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.

A short motif in Drosophila SECIS Binding Protein 2 provides differential binding affinity to SECIS RNA hairpins

Selenoproteins contain the amino acid selenocysteine which is encoded by a UGA Sec codon. Recoding UGA Sec requires a complex mechanism, comprising the cis-acting SECIS RNA hairpin in the 3′UTR of selenoprotein mRNAs, and trans-acting factors. Among these, the SECIS Binding Protein 2 (SBP2) is central to the mechanism. SBP2 has been so far functionally characterized only in rats and humans. In this work, we report the characterization of the Drosophila melanogaster SBP2 (dSBP2). Despite its shorter length, it retained the same selenoprotein synthesis-promoting capabilities as the mammalian counterpart. However, a major difference resides in the SECIS recognition pattern: while human SBP2 (hSBP2) binds the distinct form 1 and 2 SECIS RNAs with similar affinities, dSBP2 exhibits high affinity toward form 2 only. In addition, we report the identification of a K (lysine)-rich domain in all SBP2s, essential for SECIS and 60S ribosomal subunit binding, differing from the well-characterized L7Ae RNA-binding domain. Swapping only five amino acids between dSBP2 and hSBP2 in the K-rich domain conferred reversed SECIS-binding properties to the proteins, thus unveiling an important sequence for form 1 binding.

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.

Conditional equilibrium constants in multicomponent heterogeneous adsorption: The conditional affinity spectrum

The concept of conditional stability constant is extended to the competitive binding of small molecules to heterogeneous surfaces or macromolecules via the introduction of the conditional affinity spectrum (CAS). The CAS describes the distribution of effective binding energies experienced by one complexing agent at a fixed concentration of the rest. We show that, when the multicomponent system can be described in terms of an underlying affinity spectrum [integral equation (IE) approach], the system can always be characterized by means of a CAS. The thermodynamic properties of the CAS and its dependence on the concentration of the rest of components are discussed. In the context of metal/proton competition, analytical expressions for the mean (conditional average affinity) and the variance (conditional heterogeneity) of the CAS as functions of pH are reported and their physical interpretation discussed. Furthermore, we show that the dependence of the CAS variance on pH allows for the analytical determination of the correlation coefficient between the binding energies of the metal and the proton. Nonideal competitive adsorption isotherm and Frumkin isotherms are used to illustrate the results of this work. Finally, the possibility of using CAS when the IE approach does not apply (for instance, when multidentate binding is present) is explored. © 2006 American Institute of Physics.

Affinity distribution functions in multicomponent heterogeneous adsorption. Analytical inversion of isotherms to obtain affinity spectra

An analytical approach for the interpretation of multicomponent heterogeneous adsorption or complexation isotherms in terms of multidimensional affinity spectra is presented. Fourier transform, applied to analyze the corresponding integral equation, leads to an inversion formula which allows the computation of the multicomponent affinity spectrum underlying a given competitive isotherm. Although a different mathematical methodology is used, this procedure can be seen as the extension to multicomponent systems of the classical Sips’s work devoted to monocomponent systems. Furthermore, a methodology which yields analytical expressions for the main statistical properties (mean free energies of binding and covariance matrix) of multidimensional affinity spectra is reported. Thus, the level of binding correlation between the different components can be quantified. It has to be highlighted that the reported methodology does not require the knowledge of the affinity spectrum to calculate the means, variances, and covariance of the binding energies of the different components. Nonideal competitive consistent adsorption isotherm, widely used in metal/proton competitive complexation to environmental macromolecules, and Frumkin competitive isotherms are selected to illustrate the application of the reported results. Explicit analytical expressions for the affinity spectrum as well as for the matrix correlation are obtained for the NICCA case. © 2004 American Institute of Physics.

