Discovery and characterization of a novel non-competitive inhibitor of the divalent metal transporter DMT1/SLC11A2

Divalent metal transporter-1 (SLC11A2/DMT1) uses the H+ electrochemical gradient as the driving force to transport divalent metal ions such as Fe2+, Mn2+ and others metals into mammalian cells. DMT1 is ubiquitously expressed, most notably in proximal duodenum, immature erythroid cells, brain and kidney. This transporter mediates H+-coupled transport of ferrous iron across the apical membrane of enterocytes. In addition, in cells such as to erythroid precursors, following transferrin receptor (TfR) mediated endocytosis; it mediates H+-coupled exit of ferrous iron from endocytic vesicles into the cytosol. Dysfunction of human DMT1 is associated with several pathologies such as iron deficiency anemia hemochromatosis, Parkinson's disease and Alzheimer's disease, as well as colorectal cancer and esophageal adenocarcinoma, making DMT1 an attractive target for drug discovery. In the present study, we performed a ligand-based virtual screening of the Princeton database (700,000 commercially available compounds) to search for pharmacophore shape analogs of recently reported DMT1 inhibitors. We discovered a new compound, named pyrimidinone 8, which mediates a reversible linear non-competitive inhibition of human DMT1 (hDMT1) transport activity with a Ki of ∼20 μM. This compound does not affect hDMT1 cell surface expression and shows no dependence on extracellular pH. To our knowledge, this is the first experimental evidence that hDMT1 can be allosterically modulated by pharmacological agents. Pyrimidinone 8 represents a novel versatile tool compound and it may serve as a lead structure for the development of therapeutic compounds for pre-clinical assessment.

Studies of the effects of industrial change on labor markets /

Report no. L-6-L-9 published: Federal Works Agency, Work Projects Administration.

Minority employment prospects in public v. private sector labor markets /

Typescript (photocopy)

Public service employment : the impact on Washington State's nonmetropolitan labor markets /

Issued Mar. 1980.

Labor markets in the rural south : a study based on four rural southern counties /

Bibliographical footnotes.

Monopolistic insurance and competitive financial markets

This dissertation studies the interaction between insurance and financial markets. Individuals who differ only in risk can save through a competitive market. They also have access to insurance contracts offered by a monopolist firm. We show that an equilibrium exists in that economy. Fundamentally, we identify an externality imposed on the insurer's decision by the endogeneity of prices in the financial market.We argue that, because of such externality and in contrast to the pure contract theory case, equilibrium may exhibit pooling.

Trade Shocks and Local Labor Markets' Linkages: Theory and Evidence

In the past few years, there has been a concern among economists and policy makers that increased openness to international trade affects some regions in a country more than others. Recent research has found that local labor markets more exposed to import competition through their initial employment composition experience worse outcomes in several dimensions such as, employment, wages, and poverty. Although there is evidence that regions within a country exhibit variation in the intensity with which they trade with each other and with other countries, trade linkages have been ignored in empirical analyses of the regional effects of trade, which focus on differences in employment composition. In this dissertation, I investigate how local labor markets' trade linkages shape the response of wages to international trade shocks. In the second chapter, I lay out a standard multi-sector general equilibrium model of trade, where domestic regions trade with each other and with the rest of the world. Using this benchmark, I decompose a region's wage change resulting from a national import cost shock into a direct effect on prices, holding other endogenous variables constant, and a series of general equilibrium effects. I argue the direct effect provides a natural measure of exposure to import competition within the model since it summarizes the effect of the shock on a region's wage as a function of initial conditions given by its trade linkages. I call my proposed measure linkage exposure while I refer to the measures used in previous studies as employment exposure. My theoretical analysis also shows that the assumptions previous studies make on trade linkages are not consistent with the standard trade model. In the third chapter, I calibrate the model to the Brazilian economy in 1991--at the beginning of a period of trade liberalization--to perform a series of experiments. In each of them, I reduce the Brazilian import cost by 1 percent in a single sector and I calculate how much of the cross-regional variation in counterfactual wage changes is explained by exposure measures. Over this set of experiments, employment exposure explains, for the median sector, 2 percent of the variation in counterfactual wage changes while linkage exposure explains 44 percent. In addition, I propose an estimation strategy that incorporates trade linkages in the analysis of the effects of trade on observed wages. In the model, changes in wages are completely determined by changes in market access, an endogenous variable that summarizes the real demand faced by a region. I show that a linkage measure of exposure is a valid instrument for changes in market access within Brazil. By using observed wage changes in Brazil between 1991-2000, my estimates imply that a region at the 25th percentile of the change in domestic market access induced by trade liberalization, experiences a 0.6 log points larger wage decline (or smaller wage increase) than a region at the 75th percentile. The estimates from a regression of wages changes on exposure imply that a region at the 25th percentile of exposure experiences a 3 log points larger wage decline (or smaller wage increase) than a region at the 75th percentile. I conclude that estimates based on exposure overstate the negative impact of trade liberalization on wages in Brazil. In the fourth chapter, I extend the standard model to allow for two types of workers according to their education levels: skilled and unskilled. I show that there is substantial variation across Brazilian regions in the skill premium. I use the exogenous variation provided by tariff changes to estimate the impact of market access on the skill premium. I find that decreased domestic market access resulting from trade liberalization resulted in a higher skill premium. I propose a mechanism to explain this result: that the manufacturing sector is relatively more intensive in unskilled labor and I show empirical evidence that supports this hypothesis.

