mimant certaines caracteristiques du psoriasis. Nous avons demontre que cette combinaison de cytokines constitue une signature moleculaire des lesions cutanees psoriasiques. En parallele, plusieurs approches therapeutiques anti-cytokine ont ete developpees et le TNFα constitue une cible de choix. Parmi ces traitements, l’adalimumab est une IgG1 monoclonale anti-TNFα entierement humaine qui diminue l’inflammation cutanee et le score de severite clinique d’au moins 75 % chez environ 80 % des patients. Notre objectif etait d’analyser la modification du profil transcriptomique cutane et les concentrations des cytokines circulantes chez les patients psoriasiques pendant le traitement par l’adalimumab. Materiel et methodes Les patients psoriasiques ont ete traites par l’adalimumab. Au bout de 4 et 16 semaines, l’efficacite clinique de la therapie a ete evaluee par les mesures de PASI et de DLQI. Les profils transcriptomiques cutanes avant et apres traitement ont ete determines par RT-PCR quantitative et les cytokines circulantes mesurees par immuno-analyse multiplexe. Resultats Nous observons un effet clair et rapide du traitement par l’adalimumab sur l’expression des cytokines « Th17 », de l’IL-1 et de l’oncostatine M, expliquant les modifications d’expression genique par les keratinocytes (BD2, S100A7, CXCL8, CK10) et la reponse clinique. Une persistance de l’expression des cytokines et de leurs cibles keratinocytaires est egalement observee dans certaines lesions residuelles. En revanche, les concentrations seriques de cytokines sont peu correlees a l’evolution clinique et aux profils d’expression cutanes, ce qui confirme la necessite d’une caracterisation locale des cytokines dans les lesions cutanees. Fait interessant, en plus du maintien de l’expression locale des cytokines chez les patients non repondeurs, un profil cytokinique initial chez les non-repondeurs pourrait suggerer l’identification possible de marqueurs predictifs de resistance/sensibilite au traitement par l’adalimumab. Discussion Nos donnees montrent que le ciblage du TNFα dans le psoriasis a un effet tres large sur le profil d’expression des cytokines Th17 et des marqueurs de l’inflammation de la peau, ce qui explique son efficacite clinique.

Introduction Les cultures de keratinocytes en monocouche sont couramment utilisees dans les etudes in vitro, mais celles-ci ne reproduisent pas fidelement l’architecture de l’epiderme et les caracteristiques physiologiques des differents etats de differenciation cellulaire. Dans cette etude, nous decrivons un protocole simple et rapide pour la generation d’epidermes reconstruits murins (RME) a partir de keratinocytes primaires de souriceaux. Apres avoir caracterise les differentes etapes de leur differenciation, nous analysons leur reponse a la stimulation par des cytokines proinflammatoires. Materiel et methodes Les RME sont realises a partir de keratinocytes primaires issus de peaux de souriceaux nouveau-nes cultives dans des inserts en polycarbonate dans un milieu d’ensemencement. Des l’obtention d’une monocouche cellulaire, les inserts sont passes a l’interface air-liquide au contact d’un milieu de differenciation. La caracterisation des RME est effectuee par histologie et par immunohistofluorescence pour la detection de marqueurs de differenciation incluant les keratines 14, 6, 10, la loricrine, la filaggrine, l’E-Cadherine et des connexines. Leur permeabilite est eprouvee par des tests de diffusion de la sonde fluorescente Lucifer Yellow . Enfin, la reponse des RME aux cytokines IL-17A, TNFα, IL-22, IL-1α et oncostatine M est evaluee par RT-qPCR par la mesure de l’expression de marqueurs de differenciation, de peptides antimicrobiens et de chimiokines. Resultats Notre protocole permet d’obtenir des RME qui reproduisent les caracteristiques morphologiques et phenotypiques d’un epiderme de souris en seulement 5 jours apres leur passage a l’interface air-liquide comme l’atteste l’expression des marqueurs de differenciation conforme a celle d’un epiderme natif. Les RME acquierent egalement leur fonction de barriere et sont impermeables au passage de la Lucifer Yellow . Enfin, suite a leur stimulation par des cytokines proinflammatoires, les RME repondent de maniere similaire a un epiderme in vivo par une diminution d’expression de la keratine 10, de l’involucrine et de la filaggrine et une augmentation de l’expression de mediateurs de l’inflammation tels que la chimiokine CXCL-3 et les peptides antimicrobiens S100A9 et β-defensine-3. Discussion Ce nouveau protocole permet donc de realiser rapidement et facilement des RME reproduisant fidelement l’architecture et les caracteristiques physiologiques d’un epiderme, y compris leur reponse dans un contexte inflammatoire. Conclusion Ce modele de RME permet d’etudier les mecanismes physiologiques de la peau et ouvre la perspective de realiser des RME a partir de keratinocytes issus de souris genetiquement modifiees.

Objectives: Recent in vivo and in vitro studies in animals have demonstrated that cytokines of the IL-6 family are involved in cardiac hypertrophy and in protection of cardiomyocytes against apoptosis. The present study aims to analyse the capacity of human atrial cardiac cells (i.e., cardiomyocytes and fibroblasts) to display the gp130 receptor subunit, and to evaluate its functionality. Methods: Twenty human atrial biopsies were used for immunohistochemistry, in situ hybridisation, and western blot analysis or dissociated for isolation and primary culture of cardiac cells. Results: Fibroblasts present in tissue or maintained in primary culture clearly express gp130 whereas the signal in cardiomyocytes is weaker. Culture of cardiac cells with a gp130 agonist antibody enhances atrial natriuretic peptide (ANP), β myosin heavy chain (β-MHC) expression in cardiomyocytes, and significantly increases the cell surface area (μm2). This process could involve STAT3 (signal transducer and activator of transcription 3) phosphorylation. Conclusions: These results demonstrate that gp130 activation in human cardiac cells leads to cardiomyocyte hypertrophy. We discuss several hypotheses on the role of IL-6-type cytokines on cardiomyocyte functions.

En fatigue a grand nombre de cycle, il est aujourd'hui admis que la distribution des contraintes, ainsi que la taille des composants, sont responsables de variations de la limite de fatigue. Sous chargement uniaxial ou multiaxial, on peut montrer qu'une approche statistique dite du maillon le plus faible, combine a un critere multiaxial d'endurance base sur une analyse micro plastique, permet de predire la limite de fatigue de plusieurs materiaux metalliques. Quatre types de chargement sont analyses (traction-compression, torsion, flexion rotative et flexion plane), puis comparees aux resultats experimentaux, pour une fonte et deux aciers haute resistance. L'approche statistique proposee permet d'integrer un certain nombre d'aspects: la dispersion des donnees pour tous types de chargement, l'effet de gradient et l'influence de la presence de defauts materiaux. Enfin, ce modele rend egalement compte de la diminution de la limite de fatigue avec l'augmentation du volume contraint. Les predictions des probabilites de rupture sont raisonnables bien que seules des limites de fatigue relatives a des probabilites de rupture de 50% soient utilisees pour l'identification des parametres du modele.

