Modulation of Motor Vigor by Expectation of Reward Probability Trial-by-Trial Is Preserved in Healthy Ageing and Parkinson's Disease Patients

Motor improvements, such as faster movement times or increased velocity, have been associated with reward magnitude in determin-istic contexts. Yet whether individual inferences on reward probability influence motor vigor dynamically remains undetermined. We investigated how dynamically inferring volatile action-reward contingencies modulated motor performance trial-by-trial. We conducted three studies that coupled a reversal learning paradigm with a motor sequence task and used a validated hierarchical Bayesian model to fit trial-by-trial data. In Study 1, we tested healthy younger [HYA; 37 (24 females)] and older adults [HOA; 37 (17 females)], and medicated Parkinson's disease (PD) patients [20 (7 females)]. We showed that stronger predictions about the tendency of the action -reward contingency led to faster performance tempo, commensurate with movement time, on a trial-by-trial basis without robustly modulating reaction time (RT). Using Bayesian linear mixed models, we demonstrated a similar invigoration effect on performance tempo in HYA, HOA, and PD, despite HOA and PD being slower than HYA. In Study 2 [HYA, 39 (29 females)], we additionally showed that retrospective subjective inference about credit assignment did not contribute to differences in motor vigor effects. Last, Study 3 [HYA, 33 (27 females)] revealed that explicit beliefs about the reward tendency (confidence ratings) modulated performance tempo trial-by-trial. Our study is the first to reveal that the dynamic updating of beliefs about volatile action-reward contingencies positively biases motor performance through faster tempo. We also provide robust evidence for a preserved sensitivity of motor vigor to inferences about the action-reward mapping in aging and medicated PD

Modulation of motor vigour by expectation of reward probability trial-by-trial is preserved in healthy ageing and Parkinson's disease patients

Motor improvements, such as faster movement times or increased velocity, have been associated with reward magnitude in deterministic contexts. Yet whether individual inferences on reward probability influence motor vigour dynamically remains undetermined. We investigated how dynamically inferring volatile action-reward contingencies modulated motor performance trial-by-trial. We conducted three studies that coupled a one-armed bandit decision-making paradigm with a motor sequence task and used a validated hierarchical Bayesian model to fit trial-by-trial data. In Study 1, we tested healthy younger (HYA, 37 [13 males]) and older adults (HOA, 37 [20 males]), and medicated Parkinson's Disease patients (PD, 20 [13 males]). We showed that stronger predictions about the tendency of the action-reward contingency led to faster performance tempo-commensurate with movement time-on a trial-by-trial basis without robustly modulating reaction time (RT). Using Bayesian linear mixed models, we demonstrated a similar invigoration effect on performance tempo in HYA, HOA and PD, despite HOA and PD being slower than HYA. In Study 2 (HYA, 39 [10 males]), we additionally showed that retrospective subjective inference about credit assignment did not contribute to differences in motor vigour effects. Last, Study 3 (HYA, 33 [6 males]) revealed that explicit beliefs about the reward tendency (confidence ratings) modulated performance tempo trial-by-trial.Our study is the first to reveal that the dynamic updating of beliefs about volatile action-reward contingencies positively biases motor performance through faster tempo. We also provide robust evidence for a preserved sensitivity of motor vigour to inferences about the action-reward mapping in ageing and medicated PD.SIGNIFICANCE STATEMENT:Navigating a world rich in uncertainty relies on updating beliefs about the probability that our actions lead to reward. Here we investigated how inferring the action-reward contingencies in a volatile environment modulated motor vigour trial-by-trial in healthy younger and older adults, and in Parkinson's Disease patients on medication. We found an association between trial-by-trial predictions about the tendency of the action-reward contingency and performance tempo, with stronger expectations speeding the movement. We additionally provided evidence for a similar sensitivity of performance tempo to the strength of these predictions in all groups. Thus, dynamic beliefs about the changing relationship between actions and their outcome enhanced motor vigour. This positive bias was not compromised by age or Parkinson's disease

Aplicación del tratamiento mecánico biológico (TMB) para la reducción del volumen y masa de residuos sólidos urbanos destinados a enterramiento en la ciudad de Unquillo, Córdoba, Argentina

