Autism is a neurodevelopmental disorder characterized by impairments in social communication and interaction and by repetitive patterns of behaviour, interests and activities. It is perhaps the most common and handicapping neurological disorder of childhood and as such represents a significant public health problem and a huge burden for education and social service systems. Currently there is no diagnostic test or cure available for autism and the molecular mechanisms underlying autistic behaviour remain to be elucidated. Mutations in genes linked to autism adversely affect molecules involved in synapse development and plasticity including brain-derived neurotrophic factor receptor (TrkB) and its downstream effector mammalian target of rapamycin (mTOR), which is increased in several forms of syndromic autism. Here, we investigated whether TrkB, mTOR and their signaling pathways are disrupted in postmortem brain tissue from subjects with idiopathic autism, that is, cases of autism without a known genetic cause and thought to be of environmental/epigenetic origin. We next further examined the contribution of defective TrkB signaling to autistic behaviour in mice exposed to the histone deacetylase inhibitor valproic acid (VPA), a well-established model of environmental/epigenetic origin of autism. We found that TrkB signaling pathways were reduced in idiopathic autism and that these disruptions were associated with decreased excitatory postsynaptic marker PSD-95, suggesting fewer excitatory synapses. Moreover, we showed that similar molecular deficits were present in VPA-exposed mice that lacked sociability and displayed increased repetitive, stereotyped behaviour. We also determined that behavioural deficits in these mice were rescued by administration of the partial TrkB agonist LM22A-4 but not by treatment with the active tripeptide fragment of the insulin-like growth factor-1, (1-3)IGF-1. Lastly, reduced TrkB signaling in VPA-exposed mice was normalized by LM22A-4 administration combined with behavioural enrichment. The present work provides a better understanding of the molecular mechanisms that contribute to autistic behaviour and implicates TrkB signaling in autism pathogenesis. Furthermore, these data demonstrate that molecular changes observed in brains of patients with idiopathic autism differ from syndromic forms and highlight that both too much and too little signaling can be equally disruptive. The present work also shows that maternal challenge with VPA resulted in social deficits, increased repetitive, restrictive behaviour and reduced TrkB signaling in mice, pointing to epigenetic modifications as a potential underlying mechanism of molecular and behavioural disruptions in autism. Lastly, these findings suggest that pharmacological activation of TrkB using compounds such as the partial TrkB agonist LM22A-4 might play a role in treating sociability and repetitive, perseverative behaviour in autism. / Thesis / Doctor of Philosophy (PhD)

This thesis explores how to develop new lifting equipment for the membrane and filter plates of the VPA (Metso) machine satisfying all the safety requirements. The VPA is a heavy duty machine with a number of plates, developed for filtration of minerals. The plates must be replaced or removed immediately once the wear has reached a given value or an error has been detected. The new lifting system differs to a great extent from conventional system in which a fiber strap was used; the designed lifting equipment comprises of a variety of parts resulting in a higher capacity to be used ín different situations safer and satisfies the vital requirements such as being a secure and cost-effective method, issued by the customers. Several solution proposals have been developed to offer better proposals before the final candidate has been selected and theoretically motivated with FEM analysis as well as analytical calculations. Keywords - VPA, membrane and filter plate, lifting equipment, pivot supporter hinge, safety, cost effective

