Background: Serotonin (5-HT) and its neurotrophic support system, specifically brain-derived neurotrophic factor (BDNF), are thought to modulate energy homeostasis and susceptibility to obesity. Moreover, a polymorphism (5-HTTLPR) in the serotonin reuptake transporter (5-HTT) gene impairs its transcription, thereby altering serotonergic tone and potentially contributing to such susceptibility. This study aims to investigate the effect of BDNF, biallelic 5-HTTLPR, and central in-vivo 5-HTT availability in highly obese versus non-obese subjects using positron emission tomography (PET) and 5-HTT selective [11C]DASB. Methods: Thirty-eight subjects, 24 obese (body mass index, BMI, >35 kg/m2), otherwise mentally and physically healthy, and 14 non-obese (BMI ≤ 25 kg/m2), age- and sex-matched healthy controls were included in this study. Parametric images of binding potential were generated from PET data. Central 5-HTT availability, 5-HTTLPR genotype, and serum BDNF concentrations were analyzed, first in a volume of interest, then in a voxel-wise manner. Results: Overall, our results showed an absence of a linear correlation between BDNF, in-vivo central 5-HTT availability, and body mass index (BMI). 5-HTTLPR genotyping revealed BDNF and hippocampal 5-HTT availability to be negatively correlated (r = −0.57, p = 0.007) in long allelic homozygotes. However, obese subjects exhibited opposing effects of BDNF levels on 5-HTT availability in the nucleus accumbens (NAcc) relative to our non-obese controls. Conclusions: Our data did not confirm an overall correlation between serum BDNF, in-vivo central 5-HTT availability, 5-HTTLPR, and BMI. However, there is evidence that serotonergic tone linked to BDNF, specifically in the NAcc, is involved in the pathophysiology of obesity, although this needs further exploration over a wide range of reward-related eating behaviors.

Serotonin (5-HT) plays an important role as both a neurotransmitter and animmune modulator. The serotonin reuptake transporter (SERT) clears the extracellular space of 5-HT, which decreases the effects of 5-HT on target cells. This study demonstrated that the RAW264.7 macrophage cell line expresses SERT function, measured by assays of 3H-5HT uptake. The 5-HT uptake in RAW264.7 macrophages was more than 10-fold that of peritoneal macrophages, indicating that these cells are an excellent model for studying regulation of the SERT. Activation of macrophages with lipopolysaccharide (LPS) increased SERT activity in a time- and concentration-dependent manner and Western blots indicate that the increase in activity is partially due to LPS-induced increases in total SERT protein. Both unstimulated and LPS-stimulated activity was inhibited by the specific SERT inhibitor fluoxetine (IC50= 5-8 nM) and was reduced by the anti-inflammatory cytokine interleukin-10. Changes in extracellular concentrations of interleukin-lβ and tumor necrosis factor-α did not affect SERT activity.

A major obstacle for developing new antidepressants has been limited knowledge of the structure and function of a central target, the serotonin transporter (SERT). Established SERT inhibitors (SSRIs) were docked to an in silico SERT model to identify likely binding pocket amino acid residues. When mutated singly, no one of five implicated residues was critical for high affinity in vitro binding of SSRIs or cocaine. The in silico SERT model was used in ligand virtual screening (VS) of a small molecule structural library. Selected VS "hit" compounds were procured and tested in vitro; encouragingly, two compounds with novel structural scaffolds bound SERT with modest affinity. The combination of computational modeling, site-directed mutagenesis and pharmacologic characterization can accelerate binding site elucidation and the search for novel lead compounds. Such compounds may be tailored for improved serotonin receptor selectivity and reduced affinity for extraneous targets, providing superior antidepressants with fewer adverse effects. / Mylan School of Pharmacy and the Graduate School of Pharmaceutical Sciences; / Pharmacology / MS; / Thesis;

