A humanized mouse model for sequestration of Plasmodium falciparum sexual stages and in vivo evaluation of gametocytidal drugs

The development of new drugs to disrupt malaria transmission requires the establishment of an in vivo model to address the biology of Plasmodium falciparum sexual stages (gametocytes). Herein we show that chemically immune-modulated NSG mice grafted with human erythrocytes support complete sexual development of P. falciparum parasites and generate high gametocytemia. Immunohistochemistry and RT-qPCR analyses indicate an enrichment of immature gametocytes in the bone marrow and the spleen, suggesting a sequestration mechanism reminiscent to that observed in humans. Upon primaquine treatment, elimination of gametocytes from peripheral blood and from sequestration sites was observed, providing a proof of concept that these mice can be used for testing drugs. Therefore, this model allows the investigation of P. falciparum sexual commitment, gametocyte interactions with the bone marrow and spleen and provides the missing link between current in vitro assays and Phase I trials in humans for testing new malaria gametocytidal drugs

Towards novel difluorinated sugar mimetrics; syntheses and conformational analyses of highly-functionalised difluorinated cyclooctenones

Highly-functionalised difluorinated cyclooctenones were synthesised from trifluoroethanol using either metallated difluoroenol acetal or carbamate chemistry, followed by a [2,3]-Wittig rearrangement or aldol reaction. Efficient RCM reactions afforded the title compounds which showed rather restricted fluxional behaviour by VT 19F NMR. Topological characterisation by molecular modelling and NOESY/ROESY experiments offered a number of challenges, but allowed the identification of two favoured boat-chair conformers which interconverted by pseudorotation with relatively large activation barriers

cAMP-Signalling Regulates Gametocyte-Infected Erythrocyte Deformability Required for Malaria Parasite Transmission.

Blocking Plasmodium falciparum transmission to mosquitoes has been designated a strategic objective in the global agenda of malaria elimination. Transmission is ensured by gametocyte-infected erythrocytes (GIE) that sequester in the bone marrow and at maturation are released into peripheral blood from where they are taken up during a mosquito blood meal. Release into the blood circulation is accompanied by an increase in GIE deformability that allows them to pass through the spleen. Here, we used a microsphere matrix to mimic splenic filtration and investigated the role of cAMP-signalling in regulating GIE deformability. We demonstrated that mature GIE deformability is dependent on reduced cAMP-signalling and on increased phosphodiesterase expression in stage V gametocytes, and that parasite cAMP-dependent kinase activity contributes to the stiffness of immature gametocytes. Importantly, pharmacological agents that raise cAMP levels in transmissible stage V gametocytes render them less deformable and hence less likely to circulate through the spleen. Therefore, phosphodiesterase inhibitors that raise cAMP levels in P. falciparum infected erythrocytes, such as sildenafil, represent new candidate drugs to block transmission of malaria parasites

Dynamique des matières en suspension dans le panache du Rhône (Méditerranée occidentale) par télédétection spatiale " couleur de l'océan "

Coastal waters impacted by riverine inputs play a main role in the export and burial of terrigeneous particles. Ocean colour remote remote sensing allows to retrieve surface suspended particulate matter (SPM) concentrations. To improve spatial and temporal resolutions, it can be combined with bio-optical in situ measurements and numerical modelling. The Rhône river is the main source of freshwater and particulate inputs in the Gulf of Lion (Western Mediterranean Sea). The aim of the thesis is to study the seasonal variability of the Rhône river SPM inputs and their fate at the land-ocean interface. In situ bio-optical measurements have been acquired from oceanographic vessels and ProvBio autonomous profiling floats. The SPM concentrations have been retrieved from MERIS and MODIS satellite sensors. The hydro-sedimentary model (Mars-3D) is used to simulate the hydrodynamic circulation and the sediment dynamic in the Gulf of Lion using the measured Rhône liquid and solid discharges as inputs. Regional proxys have been identified and tested to follow the dynamic of SPM within the water column from in situ bio-optical measurements. A regional algorithm has been developed to map SPM concentrations from satellite sensors measurements. The combination of these two tools shows the dependence of SPM export to Rhone river freshwater discharge and wind. During flood events, the SPM are mainly exported within surface waters. From a weak to a moderate Rhône river freshwater discharge and strong wind, SPM are tranported close to the bottom. The hydro-sedimentary model allows to better understand some processes although improvement are still required.Les eaux côtières impactées par les apports fluviaux jouent un rôle majeur dans l'export et l'enfouissement des particules terrigènes. La télédétection "couleur de l'océan" renseigne sur les concentrations en matières en suspension (MES) de surface. Pour améliorer les résolutions spatiale et temporelle, elle peut être combinée à des mesures in situ bio-optiques et la modélisation numérique. Le Rhône est la principale source d'apports d'eau douce et particulaires dans le Golfe du Lion (Méditerranée Occidentale). L'objectif de la thèse est l'étude de la variabilité saisonnière des apports en MES du Rhône et leur devenir sur le plateau continental. Des mesures in situ bio-optiques ont été réalisées à partir de navires océanographiques et de plateformes autonomes ProvBio. Les concentrations en MES sont estimées à l'aide des capteurs satellitaires MERIS et MODIS. Le modèle hydro-sédimentaire (Mars-3D) simule la circulation des masses d'eau et les apports liquides et particulaires du Rhône. Des proxys régionaux sont identifiés et éprouvés afin d'assurer un suivi de la dynamique des MES sur la colonne d'eau à partir de mesures bio-optiques in situ. Un algorithme régional est développé afin de cartographier les concentrations en MES à partir des mesures satellitaires. La combinaison de ces deux outils montre la dépendance de l'export des MES au débit liquide du Rhône et aux vents. En régime de crue, les MES sont essentiellement exportées en surface. Pour un débit fluvial faible à modéré et un vent fort, elles sont transportées près du fond. Le modèle hydro-sédimentaire a permis de mieux comprendre certains processus même si des améliorations sont encore requises