1,2,3,4-Tetrahydrobenzo[h][1,6]naphthyridines as a new family of potent peripheral-to-midgorge-site inhibitors of acetylcholinesterase: synthesis, pharmacological evaluation and mechanistic studies

A series of 1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridines differently substituted at positions 1, 5, and 9 have been designed from the pyrano[3,2-c]quinoline derivative 1, a weak inhibitor of acetylcholinesterase (AChE) with predicted ability to bind to the AChE peripheral anionic site (PAS), at the entrance of the catalytic gorge. Fourteen novel benzonaphthyridines have been synthesized through synthetic sequences involving as the key step a multicomponent Povarov reaction between an aldehyde, an aniline and an enamine or an enamide as the activated alkene. The novel compounds have been tested against Electrophorus electricus AChE (EeAChE), human recombinant AChE (hAChE), and human serum butyrylcholinesterase (hBChE), and their brain penetration has been assessed using the PAMPA-BBB assay. Also, the mechanism of AChE inhibition of the most potent compounds has been thoroughly studied by kinetic studies, a propidium displacement assay, and molecular modelling. We have found that a seemingly small structural change such as a double O → NH bioisosteric replacement from the hit 1 to 16a results in a dramatic increase of EeAChE and hAChE inhibitory activities (>217- and >154-fold, respectively), and in a notable increase in hBChE inhibitory activity (> 11-fold), as well. An optimized binding at the PAS besides additional interactions with AChE midgorge residues seem to account for the high hAChE inhibitory potency of 16a (IC50 = 65 nM), which emerges as an interesting anti-Alzheimer lead compound with potent dual AChE and BChE inhibitory activities.

Efficiency and environmental regulation: a 'complex situation'

Production of desirable outputs is often accompanied by undesirable by products that have damaging effects on the environment, and whose disposal is frequently regulated by public authorities. In this paper, we compute directional technology distance functions under particular assumptions concerning disposability of bads in order to test for the existence of what we call ‘complex situations’, where the biggest producer is not the greatest polluter. Furthermore, we show that how in such situations, environmental regulation could achieve an effective reduction in the aggregate level of bad outputs without reducing the production of good outputs. Finally, we illustrate our methodology with an empirical application to a sample of Spanish tile ceramic producers.

Endeudamiento y ciclos políticos presupuestarios: el caso de los ayuntamientos catalanes

Este trabajo de investigación se dirige sobre el ámbito de los gobiernos locales y su objetivo es el de analizar cuál es el papel del endeudamiento en los ciclos políticos presupuestarios, contrastando si, en la utilización de este instrumento financiero, se da una distribución temporal estratégica en torno a las citas electorales, y si la existencia de estos ciclos puede resultar un factor explicativo del endeudamiento acumulado en los gobiernos locales. Para el contraste empírico se utilizan datos presupuestarios de los ayuntamientos catalanes con una población superior a los 10.000 habitantes, para los cuales disponemos de datos durante el periodo 1988-1999, en total 86 municipios. La metodología empleada está basada en una Prueba T para muestras relacionadas.

Efficiency and quality in local government management: the case of Spanish local authorities

This study analyses efficiency levels in Spanish local governments and their determining factors through the application of DEA (Data Envelopment Analysis) methodology. It aims to find out to what extent inefficiency arises from external factors beyond the control of the entity, or on the other hand, how much it is due to inadequate management of productive resources. The results show that on the whole, there is still a wide margin within which managers could increase local government efficiency levels, although it is revealed that a great deal of inefficiency is due to exogenous factors. It is specifically found that the size of the entity, per capita tax revenue, the per capita grants or the amount of commercial activity are some of the factors determining local government inefficiency.

Modelo para la idenfiticación de grupos estratégicos basado en el análisis envolvente de datos: aplicación al sector bancario español

Este trabajo explora la formación de grupos estratégicos en el Sector Bancario Español, a partir de una definición alternativa de grupo estratégico (GE). Un GE se define como un conjunto de empresas capaces de responder del mismo modo a perturbaciones. La capacidad de respuesta, o capacidad de adaptar la estrategia competitiva, se define a partir de las relaciones marginales (RM) entre las variables estratégicas (la pendiente de la frontera en un punto), y sirve de base para examinar la presencia de barreras a la movilidad. El Análisis Envolvente de Datos (DEA) es la herramienta utilizada para el cómputo de las RM, aunque su uso genera dos problemas que son solucionados en este trabajo; la multiplicidad de RM para las empresas situadas en la frontera (líderes estratégicos), y la imposibilidad de encontrar RM para las empresas situadas por debajo de la misma (seguidores estratégicos).

Estudi del procés d'adsorció en carbó actiu granular per eliminar colorants tèxtils

L’objectiu principal d’aquest projecte és estudiar la capacitat d’adsorció del colorant comercial Gris Lanaset G en carbó actiu granular (GAC); per assolir aquest objectiu es compara l’eficàcia d’adsorció d’aquest carbó respecte altres adsorbents i l’eficàcia d’eliminació d’un altre colorant més simple sobre aquest carbó.

The 2004 election in Spain: terrorism, accountability, and voting

In this paper the electoral consequences of the Islamist terrorist attacks on March 11, 2004 are analysed. According to a quantitative analysis based on a post-electoral survey, we show the causal mechanisms that transform voters’ reactions to the bombings into a particular electoral behaviour and estimate their relevance in the electoral results on March 14, 2004