Programa de Apoyo a los Pequeños Países Insulares en Desarrollo: algunas consideraciones iniciales = Programme of Support for Small Island Developing Countries: some initial considerations = Programme d'Aide aux Pays en Développement sur de Petites Iles: quelques considerations initiales

Aborda los problemas especificos que enfrentan los pequenos paises insulares en desarrollo, como sus limitados recursos, altos costos de produccion y de niveles de dependencia del comercio exterior, los problemas en la provision de servicios sociales, etc. Plantea algunas consideraciones iniciales para elaborar programas y proyectos de apoyo encaminados a superar dichos problemas.

Resoluciones y decisiones de la CEPAL y sus organismos subsidiarios que traen consecuencias para el CDCC = Action taken on CDCC resolutions and those of ECLAC, ECOSOC and the United Nations General Assembly with implications for CDCC = Actions relatives aux résolutions du CDCC et a celles de la CEPALC, du Conseil Economique et Social et de l'Assemblée Générale des Nations Unies ayant des incidences sur le CDCC

Revisa las acciones tomadas en relacion con las resoluciones del CDCC y aquellas de la CEPAL, Consejo Economico y Social y Asamblea General de las Naciones Unidas con implicancias para el CDCC.

Action taken on CDCC resolutions and resolutions of ECLAC and other United Nations bodies with implications for CDCC = Actions relatives aux résolutions du CDCC de la CEPALC et d'autres organismes des Nations Unies ayant des incidences sur le CDCC

Revisa las acciones seguidas en relacion con resoluciones del CDCC, la CEPAL y otros organismos de Naciones Unidas, con repercusiones para el CDCC.

Informe de la Reunión del Grupo Especial de Trabajo Establecido en Virtud de la Resolución 553(XXVI) = Report of the Meeting of the Ad Hoc Working Group Established Pursuant to Resolution 553(XXVI) = Rapport de la Réunion du Groupe de Travail Spécial Créé aux Termes de la Résolution 553(XXVI)

Incluye Bibliografía

Informe de avance del Grupo Especial de Trabajo Establecido en Virtud de la Resolución 553(XXVI) = Progress report of the Ad Hoc Working Group Established Pursuant to Resolution 553(XXVI) = Rapport sur l'état des travaux du Groupe de Travail Spécial Créé aux Termes de la Résolution 553(XXVI)

Incluye Bibliografía

Os aspectos realistas e mitológicos em Le chercheur d'or, de J. M.-G. Le Clézio

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Functional characterisation of in vitro synthesised G-protein coupled receptors in polymersomes

Membrane proteins play an indispensable role in physiological processes. It is, therefore, not surprising that many diseases are based on the malfunction of membrane proteins. Hence membrane proteins and especially G-protein coupled receptors(GPCRs)- the largest subfamily- have become an important drug target. Due to their high selectivity and sensitivity membrane proteins are also feasible for the detection of small quantities of substances with biosensors. Despite this widespread interest in GPCRs due to their importance as drug targets and biosensors there is still a lack of knowledge of structure, function and endogenous ligands for quiet a few of the previously identified receptors.rnBottlenecks in over-expression, purification, reconstitution and handling of membrane proteins arise due to their hydrophobic nature. Therefore the production of reasonable amounts of functional membrane proteins for structural and functional studies is still challenging. Also the limited stability of lipid based membrane systems hampers their application as platforms forrnscreening applications and biosensors.rnIn recent years the in vitro protein synthesis became a promising alternative to gain better yields for expression of membrane proteins in bio-mimetic membrane systems. These expression systems are based on cell extracts. Therefore cellular effects on protein expression are reduced. The open nature of the cell-free expression systems easily allows for the adjustment of reactionrnconditions for the protein of interest. The cell-free expression in the presence of bio-mimetic membrane systems allows the direct incorporation of the membrane proteins and therefore skips the time-consuming purification and reconstitution processes. Amphiphilic block-copolymers emerged as promising alternative for the less stable lipid-based membrane systems. They, likernlipids, form membraneous structures in aqueous solutions but exhibit increased mechanical and chemical stability.rnThe aim of this work was the generation of a GPCR-functionalised membrane system by combining both promising alternatives: in vitro synthesis and polymeric membrane systems. This novel platform should be feasible for the characterisation of the incorporated GPCR. Immunodetection of Dopamine receptor 1 and 2 expressed in diblock- and triblock-polymersomes demonstrated the successful in vitro expression of GPCRs in polymeric membranes. Antibodyrnbinding studies suggested a favoured orientation of dopamine receptors in triblockpolymersomes.rnA dopamine-replacement assay on DRD2-functionalised immobilised triblockpolymersomes confirmed functionality of the receptor in the polymersomes. The altered binding curve suggests an effect of the altered hydrophobic environment presented by the polymer membrane on protein activity.