The stress gradient effect on the fatigue limit is an important factor which has to be taken into account for an efficient transfer of fatigue data from laboratory tests to design of industrial components. A short review of some multiaxial high cycle fatigue criteria considering this effect is presented. On the basis of the two local mesoscopic approaches of Papadopoulos, two new non-local high cycle multiaxial fatigue criteria are developed. These proposals are based on the concept of volume influencing fatigue crack initiation. Their predictions are compared with experimental multiaxial fatigue data on four materials (a mild steel, two high strength steels and a spheroidal graphite cast iron). The accuracy of the two local Papadopoulos criteria and of the non-local proposals are compared and discussed, together with the physical interpretation of the threshold defining the volume influencing fatigue crack initiation.

M-CSF is a pleiotropic cytokine involved in the survival, proliferation, and differentiation of cells of the monocyte/macrophagelineage. M-CSF is produced by numerous cells including CD3-activated Tcells. M-CSF serum levels are increased during acute graft rejection. We tested the in vitro production of M-CSF, GM-CSF, IL-2, and IL-4 byT-cell clones costimulated by CD3 and accessory activation pathways and the effects of cyclosporin A and methylprednisolone. The nine clonesstudied and CD4+ cells purified from peripheral bloodmononuclear cells (PBMC) spontaneously produced low levels of M-CSF, which PMA and CD3 mAb strongly enhanced. In contrast to IL-2, CD28 mAbdid not further enhance this production. CsA inhibited M-CSF productionby clones and purified CD4 T cells. Addition of IL-2, anti IL-2, oranti CD25 mAb to the cultures demonstrated that CsA down-regulatedM-CSF synthesis by activated T cells through its inhibition of IL-2synthesis. These results could help to better understand the complexmechanisms of acute graft rejection and immunosuppression.

International audience; This work investigates the effect of natural and artificial surface defects and quenching on the fatigue strength of a Boron steel (22MnB5). A vast experimental campaign has been undertaken to study the high cycle fatigue behaviour and more specifically the fatigue damage mechanisms observed in quenched and untreated materials, under different loading conditions and with differents artificial defects sizes (from 25 μm to 370 μm radius). In order to test the sheet metal in shear an original test apparatus is used. The critical defect size is determined to be 100 ± 50 μm. This critical size does not appear to depend on the loading type or the microstructure of the material (i.e. ferritic-perlitic or martensitic). However, for large defects, the quenched material is more sensitive to the defect size than the untreated material. For a defect size range of 100-300 μm the slope of the Kitagawa-Takahashi diagram is approximately −1/3 and −1/6 for the quenched and untreated materials respectively. A probabilistic approach that leads naturally to a probabilistic Kitagawa type diagram is developed. This methodology can be used to explain the relationship between the influence of the heat treatment and the defect size on the fatigue behaviour of this steel.

Multiaxial high cycle fatigue modeling of materials is an issue that concerns many industrial domains (automotive, aerospace, nuclear, etc.) and in which many progress still remains to be achieved. Several approaches exist in the literature: invariants, energy, integral and critical plane approaches all of them having their advantages and drawbacks. These different formulations are usually based on mechanical quantities at the micro or mesoscales using localization schemes and strong assumptions to propose simple analytical forms. This study aims to revisit these formulations using a numerical approach based on crystal plasticity modeling coupled with explicit description of microstructure (morphology and texture) and proposes a statistical procedure for the analyses of numerical results in the HCF context. This work has three steps: First, 2.5D periodic digital microstructures based on a random grain sizes distribution are generated. Second, multiaxial cyclic loading conditions corresponding to the fatigue strength at 106 cycles are applied to these microstructures. Third, the mesoscopic Fatigue Indicator Parameters (FIPs), formulated from the different criteria existing in the literature, are identified using the finite element calculations of the mechanical fields. These mesoscopic FIP show the limits of the original criteria when it comes to applying them at the grain scale. A statistical method based on extreme value probability is used to redefine the thresholds of these criteria. These new thresholds contain the sensitivity of the HCF behavior to microstructure attributes. Finally, the biaxiality and phase shift effects are discussed at the grain scale and the loading paths of some critical grains are analyzed. Financial support of this research by Arts et Métiers Paristech is gratefully acknowledged.

This study aims to analyse the influence of geometrical defects (notches and holes) on the high cycle fatigue behaviour of an electrolytic copper based on finite element simulations of 2D polycrystalline aggregates. In order to investigate the role of each source of anisotropy on the mechanical response at the grain scale, three different material constitutive models are assigned successively to the grains: isotropic elasticity, cubic elasticity and crystal plasticity in addition to the cubic elasticity. The significant influence of the elastic anisotropy on the mechanical response of the grains is highlighted. When considering smooth microstructures, the crystal plasticity have has a slight effect in comparison with the cubic elasticity influence. However, in the case of notched microstructures, it has been shown that the influence of the plasticity is no more negligible. Finally, the predictions of three fatigue criteria are analysed. Their ability to predict the defect size effect on the fatigue strength is evaluated thanks to a comparison with experimental data from the literature.; International audience; This study aims to analyse the influence of geometrical defects (notches and holes) on the high cycle fatigue behaviour of an electrolytic copper based on finite element simulations of 2D polycrystalline aggregates. In order to investigate the role of each source of anisotropy on the mechanical response at the grain scale, three different material constitutive models are assigned successively to the grains: isotropic elasticity, cubic elasticity and crystal plasticity in addition to the cubic elasticity. The significant influence of the elastic anisotropy on the mechanical response of the grains is highlighted. When considering smooth microstructures, the crystal plasticity have has a slight effect in comparison with the cubic elasticity influence. However, in the case of notched microstructures, it has been shown that the influence of the plasticity is no more negligible. Finally, the predictions of three fatigue criteria are analysed. Their ability to predict the defect size effect on the fatigue strength is evaluated thanks to a comparison with experimental data from the literature.

Keratinocyte differentiation program leading to an organized epidermis plays a key role in maintaining the first line of defense of the skin. Epidermal integrity is regulated by a tight communication between keratinocytes and leucocytes, particularly under cytokine control. Imbalance of the cytokine network leads to inflammatory diseases such as psoriasis. Our attempt to model skin inflammation showed that the combination of IL-17A, IL-22, IL-1α, OSM and TNFα (Mix M5) synergistically increases chemokine and antimicrobial-peptide expression, recapitulating some features of psoriasis. Other characteristics of psoriasis are acanthosis and down-regulation of keratinocyte differentiation markers. Our aim was to characterize the specific roles of these cytokines on keratinocyte differentiation, and to compare with psoriatic lesion features. All cytokines decrease keratinocyte differentiation markers, but IL-22 and OSM were the most powerful, and the M5 strongly synergized the effects. In addition, IL-22 and OSM induced epidermal hyperplasia in vitro and M5 induced epidermal thickening and decreased differentiation marker expression in a mouse model, as observed in human psoriatic skin lesions. This study highlights the precise role of cytokines in the skin inflammatory response. IL-22 and OSM more specifically drive epidermal hyperplasia and differentiation loss while IL-1α, IL-17A and TNFα were more involved in the activation of innate immunity.

