Gene Disruption of Plasmodium falciparum p52 Results in Attenuation of Malaria Liver Stage Development in Cultured Primary Human Hepatocytes

Difficulties with inducing sterile and long lasting protective immunity against malaria with subunit vaccines has renewed interest in vaccinations with attenuated Plasmodium parasites. Immunizations with sporozoites that are attenuated by radiation (RAS) can induce strong protective immunity both in humans and rodent models of malaria. Recently, in rodent parasites it has been shown that through the deletion of a single gene, sporozoites can also become attenuated in liver stage development and, importantly, immunization with these sporozoites results in immune responses identical to RAS. The promise of vaccination using these genetically attenuated sporozoites (GAS) depends on translating the results in rodent malaria models to human malaria. In this study, we perform the first essential step in this transition by disrupting, p52, in P. falciparum an ortholog of the rodent parasite gene, p36p, which we had previously shown can confer long lasting protective immunity in mice. These P. falciparum P52 deficient sporozoites demonstrate gliding motility, cell traversal and an invasion rate into primary human hepatocytes in vitro that is comparable to wild type sporozoites. However, inside the host hepatocyte development is arrested very soon after invasion. This study reveals, for the first time, that disrupting the equivalent gene in both P. falciparum and rodent malaria Plasmodium species generates parasites that become similarly arrested during liver stage development and these results pave the way for further development of GAS for human use

Obinutuzumab-induced acute thrombocytopenia: Report of two cases and review of literature

International audienceObinutuzumab (GA101) is a humanized anti-CD20 monoclonal antibody used in the treatment of B-cell malignancies. Under rare occasions, obinutuzumab may induce acute and severe thrombocytopenia. However, little is known about this side effect, referred to as "obinutuzumab-induced acute thrombocytopenia" (OIAT). Here, we report 2 cases of OIAT and review the literature to inform the management and outcome of this rare but life-threatening complication. The first case is a 74 year- old woman who was treated with obinutuzumab-Cyclophosphamide, Vincristine, Prednisone (CVP) for a previously untreated follicular lymphoma. This patient experienced an acute thrombocytopenia with a drop in her platelet count from 376 G/L to 3 G/L the day after treatment. The second case is a 44 year- old woman who was treated with obinutuzumab as a pre-treatment dose (day-8) before glofitamab infusion as a 4th line therapy for mantle cell lymphoma. This patient experienced an acute thrombocytopenia with a drop in her platelet count from 76 G/L (due to splenomegaly and bone marrow involvement) to 3 G/L the day after treatment. OIAT is a rare but life-threatening complication. Physicians should be aware of this adverse event to optimally detect and treat this complication

Influence of Great Flood on the Functioning of Karst Aquifer: Example of the Fontaine de Vaucluse Karst System (SE France)

International audienceIn the experimental catchment area of the Fontaine de Vaucluse, a long term monitoring has been completed. It enables the study of the system functioning with variable hydrological conditions. Coupling flow rates and Mg2+ concentrations permits highlighting the particular contribution of water with great Mg2+ concentration during low water periods. It appears that these high Mg2+ concentrations are linked not only to the low flow rate itself, but also to flow rate of previous flood periods. Thus, the average residence time of discharged water during low flow period, which is usually linked to the severity of the low water level, seems to be influenced by previous flood period too. Great floods and related high pressures could lead to circulation of hardly mobilized water with very high residence time

Influence of Great Flood on the Functioning of Karst Aquifer: Example of the Fontaine de Vaucluse Karst System (SE France)

International audienceIn the experimental catchment area of the Fontaine de Vaucluse, a long term monitoring has been completed. It enables the study of the system functioning with variable hydrological conditions. Coupling flow rates and Mg2+ concentrations permits highlighting the particular contribution of water with great Mg2+ concentration during low water periods. It appears that these high Mg2+ concentrations are linked not only to the low flow rate itself, but also to flow rate of previous flood periods. Thus, the average residence time of discharged water during low flow period, which is usually linked to the severity of the low water level, seems to be influenced by previous flood period too. Great floods and related high pressures could lead to circulation of hardly mobilized water with very high residence time

Influence of Great Flood on the Functioning of Karst Aquifer: Example of the Fontaine de Vaucluse Karst System (SE France)

International audienceIn the experimental catchment area of the Fontaine de Vaucluse, a long term monitoring has been completed. It enables the study of the system functioning with variable hydrological conditions. Coupling flow rates and Mg2+ concentrations permits highlighting the particular contribution of water with great Mg2+ concentration during low water periods. It appears that these high Mg2+ concentrations are linked not only to the low flow rate itself, but also to flow rate of previous flood periods. Thus, the average residence time of discharged water during low flow period, which is usually linked to the severity of the low water level, seems to be influenced by previous flood period too. Great floods and related high pressures could lead to circulation of hardly mobilized water with very high residence time

