Synthesis, binding affinity and SAR of new benzolactam derivatives as dopamine D3 receptor ligands

A series of new benzolactam derivatives was synthesized and the derivatives were evaluated for theiraffinities at the dopamine D1, D2, and D3 receptors. Some of these compounds showed high D2 and/orD3 affinity and selectivity over the D1 receptor. The SAR study of these compounds revealed structuralcharacteristics that decisively influenced their D2 and D3 affinities. Structural models of the complexesbetween some of the most representative compounds of this series and the D2 and D3 receptors wereobtained with the aim of rationalizing the observed experimental results. Moreover, selected compoundsshowed moderate binding affinity on 5-HT2A which could contribute to reducing the occurrence of extrapyramidalside effects as potential antipsychotics.

Multiple non-collinear TF-map alignments of promoter regions

Background: The analysis of the promoter sequence of genes with similar expression patterns isa basic tool to annotate common regulatory elements. Multiple sequence alignments are on thebasis of most comparative approaches. The characterization of regulatory regions from coexpressedgenes at the sequence level, however, does not yield satisfactory results in manyoccasions as promoter regions of genes sharing similar expression programs often do not shownucleotide sequence conservation.Results: In a recent approach to circumvent this limitation, we proposed to align the maps ofpredicted transcription factors (referred as TF-maps) instead of the nucleotide sequence of tworelated promoters, taking into account the label of the corresponding factor and the position in theprimary sequence. We have now extended the basic algorithm to permit multiple promotercomparisons using the progressive alignment paradigm. In addition, non-collinear conservationblocks might now be identified in the resulting alignments. We have optimized the parameters ofthe algorithm in a small, but well-characterized collection of human-mouse-chicken-zebrafishorthologous gene promoters.Conclusion: Results in this dataset indicate that TF-map alignments are able to detect high-levelregulatory conservation at the promoter and the 3'UTR gene regions, which cannot be detectedby the typical sequence alignments. Three particular examples are introduced here to illustrate thepower of the multiple TF-map alignments to characterize conserved regulatory elements inabsence of sequence similarity. We consider this kind of approach can be extremely useful in thefuture to annotate potential transcription factor binding sites on sets of co-regulated genes fromhigh-throughput expression experiments.

Conserved chromosomal clustering of genes governed by chromatin regulators in Drosophila

BACKGROUND: The trithorax group (trxG) and Polycomb group (PcG) proteins are responsible for the maintenance of stable transcriptional patterns of many developmental regulators. They bind to specific regions of DNA and direct the post-translational modifications of histones, playing a role in the dynamics of chromatin structure. RESULTS: We have performed genome-wide expression studies of trx and ash2 mutants in Drosophila melanogaster. Using computational analysis of our microarray data, we have identified 25 clusters of genes potentially regulated by TRX. Most of these clusters consist of genes that encode structural proteins involved in cuticle formation. This organization appears to be a distinctive feature of the regulatory networks of TRX and other chromatin regulators, since we have observed the same arrangement in clusters after experiments performed with ASH2, as well as in experiments performed by others with NURF, dMyc, and ASH1. We have also found many of these clusters to be significantly conserved in D. simulans, D. yakuba, D. pseudoobscura and partially in Anopheles gambiae. CONCLUSION: The analysis of genes governed by chromatin regulators has led to the identification of clusters of functionally related genes conserved in other insect species, suggesting this chromosomal organization is biologically important. Moreover, our results indicate that TRX and other chromatin regulators may act globally on chromatin domains that contain transcriptionally co-regulated genes.

Transcription factor map alignment of promoter regions

We address the problem of comparing and characterizing the promoter regions of genes with similar expression patterns. This remains a challenging problem in sequence analysis, because often the promoter regions of co-expressed genes do not show discernible sequence conservation. In our approach, thus, we have not directly compared the nucleotide sequence of promoters. Instead, we have obtained predictions of transcription factor binding sites, annotated the predicted sites with the labels of the corresponding binding factors, and aligned the resulting sequences of labels—to which we refer here as transcription factor maps (TF-maps). To obtain the global pairwise alignment of two TF-maps, we have adapted an algorithm initially developed to align restriction enzyme maps. We have optimized the parameters of the algorithm in a small, but well-curated, collection of human–mouse orthologous gene pairs. Results in this dataset, as well as in an independent much larger dataset from the CISRED database, indicate that TF-map alignments are able to uncover conserved regulatory elements, which cannot be detected by the typical sequence alignments.

