Neural mechanisms of economic choices in mice

Economic choices entail computing and comparing subjective values. Evidence from primates indicates that this behavior relies on the orbitofrontal cortex. Conversely, previous work in rodents provided conflicting results. Here we present a mouse model of economic choice behavior, and we show that the lateral orbital (LO) area is intimately related to the decision process. In the experiments, mice chose between different juices offered in variable amounts. Choice patterns closely resembled those measured in primates. Optogenetic inactivation of LO dramatically disrupted choices by inducing erratic changes of relative value and by increasing choice variability. Neuronal recordings revealed that different groups of cells encoded the values of individual options, the binary choice outcome and the chosen value. These groups match those previously identified in primates, except that the neuronal representation in mice is spatial (in monkeys it is good-based). Our results lay the foundations for a circuit-level analysis of economic decisions

Long-Term Adult Feline Liver Organoid Cultures for Disease Modeling of Hepatic Steatosis.

Hepatic steatosis is a highly prevalent liver disease, yet research is hampered by the lack of tractable cellular and animal models. Steatosis also occurs in cats, where it can cause severe hepatic failure. Previous studies demonstrate the potential of liver organoids for modeling genetic diseases. To examine the possibility of using organoids to model steatosis, we established a long-term feline liver organoid culture with adult liver stem cell characteristics and differentiation potential toward hepatocyte-like cells. Next, organoids from mouse, human, dog, and cat liver were provided with fatty acids. Lipid accumulation was observed in all organoids and interestingly, feline liver organoids accumulated more lipid droplets than human organoids. Finally, we demonstrate effects of interference with β-oxidation on lipid accumulation in feline liver organoids. In conclusion, feline liver organoids can be successfully cultured and display a predisposition for lipid accumulation, making them an interesting model in hepatic steatosis research

Long-Term Adult Feline Liver Organoid Cultures for Disease Modeling of Hepatic Steatosis

Hepatic steatosis is a highly prevalent liver disease, yet research is hampered by the lack of tractable cellular and animal models. Steatosis also occurs in cats, where it can cause severe hepatic failure. Previous studies demonstrate the potential of liver organoids for modeling genetic diseases. To examine the possibility of using organoids to model steatosis, we established a long-term feline liver organoid culture with adult liver stem cell characteristics and differentiation potential toward hepatocyte-like cells. Next, organoids from mouse, human, dog

Preclinical characterization and target validation of the antimalarial pantothenamide MMV693183.

Drug resistance and a dire lack of transmission-blocking antimalarials hamper malaria elimination. Here, we present the pantothenamide MMV693183 as a first-in-class acetyl-CoA synthetase (AcAS) inhibitor to enter preclinical development. Our studies demonstrate attractive drug-like properties and in vivo efficacy in a humanized mouse model of Plasmodium falciparum infection. The compound shows single digit nanomolar in vitro activity against P. falciparum and P. vivax clinical isolates, and potently blocks P. falciparum transmission to Anopheles mosquitoes. Genetic and biochemical studies identify AcAS as the target of the MMV693183-derived antimetabolite, CoA-MMV693183. Pharmacokinetic-pharmacodynamic modelling predict that a single 30 mg oral dose is sufficient to cure a malaria infection in humans. Toxicology studies in rats indicate a \u3e 30-fold safety margin in relation to the predicted human efficacious exposure. In conclusion, MMV693183 represents a promising candidate for further (pre)clinical development with a novel mode of action for treatment of malaria and blocking transmission

Invasion and development of Plasmodium vivax in human reticulocytes : phenotype genotype association of the response to inhibitors

Parmi les cinq espèces de Plasmodium capables d'infecter l’Homme, Plasmodium vivax est la plus répandue mais aussi celle responsable de la majorité des cas de paludisme en dehors de l'Afrique. Les mécanismes d’invasion et de développement mis en place par P. vivax sont peu connus notamment du fait de l’absence de système de culture in vitro continue pour cette espèce, ce qui freine notamment le développement d’une stratégie vaccinale et l’étude de la réponse aux antipaludiques. Par exemple, le paradigme qui décrivait l’interaction entre Plasmodium vivax Duffy Binding Protein (PvDBP) et l’antigène Duffy (DARC) comme critique pour l’invasion des globules rouges est remis en cause depuis l’observation de P. vivax dans des individus dépourvus de Duffy à la surface de leurs érythrocytes. Par ailleurs, la place particulière du Cambodge au cœur du berceau des résistances aux antipaludiques pour P. falciparum, oblige à surveiller la possible émergence de souches résistantes de P. vivax. Ainsi, les travaux présentés dans cette thèse visent à améliorer la compréhension des mécanismes d’invasion et de développement de P. vivax dans les réticulocytes humain.Ces travaux se composent d’une première partie qui consiste à caractériser la susceptibilité ex vivo d’isolats cliniques de P. vivax à différents antipaludiques, à déterminer l’évolution de cette susceptibilité au cours du temps en fonction des traitements utilisés dans le pays et à identifier les génotypes associés à des différences de susceptibilité. Une deuxième partie de cette thèse comprend l’évaluation de l’inhibition de l’invasion de P. vivax dans les réticulocytes en présence d’anticorps ciblant différentes protéines parasitaires et l’association de génotypes à ces phénotypes de réponse. Enfin, une dernière partie porte sur l’analyse des cellules déficientes en Duffy et la compréhension des interactions moléculaires impliquées dans leur invasion par P. vivax.Plasmodium vivax is the most widespread of the five Plasmodium species able to infect humans and is responsible for the majority of malaria cases outside Africa. The mechanisms of invasion or development used by P. vivax remain enigmatic, notably because of the lack of continuous in vitro culture, which hampers in particular the development of a vaccine strategy and the study of the response to antimalarials. For example, the paradigm describing the interaction between Plasmodium vivax Duffy Binding Protein (PvDBP) and the Duffy antigen (DARC) as critical for the entry into red blood cells has been called into question since the observation of P. vivax in individuals without Duffy on the surface of their erythrocytes. In addition, Cambodia being a hotspot of drug resistance emergence for P. falciparum, carefully monitoring the possible emergence of resistant strains of P. vivax is critical. Thus, the work described in this thesis aims to improve the understanding of the invasion and development mechanisms of P. vivax into human reticulocytes.This work is composed of a first part which consists in characterizing the ex vivo susceptibility of clinical isolates of P. vivax to different antimalarials, determining the evolution of this susceptibility over time according to the treatments used in the country and identifying the genotypes associated with differences in susceptibility. A second part focuses on the evaluation of the inhibition of P. vivax invasion in reticulocytes in the presence of antibodies targeting different parasite proteins and the association of genotypes with these response phenotypes. Finally, a last part is dedicated to the analysis of Duffy negative cells and the study of the molecular interactions involved in their invasion by P. vivax