Determining shoal membership using affinity propagation

We propose using the affinity propagation (AP) clustering algorithm for detecting multiple disjoint shoals, and we present an extension of AP, denoted by STAP, that can be applied to shoals that fusion and fission across time. STAP incorporates into AP a soft temporal constraint that takes cluster dynamics into account, encouraging partitions obtained at successive time steps to be consistent with each other. We explore how STAP performs under different settings of its parameters (strength of the temporal constraint, preferences, and distance metric) by applying the algorithm to simulated sequences of collective coordinated motion. We study the validity of STAP by comparing its results to partitioning of the same data obtained from human observers in a controlled experiment. We observe that, under specific circumstances, AP yields partitions that agree quite closely with the ones made by human observers. We conclude that using the STAP algorithm with appropriate parameter settings is an appealing approach for detecting shoal fusion-fission dynamics.

Generating trees for permutations avoiding generalized patterns

We construct generating trees with with one, two, and three labels for some classes of permutations avoiding generalized patterns of length 3 and 4. These trees are built by adding at each level an entry to the right end of the permutation, which allows us to incorporate the adjacency condition about some entries in an occurrence of a generalized pattern. We use these trees to find functional equations for the generating functions enumerating these classes of permutations with respect to different parameters. In several cases we solve them using the kernel method and some ideas of Bousquet-Mélou [2]. We obtain refinements of known enumerative results and find new ones.

Redirecció de l'especificitat de les cél·lules T contra epítops del VIH restringit per la HLA-A2 mitjaçant transferència genética

Existeixen creixents evidències què la resposta dels limfòcits T CD8+ alpha beta citotòxics (CTLs) és un element fonamental en la infecció produïda pel VIH. Les CTLs VIH especifiques es consideren molt importants en la reducció de la càrrega viral i en la contenció de la infecció. Encara que la combinació dels antiretrovirals (HAART) ha suposat una millora considerable en la lluita contra el VIH induint una important reducció de la càrrega viral i augmentant el nombre de cèl•lules T CD4+, diverses complicacions han fet ressaltar la necessitat de noves alternatives terapèutiques. Les complicacions inclouen: manca de recuperació d’una resposta immune sòlida contra el VIH, toxicitat a llarg termini de la teràpia i el descobriment que les cèl•lules T CD4+ constitueixen un reservori pel virus. Les noves alternatives controlaran la replicació viral i reconstituiran la immunitat. L’eficàcia de la immunoteràpia cel•lular amb transferència adoptiva de CTLs virals específics s’ha provat en diferents infeccions virals humanes, incloent el VIH. Proposem una modificació de la immunoteràpia adoptiva redirigint l’especificitat de les cèl•lules T contra el VIH mitjançant la transfecció dels gens del TCR. En aquest assaig preclínic, ens aprofitarem de la tecnologia dels animals transgènics per les molècules de HLA, amb la finalitat de generar TCRs d’alta afinitat dirigits contra epitops del VIH restringits per la molècula HLA. Aquests TCRs seran induïts in vivo i seleccionats in vitro. Les cadenes alpha i beta dels TCRs VIH específics procedents de les CTLs seran clonades mitjançant tècniques de biologia molecular. Aquests TCRs VIH específics seran transferits a cèl•lules T CD8+ humanes i la seva especificitat i capacitat citolítica contra cèl•lules diana que presentin antígens de VIH-1 s’estudiaran mitjançant la combinació de diverses tècniques noves (FCC, transfecció mitjançant Nucleoefector). Finalment, una construcció retroviral adient per la seva transducció en cèl•lules T humanes s’establirà amb un TCR òptim seleccionat.