Made available in DSpace on 2014-12-17T15:25:24Z (GMT). No. of bitstreams: 1 MirianSJ.pdf: 452183 bytes, checksum: 9853a0415ed503b8235f6407599bb5a8 (MD5) Previous issue date: 2007-09-03 / The "paulistas", or be, the pioneers of the town of S?o Paulo of Piratininga, were hired by the Portuguese Crown as instrument of repression and social control between the centuries XVII and XVIII, were involved in conflicts of the Captainships of the North of the State of Brazil after expulsion of the West of Indian Company. That moment corresponds to the beginning of the conquest of the sert?o , and of the consequent resistances offered by the Indians of the interior of the continent that barred the Portuguese colonial project. The colonial sert?o was understood as all area outside of the Portuguese jurisdiction, in contrary condition to the Sugary zone. In such events, the labor of the "paulistas" was employed by the rights to his abilities in traversing the weeds. With that, we are going to detach the participation of the "paulistas" during and after the called "Guerra dos B?rbaros" in the captainship of Rio Grande, as well as the output of that space from the establishment of the groups that were mobilized for the conflict / Os paulistas , ou seja, os bandeirantes da vila de S?o Paulo de Piratininga, foram contratados pela Coroa Portuguesa como instrumento de repress?o e controle social entre os s?culos XVII e XVIII, envolvidos nos conflitos das Capitanias do Norte do Estado do Brasil ap?s a expuls?o da Companhia das ?ndias Ocidentais (WIC). Esse momento corresponde ao in?cio da conquista do sert?o, e das conseq?entes resist?ncias oferecidas pelos ?ndios do interior do continente que barraram o projeto colonial portugu?s. O sert?o colonial estava compreendido como toda ?rea fora da jurisdi??o portuguesa, em condi??o contr?ria ? zona a?ucareira. Em tais acontecimentos, foi empregada a m?o-de-obra dos paulistas pelas atribui??es ?s suas habilidades em percorrer os matos. Com isso, buscamos destacar a participa??o dos paulistas durante e ap?s a chamada Guerra dos b?rbaros na capitania do Rio Grande, bem como a produ??o desse espa?o a partir do estabelecimento dos grupos mobilizados para o conflito

Background: Serotonin (5-HT) and its neurotrophic support system, specifically brain-derived neurotrophic factor (BDNF), are thought to modulate energy homeostasis and susceptibility to obesity. Moreover, a polymorphism (5-HTTLPR) in the serotonin reuptake transporter (5-HTT) gene impairs its transcription, thereby altering serotonergic tone and potentially contributing to such susceptibility. This study aims to investigate the effect of BDNF, biallelic 5-HTTLPR, and central in-vivo 5-HTT availability in highly obese versus non-obese subjects using positron emission tomography (PET) and 5-HTT selective [11C]DASB. Methods: Thirty-eight subjects, 24 obese (body mass index, BMI, >35 kg/m2), otherwise mentally and physically healthy, and 14 non-obese (BMI ≤ 25 kg/m2), age- and sex-matched healthy controls were included in this study. Parametric images of binding potential were generated from PET data. Central 5-HTT availability, 5-HTTLPR genotype, and serum BDNF concentrations were analyzed, first in a volume of interest, then in a voxel-wise manner. Results: Overall, our results showed an absence of a linear correlation between BDNF, in-vivo central 5-HTT availability, and body mass index (BMI). 5-HTTLPR genotyping revealed BDNF and hippocampal 5-HTT availability to be negatively correlated (r = −0.57, p = 0.007) in long allelic homozygotes. However, obese subjects exhibited opposing effects of BDNF levels on 5-HTT availability in the nucleus accumbens (NAcc) relative to our non-obese controls. Conclusions: Our data did not confirm an overall correlation between serum BDNF, in-vivo central 5-HTT availability, 5-HTTLPR, and BMI. However, there is evidence that serotonergic tone linked to BDNF, specifically in the NAcc, is involved in the pathophysiology of obesity, although this needs further exploration over a wide range of reward-related eating behaviors.

