Insulin-like growth factor 2 (IGF2) protects against Huntington's disease through the extracellular disposal of protein aggregates

Impaired neuronal proteostasis is a salient feature of many neurodegenerative diseases, highlighting alterations in the function of the endoplasmic reticulum (ER). We previously reported that targeting the transcription factor XBP1, a key mediator of the ER stress response, delays disease progression and reduces protein aggregation in various models of neurodegeneration. To identify disease modifier genes that may explain the neuroprotective effects of XBP1 deficiency, we performed gene expression profiling of brain cortex and striatum of these animals and uncovered insulin-like growth factor 2 (Igf2) as the major upregulated gene. Here, we studied the impact of IGF2 signaling on protein aggregation in models of Huntington's disease (HD) as proof of concept. Cell culture studies revealed that IGF2 treatment decreases the load of intracellular aggregates of mutant huntingtin and a polyglutamine peptide. These results were validated using induced pluripotent stem cells (iPSC)-derived medium spiny neurons from HD patients and spinocerebellar ataxia cases. The reduction in the levels of mutant huntingtin was associated with a decrease in the half-life of the intracellular protein. The decrease in the levels of abnormal protein aggregation triggered by IGF2 was independent of the activity of autophagy and the proteasome pathways, the two main routes for mutant huntingtin clearance. Conversely, IGF2 signaling enhanced the secretion of soluble mutant huntingtin species through exosomes and microvesicles involving changes in actin dynamics. Administration of IGF2 into the brain of HD mice using gene therapy led to a significant decrease in the levels of mutant huntingtin in three different animal models. Moreover, analysis of human postmortem brain tissue and blood samples from HD patients showed a reduction in IGF2 level. This study identifies IGF2 as a relevant factor deregulated in HD, operating as a disease modifier that buffers the accumulation of abnormal protein species

The function of alternatively spliced isoforms of dystrophin

grantor: University of TorontoThe Duchenne Muscular Dystrophy gene encodes multiple isoforms of dystrophin generated by different promoters and by alternative splicing events at the 3' end of the transcript. Alternative splicing of the penultimate exon 78 produces two structurally different C-termini in the protein. Usage of the two dystrophin C-termini is tissue-specific, developmentally regulated, and highly conserved across species. Work in this thesis began to characterize the functional significance of the two C-termini of dystrophin by creating targeted mice specifically mutated so as to constitutively use only one of the two C-termini (Chapter II). In addition, the yeast-two hybrid system was used to identify novel dystrophin interacting proteins that bind to the mainly hydrophobic exon-79 encoded C-terminus of dystrophin (Chapter III). Lastly, the full-length cDNA sequences encoding the novel family of CAPS proteins (calcium-dependent activator protein for secretion), first identified in the two-hybrid screen, were obtained (Chapter IV). Human expression profiles indicated that CAPS-1 is a neural/endocrine specific protein while CAPS-2 is expressed ubiquitously.M.Sc

On the use of Na2SO3Na_2SO_3 as a pyrite depressant in saline systems and the presence of kaolinite

The effect of Na2SO3 as a pyrite depressant in NaCl and KCl saline media and the presence of kaolinite were evaluated by zeta potential tests. Chalcopyrite was also included in the study, because pyrite usually accompanies this mineral. Subsequently, the floatability results of both minerals in the NaCl solution were optimized based on the design of experiments (DoE). The Box–Behnken DoE was applied considering the percentage of kaolinite $(X_1)$, collector dose $(X_2)$, and depressant dose $(X_3)$ as factors. The results were modeled using artificial neural networks (ANNs) to construct contour plots and to determine the optimal conditions. In particular, maximization of the mass recovery of chalcopyrite and minimization of that of pyrite were sought. The particle swarm optimization algorithm was used as an optimization technique. The results indicated that the optimal conditions to maximize the floatability of chalcopyrite were kaolinite 6.85%, collector dose $3.58 × 10^{–3} mol$ / $dm^3$, and depressant dose $3.49 × 10^{–5} mol$ / $dm^3$. On the contrary, the optimal conditions to minimize the floatability of pyrite were 5% kaolinite, collector dose $5 × 10^{–4} mol$ / $dm^3$, and depressant dose $6.4 × 10^{–5} mol$ / $dm^3$. Under these conditions, the mass recoveries of chalcopyrite and pyrite were 66.1% and 14.0%, respectively. The results also indicated that the presence of kaolinite negatively affects the flotation of chalcopyrite, while the effect of $Na_2SO_3$ is not significant. In general, the findings suggest that $Na_2SO_3$ is a viable alternative to consider as a pyrite depressant in saline environments