Helicobacter pylori infection systematically causes chronic gastric inflammation that can persist asymptomatically or evolve toward more severe gastroduodenal pathologies, such as ulcer, mucosa-associated lymphoid tissue (MALT) lymphoma, and gastric cancer. The cag pathogenicity island ( cag PAI) of H. pylori allows translocation of the virulence protein CagA and fragments of peptidoglycan into host cells, thereby inducing production of chemokines, cytokines, and antimicrobial peptides. In order to characterize the inflammatory response to H. pylori , a new experimental protocol for isolating and culturing primary human gastric epithelial cells was established using pieces of stomach from patients who had undergone sleeve gastrectomy. Isolated cells expressed markers indicating that they were mucin-secreting epithelial cells. Challenge of primary epithelial cells with H. pylori B128 underscored early dose-dependent induction of expression of mRNAs of the inflammatory mediators CXCL1 to -3, CXCL5, CXCL8, CCL20, BD2, and tumor necrosis factor alpha (TNF-α). In AGS cells, significant expression of only CXCL5 and CXCL8 was observed following infection, suggesting that these cells were less reactive than primary epithelial cells. Infection of both cellular models with H. pylori B128ΔcagM, a cag PAI mutant, resulted in weak inflammatory-mediator mRNA induction. At 24 h after infection of primary epithelial cells with H. pylori , inflammatory-mediator production was largely due to cag PAI substrate-independent virulence factors. Thus, H. pylori cag PAI substrate appears to be involved in eliciting an epithelial response during the early phases of infection. Afterwards, other virulence factors of the bacterium take over in development of the inflammatory response. Using a relevant cellular model, this study provides new information on the modulation of inflammation during H. pylori infection.

The aim of this work is to propose simple analytical tools to predict the fatigue strength of cast aluminium components as a function of the casting process and post-cast treatment. The proposed methodology is based on the Murakami approach to predict the maximum defect size and a flexible modelling framework which leads to the construction of a probabilistic, multiaxial Kitagawa-Takahashi diagram. This framework is capable of modelling two independent co-existing fatigue damage mechanisms. This methodology will be applied to fatigue data taken from the literature as well as tests conducted on AlSi7 cast specimens manufactured via three different processes.; International audience; The aim of this work is to propose simple analytical tools to predict the fatigue strength of cast aluminium components as a function of the casting process and post-cast treatment. The proposed methodology is based on the Murakami approach to predict the maximum defect size and a flexible modelling framework which leads to the construction of a probabilistic, multiaxial Kitagawa-Takahashi diagram. This framework is capable of modelling two independent co-existing fatigue damage mechanisms. This methodology will be applied to fatigue data taken from the literature as well as tests conducted on AlSi7 cast specimens manufactured via three different processes.

In this work, an analysis of both the mechanical response at the grain scale and high cycle multiaxial fatigue criteria is undertaken using finite element (FE) simulations of polycrystalline aggregates. The metallic material chosen for investigation, a pure copper, has a Face Centred Cubic (FCC) crystalline structure. Two-dimensional polycrystalline aggregates, which are composed of 300 randomly orientated equiaxed grains, are loaded at the median fatigue strength defined at 107 cycles. In order to analyse the effect of the loading path on the local mechanical response, combined tension–torsion and biaxial tension loading cases, in-phase and out-of-phase, with different biaxiality ratios, are applied to each polycrystalline aggregate. Three different material constitutive models assigned to the grains are investigated: isotropic elasticity, cubic elasticity and crystal plasticity in addition to the cubic elasticity. First, some aspects of the mechanical response of the grains are highlighted, namely the scatter and the multiaxiality of the mesoscopic responses with respect to an uniaxial macroscopic response. Then, the distributions of relevant mechanical quantities classically used in fatigue criteria are analysed for some loading cases and the role of each source of anisotropy on the mechanical response is evaluated and compared to the isotropic elastic case. In particular, the significant influence of the elastic anisotropy on the mesoscopic mechanical response is highlighted. Finally, an analysis of three different fatigue criteria is conducted, using mechanical quantities computed at the grain scale. More precisely, the predictions provided by these criteria, for each constitutive model studied, are compared with the experimental trends observed in metallic materials for such loading conditions.; International audience; In this work, an analysis of both the mechanical response at the grain scale and high cycle multiaxial fatigue criteria is undertaken using finite element (FE) simulations of polycrystalline aggregates. The metallic material chosen for investigation, a pure copper, has a Face Centred Cubic (FCC) crystalline structure. Two-dimensional polycrystalline aggregates, which are composed of 300 randomly orientated equiaxed grains, are loaded at the median fatigue strength defined at 107 cycles. In order to analyse the effect of the loading path on the local mechanical response, combined tension–torsion and biaxial tension loading cases, in-phase and out-of-phase, with different biaxiality ratios, are applied to each polycrystalline aggregate. Three different material constitutive models assigned to the grains are investigated: isotropic elasticity, cubic elasticity and crystal plasticity in addition to the cubic elasticity. First, some aspects of the mechanical response of the grains are highlighted, namely the scatter and the multiaxiality of the mesoscopic responses with respect to an uniaxial macroscopic response. Then, the distributions of relevant mechanical quantities classically used in fatigue criteria are analysed for some loading cases and the role of each source of anisotropy on the mechanical response is evaluated and compared to the isotropic elastic case. In particular, the significant influence of the elastic anisotropy on the mesoscopic mechanical response is highlighted. Finally, an analysis of three different fatigue criteria is conducted, using mechanical quantities computed at the grain scale. More precisely, the predictions provided by these criteria, for each constitutive model studied, are compared with the experimental trends observed in metallic materials for such loading conditions.

This paper presents the results obtained with a new ball burnishing tool developed for the mechanical treatment of large flat surfaces. Several parameters can affect the mechanical behavior and fatigue of workpiece. Our study focused on the effect of the burnishing force on the surface quality and on the service properties (mechanical behavior, fatigue) of AISI 1010 steel hot-rolled plates. Experimental results assert that burnishing force not exceeding 300 N causes an increase in the ductility. In addition, results indicated that the effect of the burnishing force on the residual surface stress was greater in the direction of advance than in the cross-feed direction. Furthermore, the flat burnishing surfaces did not improve the fatigue strength of AISI 1010 steel flat specimens.