Induction of RAGE shedding by activation of G-protein-coupled receptors

The multiligand Receptor for Advanced Glycation End products (RAGE) is involved in various pathophysiological processes, including diabetic inflammatory conditions and Alzheimers disease. Full-length RAGE, a cell surface-located type I membrane protein, can proteolytically be converted by metalloproteinases ADAM10 and MMP9 into a soluble RAGE form. Moreover, administration of recombinant soluble RAGE suppresses activation of cell surface-located RAGE by trapping RAGE ligands. Therefore stimulation of RAGE shedding might have a therapeutic value regarding inflammatory diseases. We aimed to investigate whether RAGE shedding is inducible via ligand-induced activation of G protein-coupled receptors (GPCRs). We chose three different GPCRs coupled to distinct signaling cascades: the V2 vasopressin receptor (V2R) activating adenylyl cyclase, the oxytocin receptor (OTR) linked to phospholipase Cβ, and the PACAP receptor (subtype PAC1) coupled to adenylyl cyclase, phospholipase Cβ, calcium signaling and MAP kinases. We generated HEK cell lines stably coexpressing an individual GPCR and full-length RAGE and then investigated GPCR ligand-induced activation of RAGE shedding. We found metalloproteinase-mediated RAGE shedding on the cell surface to be inducible via ligand-specific activation of all analyzed GPCRs. By using specific inhibitors we have identified Ca2+ signaling, PKCα/PKCβI, CaMKII, PI3 kinases and MAP kinases to be involved in PAC1 receptor-induced RAGE shedding. We detected an induction of calcium signaling in all our cell lines coexpressing RAGE and different GPCRs after agonist treatment. However, we did not disclose a contribution of adenylyl cyclase in RAGE shedding induction. Furthermore, by using a selective metalloproteinase inhibitor and siRNAmediated knock-down approaches, we show that ADAM10 and/or MMP9 are playing important roles in constitutive and PACAP-induced RAGE shedding. We also found that treatment of mice with PACAP increases the amount of soluble RAGE in the mouse lung. Our findings suggest that pharmacological stimulation of RAGE shedding might open alternative treatment strategies for Alzheimers disease and diabetes-induced inflammation.

Targeting G protein-coupled receptor kinases (GRKs) in Heart Failure

In the human body, over 1000 different G protein-coupled receptors (GPCRs) mediate a broad spectrum of extracellular signals at the plasma membrane, transmitting vital physiological features such as pain, sight, smell, inflammation, heart rate and contractility of muscle cells. Signaling through these receptors is primarily controlled and regulated by a group of kinases, the GPCR kinases (GRKs), of which only seven are known and thus, interference with these common downstream GPCR regulators suggests a powerful therapeutic strategy. Molecular modulation of the kinases that are ubiquitously expressed in the heart has proven GRK2, and also GRK5, to be promising targets for prevention and reversal of one of the most severe pathologies in man, chronic heart failure (HF). In this article we will focus on the structural aspects of these GRKs important for their physiological and pathological regulation as well as well known and novel therapeutic approaches that target these GRKs in order to overcome the development of cardiac injury and progression of HF.