Response Surface Methodology for Copper Flotation Optimization in Saline Systems

Response surface methodology (RSM) is one of the most effective tools for optimizing processes, and it has been used in conjunction with the Analysis of Variance (ANOVA) test to establish the effect of input factors on output factors. However, when this methodology is used in mineral flotation, its polynomial model usually performs poorly. An alternative is to use artificial neural networks (ANNs) in such situations. Within this context, the ANOVA test is not the best option for these model types; moreover, it requires statistical assumptions that are difficult to satisfy in flotation. This work proposes replacing the polynomial model of the RSM with ANNs and the Sobol methods to determine the influential input factors instead of the ANOVA test. This proposal is applied to two porphyry copper ores with a high content of pyrite, clay, and dilution media. In addition, this study shows how other computational intelligence techniques, such as swarm intelligence, can be incorporated into this type of problem to improve the learning process of ANNs. The results gave an adjustment of over 0.98 for R2 using ANNs, in comparison to values of around 0.5 when the polynomial model of RSM was utilized. On the other hand, the application of Global Sensitivity Analysis (GSA) identified the aeration rate and P80 size as the most influential variables in copper recovery under the conditions studied. Additionally, we identified significant interactions that affect the recovery of copper, with the interactions between the aeration rate, frother concentration, and P80 size being the most important

A Posteriori Analysis of Analytical Models for Heap Leaching Using Uncertainty and Global Sensitivity Analyses

The heap leaching of minerals is one of the more commonly used processes in the mining industry. This process has been modeled by many authors. However, the validation, verification, and implementation of these models are difficult since there is uncertainty about the operating conditions and the leaching model parameters. This work uses the uncertainty quantification, based on uncertainty and sensitivity analysis, for studying the model strength against uncertainties in heap leaching. The uncertainty analysis (UA) is used to quantify the effect of the magnitude of the uncertainties of the input variables on the recovery of heap leaching. Global sensitivity analysis (GSA) is used to study the nature of connections between the recovery and input variables of the leaching model. In addition, GSA facilitates the detection of whether a leaching model is over-parameterized. The information obtained allows studying some applications of the kinetic model. The Mellado et al. kinetic model is used as an example. The UA results indicate that the kinetic model can estimate the recovery behavior considering the full range of uncertainties of input variables. The GSA indicates that the kinetic model is over-parameterized on the uncertainties range considered; this conclusion contradicts the results when the local sensitivity analysis is used. However, the model shows a good correlation between the results of GSA and the kinetic behavior of heap leaching. In addition, the kinetic model presents versatility because it allows the determination of operating regions for heap leaching