Luego de 20 años de mejoras graduales en la gestión de residuos, comenzando por el cierre del basural en 2002, el Municipio de Unquillo (18.000 habitantes, Provincia de Córdoba)se encuentra con desafíos como disminuir la cantidad de residuos a transferir al relleno sanitariode la ciudad de Córdoba, distante a 55 km. Para reducir los costos de transporte y disposición final de los residuos no captados por la recolección diferenciada, se estánimplementando medidas para disminuirla generación y aumentar el reciclaje. Aun así, la fracción húmeda contieneuna importante cantidad de materiales reciclables.Fil: Antonini, Sebastián. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Ingeniería Química. Cátedra de procesos y organización industrial; Argentina.Fil: Pettigiani, Eugenio. Instituto Nacional de Tecnología Industrial. Unidad de Extensión; Argentina.Fil: Reynafé, Lautaro. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Ingeniería Química. Estudiante; Argentina.Fil: Cuffia, Carolina. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Ingeniería Química. Estudiante; Argentina.Ingeniería de Procesos Químico

Potenciales mejoras en el sistema de gestión integral de residuos sólidos urbanos para la reducción del impacto ambiental, en Córdoba, Argentina

La gestión de residuos sólidos urbanos es un desafío en países en desarrollo por aumento en la generación, los elevados costos y la falta de visión sistémica. Este trabajo presenta un modelo matemático de un sistema de gestión integral de residuos sólidos urbanos para la ciudad de Córdoba, Argentina, desde la generación hasta la disposición final, y pretende aportar al proceso de diseño de políticas públicas orientadas a la reducción de su impacto ambiental. Con el análisis de los procesos actuales y los proyectos a implementar, se crearon tres escenarios en base a la variación de parámetros operativos y la capacidad de tratamiento de putrescibles y la recuperación de reciclables. Se planteó una superestructura correspondiente a una cadena de suministro inversa que contempla los nodos de generación, compostaje domiciliario, plantas de selección y acondicionamiento, planta de transferencia, plantas de reciclaje y operaciones de selección mecánica, digestión anaeróbica de putrescibles para la generación de biogás y su transformación en energía eléctrica, bioestabilización del digestato y enterramiento sanitario. Para la estimación del impacto ambiental, se utilizó la metodología del análisis de ciclo de vida usando el software SimaPro 9.1. El modelo fue implementado en el utilitario matemático GAMS el cual minimiza el impacto a la salud humana como indicador de punto final en los tres escenarios, que fueron comparados con el escenario actual. La aplicación del modelo logra configurar los flujos óptimos, de cada categoría, procesados en cada nodo. La implementación de las estrategias de separación en origen y recolección diferenciada, el fomento del compostaje domiciliario y el tratamiento de la fracción fina, rica en putrescibles, se muestran como las principales acciones para reducir el impacto ambiental.Municipal solid waste management is a challenge in developing countries due to the increase in the generation rate, high costs and lack of a systemic vision. This paper presents a mathematical model of an integrated solid urban waste management system for the city of Cordoba, Argentina, from generation to final disposal, and aims to contribute to the design process of public policies focused on reducing its environmental impact. From the analysis of the current processes and the projects to be implemented, three scenarios were created based on the variation of operational parameters, the organic fraction treatment capacity and the recyclables recovery level. A superstructure was proposed corresponding to a reverse supply chain that includes generation nodes, home composting, sorting and conditioning plants, transfer plants, mechanical sorting and recycling plants, organic fraction anaerobic digestion for biogas generation and its transformation into electrical energy, digestate biostabilization and sanitary landfill. For the estimation of the environmental impact, the life cycle analysis methodology was applied using SimaPro 9.1 software. The model was implemented in the mathematical utility GAMS, minimizing the impact on human health as an endpoint indicator in the three scenarios, which were compared with the current scenario. The application of the model is able to set up the optimal flows for each category, processed at every node. The implementation of source separation and differentiated collection strategies, the promotion of home composting and the treatment of the fine flow, rich in organic fraction, emerge as the main actions to reduce the environmental impact.Fil: Antonini, Sebastian. Universidad Nacional de Córdoba. Instituto de Investigación y Desarrollo en Ingeniería de Procesos y Química Aplicada. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación y Desarrollo en Ingeniería de Procesos y Química Aplicada; Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales; ArgentinaFil: Rodriguez, Maria Analia. Universidad Nacional de Córdoba. Instituto de Investigación y Desarrollo en Ingeniería de Procesos y Química Aplicada. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación y Desarrollo en Ingeniería de Procesos y Química Aplicada; ArgentinaFil: Alasino, Noelia Pia Ximena. Universidad Nacional de Córdoba. Instituto de Investigación y Desarrollo en Ingeniería de Procesos y Química Aplicada. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación y Desarrollo en Ingeniería de Procesos y Química Aplicada; Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales; Argentin

