Supernatant from Bifidobacterium Differentially Modulates Transduction Signaling Pathways for Biological Functions of Human Dendritic Cells

International audienceBACKGROUND:Probiotic bacteria have been shown to modulate immune responses and could have therapeutic effects in allergic and inflammatory disorders. However, the signaling pathways engaged by probiotics are poorly understood. We have previously reported that a fermentation product from Bifidobacterium breve C50 (BbC50sn) could induce maturation, high IL-10 production and prolonged survival of DCs via a TLR2 pathway. We therefore studied the roles of mitogen-activated protein kinases (MAPK), glycogen synthase kinase-3 (GSK3) and phosphatidylinositol 3-kinase (PI3K) pathways on biological functions of human monocyte-derived DCs treated with BbC50sn.METHODOLOGY/PRINCIPAL FINDINGS:DCs were differentiated from human monocytes with IL-4 and GM-CSF for 5 days and cultured with BbC50sn, lipopolysaccharide (LPS) or Zymosan, with or without specific inhibitors of p38MAPK (SB203580), ERK (PD98059), PI3K (LY294002) and GSK3 (SB216763). We found that 1) the PI3K pathway was positively involved in the prolonged DC survival induced by BbC50sn, LPS and Zymosan in contrast to p38MAPK and GSK3 which negatively regulated DC survival; 2) p38MAPK and PI3K were positively involved in DC maturation, in contrast to ERK and GSK3 which negatively regulated DC maturation; 3) ERK and PI3K were positively involved in DC-IL-10 production, in contrast to GSK3 that was positively involved in DC-IL-12 production whereas p38MAPK was positively involved in both; 4) BbC50sn induced a PI3K/Akt phosphorylation similar to Zymosan and a p38MAPK phosphorylation similar to LPS.CONCLUSION/SIGNIFICANCE:We report for the first time that a fermentation product of a bifidobacteria can differentially activate MAPK, GSK3 and PI3K in order to modulate DC biological functions. These results give new insights on the fine-tuned balance between the maintenance of normal mucosal homeostasis to commensal and probiotic bacteria and the specific inflammatory immune responses to pathogen bacteria

Paradox-Breaking RAF Inhibitors that Also Target SRC Are Effective in Drug-Resistant BRAF Mutant Melanoma

SummaryBRAF and MEK inhibitors are effective in BRAF mutant melanoma, but most patients eventually relapse with acquired resistance, and others present intrinsic resistance to these drugs. Resistance is often mediated by pathway reactivation through receptor tyrosine kinase (RTK)/SRC-family kinase (SFK) signaling or mutant NRAS, which drive paradoxical reactivation of the pathway. We describe pan-RAF inhibitors (CCT196969, CCT241161) that also inhibit SFKs. These compounds do not drive paradoxical pathway activation and inhibit MEK/ERK in BRAF and NRAS mutant melanoma. They inhibit melanoma cells and patient-derived xenografts that are resistant to BRAF and BRAF/MEK inhibitors. Thus, paradox-breaking pan-RAF inhibitors that also inhibit SFKs could provide first-line treatment for BRAF and NRAS mutant melanomas and second-line treatment for patients who develop resistance

La prise en charge de l'hypertension artérielle dans la population âgée de ville

PARIS-BIUP (751062107) / SudocSudocFranceF

Cellular interactions during tracheary elements formation and function

The survival of higher plant species on land depends on the development and function of an efficient vascular system distributing water and minerals absorbed by roots to all aerial organs. This conduction and distribution of plant sap relies on specialized cells named tracheary elements (TEs). In contrast to many other cell types in plants, TEs are functionalized by cell death that hollows the cell protoplast to make way for the sap. To maintain a stable conducting function during plant development, recovery from vascular damages as well as to adapt to environmental changes, TEs are completely dependent on direct cellular interactions with neighboring xylem parenchyma cells (XPs)

