Antidepressant treatment and emotional processing: can we dissociate the roles of serotonin and noradrenaline?

The ability to match individual patients to tailored treatments has the potential to greatly improve outcomes for individuals suffering from major depression. In particular, while the vast majority of antidepressant treatments affect either serotonin or noradrenaline or a combination of these two neurotransmitters, it is not known whether there are particular patients or symptom profiles which respond preferentially to the potentiation of serotonin over noradrenaline or vice versa. Experimental medicine models suggest that the primary mode of action of these treatments may be to remediate negative biases in emotional processing. Such models may provide a useful framework for interrogating the specific actions of antidepressants. Here, we therefore review evidence from studies examining the effects of drugs which potentiate serotonin, noradrenaline or a combination of both neurotransmitters on emotional processing. These results suggest that antidepressants targeting serotonin and noradrenaline may have some specific actions on emotion and reward processing which could be used to improve tailoring of treatment or to understand the effects of dual-reuptake inhibition. Specifically, serotonin may be particularly important in alleviating distress symptoms, while noradrenaline may be especially relevant to anhedonia. The data reviewed here also suggest that noradrenergic-based treatments may have earlier effects on emotional memory that those which affect serotonin.

The plasticity of the mirror system: how reward learning modulates cortical motor simulation of others

Cortical motor simulation supports the understanding of others' actions and intentions. This mechanism is thought to rely on the mirror neuron system (MNS), a brain network that is active both during action execution and observation. Indirect evidence suggests that alpha/beta suppression, an electroencephalographic (EEG) index of MNS activity, is modulated by reward. In this study we aimed to test the plasticity of the MNS by directly investigating the link between alpha/beta suppression and reward. 40 individuals from a general population sample took part in an evaluative conditioning experiment, where different neutral faces were associated with high or low reward values. In the test phase, EEG was recorded while participants viewed videoclips of happy expressions made by the conditioned faces. Alpha/beta suppression (identified using event-related desynchronisation of specific independent components) in response to rewarding faces was found to be greater than for non-rewarding faces. This result provides a mechanistic insight into the plasticity of the MNS and, more generally, into the role of reward in modulating physiological responses linked to empathy.

Patient and public involvement in healthcare quality improvement: how organizations can help patients and professionals to collaborate

Citizens across the world are increasingly called upon to participate in healthcare improvement. It is often unclear how this can be made to work in practice. This 4- year ethnography of a UK healthcare improvement initiative showed that patients used elements of organizational culture as resources to help them collaborate with healthcare professionals. The four elements were: (1) organizational emphasis on nonhierarchical, multidisciplinary collaboration; (2) organizational staff ability to model desired behaviours of recognition and respect; (3) commitment to rapid action, including quick translation of research into practice; and (4) the constant data collection and reflection process facilitated by improvement methods.

Compensation and Rewards for Environmental Services (CRES) and efficient design of contracts in developing countries. Behavioral insights from a natural field experiment

The use of economic incentives for biodiversity (mostly Compensation and Reward for Environmental Services including Payment for ES) has been widely supported in the past decades and became the main innovative policy tools for biodiversity conservation worldwide. These policy tools are often based on the insight that rational actors perfectly weigh the costs and benefits of adopting certain behaviors and well-crafted economic incentives and disincentives will lead to socially desirable development scenarios. This rationalist mode of thought has provided interesting insights and results, but it also misestimates the context by which ‘real individuals’ come to decisions, and the multitude of factors influencing development sequences. In this study, our goal is to examine how these policies can take advantage of some unintended behavioral reactions that might in return impact, either positively or negatively, general policy performances. We test the effect of income's origin (‘Low effort’ based money vs. ‘High effort’ based money) on spending decisions (Necessity vs. Superior goods) and subsequent pro social preferences (Future pro-environmental behavior) within Madagascar rural areas, using a natural field experiment. Our results show that money obtained under low effort leads to different consumption patterns than money obtained under high efforts: superior goods are more salient in the case of low effort money. In parallel, money obtained under low effort leads to subsequent higher pro social behavior. Compensation and rewards policies for ecosystem services may mobilize knowledge on behavioral biases to improve their design and foster positive spillovers on their development goals.

