Babesia divergens glycosylphosphatidylinositols modulate blood coagulation and induce Th2-biased cytokine profiles in antigen presenting cells

This work was supported by the the University of Tours (to IDP and FDG), the University of Montpellier (to SD and EC), the Deutsche Forschungsgemeinschaft (to RTS), the Wellcome Trust project grant 093228 (to TKS) and the Campus France/DAAD PHC PROCOPE 24931RE (to RTS and EC). The funding source has no involvement in the conduct of the research and preparation of the article.Glycosylphosphatidylinositols (GPIs) are glycolipids described as toxins of protozoan parasites due to their inflammatory properties in mammalian hosts characterized by the production of interleukin (IL)-1, IL-12 and tumor necrosis factor (TNF)-α. In the present work, we studied the cytokines produced by antigen presenting cells in response to ten different GPI species extracted from Babesia divergens, responsible for babesiosis. Interestingly, B. divergens GPIs induced the production of anti-inflammatory cytokines (IL-2, IL-5) and of the regulatory cytokine IL-10 by macrophages and dendritic cells. In contrast to all protozoan GPIs studied until now, GPIs from B. divergens did not stimulate the production of TNF-α and IL-12, leading to a unique Th1/Th2 profile. Analysis of the carbohydrate composition of the B. divergens GPIs indicated that the di-mannose structure was different from the evolutionary conserved tri-mannose structure, which might explain the particular cytokine profile they induce. Expression of major histocompatibility complex (MHC) molecules on dendritic cells and apoptosis of mouse peritoneal cells were also analysed. B. divergens GPIs did not change expression of MHC class I, but decreased expression of MHC class II at the cell surface, while GPIs slightly increased the percentages of apoptotic cells. During pathogenesis of babesiosis, the inflammation-coagulation auto-amplification loop can lead to thrombosis and the effect of GPIs on coagulation parameters was investigated. Incubation of B. divergens GPIs with rat plasma ex vivo led to increase of fibrinogen levels and to prolonged activated partial thromboplastin time, suggesting a direct modulation of the extrinsic coagulation pathway by GPIs.Publisher PDFPeer reviewe

Acetaldehyde on Pt(111) and Pt/Sn(111): A DFT Study of the Adsorption Structures and of the Vibrational Spectra

International audienc

Simulations moléculaires hybrides de lésions complexes oxydantes de l'ADN

L'ADN est en permanence exposé à un grand nombre d'événements dommageables déclenchées par des agents endogènes et exogènes. De nombreux travaux expérimentaux ont fourni des informations cruciales sur les propriétés structurelles et la réparation de certains des lésions de l'ADN. Cependant, il manque une vision mécanistique ou énergétique sur leur formation. La biochimie computationnelle a émergé comme un outil puissant pour comprendre les réactions biochimiques et les propriétés électroniques de systèmes complexes.Dans cette thèse, nous étudions la formation de lésions complexes intra-brin et inter-brin. Ces lésions tandem constituent une puissant menace à l'intégrité du génome, en raison de leur haute fréquence mutagenique. Tout d'abord, nous discutons l'attaque d'une liaison covalente entre un radical pyrimidinique. En comparant avec les bases isolees, nos simulations hybrides Car-Parrinello demontrent que la reactivité de la thymine et de la cytosine radicalaires sont inversees dans l'environnement B-helical. De plus, nos resultats montrent egalement une deformation plus importante pour la lesion G[8-5]C.Nous rationalisons également la plus grande réactivité des cytosines par rapport aux purines vers la formation multi-etapes de lésions complexes inter-brins par condensation avec un site C4' abasique. Ces résultats bases sur des simulations avec solvatation explicite et combines a la théorie de la fonctionnelle de la densité sont en accord avec les données expérimentales.DNA is continuously exposed to a vast number of damaging events triggered by endogenous and exogenous agents. Numerous experimental studies have provided key information regarding structural properties of some of the DNA lesions and their repair. However, they lack in mechanistic or energetic information pertaining to their formation. Computational Biochemistry has emerged as a powerful tool to understand biochemical reactions and electronic properties of large systems.In this thesis we study the formation of inter- and intra-strand cross-links. These tandem lesions pose a potent threat to genome integrity, because of their high mutagenic frequency. First, we discuss the formation of complex defects which arise from the attack of a pyrimidine radical onto guanine. In comparison with the reactivity of isolated nucleobases, our hybrid Car-Parrinello Molecular Dynamics simulations reveal that the reactivity of hydrogen-abstracted thymine and cytosine is reversed within a B-helix environment. Further, our data also suggest a more severe distortion of the B-helix for G[8-5]C.Second, we rationalize the higher reactivity of cytosine vs. purines toward the multistep formation of inter-strand crosslinks with a C4' oxidized a basic site, which is in qualitative agreement with experiments on isolated nucleobases, using explicit solvent simulations combined to density functional theory.LYON-ENS Sciences (693872304) / SudocSudocFranceF