Response Surface Methodology for Copper Flotation Optimization in Saline Systems

Response surface methodology (RSM) is one of the most effective tools for optimizing processes, and it has been used in conjunction with the Analysis of Variance (ANOVA) test to establish the effect of input factors on output factors. However, when this methodology is used in mineral flotation, its polynomial model usually performs poorly. An alternative is to use artificial neural networks (ANNs) in such situations. Within this context, the ANOVA test is not the best option for these model types; moreover, it requires statistical assumptions that are difficult to satisfy in flotation. This work proposes replacing the polynomial model of the RSM with ANNs and the Sobol methods to determine the influential input factors instead of the ANOVA test. This proposal is applied to two porphyry copper ores with a high content of pyrite, clay, and dilution media. In addition, this study shows how other computational intelligence techniques, such as swarm intelligence, can be incorporated into this type of problem to improve the learning process of ANNs. The results gave an adjustment of over 0.98 for R2 using ANNs, in comparison to values of around 0.5 when the polynomial model of RSM was utilized. On the other hand, the application of Global Sensitivity Analysis (GSA) identified the aeration rate and P80 size as the most influential variables in copper recovery under the conditions studied. Additionally, we identified significant interactions that affect the recovery of copper, with the interactions between the aeration rate, frother concentration, and P80 size being the most important

Ayuda ergogénica sobre entrenamiento y nutrición del deportista

Tesis (Educación Física)Las encuestas revelan que la mayoría de los deportistas cree que las ayudas ergogénicas son un componente esencial para el éxito deportivo. La lista de posibles ayudas ergogénicas es larga, pero el número de las que realmente poseen propiedades ergogénicas es mucho menor, de hecho algunas sustancias con propiedades ergogénicas pueden perjudicar el rendimiento, éstas se denominan drogas ergolíticas. Por tanto se determinará el concepto de ayuda ergogénica, sus diferentes efectos y consecuencias sobre la práctica deportiva y además en que condiciones se encuentra el conocimiento de las personas que han consumido productos con supuestos beneficios ergogénicos. Objetivos: El presente trabajo fue realizado con una muestra representativa de deportistas Chilenos entre 14 a 55 años, con el propósito de evaluar el nivel en que se encuentra el conocimiento de las personas que han consumido productos con supuestos beneficios ergogénicos. Resultados: El 28% de la muestra total refirió no haber consumido ningún producto que sea beneficioso para el rendimiento deportivo o la composición corporal y el 72% refirió haber consumido, de éste porcentaje, el 86% fueron hombres y el 14% mujeres

Programa de actividad física para personas con sobrepeso y obesidad de la comuna de La Florida

Tesis (Profesor de Educación Física para la Enseñanza Básica, Licenciado en Educación)Chile se encuentra en un rápido ascenso hacia el desarrollo, pero estos progresos lamentablemente han influido de forma negativa en la calidad de vida de la población, ya que se ha descuidado y desvalorizado la práctica de actividad física y los buenos hábitos alimenticios, situaciones que se pueden fundamentar bajo diversos aspectos, donde se destaca la presencia de horarios laborales extensos, lo que imposibilita la realización de actividad física de manera frecuente y en muchas ocasiones la incorporación de la comida con alto contenido calórico en las fuentes de alimentación. En el año 1992 la Asociación Americana del Corazón (AHA) declara que sujetos sedentarios poseen el doble de riesgo cardiovascular que un sujeto activo. Esta situación trae consigo algunos conceptos que han sido definidos por varios investigadores y autores, de esta manera se puede considerar que el sujeto sedentario es: un individuo que realiza menos de 30 minutos diarios de actividad física fuera de su horario de trabajo menos de tres veces por semana y teniendo un gasto energético por debajo de las 1.500 kilocalorías semanales. Ahora bien, se entiende por actividad física: toda actividad muscular que incrementa el gasto metabólico basal y por ejercicio físico en cambio: actividad muscular con una estructura definida (intensidad, duración y frecuencia). Esta situación de sedentarismo ha traído consigo un aumento de malos hábitos de vida, con el consecuente incremento de los factores de riesgo modificables, generando la concepción de las denominadas Enfermedades Crónicas No Trasmisibles (ECNT). Como una muestra de lo anterior, se destaca la información entregada por la encuesta de Calidad de Vida (INE-MINSAL 2000) referente a un factor de riesgo con alta prevalencia en la población, señalando que el 91 por ciento de los chilenos se enmarca dentro del grupo de sedentarios