This essay is the basis for a thesis, according to which an urban transcendent planning tool belonging to the functional ideology of the Modern Movement may be acknowledged as being of prime importance. The theme is the Plan for Bogotá, elaborated in several phases by Le Corbusier and Josep Lluís Sert & Paul Lester Wiener between 1949 and 1963, This is a work which has been very sparsely mentioned in international historiography of architecture and/or urban planning, and has generated little or no critical interest or deep analysis as part of the Latin American regional case1, or particularly, that of Bogotá. This Plan, besides its projectual and instrumental novelties (for its time), is remarkable for its historical, methodological and practical dimensions and for its dialectic between the values and principles that guided it and its final product, the city itself. Through the study of the urban event, of the processes and the product created by this experience, the codes which reverberated through the Bogotá town planning will be eventually identified, then put to work to rescue questions and answers that may contribute ideas and solutions to contemporary town planning. Several significant events point out the historical importance of the Plan. It was not only the second and last time for le Corbusier and Sert ¿ two noted CIAM protagonists ¿ to work together in town planning, 16 years after participating in the Maciá Plan for Barcelona, but also the only Plan for a Latin American city completely worked out by Le Corbusier, having signed a formal contract for that purpose. Like Sert and other renowned architects, Le Corbusier strove to leave his own imprint in Latin America2. In the Colombian scope the Plan may be considered a significant event, being the work of two emblematic figures of the Modern Movement and also for its importance for Colombian society, involving it as a whole in a project that became part of its own future development by the creation of a pioneering instrument for an integral city project, and also for its instrumental content and the legal expression of a compendium of regulations in accordance with the principles and methodology of Modern Urbanism. However, this, like many other ideas and proposals towards modernization of cities, did not transcend their time nor were they registered in Colombian history as a notably significant chapter (del Castillo, 2003). In its methodological dimension, the Bogotá Plan incorporates several instrumental measures, not used previously in Modern Town Planning, either in its international or its local versions, among which the following may be noted : the proposal of a theoretical city model, summarizing the main elements of urban politics at city, metropolitan and regional levels. The city Civic Center ¿ and its replicas at quarter or ¿barrio¿ level - represents an entirely new urban function. Urban sectors and their street network, arranged in a hierarchy according to the 7v¿s Rule, as the indispensable basic structure for circulation and urban design at an intermediate scale and as a deductive result of Corbusian thought about the shape of cities at that date (Le Corbusier 1951: Jeanneret et al. 1951), 1959 (Bannen Lanata 1991; Cortés 1995; Salmona 2003). The graphic image of the Plan and its version for the CIAM grille, which consisted of a series of plans systematically arranged to show both the form and analysis of the proposals for the city, to be shown in comparison with other plans at the CIAM 8 meeting on The Heart of the City.

Tez (Doktora) - Süleyman Demirel Üniversitesi, Fen Bilimleri Enstitüsü, Makina Mühendisliği Anabilim Dalı, 2009. / Kaynakça var.

