Time representation in reinforcement learning models of the basal ganglia

Reinforcement learning (RL) models have been influential in understanding many aspects of basal ganglia function, from reward prediction to action selection. Time plays an important role in these models, but there is still no theoretical consensus about what kind of time representation is used by the basal ganglia. We review several theoretical accounts and their supporting evidence. We then discuss the relationship between RL models and the timing mechanisms that have been attributed to the basal ganglia. We hypothesize that a single computational system may underlie both RL and interval timing—the perception of duration in the range of seconds to hours. This hypothesis, which extends earlier models by incorporating a time-sensitive action selection mechanism, may have important implications for understanding disorders like Parkinson's disease in which both decision making and timing are impaired

Inhibition of HIV-1 Replication in Human Monocyte-Derived Macrophages by Parasite Trypanosoma cruzi

and HIV-1 to date.0.01). inhibits HIV-1 replication at several replication stages in macrophages, a major cell target for both pathogens

Activity of Estafietin and Analogues on <i>Trypanosoma cruzi</i> and <i>Leishmania braziliensis</i>

Sesquiterpene lactones are naturally occurring compounds mainly found in the Asteraceae family. These types of plant metabolites display a wide range of biological activities, including antiprotozoal activity and are considered interesting structures for drug discovery. Four derivatives were synthesized from estafietin (1), isolated from Stevia alpina (Asteraceae): 11&#946;H,13-dihydroestafietin (2), epoxyestafietin (3a and 3b), 11&#946;H,13-methoxyestafietin, (4) and 11&#946;H,13-cianoestafietin. The antiprotozoal activity against Trypanosoma cruzi and Leishmania braziliensis of these compounds was evaluated. Epoxyestafietin was the most active compound against T. cruzi trypomastigotes and amastigotes (IC50 values of 18.7 and 2.0 &#181;g/mL, respectively). Estafietin (1) and 11&#946;H,13-dihydroestafietin (2) were the most active and selective compounds on L. braziliensis promastigotes (IC50 values of 1.0 and 1.3 &#956;g/mL, respectively). The antiparasitic activity demonstrated by estafietin and some of its derivatives make them promising candidates for the development of effective compounds for the treatment of Chagas disease and leihsmaniasis

In Silico Study of Structural and Geometrical Requirements of Natural Sesquiterpene Lactones with Trypanocidal Activity

Chagas’ disease, caused by the intracellular protozoan Trypanosoma cruzi, is one of the most serious health problems throughout South America. Despite the progress that has been made in the study of its biochemistry and physiology, more efficient chemotherapies to control this parasitic infection are still lacking. In this paper we report the trypanocidal and cytotoxic activities of a series of sesquiterpene lactones, isolated from Asteraceae medicinal plants. The significant trypanocidal activity and high selectivity indexes found for many of the compounds evaluated, prompted us to undertake a quantitative structure-activity relationship study. A model using 3D molecular descriptors allowed us to set up a high correlation of the observed activity and the atomic spatial arrangement of these sesquiterpene lactones closely related to steric parameters.Fil: Fabian, Lucas Emanuel. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; ArgentinaFil: Sulsen, V.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Metabolismo del Fármaco (i); ArgentinaFil: Frank, Fernanda Maria. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Estudios de la Inmunidad Humoral "Profesor R. A. Margni"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica; ArgentinaFil: Cazorla, Silvia Ines. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Estudios de la Inmunidad Humoral "Profesor R. A. Margni"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica; ArgentinaFil: Malchiodi, Emilio Luis. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; ArgentinaFil: Martino, Virginia Susana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Metabolismo del Fármaco (i); ArgentinaFil: Lizarraga, Emilio Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Tucumán. Instituto de Quimica del Noroeste; ArgentinaFil: Catalan, Cesar Atilio Nazareno. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Tucumán. Instituto de Quimica del Noroeste; ArgentinaFil: Moglioni, Albertina Gladys. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; ArgentinaFil: Muschietti, L.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Metabolismo del Fármaco (i); ArgentinaFil: Finkielsztein, L.. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentin

Redirection of the immune response to the functional catalytic domain of the cystein proteinase cruzipain improves protective immunity against Trypanosoma cruzi infection.

Despite the strong immune responses elicited after natural infection with Trypanosoma cruzi or vaccination against it, parasite survival suggests that these responses are insufficient or inherently inadequate. T. cruzi contains a major cystein proteinase, cruzipain, which has a catalytic N-terminal domain and a C-terminal extension. Immunizations that employed recombinant cruzipain or its N- and C-terminal domains allowed evaluation of the ability of cruzipain to circumvent responses against the catalytic domain. This phenomenon is not a property of the parasite but of cruzipain itself, because recombinant cruzipain triggers a response similar to that of cruzipain during natural or experimental infection. Cruzipain is not the only antigen with a highly immunogenic region of unknown function that somehow protects an essential domain for parasite survival. However, our studies show that this can be reverted by using the N-terminal domain as a tailored immunogen able to redirect host responses to provide enhanced protection