Exploring a Tetrahydroquinoline Antimalarial Hit from the Medicines for Malaria Pathogen Box and Identification of its Mode of Resistance as PfeEF2

New antimalarial treatments with novel mechanism of action are needed to tackle Plasmodium falciparum infections that are resistant to first-line therapeutics. Here we report the exploration of MMV692140 ( 2 ) from the Pathogen Box, a collection of 400 compounds that was made available by Medicines for Malaria Venture (MMV) in 2015. Compound 2 was profiled in in vitro models of malaria and was found to be active against multiple life-cycle stages of Plasmodium parasites. The mode of resistance, and putatively its mode of action, was identified as Plasmodium falciparum translation elongation factor 2 ( Pf eEF2), which is responsible for the GTP-dependent translocation of the ribosome along mRNA. The compound maintains activity against a series of drug-resistant parasite strains. The structural motif of the tetrahydroquinoline ( 2 ) was explored in a chemistry program with its structure-activity relationships examined, resulting in the identification of an analog with 30-fold improvement of antimalarial asexual blood stage potency

Soil organic carbon models need independent time-series validation for reliable prediction

Numerical models are crucial to understand and/or predict past and future soil organic carbon dynamics. For those models aiming at prediction, validation is a critical step to gain confidence in projections. With a comprehensive review of ~250 models, we assess how models are validated depending on their objectives and features, discuss how validation of predictive models can be improved. We find a critical lack of independent validation using observed time series. Conducting such validations should be a priority to improve the model reliability. Approximately 60% of the models we analysed are not designed for predictions, but rather for conceptual understanding of soil processes. These models provide important insights by identifying key processes and alternative formalisms that can be relevant for predictive models. We argue that combining independent validation based on observed time series and improved information flow between predictive and conceptual models will increase reliability in predictions

Generation of a mutator parasite to drive resistome discovery in Plasmodium falciparum

In vitro evolution of drug resistance is a powerful approach for identifying antimalarial targets, however, key obstacles to eliciting resistance are the parasite inoculum size and mutation rate. Here we sought to increase parasite genetic diversity to potentiate resistance selections by editing catalytic residues of Plasmodium falciparum DNA polymerase δ. Mutation accumulation assays reveal a ~5–8 fold elevation in the mutation rate, with an increase of 13–28 fold in drug-pressured lines. Upon challenge with the spiroindolone PfATP4-inhibitor KAE609, high-level resistance is obtained more rapidly and at lower inocula than wild-type parasites. Selections also yield mutants with resistance to an “irresistible” compound, MMV665794 that failed to yield resistance with other strains. We validate mutations in a previously uncharacterised gene, PF3D7_1359900, which we term quinoxaline resistance protein (QRP1), as causal for resistance to MMV665794 and a panel of quinoxaline analogues. The increased genetic repertoire available to this “mutator” parasite can be leveraged to drive P. falciparum resistome discovery

Generation of a mutator parasite to drive resistome discovery in Plasmodium falciparum.

In vitro evolution of drug resistance is a powerful approach for identifying antimalarial targets, however, key obstacles to eliciting resistance are the parasite inoculum size and mutation rate. Here we sought to increase parasite genetic diversity to potentiate resistance selections by editing catalytic residues of Plasmodium falciparum DNA polymerase δ. Mutation accumulation assays reveal a ~5-8 fold elevation in the mutation rate, with an increase of 13-28 fold in drug-pressured lines. Upon challenge with the spiroindolone PfATP4-inhibitor KAE609, high-level resistance is obtained more rapidly and at lower inocula than wild-type parasites. Selections also yield mutants with resistance to an irresistible compound, MMV665794 that failed to yield resistance with other strains. We validate mutations in a previously uncharacterised gene, PF3D7_1359900, which we term quinoxaline resistance protein (QRP1), as causal for resistance to MMV665794 and a panel of quinoxaline analogues. The increased genetic repertoire available to this mutator parasite can be leveraged to drive P. falciparum resistome discovery

Soil organic carbon models need independent time-series validation for reliable prediction

International audienceAbstract Numerical models are crucial to understand and/or predict past and future soil organic carbon dynamics. For those models aiming at prediction, validation is a critical step to gain confidence in projections. With a comprehensive review of ~250 models, we assess how models are validated depending on their objectives and features, discuss how validation of predictive models can be improved. We find a critical lack of independent validation using observed time series. Conducting such validations should be a priority to improve the model reliability. Approximately 60% of the models we analysed are not designed for predictions, but rather for conceptual understanding of soil processes. These models provide important insights by identifying key processes and alternative formalisms that can be relevant for predictive models. We argue that combining independent validation based on observed time series and improved information flow between predictive and conceptual models will increase reliability in predictions