This paper presents an easy to handle but efficient fatigue life prediction method based on a plasticity analysis carried out at the scale of the grains, i.e. the mesoscopic scale. The different steps of the model are described in the case of in-phase as well as out-of-phase bending-torsion load conditions. One striking feature of this method is that the definition of the critical material plane and the estimation of the number of cycles to initiation are made by means of analytical expressions that are functions of the loading parameters such as amplitudes, means and phase angles. The identification of the model parameters is readily carried out by means of one SN curve and two fatigue limits. This model is able to reflect the influence of the phase shift on damage accumulation with the introduction of no adjustable parameters. Furthermore, the comparison between the predictions and in-phase and out-of-phase fatigue data found in the literature leads to very good correlation.

In this paper, a new life prediction method for high cycle multiaxial fatigue of metallic materials is presented. It is based on a local approach introduced by Dang Van and developed by Papadopoulos, where accumulated plastic strain due to external loading is estimated at a scale of the order of a few grains. Its evaluation requires the use of a critical plane type fatigue criterion. As soon as the accumulated plastic mesostrain, considered as the damage variable, reaches a critical value, a crack is considered to be initiated. The complex and combined cases of loading (multiaxial and variable amplitude loading) can be analysed with this new method. In particular, attention is given to a description of the damaging effect of the loading path shape on fatigue strength. The application of hardening plasticity laws at the local scale allows one to estimate and sum the damage caused by elementary loading events like transitions.

We have used a mouse bone marrow transplantation (BMT) model to study the safety of retrovirus-mediated transfer of anti-HIV genes (RevM10 and HIV-1 pol antisense) into hematopoietic stem/progenitor cells (HSPCs). In particular, we have monitored the hematologic recovery post-BMT and transgene expression in myeloid and lymphoid lineages, and analyzed tissue sections for evidence of any transgene-related pathological condition. Expression of anti-HIV genes had no effect on kinetics of hematologic recovery post-BMT. The average time to reach 20% of normal cell counts was 15-17 days for white blood cells and 12-14 days for platelets, and the average time to reach complete recovery was 42-56 days for leukocytes and 104-161 days for platelets. Hematocrit levels were not significantly affected by irradiation and transplantation procedures. Donor chimerism was uniformlyor =90% in all transplanted animals. At 4-5 weeks post-BMT transgene expression was detected in peripheral blood leukocytes in 100% of the animals and ranged from 4.5 to 44.7%. In a majority of the animals the percentage of transgene-expressing cells in circulation decreased over time but remained detectable for the length of the study (6 months). Expression was detected in all analyzed cell lineages (RBCs, platelets, monocytes, granulocytes, and T and B cells). Relative counts of various leukocytes (Mac1+ monocytes, Gr1+ granulocytes, CD3+ T cells, and B220+ B cells) were normal. There were no treatment-related histopathological changes in a wide range of tissues examined. In addition, there were no treatment effects on differential leukocyte counts, and morphology of peripheral blood and bone marrow brush smears. In summary, transfer and expression of the RevM10 and the HIV-1 antisense genes into hematopoietic stem/progenitor cells in vivo appears safe. We propose that the mouse bone marrow transplantation model could be used to evaluate some safety aspects of HSPC-based gene therapies.

Class switch recombination (CSR) is a deletional DNA recombination occurring in IgM+IgD+ B cells and overwhelmingly recognized for thereby generating IgG, IgA, and IgE Abs with the same antigenic specificity but new effector functions. In an interesting and well documented paper, Stavnezer and

The aim of this paper is to present a high cycle multiaxial fatigue life prediction method for metallic materials based on Papadopoulos' previous works and limited to constant amplitude loading. The initiation process of a crack is treated as a mesoscopic phenomenon taking place on a scale of the order of a grain or a few grains. The damage variable chosen is the accumulated plastic strain at this mesoscopic scale. Its estimation requires a macro-meso passage and the location of the plane subjected to maximum damage. Initiation is achieved as soon as a critical value of the accumulated plastic mesostrain is reached in these grains, so-orientated that their easy glide directions coincide with a particular direction of the critical plane. The detrimental effect of out-of-phase loading on damage accumulation is taken into account through a newly defined coefficient estimated from mechanical loading parameters; no adjustable parameter is required. A good agreement has been found between the predicted and experimental results for in-phase and out-of-phase sinusoidal constant amplitude loadings by examining a large amount of experimental data.

Lymphocytes and dendritic cells (DCs) are critical for immune responses, yet how they develop from pluripotent hematopoietic stem cells is poorly defined. In humans and mice, it is possible to isolate phenotypically defined subsets of bone marrow (BM) cells that represent intermediate progenitors without long-term repopulating characteristics but with specific lineage differentiation properties. For instance, murine BM CD34+ CD45RA+ cells are progenitors for B and T lymphocytes with no in vivo repopulation activity. In human BM, a small subset (5%) of cells having the phenotype CD34+ Lin- CD10+ CD45RA+ CD38+ Thy-1- c-kit- represents a new class of hematopoietic progenitor cells that gives rise to lymphocytes [T, B, and natural killer (NK) cells] and to DCs but does not produce myeloid or erythroid cells. The identification of such progenitor cells provides the opportunity to define the differentiation and growth requirements for the production of lymphocytes and DCs. Genes involved in lineage specification can also be studied. Altogether, these studies have fundamental implications for understanding the biology of pivotal lineages of immune cells. This understanding could be used to treat a variety of immunodeficiencies and to design novel immunotherapies particularly in the context of hematopoietic cell transplantation.

The pathogenesis of inflammatory skin diseases such as psoriasis involves the release of numerous proinflammatory cytokines, including members of the IL-1 family. Here we report overexpression of IL-1α, IL-1β, and IL-1 receptor antagonist mRNA, associated to expression of IL-23p19, IL-17A, and IL-22 in skin cells, upon topical application of the TLR7 agonist imiquimod (IMQ) in C57BL/6J mice. IMQ-induced skin inflammation was partially reduced in mice deficient for both IL-1α/IL-1β or for IL-1 receptor type 1 (IL-1R1), but not in IL-1α- or IL-1β-deficient mice, demonstrating the redundant activity of IL-1α and IL-1β for skin inflammation. NLRP3 or apoptosis-associated Speck-like protein containing a Caspase recruitment domain-deficient mice had no significant reduction of skin inflammation in response to IMQ treatment, mainly due to the redundancy of IL-1α. However, IMQ-induced skin inflammation was abolished in the absence of MyD88, the adaptor protein shared by IL-1R and TLR signaling pathways. These results are consistent with the TLR7 dependence of IMQ-induced skin inflammation. Thus, IL-1R1 contributes to the IMQ-induced skin inflammation, and disruption of MyD88 signaling completely abrogates this response.

