Short and long crack growth behavior of welded ferritic stainless steel

International audienceTo analyze the influence of welding on fatigue crack growth, several geometrical configurations have been tested using notched specimens with notch located within base metal and welded joint. This methodology has shown that fatigue crack growth rate was similar for base metal and welded part for the ferritic stainless steel F18TNb (corresponding to AISI 441 or EN 1.4509 grades) considering long crack. Whereas for short crack, the microstructure induced by the welding process was evidenced to drastically increase the resulting crack growth rate. The tested configurations have been systematically modeled by finite element analysis to obtain reliable shape function and SIF assessment for the chosen geometries. Then fatigue crack growth behavior is discussed on the basis of both SIF values and the influence of microstructure in crack path and crack growth rate

Fissuration dans un joint soudé en alliages de titane sous sollicitation multiaxiale

National audienc

Influence of a 3D realistic crack path in the driving forces for fatigue crack growth under mode I+II loading

International audienceThe aim of this paper is to test the influence of different crack path models, from oversimplification currently used in literature of a straight crack front orthogonal to the specimen sides to a realistic 3D crack path. On the basis of experimental features observed for Ti17 and Ti6242 alloys under multiaxial loading, a sensitivity analysis is proposed to address the impact of realistic 3D crack path on SIF and FCGR assessment

Crack growth behavior in dissimilar welded Ti based alloys under biaxial fatigue loading

International audienceThis study aims at describing fatigue crack growth in dissimilar welding of Ti based alloys under macroscopic multiaxial loading. The proposed methodology involves the experimental analysis of fatigue crack behavior under equibiaxial tension and macroscopic combination of mode I and II for Ti17, Ti6242 and laser welded specimen of both base metals. Based on these experiments, crack path, fatigue crack growth rate and crack interaction with microstructure have been addressed. The 3D finite element analysis of cracks shapes has enabled to derive stress intensity factor (SIF) investigated for opening, in-plane and out-of-plane shear modes based on linear elastic fracture mechanics assumptions. Finally, an equivalent SIF has been proposed to take into account the local mode mixity induced by both macroscopic shear and 3D crack shape. As a conclusion, the dissimilar welding of Ti based alloys increase the fatigue crack growth rate (FCGR) for any macroscopic loading - with or without shear. Moreover, the microstructure of Ti6242 alloy, is well known to inhibit FCGR by multiples local bifurcation of crack path induced by the coarse microstructure of this alloy. This point was confirmed during equibiaxial tension but anomalous and very high FCGR was observed for macroscopic mode I + II loading. For the welded material, the fatigue crack to microstructure interactions have shown that the FCGR was clearly limited by coarse alpha needles inducing local bifurcation and conversely that in both fusion zone and heat-affected zone, local refinement of alpha needles could not slow down the crack propagation

Sol-gel and peptides: an attractive route to unprecedented biomaterials

International audienc

Sol-gel and peptides: an attractive route to unprecedented biomaterials

International audienc

The presence of PEG on nanoparticles presenting the c[RGDfK]- and/or ATWLPPR peptides deeply affects the RTKs-AKT-GSK3β-eNOS signaling pathway and endothelial cells survival

International audienceCovering the surface of a nanoparticle with polyethylene glycol (PEG) is a common way to prevent non-specific interactions but how its presence impacts on the activity of targeting ligands is still poorly documented. We synthesized a set of 9 silica nanoparticles grafted with c[RGDfK]-, a peptide targeting integrin αvß3 (cRGD), and/or with ATWLPPR, an anti-neuropilin 1 peptide (ATW). We then added various PEGs, and studied NPs binding on primary endothelial cells, the downstream activated signaling pathways and the impact on apoptosis. Our results show that the presence of PEG2000 on cRGD/ATW nanoparticles moderately improves cell binding but induces a 6000 times augmentation of AKT-dependent cell response due to the recruitment of other Receptor Tyrosine Kinases. Augmenting the length of the spacer that separates the peptides from the silica (using PEG3000) mainly resulted in a loss of specificity. Finally, the PEG-mediated hyperactivation of AKT did not protect endothelial cell from dying in the absence of serum, while its moderate activation obtained without PEG did. Finally, PEGylation of cRGD/ATW-NPs can generate nanoparticles with potent capacities to activate the AKT-GSK3β-eNOS cascade and to affect the resistance of endothelial cells to apoptosis. Thus, the impact of PEGylation should be precisely considered in order to avoid the apparition of counter-productive biological responses