Alternativas para la reducción del volumen y masa de residuos sólidos urbanos destinados a enterramiento en la ciudad de Unquillo mediante la implementación de tratamiento mecánico biológico (TMB)

Luego de 20 años de mejoras graduales en la gestión de residuos, comenzando por el cierre del basural en 2002, el Municipio de Unquillo (18.000 habitantes, Provincia de Córdoba) se encuentra con desafíos como disminuir la cantidad de residuos a transferir al relleno sanitario de la ciudad de Córdoba, distante a 55 km. Para reducir los costos de transporte y disposición final de los residuos no captados por la recolección diferenciada, se están implementando medidas para disminuirla generación y aumentar el reciclaje. Aun así, la fracción húmeda contiene una importante cantidad de materiales reciclables. En el presente trabajo se desarrolla una prueba piloto de tratamiento mecánico biológico (TMB) de esta fracción de residuos sólidos urbanos (RSU). El TMB combina la clasificación y procesamiento mecánico con el tratamiento biológico, con el objetivo de reducir la masa y volumen y estabilizar los RSU. Se realizaron dos pruebas de TMB, en verano y en invierno, que procesaron más de dos toneladas de RSU. El presenta trabajo tiene como objetivo valorar el potencial que (TMB) tiene como alternativa tecnológica de tratamiento de los RSU antes de derivarlos a disposición final. Los resultados muestran que es posible recuperar un 27% en peso de materiales reciclables y derivar a compostaje un 44% con lo que sólo se debería enviar a disposición menos de 30% de la masa recibida. Además, se estimó que el rendimiento de cada operario en la separación es de unos 70 kg/hora.En términos económicos, el costo del personal adicional 1.117 mil pesos al año, se compensa por los ahorros deFil: Antonini, Sebastian. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Ingeniería Química; Argentina.Fil: Pettigiani, Eugenio. Instituto Nacional de Tecnología Industrial. Unidad de Extensión Córdoba; Argentina.Fil: Silva, Federico. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Ingeniería Química. Estudiante; Argentina.Fil: Cravero, Leandro. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Ingeniería Química. Estudiante; Argentina.Fil: Reynafé, Lautaro. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Ingeniería Química. Estudiante; Argentina.Fil: Cuffia, Carolina. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Ingeniería Química. Estudiante; Argentina.Ingeniería de Procesos Químico

Protein aggregation of the p63 transcription factor underlies severe skin fragility in AEC syndrome.

The p63 gene encodes a master regulator of epidermal commitment, development, and differentiation. Heterozygous mutations in the C-terminal domain of the p63 gene can cause ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome, a life-threatening disorder characterized by skin fragility and severe, long-lasting skin erosions. Despite deep knowledge of p63 functions, little is known about mechanisms underlying disease pathology and possible treatments. Here, we show that multiple AEC-associated p63 mutations, but not those causative of other diseases, lead to thermodynamic protein destabilization, misfolding, and aggregation, similar to the known p53 gain-of-function mutants found in cancer. AEC mutant proteins exhibit impaired DNA binding and transcriptional activity, leading to dominant negative effects due to coaggregation with wild-type p63 and p73. Importantly, p63 aggregation occurs also in a conditional knock-in mouse model for the disorder, in which the misfolded p63 mutant protein leads to severe epidermal defects. Variants of p63 that abolish aggregation of the mutant proteins are able to rescue p63's transcriptional function in reporter assays as well as in a human fibroblast-to-keratinocyte conversion assay. Our studies reveal that AEC syndrome is a protein aggregation disorder and opens avenues for therapeutic intervention.This work was supported by Telethon Grants GGP09230 and GGP16235 (to C.M.), ERA-Net Research Program on Rare Diseases (ERARE-2) Skin-Dev (C.M.), Italian Association for Cancer Research Grant IG2011-N.11369 (to C.M.), Fondation Dind-Cottier pour la recherche sur la peau (C.M.), DFG Grant DO 545/8-1 (to V.D.), the Centre for Biomolecular Magnetic Resonance, and the Cluster of Excellence Frankfurt (Macromolecular Complexes). P.G. is supported by a Lichtenberg Professorship of the Volkswagen Foundation. C.R. is a PhD student in molecular oncology at the European School of Molecular Medicine

Protein aggregation of the p63 transcription factor underlies severe skin fragility in AEC syndrome.