Cellular interactions during tracheary elements formation and function

The survival of higher plant species on land depends on the development and function of an efficient vascular system distributing water and minerals absorbed by roots to all aerial organs. This conduction and distribution of plant sap relies on specialized cells named tracheary elements (TEs). In contrast to many other cell types in plants, TEs are functionalized by cell death that hollows the cell protoplast to make way for the sap. To maintain a stable conducting function during plant development, recovery from vascular damages as well as to adapt to environmental changes, TEs are completely dependent on direct cellular interactions with neighboring xylem parenchyma cells (XPs)

Approches synthétiques d un métabolite de caroténoïdes, isolé de l algue Skeletonema Costatum, actif sur les tumeurs solides

La thérapeutique anticancéreuse est toujours en quête de nouvelles molécules sélectives et efficaces. Le milieu naturel en est le principal réservoir et son exploitation remonte à des temps anciens. L exploration du milieu marin est quant à elle plus récente. Son potentiel est très vaste et de nombreux médicaments d origine marine sont aujourd hui commercialisés. A ce titre, une molécule issue de la dégradation de caroténoïdes a été isolée par l IFREMER d une algue marine : Skeletonema Costatum. Son potentiel cytotoxique en fait une cible très intéressante notamment dans la lutte contre certains cancers. Le premier des objectifs de ce travail a été de synthétiser cette molécule en quantité importante, puisqu en effet 3 m3 de culture sont nécessaires à l extraction de seulement 20 mg de produit. Dans un second temps, une étude stéréochimique devra nous permettre de déterminer exactement la configuration relative de la molécule cible, celle-ci étant à ce jour inconnue, et ainsi permettre la réalisation de nouveaux tests biologiques. La synthèse totale passe tout d abord par un intermédiaire clé : le 4-hydroxy-2,2-diméthyl-6-méthylènecyclohexanecarbaldéhyde obtenu sous forme d éther silylé après 10 étapes et un rendement global de 7 %. Une fonctionnalisation ultérieure de cet intermédiaire est nécessaire pour obtenir la molécule désirée d une part au niveau de l aldéhyde et d autre part au niveau de l insaturation exocyclique. L introduction de la chaîne latérale pour conduire à l enchaînement -dicétone a été envisagée de diverses manières en passant par plusieurs intermédiaires. Les essais de fonctionnalisation de l aldéhyde par la réaction d aldolisation en milieu basique ou de type Mukaiyama par utilisation de différents acides de Lewis ont échoués. La formation de composés inattendus comme des dérivés furaniques ont été obtenus en hydratant la fonction alcyne terminale d un intermédiaire hydroxyacétylénique. Seuls les intermédiaires cétosulfoniques et -oxy- -diazocarbonylés, issus respectivement de la condensation de l anion du phénylsulfinylpropanone et de la diazoacétone ont permis l accès à la -dicétone. L introduction d un alcool tertiaire au niveau de l alcène exocyclique a été testée sur différents synthons provenant de la modification fonctionnelle de l aldéhyde intermédiaire. Cette étape, nécessairement antérieure à l introduction de la chaîne latérale, a réussi par époxydation suivie de l ouverture par LiAlH4 de l époxyde formé. La non sélectivité de la réaction d époxydation a conduit à quatre diastéréoisomères qui ont pu être séparés dans la suite de la synthèse et conduire pour deux d entre eux, après aménagement fonctionnel à deux stéréoisomères de la cible finale. Les analyses stéréochimiques de chacun de ces diastéréomères nous ont ainsi permis de déterminer la configuration de l une des molécules isolées. Des tests biologiques permettront par la suite d attribuer à chacune de ces molécules une activité propre en vue d une application biomédicale.New selective and effective molecules are essential in cancer chemotherapeutic. Nature is the first source and its exploration began a long time ago. Potential of the marine s world is large and nowadays, lot of drugs which comes from ocean are used. So, a new molecule which comes from carotenoid metabolite degradation was isolated by IFREMER from seaweed Skeletonema Costatum. Its potent cytotoxicity is attractive in cancer fighting. We have first to synthesize this molecule in large scale in order to carry out new biological tests. Indeed, 3 m3 of seaweeds give only 20 mg of product. In a second time, stereochemistry study has to determine the unknown relative configuration. The 4-(tert-butyl-diméthylsilanyloxy)-2,2-dimethyl-6-methylene-cyclohexanecarbal-dehyde intermediate was obtained in a 7% yields over 10 steps. Next, functionalisation of the aldehyde and of the exocyclic alkene is necessary to obtain the desired molecule. Direct and indirect introduction of the -dicarbonyl chain have been studied starting from the available aldehyde. The first way based on aldolisation catalysed by Lewis acid or in basic conditions has failed. Indirect functionalisation of acetylenics via hydration of propargylic alcohol or ketone led to unexpected aldehydic or furanic compounds. Only anionic condensation of diazoacetone or 1-phenylsulfonylpropanone leads us to 1,3-diketone. Next, investigations about tertiary alcohol introduction on different functionalized aldehydes have been studied by acid hydration and oxymercuration-demercuration but were unsuccessful. This introduction had to be done before 1,3-diketone s one, in the reduce form of the key aldehyde intermediate. So, only non stereoselective epoxidation led us to four diastereomers after reduction of the epoxyde group by LiAlH4. Finally, two diastereomers among four of the final molecule have been isolated after functionalisation. Biological tests could credit on these molecules own activity for biomedical applies.LE MANS-BU Sciences (721812109) / SudocSudocFranceF