Recognition by the Thyroid Hormone Receptor of Canonical DNA Response Elements

To shed more light on the molecular requirements for recognition of thyroid response elements (TRES) by thyroid receptors (TRs), we compared the specific aspects of DNA TRE recognition by different TR constructs. Using fluorescence anisotropy, we performed a detailed and hierarchical study of TR-TRE binding. This wits done by comparing the binding affinities of three different TR constructs for four different TRE DNA elements, including palindromic sequences and direct repeats (F2, PAL, DR-1, and DR-4) as well as their interactions with nonspecific DNA sequences. The effect of MgCl(2) on suppressing of nonselective DNA binding to TR was also investigated. Furthermore, we determined the dissociation constants of the hTR beta DBD (DNA binding domain) and hTR beta DBD-LBD (DNA binding and ligand binding domains) for specific TRES. We found that a minimum DNA recognition peptide derived from DBD (H1TR) is sufficient for recognition and interaction with TREs, whereas scrambled DNA sequences were unrecognized. Additionally, we determined that the TR DBD binds to F2, PAL, and DR-4 with high affinity and similar K(d) values. The TR DBD-LBD recognizes all the tested TRES but binds preferentially to F2, with even higher affinity. Finally, our results demonstrate the important role played by LBDs in modulating TR-DNA binding.

Statistical coupling analysis of aspartic proteinases based on crystal structures of the Trichoderma reesei enzyme and its complex with pepstatin A

The crystal structures of an aspartic proteinase from Trichoderma reesei (TrAsP) and of its complex with a competitive inhibitor, pepstatin A, were solved and refined to crystallographic R-factors of 17.9% (R(free)=21.2%) at 1.70 angstrom resolution and 15.81% (R(free) = 19.2%) at 1.85 angstrom resolution, respectively. The three-dimensional structure of TrAsP is similar to structures of other members of the pepsin-like family of aspartic proteinases. Each molecule is folded in a predominantly beta-sheet bilobal structure with the N-terminal and C-terminal domains of about the same size. Structural comparison of the native structure and the TrAsP-pepstatin complex reveals that the enzyme undergoes an induced-fit, rigid-body movement upon inhibitor binding, with the N-terminal and C-terminal lobes tightly enclosing the inhibitor. Upon recognition and binding of pepstatin A, amino acid residues of the enzyme active site form a number of short hydrogen bonds to the inhibitor that may play an important role in the mechanism of catalysis and inhibition. The structures of TrAsP were used as a template for performing statistical coupling analysis of the aspartic protease family. This approach permitted, for the first time, the identification of a network of structurally linked residues putatively mediating conformational changes relevant to the function of this family of enzymes. Statistical coupling analysis reveals coevolved continuous clusters of amino acid residues that extend from the active site into the hydrophobic cores of each of the two domains and include amino acid residues from the flap regions, highlighting the importance of these parts of the protein for its enzymatic activity. (C) 2008 Elsevier Ltd. All rights reserved.

Conformational differences between the wild type and V30M mutant transthyretin modulate its binding to genistein: Implications to tetramer stability and ligand-binding

Transthyretin (TTR) is a tetrameric beta-sheet-rich transporter protein directly involved in human amyloid diseases. It was recently found that the isoflavone genistein (GEN) potently inhibits TTR amyloid fibril formation (Green et al., 2005) and is therefore a promising candidate for TTR amyloidosis treatment. Here we used structural and biophysical approaches to characterize genistein binding to the wild type (TTRwt) and to its most frequent amyloidogenic variant, the V30M mutant. In a dose-dependent manner, genistein elicited considerable increases in both mutant and TTRwt stability as demonstrated by high hydrostatic pressure (HHP) and acid-mediated dissociation/denaturation assays. TTR:GEN crystal complexes and isothermal titration calorimetry (ITC) experiments showed that the binding mechanisms of genistein to the TTRwt and to V30M are different and are dependent on apoTTR structure conformations. Furthermore, we could also identify potential allosteric movements caused by genistein binding to the wild type TTR that explains, at least in part, the frequently observed negatively cooperative process between the two sites of TTRwt when binding ligands. These findings show that TTR mutants may present different ligand recognition and therefore are of value in ligand design for inhibiting TTR amyloidosis. (C) 2010 Elsevier Inc. All rights reserved.