Hypertensive leg ulcer (HLU) is an inflammatory disease characterized by intense pain, alteration of vascularization, and skin necrosis. The optimal treatment relies on surgical removal of necrotic tissues covered by a split-skin graft. We studied the histomorphology of the lesions and investigated the involvement of inflammatory cells and cytokines to further define the physiopathology of HLU. We report epidermis acanthosis and a preferential occlusion of the precapillary arterioles with infiltration of neutrophils, macrophages, and T lymphocytes in the dermis. OSM, IL-1β, and IL-6 were overexpressed in the ulcer, whereas the Th17-derived cytokines were not. In vitro , the addition of IL-1β and OSM promoted acanthosis and destructuring of reconstructed epidermis. Exogenous IL-1β and OSM synergistically induced epidermal acanthosis in mice. These data show that OSM and IL-1β are not only a biological characteristic signature of HLU, but these cytokines reflect a specific inflammatory state, directly involved in the pathogenesis. We suggest that anti-cytokine biotherapies could be an alternative strategy to surgery to treat HLU.

During forging and machining manufacturing processes, the material is subject to large strains at high strain rates which provoke local heating and microstructural changes. Modelling of these phenomena requires precise knowledge of the stress–strain constitutive equations for a large range of strains, strain rates and temperatures. An experimental study of the rheology of both hyper- and hypo-eutectoid steels (with different microstructures) over a temperature range from 20 °C to 1000 °C and with strain rates from 10 − 2 to 10 5 s − 1 has been undertaken. These tests were performed in compression on cylindrical specimens and in shear using hat-shaped specimens. Both a GLEEBLE 3500 thermomechanical testing machine and a Split-Hopkinson Pressure Bar apparatus were used. From these tests, three deformation domains have been identified as a function of the material behaviour and of the changes in the deformed microstructure. Each domain was characterized by its behaviour, including the competition between hardening and softening, strain rate sensitivity on the flow stress and the softening phenomenon (i.e. recrystallisation or recovery, etc.). Finally, based on thermodynamical considerations, the conditions of thermoplastic instability (i.e. shear bands, twinning, heterogeneities, etc.) and microstructural changes are highlighted using process maps of the dissipated power repartition.

Lien vers la version éditeur: http://www.sciencedirect.com/science/article/pii/S0142112312002472; International audience; This article is dedicated to the high cycle fatigue behaviour of cast hypo-eutectic Al-Si alloys and in particular the AlSi7Cu05Mg03 alloy. In a vast experimental campaign undertaken to investigate the fatigue damage mechanisms operating in this alloy, subject to complex loading conditions, it was shown that two different coexisting fatigue damage mechanisms occur in this materials, depending on the presence of different microstructural heterogeneities (i.e. micro-shrinkage pores, Si particles, Fe-rich intermetallic phases, DAS of the Al-matrix, etc.). In order to take into account both of these damage mechanisms, a probabilistic approach using the weakest link concept is introduced to model the competition between the two mechanisms. This approach leads naturally to a probabilistic Kitagawa type diagram, which explains the relationship between the fatigue behaviour of the material and the different casting processes or post-treatments (e.g. gravity casting and HIP). It is shown that the sensitivity to the different loading modes (i.e. uniaxial with and without mean stress, torsion and equibiaxial tension) depends on the microstructural heterogeneities responsible for crack initiation. For a porosity-free alloy, the predictions are very good for combined tension-torsion loading modes. When pores are present and control the fatigue strength, the predictions are very satisfactory for the uniaxial loads with different R-ratios and slightly conservative for multiaxial loads (i.e. torsion and equibiaxial tension). Never-the-less, they are much better than the predictions of the Dang Van criterion [1].

Lien vers la version éditeur: http://www.sciencedirect.com/science/article/pii/S0142112312002356; International audience; This article is dedicated to the high cycle fatigue behaviour of cast hypo-eutectic Al-Si alloys. In particular, the AlSi7Cu05Mg03 alloy is investigated. It presents the results of a vast experimental campaign undertaken to investigate the fatigue behaviour, and more specifically the fatigue damage mechanisms observed under complex loading conditions: plane bending with different load ratios, fully reversed torsion and equibiaxial bending with a load ratio of R = 0.1. A specific test set-up has been designed to create an equibiaxial stress state using disk shaped specimens. A tomographic analysis is also presented with the aim of characterising the micro-shrinkage pore population of the material. It is shown that two distinct and coexisting fatigue damage mechanisms occur in this material, depending on the presence of different microstructural heterogeneities (i.e. micro-shrinkage pores, Silicon particles in the eutectic zones, Fe-rich intermetallic phases, etc.). Furthermore, it is concluded that the effect of an equibiaxial tensile stress state is not detrimental in terms of high cycle fatigue. It is also shown that the Dang Van criterion is not able to simultaneously predict the multiaxial effect (i.e. torsion and equibiaxial tension) and the mean stress effect for this material.

The CD34 antigen is expressed on most, if not all, human hematopoietic stem cells (HSCs) and hematopoietic progenitor cells, and its use for the enrichment of HSCs with repopulating potential is well established. However, despite homology between human and murine CD34, its expression on subsets of primitive murine hematopoietic cells has not been examined in full detail. To address this issue, we used a novel monoclonal antibody against murine CD34 (RAM34) to fractionate bone marrow (BM) cells that were then assayed in vitro and in vivo with respect to differing functional properties. A total of 4% to 17% of murine BM cells expressed CD34 at intermediate to high levels, representing a marked improvement over the resolution obtained with previously described polyclonal anti-CD34 antibodies. Sixty percent of CD34+ BM cells lacked lineage (Lin) markers expressed on mature lymphoid or myeloid cells. Eighty-five percent of Sca-1+Thy-1(10)Lin- /10 cells that are highly enriched in HSCs expressed intermediate, but not high, levels of CD34 antigen. The remainder of these phenotypically defined stem cells were CD34-. In vitro colony-forming cells, day-8 and -12 spleen colony-forming units (CFU-S), primitive progenitors able to differentiate into B lymphocytes in vitro or into T lymphocytes in SCID mice, and stem cells with radioprotective and competitive long-term repopulating activity were all markedly enriched in the CD34+ fraction after single-parameter cell sorting. In contrast, CD34-BM cells were depleted of such activities at the cell doses tested and were capable of only short-term B-cell production in vitro. The results indicate that a significant proportion of murine HSCs and multilineage progenitor cells express detectable levels of CD34, and that the RAM34 monoclonal antibody is a useful tool to subset primitive murine hematopoietic cells. These findings should facilitate more direct comparisons of the biology of CD34+ murine and human stem and progenitor cells.