3,4-(±)-Methylenedioxymethamphetamine (MDMA, Ecstasy) is a widely abused amphetamine derivative with potent stimulant properties. The neuropharmacological effects of MDMA are biphasic in nature. MDMA initially causes synaptic monoamine release, primarily of serotonin (5-HT), producing hyperthermia and hyperactivity (5-HT syndrome). Conversely, the long-term effects of MDMA manifest as a prolonged depletion in 5-HT, and structural damage to serotonergic nerve terminals. Monoamine transporter systems at the plasma membrane and storage vesicles of 5-HT neurons have been implicated in MDMA toxicity. Nonetheless, many mechanistic questions remain regarding the precise role of uptake transporters in MDMA neurotoxicity. The present study was designed to address the importance of the serotonin reuptake transporter (SERT) and the vesicular monoamine transporter 2 (VMAT2) to the physiological, behavioral and neurotoxic responses to MDMA. SERT functions as a primary regulator of 5-HT homeostasis, mediating the reuptake of 5-HT from the synaptic space following its release during neurotransmission. SERT is a molecular target site for MDMA and many antidepressant agents such as the selective serotonin reuptake inhibitor (SSRI) class. Pharmacological inhibition of SERT protects against MDMA-induced serotonergic neurotoxicity. Thus, the effects of MDMA are in part mediated by an ability to interact with and inhibit SERT. Using a SERT-knockout (SERT-KO) rat model, we determined that SERT deficiency modulated the acute toxicities of MDMA, such as hyperthermia and hyperactivity, whilst completely preventing long-term depletions in tissue 5-HT levels, indicating the abolishment of neurotoxicity. Disruption of vesicular monoamine storage via interaction with VMAT2 has also been implicated in MDMA neurotoxicity. VMAT2 participates in the transport of monoamine neurotransmitters, in particular 5-HT and dopamine (DA), into intra-neuronal storage vesicles. As such, VMAT2 is critical in maintaining neuronal health by preventing neurotransmitter oxidation within the cytosol. Pharmacological inhibition of VMAT2 with Ro4-1284 reduced MDMA-induced hyperactivity and averted hyperthermia along with persistent serotonergic deficits. Overall, our results corroborate the hypothesis that SERT and VMAT2 are critical to the in vivo effects of MDMA. Furthermore, given that VMAT2 inhibition diminished the behavioral response to MDMA in rats, pharmacological manipulation of this transporter could be used in the treatment of MDMA abuse and overdose.

High doses of 3,4-methylenedioxymethamphetamine (MDMA; "Ecstasy") are known to reduce levels of various serotonergic markers outside of the raphe nuclei. To test the hypothesis that these deficits reflect a degeneration of distal axons/terminals, we investigated the effects of an MDMA binge (10mg/kg x 4) on the relative protein and genetic expression of several serotonergic markers in rats, as well as the effects of this compound on the quantity of serotonergic terminals in these animals. In experiment I, we examined whether MDMA alters serotonin transporter (SERT) levels as determined by lysate binding and immunoblotting analyses. Both methods of analysis revealed MDMA-induced reductions in regional SERT content. Experiment II investigated MDMA-induced changes in terminal-specific levels of SERT and the vesicular monoamine transporter 2 (VMAT-2) in the hippocampus, a region with sparse dopaminergic innervation, after lesioning noradrenergic input with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4). Animals were administered 100 mg/kg DSP-4 or saline 1 week prior to MDMA (or saline). As determined by immunoblotting of synaptosomal tissue, the DSP-4/MDMA group showed little change in hippocampal VMAT-2 protein expression compared to DSP-4/Saline controls, despite large reductions in SERT levels in all regions examined in the MDMA-treated animals. Experiment III examined whether MDMA alters genetic expression of SERT and VMAT-2. When compared to saline-treated controls, animals given MDMA showed a striking decrease in SERT gene expression (and a lesser effect on VMAT-2) in dorsal/median raphe as assessed by quantitative RT-PCR. Experiment IV(a) investigated the effects of MDMA on gene and protein expression of tryptophan hydroxylase (TPH) in the hippocampus. Levels of TPH protein were unchanged between treatment groups, while transcript levels were decreased 15-fold in the dorsal/median raphe. In experiment IV(b), flow cytometry was used to measure whether MDMA alters the quantity of serotonergic terminals in the hippocampus. MDMA-treated animals showed an increase in the number of serotonergic synaptosomes identified by co-labeling for synaptosome-associated protein of 25 kDa (SNAP-25) and TPH. These results demonstrate that MDMA causes substantial regulatory changes in the expression of serotonergic markers with no evidence for synaptic loss, questioning the need to invoke distal axotomy as an explanation of MDMA-related serotonergic deficits.