Measuring the effectiveness of two public policies on the sectors of labor markets and urban infraestructure. Experimental and quasi-experimental evidence from developing countries

La tesis presenta evidencia rigurosa de la efectividad de las políticas públicas utilizando metodologías experimentales y cuasi-experimentales. La tesis comienza con una introducción completa y una revisión rigurosa de las metodologías que se utilizarán en el análisis posterior de los datos. El primer capítulo, "Habilidades personales y habilidades técnicas en programas de formación de jóvenes. Evidencia Experimental de Largo Plazo de República Dominicana ", evalúa el impacto de un programa de empleo de los jóvenes en una serie de variables de interés. El programa ofrece capacitación en las habilidades vocacionales y en las habilidades no cognitivas a jóvenes en riesgo de exclusión social. Cabe destacar que la metodología utilizada para evaluar el programa es un ensayo controlado aleatorio, que proporciona evidencia robusta del efecto causal del programa. Mientras que estudios previos analizaron el impacto de los programas para jóvenes relacionados, ningún estudio anterior había evaluado los efectos de 4 años después de la implementación del programa. Esto representa una contribución importante debido a que las ganancias a corto plazo de varios programas de desarrollo han demostrado no ser sostenida en el tiempo. Esto es también lo que este estudio encuentra para los resultados del mercado de trabajo: mientras que el programa genera una mejora a corto plazo de los resultados de empleo para las mujeres, este efecto se disipa en el largo plazo. Sin embargo, el programa parece conducir a cambios persistentes en las expectativas del mercado de trabajo de las mujeres: las mujeres que asistieron al entrenamiento de informar una visión más optimista de las perspectivas del mercado de trabajo hasta 4 años después del programa...

Un marco analítico de la discriminación laboral. Teorias, modalidades y estudios para Colombia

Este documento presenta un resumen de las principales corrientes teóricas que han tratado de dar una explicación a la discriminación laboral, asi como una exposición pedagógica de las principales modalidades mediante las cuales dicha discriminación se manifiesta. Se realiza un particular análisis de las consecuencias que dicha discriminación tiene, en particular para el caso de los jóvenes de América Latina, y finalmente se realiza una revisión de los estudios que sobre el tema se han realizado en Colombia, sus aspectos metodológicos y las conclusiones a las que dichos estudios han llegado.

¿Es correcto vincular la política social a la informalidad en México?: una prueba simple de las premisas de esta hipótesis

Incluye Bibliografía

Disinflation with labor market frictions

This paper studies disinflationary shocks in a non-linear New Keynesian model with search and matching frictions and moral hazard in the labor markets. Our focus is on understanding the wage formation process as well as welfare costs of disinflations in the presence of such labor market frictions.

The presence of imperfect information in labor markets imposes a lower bound on worker surplus that varies endogenously. Consequently equilibrium can take two forms depending on whether the no shirking condition is binding or not. We also evaluate both regimes from a welfare perspective when the economy is subject to a perfectly credible disinflationary shock.