Synthesis, binding affinity, and molecular docking analysis of new benzofuranone derivative as pontential antipsychotics

The complex etiology of schizophrenia has prompted researchers to develop clozapine-related multitargetstrategies to combat its symptoms. Here we describe a series of new 6-aminomethylbenzofuranones in aneffort to find new chemical structures with balanced affinities for 5-HT2 and dopamine receptors. Throughbiological and computational studies of 5-HT2A and D2 receptors, we identified the receptor serine residuesS3.36 and S5.46 as the molecular keys to explaining the differences in affinity and selectivity betweenthese new compounds for this group of receptors. Specifically, the ability of these compounds to establishone or two H-bonds with these key residues appears to explain their difference in affinity. In addition, wedescribe compound 2 (QF1004B) as a tool to elucidate the role of 5-HT2C receptors in mediating antipsychoticeffects and metabolic adverse events. The compound 16a (QF1018B) showed moderate to high affinitiesfor D2 and 5-HT2A receptors, and a 5-HT2A/D2 ratio was predictive of an atypical antipsychotic profile.

Prediction of enzyme function by combining sequence similarity and protein interactions

Background: A number of studies have used protein interaction data alone for protein function prediction. Here, we introduce a computational approach for annotation of enzymes, based on the observation that similar protein sequences are more likely to perform the same function if they share similar interacting partners. Results: The method has been tested against the PSI-BLAST program using a set of 3,890 protein sequences from which interaction data was available. For protein sequences that align with at least 40% sequence identity to a known enzyme, the specificity of our method in predicting the first three EC digits increased from 80% to 90% at 80% coverage when compared to PSI-BLAST. Conclusion: Our method can also be used in proteins for which homologous sequences with known interacting partners can be detected. Thus, our method could increase 10% the specificity of genome-wide enzyme predictions based on sequence matching by PSI-BLAST alone.

The Multiscenario Multienvironment BioSecure Multimodal Database (BMDB)

A new multimodal biometric database designed and acquired within the framework of the European BioSecure Network of Excellence is presented. It is comprised of more than 600 individuals acquired simultaneously in three scenarios: 1) over the Internet, 2) in an office environment with desktop PC, and 3) in indoor/outdoor environments with mobile portable hardware. The three scenarios include a common part of audio/video data. Also, signature and fingerprint data have been acquired both with desktop PC and mobile portable hardware. Additionally, hand and iris data were acquired in the second scenario using desktop PC. Acquisition has been conducted by 11 European institutions. Additional features of the BioSecure Multimodal Database (BMDB) are: two acquisitionsessions, several sensors in certain modalities, balanced gender and age distributions, multimodal realistic scenarios with simple and quick tasks per modality, cross-European diversity, availability of demographic data, and compatibility with other multimodal databases. The novel acquisition conditions of the BMDB allow us to perform new challenging research and evaluation of eithermonomodal or multimodal biometric systems, as in the recent BioSecure Multimodal Evaluation campaign. A description of this campaign including baseline results of individual modalities from the new database is also given. The database is expected to beavailable for research purposes through the BioSecure Association during 2008.

Recursos sobre protección de los derechos de la mujer en Internet

Con el objetivo de contribuir a salvaguardar los derechos fundamentales de las mujeres, hemos realizado este trabajo en el que intentamos recoger de la manera más exhaustiva que permita un medio tan voluble y cambiantecomo internet, los recursos existentes en la red sobre la Protección de los Derechos de la Mujer, y de esta manera facilitar el acceso a los mismos. La intención que ha guiado desde un principio a la elaboración de estaobra ha sido proporcionar un recurso de información práctica a aquellos profesionalesque desarrollan tareas relacionadas con la protección de los derechos de la mujer, así como a cualquier otra persona interesada o que necesite estar informada sobre esta temática. Así pues, el objetivo que nos hemos marcado no ha sido otro que el dedesarrollar una guía que permita a sus usuarios/as encontrar en internet aquellas direcciones sobre Derechos de la Mujer que facilitan un contenido sustancial e interesante.