A model-based assessment of the soil C storage potential at the national scale: A case study from France

International audienceThe recent controversy about the 4 per 1000 initiative has emphasized the need for a quantitative assessment of the C storage potential of agricultural soils. Moreover a clear distinction is required between the biophysically and the economically achievable potentials. Here we used a modelling approach at a fine spatial-scale resolution (< 8 km2) to quantify the additional C storage in agricultural soils of mainland France following the implementation, when feasible, of a range of soil C storing practices (i.e. cover crops, reduced tillage, new C inputs, grazing instead of mowing,…). The additional cost for farmers was also calculated, thus yielding the cost per Mg of additional C stored in soils. Results showed that the average additional C storage calculated over 30 years ranged between +0.028 and + 0.466 Mg C ha-1 yr-1 (i.e. between +0.5 and +7.2‰) for the different tested practices, with a very high spatial variability over France for each practice related to initial C stocks and pedo-climatic conditions. The storing practices where then ranked according to the cost of the additional C stored in soils (expressed in euro per Mg of C) and an optimal cost-efficient strategy was proposed at the national level

Stocker du carbone dans les sols français. Quel potentiel au regard de l'objectif 4 pour 1000 et à quel coût ?

L'initiative "4 pour mille : les sols pour la sécurité alimentaire et le climat" propose d'augmenter chaque année d'un quatre millième le stock de carbone présent dans tous les sols du monde. À la demande de l'Ademe et du ministère de l'Agriculture et de l'Alimentation, l'Inra (devenu aujourd'hui INRAE) a conduit une étude, centrée sur la France métropolitaine, visant à estimer le potentiel de stockage de carbone des sols agricoles et forestiers et, in fine, à mesurer la contribution potentielle de ce levier à l'objectif de réduction des émissions nettes de gaz à effet de serre. Diverses pratiques candidates (cultures intermédiaires, apport de nouvelles ressources organiques, gestion des prairies, agroforesterie…) ont été évaluées. Les résultats obtenus ont montré une forte variabilité du stockage additionnel de carbone. L'étude a également permis d'estimer le coût supplémentaire, pour les agriculteurs, de mise en oeuvre de ces pratiques de stockage, puis une allocation de l'effort de stockage entre les pratiques et les régions a été effectuée. Ces données permettront aux différents acteurs concernés de faire les meilleurs choix pour stocker davantage de carbone dans les sols. Cet ouvrage s'adresse aux décideurs chargés de l'élaboration des politiques publiques climatiques dans le domaine agricole, aux responsables territoriaux, aux aménageurs, aux ingénieurs et techniciens, aux agriculteurs et à l'ensemble des citoyens intéressés par la problématique de l'agriculture et du changement climatique

Stocker du carbone dans les sols français: Quel potentiel et à quel coût ?

International audienceL’initiative « 4 pour 1 000 : les sols pour la sécurité alimentaire et le climat » propose d’augmenter chaque année d’un quatre millième le stock de carbone présent dans tous les sols du monde. À la demande de l’Ademe et du ministère de l’Agriculture et de l’Alimentation, l’Inra (devenu aujourd’hui INRAE) a conduit une étude, centrée sur la France métropolitaine, visant à estimer le potentiel de stockage de carbone des sols agricoles et forestiers et, in fine, à mesurer la contribution potentielle de ce levier à l’objectif de réduction des émissions nettes de gaz à effet de serre. Diverses pratiques candidates (cultures intermédiaires, apport de nouvelles ressources organiques, gestion des prairies, agroforesterie …) ont été évaluées. Les résultats obtenus ont montré une forte variabilité du stockage additionnel de carbone. L’étude a également permis d’estimer le coût supplémentaire, pour les agriculteurs, de mise en œuvre de ces pratiques de stockage, puis une allocation de l’effort de stockage entre les pratiques et les régions a été effectuée. Ces données permettront aux différents acteurs concernés de faire les meilleurs choix pour stocker davantage de carbone dans les sols. Cet ouvrage s’adresse aux décideurs chargés de l’élaboration des politiques publiques climatiques dans le domaine agricole, aux responsables territoriaux, aux aménageurs, aux ingénieurs et techniciens, aux agriculteurs et à l’ensemble des citoyens intéressés par la problématique de l’agriculture et du changement climatique