Mecanismo de interacción, calcio dependiente, entre Calcineurina y PERK, involucrado en el Estrés de Retículo Endoplásmico. Ca2+ -dependent mechanism of interaction between Calcineurin and PERK involved in Endoplasmic Reticulum Stress.

El Estrés de Retículo Endoplásmico (RE) es inducido por la acumulación de proteínas sin plegar en el lumen de la organela. Esto se puede observar en diversas situaciones fisio-patológicas como durante una infección viral o en proceso isquémico. Además, contribuye a la base molecular de numerosas enfermedades ya sea índole metabólico (Fibrosis quística o Diabetes Miellitus) o neurodegenerativas como mal de Alzheimer o Parkinson (Mutat Res, 2005, 569). Para restablecer la homeostasis en la organela se activa una señal de transducción (UPR), cuya respuesta inmediata es la atenuación de la síntesis de proteína debido a la fosforilación de subunidad alpha del factor eucariótico de iniciación de translación (eIF2α) vía PERK. Esta es una proteína de membrana de RE que detecta estrés. Bajo condiciones normales, PERK está inactiva debido a la asociación de su dominio luminar con la chaperona BIP (Nat Cell Biol, 2000, 2: 326). Frente a una situación de estrés, la chaperona se disocia causando desinhibición. Recientemente, (Plos One 5: e11925) se observó, bajo condiciones de estrés, un aumento de Ca2+ citosólico y un rápido incremento de la expresión de calcineurina (CN), una fosfatasa citosólica dependiente de calcio, heterodimérica formada por una subunidad catalítica (CN-A) y una regulatoria (CN-B). Además, CN interacciona, sin intermediarios, con el dominio citosólico de PERK favoreciendo su trans-autofosforilación. Resultados preliminares indican que, astrocitos CNAβ-/- exhibieron, en condiciones basales, un mayor número de células muertas y de niveles de eIF2α fosforilado que los astrocitos CNAα-/-. Hipótesis: CNAβ/B interacciona con PERK cuando el Ca2+ citosólico esta incrementado luego de haberse inducido Estrés de RE, lo cual promueve dimerización y auto-fosforilación de la quinasa, acentuándose así la fosforilación de eIF2α e inhibición de la síntesis de proteínas. Esta activación citosólica de PERK colaboraría con la ya descrita, desinhibición luminal llevada cabo por BIP. Cuando el Ca2+ citosólico retorna a los niveles basales, PERK fosforila a CN, reduciendo su afinidad de unión y disociándose el complejo CN/PERK. Objetivo general: Definir las condiciones por las cuales CN interacciona con PERK y regula la fosforilación de eIF2α e inhibición de la síntesis de proteína. Objetivos específicos: I-Estudiar la diferencia de afinidades y dependencia de Ca2+, de las dos isoformas de CN (α y β) en su asociación con PERK. Además verificar la posible participación de la subunidad B de CN en esta interacción. II-Determinar si la auto-fosforilación de PERK es diferencialmente regulada por las dos isoformas de CN. III-Discernir la relación del estado de fosforilación de CN con su unión a PERK. IV-Determinar efectos fisiológicos de la interacción de CN-PERK durante la respuesta de Estrés de RE. Para llevar a cabo este proyecto se realizarán experimentos de biología molecular, interacción proteína-proteína, ensayos de fosforilación in vitro y un perfil de polisoma con astrocitos CNAβ-/- , CNA-/- y astrocitos controles. Se espera encontrar una mayor afinidad de unión a PERK de la isoforma β de CN y en condiciones donde la concentración de Ca2+ sea del orden micromolar e imite niveles del ión durante un estrés. Con respecto al estado de fosforilación de CN, debido a los resultados preliminares, donde solo se la encontró fosforilada en condiciones basales, se piensa que CN podría interactuar con mayor afinidad con PERK cuando CN se encuentre desfosforilada. Por último, se espera encontrar un aumento de eIF2α fosforilado y una acentuación de la atenuación de la síntesis de proteína como consecuencia de la mayor activación de PERK por su asociación con la isoforma β de CN en astrocitos donde el Estrés de RE se indujo por privación de oxigeno y glucosa. Estos experimentos permitirán avanzar en el estudio de una nueva función citoprotectora de CN recientemente descrita por nuestro grupo de trabajo y sus implicancias en un modelo de isquemia. The accumulation of unfolded proteins into the Endoplasmic Reticulum (ER) activates a signal transduction cascade called Unfolding Protein Response (UPR), which attempts to restore homeostasis in the organelle. (PKR)-like-ER kinase (PERK) is an early stress response transmembrane protein that is generally inactive due to its association with the chaperone BIP. During ER stress, BIP is tritrated by the unfolded protein, leading PERK activation and phosphorylation of eukaryotic initiation factor-2 alpha (eIF2alpha), which attenuates protein síntesis. If ER damage is too great and homeostasis is not restored within a certain period of time, an apoptotic response is elicited. We recently demonstrated a cytosolic Ca2+ increase in Xenopus oocytes after induce ER stress. Moreover, calcineurin A/B, a an heterotrimeric Ca2+ dependent phosphatases (CN-A/B), associates with PERK increasing its auto-phosphorylation and significantly enhancing cell viability. Preliminary results suggest that, CN-Aβ-/- knockout astrocytes exhibit a significant higher eIF2α phosphorylated level compared to CN-Aα-/- astrocytes. Our working hypothesis establishes that: CN binds to PERK when cytosolic Ca2+ is initially increased by ER stress, promoting dimerization and autophosphorylation, which leads to phosphorylation of elF2α and subsequently attenuation of protein translation. When cytosolic Ca2+ returns to resting levels, PERK phosphorylates CN, reducing its binding affinity so that the CN/PERK complex dissociates. The goal of this project is to determine the conditions by which CN binding to PERK attenuates protein translation during the ER stress response and subsequently, to determine how the interaction of CN with PERK is terminated when stress is removed. To perform this project is planed to do molecular biology experiments, pull down assays, in vitro phosphorylations and assess overall mRNA translation efficiency doing a polisome profile.