Made available in DSpace on 2014-12-17T14:34:43Z (GMT). No. of bitstreams: 1 EudesioES_DISSERT.pdf: 1579065 bytes, checksum: f1cbc613ecde5c2fc465e31df0416a8d (MD5) Previous issue date: 2012-02-24 / This work is part of the research group studying agribusiness chains, by characterizing agroindustrial chain of cashew nuts in Rio Grande do Norte, with special emphasis on Sert?o de Apodi Citizenship Territory, showing their different flows and linkages and analyzes generating jobs and income in the production of this good, from the experience of COOPAPI, using as a methodology for analyzing the input-output matrix. And this is justified by the fact that Brazil is in the context as the world's fifth largest producer of cashew nuts and the production of this product focus in the Northeast, especially the Rio Grande do Norte, which is the second largest producer of region, behind only the state of Cear?, which is the largest producer in the country. Moreover, in recent years the state has increased its insertion in international markets this product, particularly the Mossor?-Assu Territory, which constitutes the largest producer in the state, particularly the municipality of Serra do Mel, which has an arrangement different yield, based on the model of integrated rural development, embodied in family farming. Nevertheless, the Sert?o de Apodi Citizenship appear as the fourth among the Citizenship territories of Rio Grande do Norte in the ranking of the production of cashew nuts, but the prevailing model of Cooperatives in the Territory, based on the Solidarity Economy, i,e, different from the old cooperative, which is based on the precepts as patronage, with cooperative owners, favor, etc.., encourages scientific research. In this, after a careful analysis of data from field research, it was noticed that among the links in the chain, the production link is what generates the most jobs, while the processing link commands to generate income, but a portion meaningful occupations and income are generated outside the territory, especially out of state RN, denouncing the gap in supply of some specific demands within the chain / Este trabalho se insere no grupo das pesquisas que estudam cadeias agroindustriais, pois caracteriza a cadeia agroindustrial de castanha de caju no Rio Grande do Norte, com especial destaque ao Territ?rio da Cidadania do Sert?o de Apodi, evidenciando os seus diferentes fluxos e encadeamentos e analisa a gera??o de ocupa??o e renda na produ??o deste bem, a partir da experi?ncia da COOPAPI. Utilizando como metodologia de an?lise a matriz de insumo-produto. E isso se justifica no fato de que o Brasil se insere no contexto mundial como o quinto maior produtor da castanha de caju e a produ??o deste produto se concentrar na regi?o Nordeste, com destaque para o Rio Grande do Norte, que ? o segundo maior produtor da regi?o, atr?s apenas do estado de Cear? que ? o maior produtor do pa?s. Al?m disso, nos ?ltimos anos o estado potiguar tem aumentado a sua inser??o no mercado internacional deste produto, particularmente o Territ?rio Assu-Mossor?, que se configura como o maior produtor do estado, em especial o munic?pio de Serra do Mel, que apresenta um arranjo produtivo diferente, baseado no modelo de desenvolvimento rural integrado, consubstanciado na agricultura familiar. N?o obstante, o Territ?rio da Cidadania do Sert?o de Apodi constar como o quarto dentre os territ?rios da Cidadania do Rio Grande do Norte no ranking da produ??o de castanha de caju, por?m o modelo de Cooperativismo vigente neste Territ?rio, baseado na Economia Solid?ria, isto ?, diferente do velho cooperativismo, que se fundamenta nos preceitos como clientelismo, de cooperativas com donos, favorecimento, etc., motiva a investiga??o cient?fica. Nisso, ap?s uma an?lise cuidadosa dos dados da pesquisa de campo, percebeu-se que dentre os elos da cadeia, o elo da produ??o ? o que mais gera ocupa??es, ao passo que o macrossegmento de processamento comanda a gera??o de renda, mas uma parcela significativa das ocupa??es e a renda geradas s?o fora do territ?rio, sobretudo fora do estado potiguar, o que denuncia lacuna em termos de suprimento de algumas demandas espec?ficas dentro da cadeia