Unravelling the Metastable Nature of the Single Site Tungsten Hydride Metathesis Catalyst Supported on γ-Alumina from First Principles

We explore the structure and formation mechanism of the surface tungsten hydride complex supported on alumina, which is a catalyst for alkane and alkene metathesis and cross-metathesis. We show that the kinetics for the formation reaction of the hydride from the grafted alkylidyne–alkyl W complex strongly favors the creation of a metastable WVI trihydride, which is less coordinated by the alumina surface than the most stable isomer. The reaction network for the hydride formation involves hydrogenation of the WC or WC bond, hydrogenolysis of W–C bonds, and a second grafting step. The creation of metastable surface complexes is proposed to be a key path for the design of active and selective catalysts

Theoretical elucidation of the selectivity changes for the hydrogenation of unsaturated aldehydes on Pt(111)

International audienceOn the basis of density functional theory calculations and an original use of a generalized Brönsted–Evans–Polanyi relationship, the key question of the change of selectivity has been solved for hydrogenation of three unsaturated aldehydes (acrolein, crotonaldehyde and prenal) on a Pt(1 1 1) surface. This study supports the idea that the selectivity in favor of the unsaturated alcohol (UOL) is controlled by adsorption thermodynamics of this partially hydrogenated product while the selectivity in favor of the other compound in competition (saturated aldehyde, SAL) obeys a more subtle kinetic control. The present work demonstrates the efficiency and the potentiality of the exposed correlation

Metal–support interaction effects on chemo–regioselectivity: Hydrogenation of crotonaldehyde on Pt 13 /CeO 2 (1 1 1)

International audienc

C–H versus O–H Bond Dissociation for Alcohols on a Rh(111) Surface: A Strong Assistance from Hydrogen Bonded Neighbors

International audienceDensity functional theory (DFT) calculations show that hydrogen bonded neighbors can assist or hinder alcohol dehydrogenation on a metal catalyst. This critical role on C–H and O–H bond ruptures is addressed through two main cases: (i) the intermolecular hydrogen bond in the coadsorption of ethanol and water, and (ii) the intramolecular hydrogen bonds in glycerol. In the case of ethanol dehydrogenation, we show that the best catalyst is not bare Rh(111) but a surface with preadsorbed water or ethanol, the reactant ethanol being hydrogen bonded to the chemisorbed molecule, in a favorable configuration for O–H dissociation at the Rh surface. In addition, the intrinsic C–H/O–H reactivity is altered by hydrogen bonded neighbors. The O–H bond dissociation barrier is lowered by up to 0.25 eV. Conversely, the C–H bond scission is slightly inhibited (barrier increased by 0.1 eV maximum). As a result, O–H dissociation becomes favored. Glycerol reactivity is modulated by intramolecular H-bonds, with an additional constraint imposed by the carbon skeleton. Its reactivity is different from that of an isolated ethanol molecule, again with a preference for O–H cleavage