Spanning tests in return and stochastic discount factor mean-variance frontiers: A unifying approach

We propose new spanning tests that assess if the initial and additional assets share theeconomically meaningful cost and mean representing portfolios. We prove their asymptoticequivalence to existing tests under local alternatives. We also show that unlike two-step oriterated procedures, single-step methods such as continuously updated GMM yield numericallyidentical overidentifyng restrictions tests, so there is arguably a single spanning test.To prove these results, we extend optimal GMM inference to deal with singularities in thelong run second moment matrix of the influence functions. Finally, we test for spanningusing size and book-to-market sorted US stock portfolios.

A unifying approach to the empirical evaluation of asset pricing models

Two main approaches are commonly used to empirically evaluate linear factor pricingmodels: regression and SDF methods, with centred and uncentred versions of the latter.We show that unlike standard two-step or iterated GMM procedures, single-step estimatorssuch as continuously updated GMM yield numerically identical values for prices of risk,pricing errors, Jensen s alphas and overidentifying restrictions tests irrespective of the modelvalidity. Therefore, there is arguably a single approach regardless of the factors being tradedor not, or the use of excess or gross returns. We illustrate our results by revisiting Lustigand Verdelhan s (2007) empirical analysis of currency returns.

Duality in mean-variance frontiers with conditioning information

Portfolio and stochastic discount factor (SDF) frontiers are usually regarded as dual objects, and researchers sometimes use one to answer questions about the other. However, the introduction of conditioning information and active portfolio strategies alters this relationship. For instance, the unconditional portfolio frontier in Hansen and Richard (1987) is not dual to the unconditional SDF frontier in Gallant, Hansen and Tauchen (1990). We characterise the dual objects to those frontiers, and relate them to the frontiers generated with managed portfolios, which are commonly used in empirical work. We also study the implications of a safe asset and other special cases.

Sistema de gestión de información de jugadores de baloncesto

Proyecto para la gestión de información relativa a jugadores profesionales de baloncesto a nivel mundial, así como de sus estadísticas de juego y contratos.

Experiencia con Telaprevir en una corte de pacientes monoinfectados y coinfectados en un hospital de tercer nivel

Objetivos: avaluar tasas de respuestas y seguridad, a las 24 semanas del inicio de tratamiento, en pacientes monoinfectados por VHC y coinfectados VIH/VHC con Telaprevir. Métodos: estudio descriptivo transversal de los pacientes mono y coinfectados (tanto “naive”, recaedores, no respondedores y respondedores parciales), tratados con Telaprevir en una Unidad de Enfermedades Infecciosas. Se recogieron los datos demográficos de cada paciente, datos analíticos, inmunológicos y virológicos así como la determinación de polimorfismo IL B28. Se recogen datos basales y a las 4, 8, 12 y 24 semanas. Resultados: un total de 43 pacientes analizados que iniciaron tratamiento con Telaprevir. Completan tratamiento hasta 12 semanas los 43, y hasta la semana 24 con Peginterferon y Rivabirina un total de 35 pacientes. Un 48% eran pacientes monoinfectados y un 51% coinfectados VIH-VHC. Un 80% eran hombres y un 20% mujeres, con una edad media de 52 años +/- 8´79. A las 12 semanas, un 76% de los pacientes monoinfectados y un 86% de los coinfectados tenían indetectable VHC, y a las 24 semanas un 86% de los monoinfectados y un 90% de los coinfectados, mantenían respuesta viral en tratamiento, sin ser estas diferencias estadísticamente significativas. De la misma forma no se encontraron diferencias estadísticamente significativas en las proporciones de efectos secundarios. Conclusiones: la efectividad y la seguridad del tratamiento con triple terapia que incluye Teleprevir en la infección crónica de VHC, son similares en pacientes monoinfectados y coinfectados.

Multiple city

Concurs d'idees per a l'ordenació de l'àmbit sector 'Eixample Nord' al terme municipal de Vilanova i la Geltrú

Estudio de base y definición de proyectos piloto para un PROGRAMA NACIONAL DE ELECTRIFICACIÓN RURAL EN PARAGUAY

El presente Informe es el Informe Final de los servicios de Cooperación Técnica “Programa Nacional de Electrificación Rural de Paraguay” CT 1039. Contiene los resultados de todas las actividades realizadas e integra los contenidos revisados de documentos anteriores. Los trabajos realizados para este informe han sido dirigidos por el Ing. Xavier Vallvé. Los autores del informe son los Ing. Pol Arranz-Piera, Ing. Jean-Claude Pulfer, con la colaboración del Ing. Enrique Velo y las aportaciones del Lic. Jaume Serrasolses y Sr. Jorge Sneij.