Label Space Reduction in All-Optical Label Switchiing Networks

Report for the scientific sojourn at the Department of Information Technology (INTEC) at the Ghent University, Belgium, from january to june 2007. All-Optical Label Swapping (AOLS) forms a key technology towards the implementation of All-Optical Packet Switching nodes (AOPS) for the future optical Internet. The capital expenditures of the deployment of AOLS increases with the size of the label spaces (i.e. the number of used labels), since a special optical device is needed for each recognized label on every node. Label space sizes are affected by the wayin which demands are routed. For instance, while shortest-path routing leads to the usage of fewer labels but high link utilization, minimum interference routing leads to the opposite. This project studies and proposes All-Optical Label Stacking (AOLStack), which is an extension of the AOLS architecture. AOLStack aims at reducing label spaces while easing the compromise with link utilization. In this project, an Integer Lineal Program is proposed with the objective of analyzing the softening of the aforementioned trade-off due to AOLStack. Furthermore, a heuristic aiming at finding good solutions in polynomial-time is proposed as well. Simulation results show that AOLStack either a) reduces the label spaces with a low increase in the link utilization or, similarly, b) uses better the residual bandwidth to decrease the number of labels even more.

Marine biotoxins in the Catalan littoral: could biosensors be integrated into monitoring programmes?

Aquest article descriu els sensors enzimàtics i immunosensors electroquímics que s’han desenvolupat als nostres grups per a la detecció de la biotoxina marina àcid okadaic (OA), i discuteix la possibilitat d’integrar-los en programes de seguiment. Els sensors enzimàtics per a OA que es presenten es basen en la inhibició de la proteïna fosfatasa (PP2A) per aquesta toxina i la mesura electroquímica de l’activitat enzimàtica mitjançant l’ús de substrats enzimàtics apropiats, electroquímicament actius després de la seva desfosforació per l’enzim. Els immunosensors electroquímics descrits en aquest article es basen en un enzimoimmunoassaig sobre fase sòlida competitiu indirecte (ciELISA), amb fosfatasa alcalina (ALP) o peroxidasa (HRP) com a marcatges, i un sistema de reciclatge enzimàtic amb diaforasa (DI). Els biosensors presentats aquí s’han aplicat a l’anàlisi de dinoflagel·lats, musclos i ostres. Les validacions preliminars amb assaigs colorimètrics i LC-MS/MS han demostrat la possibilitat d’utilitzar les bioeines desenvolupades per al cribratge preliminar de biotoxines marines en mostres de camp o de cultiu, que ofereixen informació complementària a la cromatografia. En conclusió, tot i que encara cal optimitzar alguns paràmetres experimentals, la integració dels biosensors a programes de seguiment és viable i podria proporcionar avantatges respecte a altres tècniques analítiques pel que fa al temps d’anàlisi, la simplicitat, la selectivitat, la sensibilitat, el fet de poder ser d’un sol ús i l’efectivitat de cost. This article describes the electrochemical enzyme sensors and immunosensors that have been developed by our groups for the detection of marine biotoxin okadaic acid (OA), and discusses the possibility of integrating them into monitoring programmes. The enzyme sensors for OA reported herein are based on the inhibition of immobilised protein phosphatase 2A (PP2A) by this toxin and the electrochemical measurement of the enzyme activity through the use of appropriate enzyme substrates, which are electrochemically active after dephosphorylation by the enzyme. The electrochemical immunosensors described in this article are based on a competitive indirect Enzyme- Linked ImmunoSorbent Assay (ciELISA), using alkaline phosphatase (ALP) or horseradish peroxidase (HRP) as labels, and an enzymatic recycling system with diaphorase (DI). The biosensors presented herein have been applied to the analysis of dinoflagellates, mussels and oysters. Preliminary validations with colorimetric assays and LC-MS/MS have demonstrated the possibility of using the developed biotools for the preliminary screening of marine biotoxins in field or cultured samples, offering complementary information to chromatography. In conclusion, although optimisation of some experimental parameters is still required, the integration of biosensors into monitoring programmes is viable and may provide advantages over other analytical techniques in terms of analysis time, simplicity, selectivity, sensitivity, disposability of electrodes and cost effectiveness.