Conscious procreation: neo-malthusianism in southern Europe and Latin America in around 1900

One main concern of Ecological Economics is the balance between human population and natural resources. This is rightly named the Malthusian question because Malthus predicted that human populations, if unchecked, would grow exponentially while agricultural production (and other land-based productions) would be subject to decreasing returns to the labour input. This article shows that over one hundred years ago, there was in Europe and America a successful social movement that called itself Neo-Malthusianism. In contrast to Malthus’ pessimism, it believed that population growth could be stopped among the poor classes by voluntary decisions. Women were entitled to choose the number of children they wanted to have. The movement did not appeal to the State to impose restrictions on population growth. On the contrary, in Southern Europe it was based on "bottom up" activism against governments and the Catholic Church.

Human capital as a factor of growth and employment at the regional level. The case of Spain

We use statistical techniques to quantify the effects of school attainment on individual wages, participation rates and employment probabilities in Spain, and to measure the contribution of education to labour productivity at the regional level. These estimates are then combined with data on private and public expenditure on education and with information on taxes and social benefits to construct measures of the private and social returns to schooling, to explore the effects of public policies on private incentives to invest in human capital, and to analyse the long-term effects of schooling on public finances. The results are used, together with estimates of the returns to alternative assets, to draw some tentative conclusions regarding the adequacy of the aggregate investment patterns observed in the regions of Spain, and to identify changes in the design of national and EU cohesion and growth policies that may help enhance their effectiveness.