La nano encapsulation de l'insuline en vue de son administration par voie orale

STRASBOURG ILLKIRCH-Pharmacie (672182101) / SudocSudocFranceF

The enigmatic mechanisms by which Plasmodium vivax infects Duffy-negative individuals

International audienceThe absence of the Duffy protein at the surface of erythrocytes was considered for decades to confer full protection against Plasmodium vivax as this blood group is the receptor for the key parasite ligand P. vivax Duffy binding protein (PvDBP). However, it is now clear that the parasite is able to break through this protection and induce clinical malaria in Duffy-negative people, although the underlying mechanisms are still not understood. Here, we briefly review the evidence of Duffy-negative infections by P. vivax and summarize the current hypothesis at the basis of this invasion process. We discuss those in the perspective of malaria-elimination challenges, notably in African countries

Impact of the first-line treatment shift from dihydroartemisinin/piperaquine to artesunate/mefloquine on Plasmodium vivax drug susceptibility in Cambodia

International audienceBackground Cambodia is the epicentre of the emergence of Plasmodium falciparum drug resistance. Much less is known regarding the drug susceptibility of the co-endemic Plasmodium vivax. Only in vitro drug assays can determine the parasite’s intrinsic susceptibility, but these are challenging to implement for P. vivax and rarely performed. Objectives To evaluate the evolution of Cambodian P. vivax susceptibility to antimalarial drugs and determine their association with putative markers of drug resistance. Methods In vitro response to three drugs used in the past decade in Cambodia was measured for 52 clinical isolates from Eastern Cambodia collected between 2015 and 2018 and the sequence and copy number variation of their pvmdr1 and pvcrt genes were analysed. pvmdr1 polymorphism was also determined for an additional 250 isolates collected in Eastern Cambodia between 2014 and 2019. Results Among the 52 cryopreserved isolates tested, all were susceptible to the three drugs, with overall median IC50s of 16.1 nM (IQR 11.4–22.3) chloroquine, 3.4 nM (IQR 2.1–5.0) mefloquine and 4.6 nM (IQR 2.7–7.0) piperaquine. A significant increase in chloroquine and piperaquine susceptibility was observed between 2015 and 2018, unrelated to polymorphisms in pvcrt and pvmdr1. Susceptibility to mefloquine was significantly lower in parasites with a single mutation in pvmdr1 compared with isolates with multiple mutations. The proportion of parasites with this single mutation genotype increased between 2014 and 2019. Conclusions P. vivax with decreased susceptibility to mefloquine is associated with the introduction of mefloquine-based treatment during 2017–18

Pro-Inflammatory Cytokines at Ultra-Low Dose Exert Anti-Inflammatory Effect In Vitro: A Possible Mode of Action Involving Sub-Micron Particles?

Tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) are pro-inflammatory cytokines involved in acute and chronic inflammatory diseases. Indeed, immunotherapy blocking these 2 cytokines has been developed. Micro-immunotherapy (MI) also uses ultra-low doses (ULD) of pro-inflammatory cytokines, impregnated on lactose-sucrose pillules, to counteract their overexpression. The study has been conducted with 2 objectives: examine the anti-inflammatory effect in vitro and the capacity of 2 unitary medicines, TNF-α (27 CH) and IL-1β (27 CH), to reduce the secretion of TNF-α in human primary monocytes and THP-1 cells differentiated with phorbol-12-myristate-13-acetate, after lipopolysaccharide (LPS) exposure; then, investigate the presence of particles possibly containing starting materials using tunable resistive pulse sensing technique. The results show that the unitary medicines, tested at 3 pillules concentrations (5.5, 11 and 22 mM), have reduced the secretion of TNF-α in both models by about 10-20% vs. vehicle control, depending on concentration. In this exploratory study, particles (150-1000 nm) have been detected in MI ULD-impregnated pillules and a hypothesis for MI medicines mode of action has been proposed. Conscious that more evaluations are necessary, authors are cautious in the conclusions because the findings described in the study are still limited, and future investigations may lead to different hypothesis.The study was entirely funded by Labo’Life France.Ye