Introduction Les carcinomes epidermoides cutanes (CEC) sont les cancers de la peau les plus frequents, leur physiopathologie reste mal connue et ils repondent peu aux traitements chimiotherapeutiques classiques. Pendant le developpement tumoral, une reponse inflammatoire s’installe et un dialogue s’etablit entre les cellules immunitaires et les cellules tumorales par le biais de la secretion de facteurs solubles tels que les cytokines. Ainsi, la presence d’interleukine (IL)-12 et d’interferon γ (IFNγ) est associee a une reponse antitumorale (type 1) alors que la production d’IL-4 est associee a une reponse pro-tumorale (type 2). La modification de cet equilibre cytokinique peut donc contribuer au developpement ou a la suppression de la tumeur. Le LITEC etudie le role des cytokines dans les maladies inflammatoires cutanees (psoriasis, cicatrisation pathologique). Nos travaux montrent que l’oncostatine M (OSM) module la proliferation, la migration et la differenciation des keratinocytes normaux en culture et entraine une hyperplasie epidermique chez la souris. Ainsi, nous faisons l’hypothese que l’OSM pourrait egalement agir sur les keratinocytes tumoraux et etre impliquee dans le developpement des CEC. Materiel et methodes Une etude ex vivo a permis d’etablir les profils cytokiniques de CEC humains par RT-qPCR en etudiant l’expression des cytokines du micro-environnement tumoral. Une etude in vitro a permis de caracteriser les effets de l’OSM sur les keratinocytes murins transformes de la lignee PDVC57. Enfin, nous avons etudie les profils cytokiniques de CEC murins in vivo obtenus apres injection sous-cutanee des cellules PDVC57. Resultats L’OSM, l’IL-6 et l’IL-1β sont surexprimees dans les CEC humains, temoins d’un environnement pro-inflammatoire. L’expression des marqueurs de type 1, comme l’IL-12 et l’IFNγ, est aussi augmentee. In vitro, l’OSM exerce un effet direct sur les keratinocytes tumoraux PDVC57 en entrainant la phosphorylation des proteines ERK et STAT3. Elle induit leur migration, leur proliferation et augmente l’expression de genes codant des marqueurs associes a la proliferation cellulaire comme la cytokeratine 6. Enfin, nous avons mis en place un modele murin de CEC et montre une surexpression d’OSM, d’IL-6 et d’IL-1β dans ces tumeurs, comme observe chez l’Homme. L’expression des cytokines de type 1 comme l’IFNγ et de type 2 comme l’IL-4 est aussi augmentee. Discussion Nos resultats suggerent que l’OSM jouerait un role direct sur les CEC, ce qui est en accord avec les etudes montrant l’implication de l’OSM dans le developpement du cancer du sein ou de l’endometre. Conclusion Pour confirmer le role de l’OSM, nous souhaitons analyser le developpement de ces CEC chez des souris dont le gene codant pour l’OSM a ete invalide. A terme, connaissant l’efficacite des therapies anti-cytokines dans le traitement des pathologies inflammatoires, nous esperons pouvoir utiliser ces memes approches pour le traitement des CEC.

The skin represents the first line defense against various stresses including pathogens and injuries. Cutaneous homeostasis and defenses are maintained by permanent cross talk among dermal fibroblasts, keratinocytes, and cells of the immune system residing in or recruited to skin, through the production of cytokines and chemokines. In this chapter, we discuss the biological effects of IL-22 on keratinocytes and more particularly its position in skin inflammation and in the development of inflammatory skin diseases such as psoriasis.

The objective of this work is to propose an anisotropic fatigue criterion for the sizing of industrial forged components. The results from different experimental campaigns using three different rolled steels are first presented. The effect of inclusions and the microstructure on the fatigue behaviour are investigated. For the two ferrite-pearlitic steels tested, the presence of a microstructure consisting of elongated grains has no observable effects on the fatigue behaviour. For two of the three steels studied the presence of non-metallic inclusions, elongated in the rolling direction, form the origin of the anisotropic fatigue behaviour. The proposed probabilistic model is based on the competition between two possible fatigue crack initiation mechanisms. The anisotropic character of the fatigue resistance of forged components is taken into account by the definition of the geometry and the orientation of the non-metallic inclusion. This criterion results in the establishment of a probabilistic Kitagawa type diagram. This work was undertaken with the framework of the Optiforge project which was supported by the French “Agence National de la Recherche”. These results are the product of cooperation between industry partners (Ascoforge, Ascometal, Cetim, PSA, Setforge and Transvalor) and academic partners (INSA Lyon-MATEIS, ENSMP-CEMEF, Arts et Métiers PARISTECH Angers-LAMPA).

Severe burns in children are conventionally treated with split-thickness skin autografts or epidermal sheets. However, neither early complete healing nor quality of epithelialization is satisfactory. An alternative approach is to graft isolated keratinocytes. We evaluated paediatric foreskin and auricular skin as donor sources, autologous keratinocyte transplantation, and compared the graft efficiency to the in vitro capacities of isolated keratinocytes to divide and reconstitute epidermal tissue. Keratinocytes were isolated from surgical samples by enzymatic digestion. Living cell recovery, in vitro proliferation and epidermal reconstruction capacities were evaluated. Differentiation status was analysed, using qRT-PCR and immunolabelling. Eleven children were grafted with foreskin-derived (boys) or auricular (girls) keratinocyte suspensions dripped onto deep severe burns. The aesthetic and functional quality of epithelialization was monitored in a standardized way. Foreskin keratinocyte graft in male children provides for the re-epithelialization of partial deep severe burns and accelerates wound healing, thus allowing successful wound closure, and improves the quality of scars. In accordance, in vitro studies have revealed a high yield of living keratinocyte recovery from foreskin and their potential in terms of regeneration and differentiation. We report a successful method for grafting paediatric males presenting large severe burns through direct spreading of autologous foreskin keratinocytes. This alternative method is easy to implement, improves the quality of skin and minimizes associated donor site morbidity. In vitro studies have highlighted the potential of foreskin tissue for graft applications and could help in tissue selection with the prospect of grafting burns for girls.

Cutaneous homeostasis and defenses are maintained by permanent cross-talk among particular epidermal keratinocytes and immune cells residing or recruited in the skin, through the production of cytokines. If required, a coordinated inflammatory response is triggered, relayed by specific cytokines. Due to numerous reasons, troubles in the resolution of this phenomenon could generate a cytokine-mediated vicious circle, promoting skin chronic inflammation, the most common being atopic dermatitis and psoriasis. In this paper, we discuss the biological effects of cytokine on keratinocytes, more particularly on specific or shared cytokines involved in atopic dermatitis or psoriasis. We report and discuss monolayer or 3D in vitro models of keratinocytes stimulated by specific sets of cytokines to mimic atopic dermatitis or psoriasis. IL-22, TNFa, IL-4, and IL-13 combination is able to mimic an “atopic dermatitis like” state. In psoriasis lesions, over expression of IL-17 is observed whereas IL-4 and IL-13 were not detected; the replacement of IL-4 and IL-13 by IL-17 from this mix is able to mimic in vitro a “psoriasis like” status on keratinocytes. We conclude that specific cytokine environment deregulation plays a central role on skin morphology and innate immunity, moving towards specific pathologies and opening the way to new therapeutic strategies.