Exploring Heterocycle-Spermine Conjugates as Modulators of Oncogenic microRNAs Biogenesis

International audienceTargeting biologically relevant noncoding RNAs using small molecules is currently one of the major challenges of medicinal chemistry but holds a great potential for future therapeutic applications. In this context, oncogenic microRNAs represent a particularly promising target, and various examples of RNA binders have been reported as inhibitors of the biogenesis of these microRNAs. Here, we report the biochemical evaluation and molecular docking studies of five heterocycle-spermine conjugates revealing that a structure-based design of efficient and especially selective inhibitors can be performed based on the secondary and tertiary configuration of the targeted RNA

Quantitative 13 C-isotope labelling-based analysis to elucidate the influence of environmental parameters on the production of fermentative aromas during wine fermentation

Nitrogen and lipids are key nutrients of grape must that influence the production of fermentative aromas by wine yeast, and we have previously shown that a strong interaction exists between these two nutrients. However, more than 90% of the acids and higher alcohols (and their acetate ester derivatives) were derived from intermediates produced by the carbon central metabolism (CCM). The objective of this study was to determine how variations in nitrogen and lipid resources can modulate the contribution of nitrogen and carbon metabolisms for the production of fermentative aromas. A quantitative analysis of metabolism using 13 C-labelled leucine and valine showed that nitrogen availability affected the part of the catabolism of N-containing compounds, the formation of α-ketoacids from CCM and the redistribution of fluxes around these precursors, explaining the optimum production of higher alcohols occurring at an intermediate nitrogen content. Moreover, nitrogen content modulated the total production of acids and higher alcohols differently, through variations in the redox state of cells. We also demonstrated that the phytosterol content, modifying the intracellular availability of acetyl-CoA, can influence the flux distribution, especially the formation of higher alcohols and the conversion of α-ketoisovalerate to α-ketoisocaproate

Combined effects of nutrients and temperature on the production of fermentative aromas by Saccharomyces cerevisiae during wine fermentation.

Volatile compounds produced by yeast during fermentation greatly influence the organoleptic qualities of wine. We developed a model to predict the combined effects of initial nitrogen and phytosterol content and fermentation temperature on the production of volatile compounds. We used a Box-Behnken design and response surface modeling to study the response of Lalvin EC1118® to these environmental conditions. Initial nitrogen content had the greatest influence on most compounds; however, there were differences in the value of fermentation parameters required for the maximal production of the various compounds. Fermentation parameters affected differently the production of isobutanol and isoamyl alcohol, although their synthesis involve the same enzymes and intermediate. We found differences in regulation of the synthesis of acetates of higher alcohols and ethyl esters, suggesting that fatty acid availability is the main factor influencing the synthesis of ethyl esters whereas the production of acetates depends on the activity of alcohol acetyltransferases. We also evaluated the effect of temperature on the total production of three esters by determining gas-liquid balances. Evaporation largely accounted for the effect of temperature on the accumulation of esters in liquid. Nonetheless, the metabolism of isoamyl acetate and ethyl octanoate was significantly affected by this parameter. We extended this study to other strains. Environmental parameters had a similar effect on aroma production in most strains. Nevertheless, the regulation of the synthesis of fermentative aromas was atypical in two strains: Lalvin K1M® and Affinity™ ECA5, which produces a high amount of aromatic compounds and was obtained by experimental evolution

A priori assessment of ecotoxicological risks linked to building a hospital

International audienceHospital wastewaters contain a large number of chemical pollutants such as disinfectants, detergents, and drug residues. A part of these pollutants is not eliminated by traditional urban waste water treatment plants, leading to a major risk for the aquatic ecosystems receiving these effluents. After having formulated a specific methodology in order to assessment ecotoxicological risk for such a situation, we applied it to the project to build a new hospital shared by several towns in the French Alps. This methodology is based on the ecotoxicological characterisation of the hospital wastewater using a battery of three chronic bioassays (Pseudokirchneriella subcapitata, Heterocypris incongruens and Brachionus calyciflorus) and of genotoxicity tests (Ames fluctuation assay on Salmonella typhimurium, and a Fpg-modified comet assay on the trout liver cell line RTL-W1). The formulated methodology highlights a moderate risk of the hospital wastewater for the organisms of the water column of the river concerned. Nevertheless, this discharge contributes significantly to the global ecotoxicological risk when taking into account all the releases of the watershed into the river. This leads to recommending the implementation of a specific treatment system in the urban WWTP, or upstream to it, in view to protecting the aquatic organisms. (C) 2012 Elsevier Ltd. All rights reserved