Decomposing differences in total factor productivity across firm size

This paper investigates the extent to which the gap in total factor productivity between small and large firms is due to differences in the endowment of factors determining productivity and to the returns associated with these factors. We place particular emphasis on the contribution of differences in the propensity to innovate and in the use of skilled labor across firms of different size. Empirical evidence from a representative sample of Spanish manufacturing firms corroborates that both differences in endowments and returns to innovation and skilled labor significantly contribute to the productivity gap between small and large firms. In addition, it is observed that the contribution of innovation to this gap is caused only by differences in quantity, while differences in returns have no effect; in the case of human capital, however, most of the effect can be attributed to increasing differences in returns between small and large firms.

Education and Economic Development in India

This brief survey examines the returns to education in India , and then examines the role of education on both economic growth and economic development with particular reference to India. Throughout, the objective is to draw out the implications of the empirical results for education policy. The results suggest that female education is of particular importance in India. They also suggest that perhaps because of the externalities it generates, primary education is more important than might be deduced from its relatively low private rate of return.

Bayesian Model Averaging in the Instrumental Variable Regression Model

This paper considers the instrumental variable regression model when there is uncertainty about the set of instruments, exogeneity restrictions, the validity of identifying restrictions and the set of exogenous regressors. This uncertainty can result in a huge number of models. To avoid statistical problems associated with standard model selection procedures, we develop a reversible jump Markov chain Monte Carlo algorithm that allows us to do Bayesian model averaging. The algorithm is very exible and can be easily adapted to analyze any of the di¤erent priors that have been proposed in the Bayesian instrumental variables literature. We show how to calculate the probability of any relevant restriction (e.g. the posterior probability that over-identifying restrictions hold) and discuss diagnostic checking using the posterior distribution of discrepancy vectors. We illustrate our methods in a returns-to-schooling application.

Marriage as a Rat Race: Noisy Pre-Marital Investments with Assortative Matching

We study the incentive to invest to improve marriage prospects, in a frictionless marriage market with non-transferable utility. Stochastic returns to investment eliminate the multiplicity of equilibria in models with deterministic returns, and a unique equilibrium exists under reasonable conditions. Equilibrium investment is efficient when the sexes are symmetric. However, when there is any asymmetry, including an unbalanced sex ratio, investments are generically excessive. For example, if there is an excess of boys, then there is parental over-investment in boys and under-investment in girls, and total investment will be excessive.

Matching and Sorting in a Global Economy

We develop a neoclassical trade model with heterogeneous factors of production. We consider a world with two factors, labor and .managers., each with a distribution of ability levels. Production combines a manager of some type with a group of workers. The output of a unit depends on the types of the two factors, with complementarity between them, while exhibiting diminishing returns to the number of workers. We examine the sorting of factors to sectors and the matching of factors within sectors, and we use the model to study the determinants of the trade pattern and the effects of trade on the wage and salary distributions. Finally, we extend the model to include search frictions and consider the distribution of employment rates.

Tax smoothing in a business cycle model with capital-skill complementarity

This paper undertakes a normative investigation of the quantitative properties of optimal tax smoothing in a business cycle model with state contingent debt, capital-skill complementarity, endogenous skill formation and stochastic shocks to public consumption as well as total factor and capital equipment productivity. Our main finding is that an empirically relevant restriction which does not allow the relative supply of skilled labour to adjust in response to aggregate shocks, signi cantly changes the cyclical properties of optimal labour taxes. Under a restricted relative skill supply, the government fi nds it optimal to adjust labour income tax rates so that the average net returns to skilled and unskilled labour hours exhibit the same dynamic behaviour as under fl exible skill supply.

Does Internationalization Alter the R&D-Productivity Relationship?

R&D investment is an important driver of productivity gains. However, firms differ in their ability to appropiate the returns to their R&D efforts. This paper analyses to what extent firm's internationalization influences the endogenous relation between R&D and productivity. In particular, we assess the contribution of R&D to productivity for a panel of UK firms that differ in their degree of internationalization. We find that, on average, multinationals obtain higher gains from their investment in R&D. However, the influence of internationalization on the contribution of R&D to productivity varies along the distribution of the returns to R&D. Keywords: R&D, Multinationals, Productivity. JEL Codes: C14, D24, F23.