An analysis of high cycle multiaxial fatigue behaviour is conducted through the numerical simulation of polycrystalline aggregates using the finite element method. The metallic material chosen for investigation is pure copper, which has a Face Centred Cubic (FCC) crystalline microstructure. The elementary volumes are modelled in 2D using an hypothesis of generalised plane strain and consist of 300 equi-probability, randomly oriented grains with equiaxed geometry. The aggregates are loaded at levels equivalent to the average macroscopic fatigue strength at 10 7 cycles. The goal is to compute the mechanical quantities at the mesoscopic scale (i.e., average within the grain) after stabilization of the local cyclic behaviour. The results show that the mesoscopic mechanical variables are characterised by high dispersion. A statistical analysis of the response of the aggregates is undertaken for different loading modes: fully reversed tensile loads, torsion and combined in-phase tension–torsion. Via the calculation of the local mechanical quantities for a sufficiently large number of different microstructures, a critical analysis of certain multiaxial endurance criteria (Crossland, Dang Van and Matake) is conducted. In terms of material behaviour models, it is shown that elastic anisotropy strongly affects the scatter of the mechanical parameters used in the different criteria and that its role is predominant compared to that of crystal plasticity. The analysis of multiaxial endurance criteria at both the macroscopic and mesoscopic scales clearly show that the critical plane type criteria (Dang Van and Matake) give an adequate estimation of the shear stress but badly reflect the scatter of the normal stress or the hydrostatic stress.

Acanthamoeba castellanii is a free-living amoebae commonly found in water systems. Free-living amoebae might be pathogenic but are also known to bear phagocytosis-resistant bacteria, protecting these bacteria from water treatments. The mode of action of these treatments is poorly understood, particularly on amoebae. It is important to examine the action of these treatments on amoebae in order to improve them. The cellular response to chlorine, chlorine dioxide, and monochloramine was tested on A. castellanii trophozoites. Doses of disinfectants leading to up to a 3-log reduction were compared by flow cytometry and electron microscopy. Chlorine treatment led to size reduction, permeabilization, and retraction of pseudopods. In addition, treatment with chlorine dioxide led to a vacuolization of the cytoplasm. Monochloramine had a dose-dependent effect. At the highest doses monochloramine treatment resulted in almost no changes in cell size and permeability, as shown by flow cytometry, but the cell surface became smooth and dense, as seen by electron microscopy. We show that these disinfectants globally induced size reduction, membrane permeabilization, and morphological modifications but that they have a different mode of action on A. castellanii .

Une analyse du comportement en fatigue multiaxiale a grand nombre de cycles est conduite a travers la simulation numerique d’agregats polycristallins. Le materiau metallique choisi est un cuivre de microstructure CFC. Le VER, constitue d’un ensemble de 300 grains d’orientation aleatoire equiprobable et de geometrie equiaxe, est sollicite au niveau de la limite de fatigue definie pour un nombre de cycles de 107 cycles, le but etant de calculer les quantites mecaniques relatives a l’echelle mesoscopique (moyenne a l’echelle du grain) apres stabilisation du comportement cyclique local. Les resultats de la simulation montrent la grande dispersion des variables mecaniques a cette echelle mesoscopique. Une analyse statistique de la reponse de l’agregat est proposee pour differents chargements purement alternes : traction, torsion, traction-torsion combinees en-phase. Grâce a la connaissance des quantites mecaniques locales pour un nombre suffisamment grand de microstructures differentes, une analyse critique de certains criteres d’endurance multiaxiaux (Crossland et Dang Van) est conduite.

International audience; Most of crustacean immune responses are well described for the aquatic forms whereas almost nothing is known for the isopods that evolved a terrestrial lifestyle. The latter are also infected at a high prevalence with Wolbachia, an endosymbiotic bacterium which affects the host immune system, possibly to improve its transmission. In contrast with insect models, the isopod Armadillidium vulgare is known to harbor Wolbachia inside the haemocytes. Methodology/Principal Findings A. vulgare we characterized three haemocyte types (TEM, flow cytometry): the hyaline and semi-granular haemocytes were phagocytes, while semi-granular and granular haemocytes performed encapsulation. They were produced in the haematopoietic organs, from central stem cells, maturing as they moved toward the edge (TEM). In infected individuals, live Wolbachia (FISH) colonized 38% of the haemocytes but with low, variable densities (6.45±0.46 Wolbachia on average). So far they were not found in hyaline haemocytes (TEM). The haematopoietic organs contained 7.6±0.7×10Wolbachia, both in stem cells and differentiating cells (FISH). While infected and uninfected one-year-old individuals had the same haemocyte density, in infected animals the proportion of granular haemocytes in particular decreased by one third (flow cytometry, Pearson's test = 12 822.98,  = 2

International audience; Fatigue phenomena, which appear generally below the yield stress, is the cause of more than 80 % of in-service mechanical failures. However, the optimization of the weight and cost when designing mechanical components or structures, linked to improved performance, leads to increasingly stressed components. Therefore a fatigue design approach must be done by the engineer. This paper shows the experience gained over five academic years of teaching fatigue the assessment of automotive components using a reliability approach to predict probability of failure, in the engineering school, Arts et Métiers ParisTech, in France. The choice was made to present a comprehensive fatigue assessment approach using a method, initially developed in the automotive industry and since extended to the aeronautical and mechanical industries. This method is known as the "Stress-Strength interference analysis". The "Stress" represents the distribution of the driver severity, and the "Strength" represents the distribution of the fatigue strength of all the components. A suspension arm is used to illustrate the approach. The Dang Van multiaxial fatigue criterion is implemented in a Finite Elements Code and a danger coefficient is visualized on the meshed structure. The fatigue analysis is interpreted with respect to the target reliability sought by the car- manufacturer.

International audience; L'objectif de cette étude est de proposer un critère de fatigue anisotrope pour le dimensionnement en fatigue de pièces industrielles forgées. Des résultats de différentes campagnes d'essais obtenus sur 3 nuances d'acier laminés sont tout d'abord présentés. Une attention particulière est portée à l'observation et à l'analyse des mécanismes d'amorçage à l'origine du comportement anisotrope en fatigue. Un critère de fatigue probabiliste permettant de tenir compte de la compétition possible entre différents types de mécanismes d'amorçage est ensuite développé. Ce critère permet notamment de tracer un diagramme de type Kitagawa probabiliste.

(IF : 2,984); International audience; Objective. The effects of statins (3-hydroxy-3-methylglutaryl coenzyme A reductase-HMGR-inhibitors) on the inflammatory response remain unclear. HMGR is implicated in the mevalonate pathway, directly upstream of cholesterol biosynthesis. We studied the impairment by this pathway of cytokine production by peripheral blood mononuclear cells (PBMCs) and THP-1 cells. The aim was to identify a specific cytokine "signature" of cells under simvastatin treatment in order to link pharmacological inhibition of the mevalonate pathway and inflammation. Methods. Normal human PBMCs and THP-1 cells were cultured with inhibitors of HMGR (simvastatin), geranylgeranyltransferase (GGTI-298), farnesyltransferase (FTI-277), and/or caspase-1 (Z-VAD(Ome)-FMK). Following culture, cytokine production, caspase-1 activity, IL-1beta mRNA and Rac-1 activity were determined. Results. Pharmacological inhibition of the mevalonate pathway specifically enhanced the release of IL-1alpha, IL-1beta and IL-18 and inhibited IL-1ra production by LPS-activated PBMCs and THP-1 cells. Simvastatin did not modify pro-IL-1beta expression, but enhanced caspase-1 activity, the enzyme responsible for IL-1beta and IL-18 maturation. GGTI-298 also enhanced IL-1-family cytokine production, showing that geranylgeranylation is involved in caspase-1 activation. Additionally, simvastatin enhanced Rac-1 activity. Conclusion. Pharmacological inhibition of the mevalonate pathway by statins highlighted the specific induction of the proinflammatory cytokines of the IL-1 family whose maturation is either directly (i.e. IL-1beta and IL-18), or indirectly (i.e. IL-1alpha) dependant on caspase-1.