Real-Time Recognition System for Traffic Signs

The aim of this thesis project is to develop the Traffic Sign Recognition algorithm for real time. Inreal time environment, vehicles move at high speed on roads. For the vehicle intelligent system itbecomes essential to detect, process and recognize the traffic sign which is coming in front ofvehicle with high relative velocity, at the right time, so that the driver would be able to pro-actsimultaneously on instructions given in the Traffic Sign. The system assists drivers about trafficsigns they did not recognize before passing them. With the Traffic Sign Recognition system, thevehicle becomes aware of the traffic environment and reacts according to the situation.The objective of the project is to develop a system which can recognize the traffic signs in real time.The three target parameters are the system’s response time in real-time video streaming, the trafficsign recognition speed in still images and the recognition accuracy. The system consists of threeprocesses; the traffic sign detection, the traffic sign recognition and the traffic sign tracking. Thedetection process uses physical properties of traffic signs based on a priori knowledge to detect roadsigns. It generates the road sign image as the input to the recognition process. The recognitionprocess is implemented using the Pattern Matching algorithm. The system was first tested onstationary images where it showed on average 97% accuracy with the average processing time of0.15 seconds for traffic sign recognition. This procedure was then applied to the real time videostreaming. Finally the tracking of traffic signs was developed using Blob tracking which showed theaverage recognition accuracy to 95% in real time and improved the system’s average response timeto 0.04 seconds. This project has been implemented in C-language using the Open Computer VisionLibrary.

Product placement in movies: a cross cultural study between Brazil and the USA

The broader objective of this study undertaking can briefly be articulated in particulate aims as follows: to measure the attitudes of consumers regarding the brand displayed by this strategy as well as to highlight recall, recognition and purchase intentions generated by product placement on consumers. In addition, check the differences and similarities between the behavior of Brazilian and American consumers caused by the influence of product placements. The study was undertaken targeting consumer audience in Brazil and the U.S. A rang3 modeling set ups were performed in order to realign study instruments and hypothesis towards the research objectives. This study gave focus on the following hypothesized models. H1: Consumers / Participants who viewed the brands / products in the movie have a higher brand / product recall compared to the consumers / participants who did not view the brands / products in the movie. H2: US Consumers / Participants are able to recognize and recall brands / products which appear in the background of the movie than Brazil. H3: Consumers / participants from USA are more accepting of product placements compared to their counterparts in Brazil. H4: There are discernible similarities in consumer / participant brand attitudes and purchase intentions in consumers / participants from USA and Brazil in spite of the fact that their country of origin is different. Cronbach’s Alpha Coefficient ensured the reliability of survey instruments. The study involved the use of the Structural Equation Modeling (SEM) for the hypothesis testing. This study used the Confirmatory Factor Analysis (CFA) to assess both the convergent and discriminant validities instead of using the Exploratory Factor Analysis (EFA) or the Principal Component Analysis (PCA). This reinforced for the use of the regression Chi Square and T statistical tests in further. Only hypothesis H3 was rejected, the rest were not. T test provided insight findings on specific subgroup significant differences. In the SEM testing, the error variance for product placement attitudes was negative for both the groups. On this The Heywood Case came in handy to fix negative values. The researcher used both quantitative and qualitative approach where closed ended questionnaires and interviews respectively were used to collect primary data. The results were additionally provided with tabulations. It can be concluded that, product placement varies markedly in the U.S. from Brazil based on the influence a range of factors provided in the study. However, there are elements of convergence probably driven by the convergence in technology. In order, product placement to become more competitive in the promotional marketing, there will be the need for researchers to extend focus from the traditional variables and add knowledge on the conventional marketplace factors that is the sell-ability of the product placement technologies and strategies.