Introduction d'une technique de trachéotomie percutanée dans un département d'anesthésie réanimation

ANGERS-BU Médecine-Pharmacie (490072105) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Different combinations of laccase paralogs nonredundantly control the amount and composition of lignin in specific cell types and cell wall layers in Arabidopsis

Vascular plants reinforce the cell walls of the different xylem cell types with lignin phenolic polymers. Distinct lignin chemistries differ between each cell wall layer and each cell type to support their specific functions. Yet the mechanisms controlling the tight spatial localization of specific lignin chemistries remain unclear. Current hypotheses focus on control by monomer biosynthesis and/or export, while cell wall polymerization is viewed as random and nonlimiting. Here, we show that combinations of multiple individual laccases (LACs) are nonredundantly and specifically required to set the lignin chemistry in different cell types and their distinct cell wall layers. We dissected the roles of Arabidopsis thaliana LAC4, 5, 10, 12, and 17 by generating quadruple and quintuple loss-of-function mutants. Loss of these LACs in different combinations led to specific changes in lignin chemistry affecting both residue ring structures and/or aliphatic tails in specific cell types and cell wall layers. Moreover, we showed that LAC-mediated lignification has distinct functions in specific cell types, waterproofing fibers, and strengthening vessels. Altogether, we propose that the spatial control of lignin chemistry depends on different combinations of LACs with nonredundant activities immobilized in specific cell types and cell wall layers

A sound insulation prediction model for floor structures in wooden buildings using neural networks approach

Reliable prediction tools are yet to be developed for estimating the accurate acoustic performance of lightweight structures, which are vital especially in the design process. This paper presents a sound insulation prediction model based on artificial Neural Networks (NN) to estimate acoustic performance for airborne and impact sound insulation of floor structures. At an initial stage, the prediction model was developed and tested for a small amount of data, specifically 67 laboratory measurement curves in one third octave bands. The results indicate that the model can predict the weighted airborne reduction index Rw for various floors with a maximum error of 1 dB. The accuracy decreases with errors up to 9 dB for the weighted index for impact sound Ln,w, in cases of complex floor configurations due to large error deviations in high frequency bands between the real and estimated values. The model also shows a very good accuracy in predicting the airborne and impact sound insulation curves in the low frequencies, which are of higher interest usually in building acoustics

1-(5-tert-butyl-2-phenyl-2H-pyrazol-3-yl)-3-[2-fluoro-4-(1-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-B]pyridin-7-yloxy)-phenyl]-urea and related compounds and their use in therapy

The present invention pertains generally to the field of therapeutic compds., and more specifically to certain compds. of the following formula (I) (for convenience, collectively referred to herein as "IP compds.")​, which, inter alia, are useful in the treatment of cancer, e.g., cancer characterized by (e.g., driven by) mutant RAS ("mutant RAS cancer")​. The present invention also pertains to pharmaceutical compns. comprising such compds., and the use of such compds. and compns. in the treatment of cancer, e.g., mutant RAS cancer