The p63 gene encodes a master regulator of epidermal commitment, development, and differentiation. Heterozygous mutations in the C-terminal domain of the p63 gene can cause ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome, a life-threatening disorder characterized by skin fragility and severe, long-lasting skin erosions. Despite deep knowledge of p63 functions, little is known about mechanisms underlying disease pathology and possible treatments. Here, we show that multiple AEC-associated p63 mutations, but not those causative of other diseases, lead to thermodynamic protein destabilization, misfolding, and aggregation, similar to the known p53 gain-of-function mutants found in cancer. AEC mutant proteins exhibit impaired DNA binding and transcriptional activity, leading to dominant negative effects due to coaggregation with wild-type p63 and p73. Importantly, p63 aggregation occurs also in a conditional knock-in mouse model for the disorder, in which the misfolded p63 mutant protein leads to severe epidermal defects. Variants of p63 that abolish aggregation of the mutant proteins are able to rescue p63's transcriptional function in reporter assays as well as in a human fibroblast-to-keratinocyte conversion assay. Our studies reveal that AEC syndrome is a protein aggregation disorder and opens avenues for therapeutic intervention.This work was supported by Telethon Grants GGP09230 and GGP16235 (to C.M.), ERA-Net Research Program on Rare Diseases (ERARE-2) Skin-Dev (C.M.), Italian Association for Cancer Research Grant IG2011-N.11369 (to C.M.), Fondation Dind-Cottier pour la recherche sur la peau (C.M.), DFG Grant DO 545/8-1 (to V.D.), the Centre for Biomolecular Magnetic Resonance, and the Cluster of Excellence Frankfurt (Macromolecular Complexes). P.G. is supported by a Lichtenberg Professorship of the Volkswagen Foundation. C.R. is a PhD student in molecular oncology at the European School of Molecular Medicine

Disease-related p63 DBD mutations impair DNA binding by distinct mechanisms and varying degree

Abstract The transcription factor p63 shares a high sequence identity with the tumour suppressor p53 which manifests itself in high structural similarity and preference for DNA sequences. Mutations in the DNA binding domain (DBD) of p53 have been studied in great detail, enabling a general mechanism-based classification. In this study we provide a detailed investigation of all currently known mutations in the p63 DBD, which are associated with developmental syndromes, by measuring their impact on transcriptional activity, DNA binding affinity, zinc binding capacity and thermodynamic stability. Some of the mutations we have further characterized with respect to their ability to convert human dermal fibroblasts into induced keratinocytes. Here we propose a classification of the p63 DBD mutations based on the four different mechanisms of DNA binding impairment which we identified: direct DNA contact, zinc finger region, H2 region, and dimer interface mutations. The data also demonstrate that, in contrast to p53 cancer mutations, no p63 mutation induces global unfolding and subsequent aggregation of the domain. The dimer interface mutations that affect the DNA binding affinity by disturbing the interaction between the individual DBDs retain partial DNA binding capacity which correlates with a milder patient phenotype

Protein aggregation of the p63 transcription factor underlies severe skin fragility in AEC syndrome

The p63 gene encodes a master regulator of epidermal commitment, development, and differentiation. Heterozygous mutations in the C-terminal domain of the p63 gene can cause ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome, a life-threatening disorder characterized by skin fragility and severe, long-lasting skin erosions. Despite deep knowledge of p63 functions, little is known about mechanisms underlying disease pathology and possible treatments. Here, we show that multiple AEC-associated p63 mutations, but not those causative of other diseases, lead to thermodynamic protein destabilization, misfolding, and aggregation, similar to the known p53 gain-of-function mutants found in cancer. AEC mutant proteins exhibit impaired DNA binding and transcriptional activity, leading to dominant negative effects due to coaggregation with wild-type p63 and p73. Importantly, p63 aggregation occurs also in a conditional knock-in mouse model for the disorder, in which the misfolded p63 mutant protein leads to severe epidermal defects. Variants of p63 that abolish aggregation of the mutant proteins are able to rescue p63's transcriptional function in reporter assays as well as in a human fibroblast-to-keratinocyte conversion assay. Our studies reveal that AEC syndrome is a protein aggregation disorder and opens avenues for therapeutic intervention