Purification, characterization, crystallization and theoretical molecular modeling of gyroxin fraction from Crotalus durissus terrificus venom (Laurenti, 1768)

The venom of Crotalus durissus terrificus snakes presents various substances, including a serine protease with thrombin-like activity, called gyroxin, that clots plasmatic fibrinogen and promote the fibrin formation. The aim of this study was to purify and structurally characterize the gyroxin enzyme from Crotalus durissus terrificus venom. For isolation and purification, the following methods were employed: gel filtration on Sephadex G75 column and affinity chromatography on benzamidine Sepharose 6B; 12% SDS-PAGE under reducing conditions; N-terminal sequence analysis; cDNA cloning and expression through RT-PCR and crystallization tests. Theoretical molecular modeling was performed using bioinformatics tools based on comparative analysis of other serine proteases deposited in the NCBI (National Center for Biotechnology Information) database. Protein N-terminal sequencing produced a single chain with a molecular mass of similar to 30 kDa while its full-length cDNA had 714 bp which encoded a mature protein containing 238 amino acids. Crystals were obtained from the solutions 2 and 5 of the Crystal Screen Kit (R), two and one respectively, that reveal the protein constitution of the sample. For multiple sequence alignments of gyroxin-like B2.1 with six other serine proteases obtained from snake venoms (SVSPs), the preservation of cysteine residues and their main structural elements (alpha-helices, beta-barrel and loops) was indicated. The localization of the catalytic triad in His57, Asp102 and Ser198 as well as S1 and S2 specific activity sites in Thr193 and Gli215 amino acids was pointed. The area of recognition and cleavage of fibrinogen in SVSPs for modeling gyroxin B2.1 sequence was located at Arg60, Arg72, Gln75, Arg81, Arg82, Lis85, Glu86 and Lis87 residues. Theoretical modeling of gyroxin fraction generated a classical structure consisting of two alpha-helices, two beta-barrel structures, five disulfide bridges and loops in positions 37, 60, 70, 99, 148, 174 and 218. These results provided information about the functional structure of gyroxin allowing its application in the design of new drugs.

A novel algorithm for feature selection using Harmony Search and its application for non-technical losses detection

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Propolis Immunomodulatory Action In Vivo on Toll-Like Receptors 2 and 4 Expression and on Pro-Inflammatory Cytokines Production in Mice

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Structural basis for branching-enzyme activity of glycoside hydrolase family 57: Structure and stability studies of a novel branching enzyme from the hyperthermophilic archaeon Thermococcus Kodakaraensis KOD1

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Kinetic and mechanistic characterization of the Sphingomyelinases D from Loxosceles intermedia spider venom

Envenomation by arachnids of the genus Loxosceles leads to local dermonecrosis and serious systemic toxicity mainly induced by sphingomyelinases D (SMase D). These enzymes catalyze the hydrolysis of sphingomyelin resulting in the formation of ceramide-phosphate and choline as well as the cleavage of lysophosphatidyl choline generating the lipid mediator lysophosphatidic acid. We have, previously, cloned and expressed two functional SMase D isoforms, named P1 and P2, from Loxosceles intertnedia venom and comparative protein sequence analysis revealed that they are highly homologous to SMase I from Loxosceles laeta which folds to form an (alpha/beta)(8) barrel. In order to further characterize these proteins, pH dependence kinetic experiments and chemical modification of the two active SMases D isoforms were performed. We show here that the amino acids involved in catalysis and in the metal ion binding sites are strictly conserved in the SMase D isoforms from L. intermedia. However, the kinetic studies indicate that SMase P1 hydrolyzes sphingomyelin less efficiently than P2, which can be attributed to a substitution at position 203 (Pro-Leu) and local amino acid substitutions in the hydrophobic channel that could probably play a role in the substrate recognition and binding. (c) 2005 Elsevier Ltd. All rights reserved.