Lien vers la version éditeur: http://www.sciencedirect.com/science/article/pii/S0142112308002156; International audience; This paper attempts to improve the understanding of the multiaxial high cycle fatigue response of micro sized stress concentrations or notches of different geometries. The investigation is composed of an experimental part and a numerical part. In the former, three types of micro-notches or "artificial defects" are compared: spherical, elliptical and circumferential. All types have the same basic dimensions, the difference being the 3D geometry. The notches were machined on the surface of smooth cylindrical specimens made of mild steel. The fatigue limits under reversed tension (push-pull) and reversed torsional loading conditions for different micro-notch sizes have been experimentally determined. In the numerical part, finite elements simulations using a cyclic elasto-plastic material behaviour law show that the mechanical state ahead of the different stress concentrations change drastically with the loading mode and the geometry of the artificial defect. From a fatigue point of view, it is shown that a stress gradient correction is required for all the loading, size and geometry configurations. Once the gradient correction is made and a proper multiaxial criterion is used, it appears that the size effect due to increasing the loaded surface area at the notch tip for the different geometries is negligible compared to the gradient effect.

Summary Interleukin (IL)-22 is a T cell-derived cytokine that has been reported recently to induce cutaneous inflammation in an experimental murine model of psoriasis, and to induce in vitro an inflammatory-like phenotype. In the present study, we assessed the presence of IL-22 and the IL-22 receptor 1 (IL-22R1) in skin lesions, skin-derived T cells, as well as IL-22 levels in sera from patients with psoriasis. IL-22R1 and IL-10R2 transcripts are expressed at a similar level in psoriatic and healthy skin. In contrast, IL-22 mRNA expression was up-regulated in psoriatic skin lesions compared to normal skin, whereas IL-22 mRNA levels in peripheral blood mononuclear cells from psoriatic patients and normal subjects were similar. Circulating IL-22 levels were significantly higher in psoriatic patients than in normal subjects. T cells isolated from psoriatic skin produced higher levels of IL-22 in comparison to peripheral T cells isolated from the same patients. IL-10 was expressed at similar levels in skin biopsies and peripheral blood mononuclear cells of psoriatic patients and normal subjects. Finally, we show here that supernatants of lesional psoriatic skin-infiltrating T cells induce an inflammatory response by normal human epidermal keratinocytes, resembling that observed in psoriatic lesions. Taken together, the results reported in this study indicate that IL-22 is a cytokine produced by skin-infiltrating lymphocytes that is potentially involved in initiation and/or maintenance of the pathogenesis of psoriasis.

The multiaxial fatigue loading in the high-cycle regime leads to localized mesoscopic plastic strain that occurs in some preferential directions of individual grains for most metallic materials. Crack initiation modeling is difficult in this fatigue regime because the scale where the mechanisms operate is not the engineering scale (macroscopic scale), and local plasticity and damage act simultaneously. This article describes a damage model based on the interaction between mesoplasticity and local damage for the infinite and the finite fatigue life regimes. Several salient effects are accounted for via a simple localization rule, which connects the macroscopic scale with the mesoscopic one, and by the model presented here, which describes the coupled effects of mesoplasticity and damage growth. Irreversible thermodynamics concepts with internal state variables are used to maintain a balance between extensive descriptions of plastic flow and damage events. Cyclic hardening behavior is described by a combined isotropic and kinematic hardening rule while the damage evolution is governed notably by the accumulated plastic mesoscopic strain. In this study, predictions are compared to fatigue tests performed on a mild steel (C36) under different loading modes. All the experiments are carried out under in-phase loading conditions: reversed tension, torsion, and combined tension—torsion. The mean stress effect is also studied through tests conducted under tension. The predicted Wöhler curves under any loading mode can be readily obtained with this model, but the main feature of this approach is to ensure a clear link between the mesoscopic parameters like the hardening behavior of individual grains and the subsequent local damage.

(IF : 15,664); International audience; Damage to the adult motor cortex leads to severe and frequently irreversible deficits in motor function. Transplantation of embryonic cortical neurons into the damaged adult motor cortex was previously shown to induce partial recovery, but reports on graft efferents have varied from no efferent projections to sparse innervation. Here, we grafted embryonic cortical tissue from transgenic mice overexpressing a green fluorescent protein into the damaged motor cortex of adult mice. Grafted neurons developed efferent projections to appropriate cortical and subcortical host targets, including the thalamus and spinal cord. These projections were not a result of cell fusion between the transplant and the host neurons. Host and transplanted neurons formed synaptic contacts and numerous graft efferents were myelinated. These findings demonstrate that there is substantial anatomical reestablishment of cortical circuitry following embryonic cortex grafting into the adult brain. They suggest that there is an unsuspected potential for neural cell transplantation to promote reconstruction after brain injury.

Cutaneous inflammatory diseases such as psoriasis vulgaris and atopic dermatitis are associated with altered keratinocyte function, as well as with a particular cytokine production profile of skin-infiltrating T lymphocytes. In this study we show that normal human epidermal keratinocytes express a functional type II oncostatin-M (OSM) receptor (OSMR) consisting of the gp130 and OSMRβ components, but not the type I OSMR. The type II OSMR is expressed in skin lesions from both psoriatic patients and those with atopic dermatitis. Its ligand, OSM, induces via the recruitment of the STAT3 and MAP kinase pathways a gene expression profile in primary keratinocytes and in a reconstituted epidermis that is characteristic of proinflammatory and innate immune responses. Moreover, OSM is a potent stimulator of keratinocyte migration in vitro and increases the thickness of a reconstituted epidermis. OSM transcripts are enhanced in both psoriatic and atopic dermatitic skin as compared with healthy skin and mirror the enhanced production of OSM by T cells isolated from diseased lesions. Results from a microarray analysis comparing the gene-modulating effects of OSM with those of 33 different cytokines indicate that OSM is a potent keratinocyte activator similar to TNF-α, IL-1, IL-17, and IL-22 and that it acts in synergy with the latter cytokines in the induction of S100A7 and β-defensin 2 expression, characteristic of psoriatic skin. Taken together, these results demonstrate that OSM and its receptor play an important role in cutaneous inflammatory responses in general and that the specific effects of OSM are associated with distinct inflammatory diseases depending on the cytokine environment.