Infrastructures and productivity: an updated survey

The relationship between infrastructures and productivity has been the subject of an ongoing debate during the last two decades. The available empirical evidence is inconclusive and its interpretation is complicated by econometric problems that have not been fully solved. This paper surveys the relevant literature, focusing on studies that estimate aggregate production functions or growth regressions, and extracts some tentative conclusions. On the whole, my reading of the evidence is that there are sufficient indications that public infrastructure investment contributes significantly to productivity growth, at least for countries where a saturation point has not been reached. The returns to such investment are probably quite high in early stages, when infrastructures are scarce and basic networks have not been completed, but fall sharply thereafter. Hence, appropriate infrastructure provision is probably a key input for development policy, even if it does not hold the key to rapid productivity growth in advanced countries where transportation and communications needs are already adequately served.

Human capital and productivity

This paper surveys the empirical literature on human capital and productivity and summarizes the results of my own work on the subject. On balance, the available evidence suggests that investment in education has a positive, significant and sizable effect on productivity growth. According to my estimates, moreover, the social returns to investment in human capital are higher than those on physical capital in most EU countries and in many regions of Spain.

Sectoral composition and macroeconomic dynamics

We analyze the transitional dynamics of a model with heterogeneous consumption goods. In this model, convergence is driven by two different forces: the typical diminishing returns to capital and the sectoral change inducing the variation in relative prices. We show that this second force affects the growth rate if the two consumption goods are not Edgeworth independent and if these two goods are produced with technologies exhibiting different capital intensities. Because the afore mentioned dynamic sectoral change arises only under heterogeneous consumption goods, the transitional dynamics of this model exhibits striking differences with the growth model with a single consumption good. We also show that these differences in the transitional dynamics can give raise to large discrepancies in the welfare cost of shocks between the economy with a unique consumption good and the economy with multiple consumption goods.

Changes in wage structure in Mexico going beyond the mean: An analysis of differences in distribution, 1987-2008

This paper conducts an empirical analysis of the relationship between wage inequality, employment structure, and returns to education in urban areas of Mexico during the past two decades (1987-2008). Applying Melly’s (2005) quantile regression based decomposition, we find that changes in wage inequality have been driven mainly by variations in educational wage premia. Additionally, we find that changes in employment structure, including occupation and firm size, have played a vital role. This evidence seems to suggest that the changes in wage inequality in urban Mexico cannot be interpreted in terms of a skill-biased change, but rather they are the result of an increasing demand for skills during that period.

Effect of malaria and fever on energy metabolism in Gambian children.

The aim of the present study was to measure the changes in resting energy expenditure (REE) induced by malaria and to assess to what extent they are related to fever and nutritional status. The REE of 19 Gambian children (mean age +/- SEM, 9 +/- 1 y; weight, 24 +/- 2 kg; expected weight for height 86 +/- 1%) were measured with a hood system at repeated intervals at the onset of malaria crisis (test A), 3 to 4 d after therapy (test B), and 14 to 21 d later (test C). Axillary temperature averaged 39.2 +/- 0.1, 36.6 +/- 0.1, and 36.7 +/- 0.1 degrees C in the tests A, B, and C, respectively. REE in test A was significantly higher than REE in test B (223 +/- 10 versus 174 +/- 8 kJ/kg.d, p less than 0.0001), but in test C (169 +/- 8 kJ/kg.d), it did not differ from that observed in test B. The percentage of increase in REE was significantly correlated with the difference in axillary temperature (r = 0.46, p less than 0.05); the slope of the regression line indicated an increase of 6.9% in REE/degree C of fever. Furthermore, the individual increase in REE/degree C was correlated to the percentage of weight for height of the children (r = 0.54, p less than 0.05), indicating that the child's nutritional status influences the magnitude of the hypermetabolism due to fever. We concluded that Gambian children suffering from an acute episode of malaria have an increase in REE averaging 30%; however, REE promptly returns to baseline value a few days after the beginning of therapy.