Estudio comparativo de conocimientos y percepciones ambientales sobre la Reserva de la Biosfera de Sian Ka'an entre estudiantes de primaria de comunidades maya, México

El estudio analiza y compara las percepciones y conocimientos ambientales que estudiantes de primaria del municipio maya de Felipe Carrillo Puerto tienen sobre la vecina Reserva de la Biósfera de Sian Ka’an (RBSK) en términos de biodiversidad, con el fin de evaluar y elaborar programas de Educación Ambiental (EA) dirigidos a promover la protección de este espacio natural. Se analizan dibujos, cuestionarios y encuestas recogidos en tres comunidades maya que difieren en su proximidad a la RBSK y en su nivel de urbanización. Los resultados indican que los niños en general desconocen la RBSK y la biodiversidad de la zona. Para aumentar el conocimiento ambiental de los alumnos se propone potenciar el conocimiento vivencial, mantener la lengua y cultura maya y el contacto de ésta con la naturaleza y potenciar la afinidad del maestro por la temática ambiental y por la RBSK.

Sound Texture Modelling

In the PhD thesis “Sound Texture Modeling” we deal with statistical modelling or textural sounds like water, wind, rain, etc. For synthesis and classification. Our initial model is based on a wavelet tree signal decomposition and the modeling of the resulting sequence by means of a parametric probabilistic model, that can be situated within the family of models trainable via expectation maximization (hidden Markov tree model ). Our model is able to capture key characteristics of the source textures (water, rain, fire, applause, crowd chatter ), and faithfully reproduces some of the sound classes. In terms of a more general taxonomy of natural events proposed by Graver, we worked on models for natural event classification and segmentation. While the event labels comprise physical interactions between materials that do not have textural propierties in their enterity, those segmentation models can help in identifying textural portions of an audio recording useful for analysis and resynthesis. Following our work on concatenative synthesis of musical instruments, we have developed a pattern-based synthesis system, that allows to sonically explore a database of units by means of their representation in a perceptual feature space. Concatenative syntyhesis with “molecules” built from sparse atomic representations also allows capture low-level correlations in perceptual audio features, while facilitating the manipulation of textural sounds based on their physical and perceptual properties. We have approached the problem of sound texture modelling for synthesis from different directions, namely a low-level signal-theoretic point of view through a wavelet transform, and a more high-level point of view driven by perceptual audio features in the concatenative synthesis setting. The developed framework provides unified approach to the high-quality resynthesis of natural texture sounds. Our research is embedded within the Metaverse 1 European project (2008-2011), where our models are contributting as low level building blocks within a semi-automated soundscape generation system.

GMODI : Gestión y mantenimiento Online de departamentos informáticos

La finalitat d'aquest projecte és la d'aconseguir d'una banda la gestió de recanvis per als equips informàtics de l'empresa tals com, tonners d'impressores làser i faxos, cartutxos de tinta, escàners i terminals de fàbrica i finalment impressores d'impressió tèrmica per a etiquetes dels productes de la nostra fàbrica. Per l'altre costat tindrem el manteniment dels equips informàtics de l'empresa, és dir els PC's de feina.

Registre d'entrades i eixides per a l'administració pública

Aquesta memòria representa la definició del meu projecte final de carrera amb una aplicació destinada al registre d'entrades i eixides de l'Administració pública. He emprat eines de plataformes lliures i obertes per al desenvolupament del projecte, amb tecnologia J2EE. A més, hi ha l'objectiu de fer servir i provar arquitectures d'última generació com Enterprise JavaBeans Preview_2 (EJB) 3.0 (5/11/04) per a la lògica de negoci, Hibernate 3.0 alpha (actualment hi ha la beta 1.0 publicada el 20/12/04) com a

Construcció d'un SIG i sincronització de les etiquetes amb els objectes representats a GEOMEDIA PROFESSIONAL 5.2

En aquest treball de fi de carrera s'estudia en què consisteix en SIG i les seves característiques, en concret es realitza l'estudi d'un SIG comercial, GEOMEDIA PROFESSIONAL 5.2 D'aquest producte es presenta el problema de sincronització de les etiquetes amb les entitats que etiqueten, i es planteja una solució a aquest problema, mitjançant el desenvolupament d'una aplicació implementada amb MICROSOFT VISUAL BASIC 6.0