Active Targeted Nanoemulsions for Repurposing of Tegaserod in Alzheimer’s Disease Treatment

International audienceBackground and Purpose: The activation of 5-HT4 receptors with agonists has emerged as a valuable therapeutic strategy to treat Alzheimer’s disease (AD) by enhancing the nonamyloidogenic pathway. Here, the potential therapeutic effects of tegaserod, an effective agent for irritable bowel syndrome, were assessed for AD treatment. To envisage its efficient repurposing, tegaserod-loaded nanoemulsions were developed and functionalized by a blood–brain barrier shuttle peptide.Results: The butyrylcholinesterase inhibitory activity of tegaserod and its neuroprotective cellular effects were highlighted, confirming the interest of this pleiotropic drug for AD treatment. In regard to its drugability profile, and in order to limit its peripheral distribution after IV administration, its encapsulation into monodisperse lipid nanoemulsions (Tg-NEs) of about 50 nm, and with neutral zeta potential characteristics, was performed. The stability of the formulation in stock conditions at 4 °C and in blood biomimetic medium was established. The adsorption on Tg-NEs of peptide-22 was realized. The functionalized NEs were characterized by chromatographic methods (SEC and C18/HPLC) and isothermal titration calorimetry, attesting the efficiency of the adsorption. From in vitro assays, these nanocarriers appeared suitable for enabling tegaserod controlled release without hemolytic properties.Conclusion: The developed peptide-22 functionalized Tg-NEs appear as a valuable tool to allow exploration of the repurposed tegaserod in AD treatment in further preclinical studies

S-Ethyl-Isothiocitrullin-Based Dipeptides and 1,2,4-Oxadiazole Pseudo-Dipeptides: Solid Phase Synthesis and Evaluation as NO Synthase Inhibitors

International audienceWe previously reported dipeptidomimetic compounds as inhibitors of neuronal and/or inducible NO synthases (n/iNOS) with significant selectivity against endothelial NOS (eNOS). They were composed of an S-ethylisothiocitrullin-like moiety linked to an extension through a peptide bond or a 1,2,4-oxadiazole link. Here, we developed two further series where the extension size was increased to establish more favorable interactions in the NOS substrate access channel. The extension was introduced on the solid phase by the reductive alkylation of an amino-piperidine moiety or an aminoethyl segment in the case of dipeptide-like and 1,2,4-oxadiazole compounds, respectively, with various benzaldehydes. Compared to the previous series, more potent inhibitors were identified with IC 50 in the micromolar to the submicromolar range, with significant selectivity toward nNOS. As expected, most compounds did not inhibit eNOS, and molecular modeling was carried out to characterize the reasons for the selectivity toward nNOS over eNOS. Spectral studies showed that compounds were interacting at the heme active site. Finally, selected inhibitors were found to inhibit intra-cellular iNOS and nNOS expressed in RAW264.7 and INS-1 cells, respectively

3D structures of the Plasmodium vivax subtilisin-like drug target SUB1 reveal conformational changes to accommodate a substrate-derived α-ketoamide inhibitor

International audienceThe constant selection and propagation of multi-resistant Plasmodium sp. parasites require the identification of new antimalarial candidates involved in as-yet untargeted metabolic pathways. Subtilisin-like protease 1 (SUB1) belongs to a new generation of drug targets because it plays a crucial role during egress of the parasite from infected host cells at different stages of its life cycle. SUB1 is characterized by an unusual pro-region that tightly interacts with its cognate catalytic domain, thus precluding 3D structural analysis of enzyme–inhibitor complexes. In the present study, to overcome this limitation, stringent ionic conditions and controlled proteolysis of recombinant full-length P. vivax SUB1 were used to obtain crystals of an active and stable catalytic domain (PvS1 Cat ) without a pro-region. High-resolution 3D structures of PvS1 Cat , alone and in complex with an α-ketoamide substrate-derived inhibitor (MAM-117), showed that, as expected, the catalytic serine of SUB1 formed a covalent bond with the α-keto group of the inhibitor. A network of hydrogen bonds and hydrophobic interactions stabilized the complex, including at the P1′ and P2′ positions of the inhibitor, although P′ residues are usually less important in defining the substrate specificity of subtilisins. Moreover, when associated with a substrate-derived peptidomimetic inhibitor, the catalytic groove of SUB1 underwent significant structural changes, particularly in its S4 pocket. These findings pave the way for future strategies for the design of optimized SUB1-specific inhibitors that may define a novel class of antimalarial candidates