O autismo é um transtorno complexo do desenvolvimento caracterizado por inúmeros prejuízos comportamentais, tais como perdas na comunicação, socialização e indução da inflexibilidade cognitiva. A reprodução de modelos experimentais de autismo é bastante importante no estudo desse transtorno. A exposição pré-natal ao VPA reproduz sintomas similares àqueles encontrados na condição humana de autismo. Apesar de o VPA ser considerado um provável teratógeno em humanos, pouco se sabe sobre seus mecanismos de ação, ou até mesmo, como ele é capaz de induzir o autismo. O VPA parece influenciar o metabolismo do zinco durante o período pré-natal, podendo comprometer o desenvolvimento fetal normal. Esse estudo foi dividido em duas partes: (1) reproduzir um modelo de autismo induzido por VPA pré-natal (400 mg/kg no GD 12,5) e (2) avaliar se a administração de zinco pré-natal (2 mg/kg 1h após) previne ou ameniza os prejuízos comportamentais e a expressão de TH-estriatal associados ao autismo causados pela exposição pré-natal ao VPA em ratos. Foram avaliados parâmetros reprodutivos, anormalidades comportamentais na comunicação (vocalização ultrassônica), comportamentos repetitivos e na cognição (labirinto em T) e interação social (comportamento de brincar), além de verificar o sistema dopaminérgico por meio da expressão proteica de TH-estriatal na prole masculina e feminina de ratas. O VPA causou danos reprodutivos, prejuízos na vocalização ultrassônica, comportamento repetitivo/restrito, inflexibilidade cognitiva, comprometimento na socialização com diminuição da brincadeira e redução nos níveis de TH- estriatal na prole masculina. A administração de zinco não foi capaz de impedir os danos reprodutivos causados pelo VPA, porém amenizou a inflexibilidade cognitiva e atenuou a brincadeira social, sem reestabelecer os níveis de TH-estriatal. A prole feminina foi menos afetada que a masculina, apresentando apenas a vocalização ultrassônica alterada. O zinco reestabeleceu esse dano. A redução da TH-estriatal na prole masculina sugere que, possivelmente o fenótipo tipo-autista investigado no presente estudo, esteja relacionado a modificações funcionais no sistema dopaminérgico. / Autism is a complex developmental disorder characterized by numerous behavioral impairments, such as communication, socialization and induction of cognitive inflexibility. Reproduction of experimental models of autism is an important tool in the study of this disorder. Prenatal exposure to VPA reproduces symptoms similar to those found in the human condition of autism. The VPA is known as a potential teratogen in humans and its mechanisms of action is not well understood. VPA appears to influence the zinc metabolism during the prenatal period, compromising normal fetal development. This study was done into two parts: (1st) obtain an autism model induced by prenatal VPA (400 mg/kg 12.5 GD) and (2nd) evaluate whether prenatal administration of zinc (2 mg/kg after 1h) prevents or reverses the behavioral impairments and protein striatal TH-expression associated with autism caused by prenatal exposure to VPA in rats. It was evaluated the reproductive parameters, abnormal behavior in the communication (ultrasonic vocalization test), repetitive behavior and cognitive capacity (T-maze test) and social interaction (play behavior test), and the evaluation of the dopaminergic system by quantification of TH-striatal expression in male and female offspring of rats. The VPA was able to cause reproductive damage, impairment in ultrasonic vocalization, repetitive/restricted behavior and cognitive inflexibility, impairment in socialization with decreased play behavior and reduction in striatal TH levels in male offspring. The zinc administration has not been able to prevent reproductive damage caused by VPA, but ameliorates the cognitive inflexibility and attenuated the social play behavior, without restoring TH-striatal levels. The offspring females were less affected as males, with alterations into ultrasonic vocalization only and zinc reestablished this damage. The reduction in striatal TH-male offspring suggests that the autistic-like phenotype, investigated in this study is, may be is related to functional modifications in the dopaminergic system.

O autismo é um transtorno complexo do desenvolvimento caracterizado por inúmeros prejuízos comportamentais, tais como perdas na comunicação, socialização e indução da inflexibilidade cognitiva. A reprodução de modelos experimentais de autismo é bastante importante no estudo desse transtorno. A exposição pré-natal ao VPA reproduz sintomas similares àqueles encontrados na condição humana de autismo. Apesar de o VPA ser considerado um provável teratógeno em humanos, pouco se sabe sobre seus mecanismos de ação, ou até mesmo, como ele é capaz de induzir o autismo. O VPA parece influenciar o metabolismo do zinco durante o período pré-natal, podendo comprometer o desenvolvimento fetal normal. Esse estudo foi dividido em duas partes: (1) reproduzir um modelo de autismo induzido por VPA pré-natal (400 mg/kg no GD 12,5) e (2) avaliar se a administração de zinco pré-natal (2 mg/kg 1h após) previne ou ameniza os prejuízos comportamentais e a expressão de TH-estriatal associados ao autismo causados pela exposição pré-natal ao VPA em ratos. Foram avaliados parâmetros reprodutivos, anormalidades comportamentais na comunicação (vocalização ultrassônica), comportamentos repetitivos e na cognição (labirinto em T) e interação social (comportamento de brincar), além de verificar o sistema dopaminérgico por meio da expressão proteica de TH-estriatal na prole masculina e feminina de ratas. O VPA causou danos reprodutivos, prejuízos na vocalização ultrassônica, comportamento repetitivo/restrito, inflexibilidade cognitiva, comprometimento na socialização com diminuição da brincadeira e redução nos níveis de TH- estriatal na prole masculina. A administração de zinco não foi capaz de impedir os danos reprodutivos causados pelo VPA, porém amenizou a inflexibilidade cognitiva e atenuou a brincadeira social, sem reestabelecer os níveis de TH-estriatal. A prole feminina foi menos afetada que a masculina, apresentando apenas a vocalização ultrassônica alterada. O zinco reestabeleceu esse dano. A redução da TH-estriatal na prole masculina sugere que, possivelmente o fenótipo tipo-autista investigado no presente estudo, esteja relacionado a modificações funcionais no sistema dopaminérgico. / Autism is a complex developmental disorder characterized by numerous behavioral impairments, such as communication, socialization and induction of cognitive inflexibility. Reproduction of experimental models of autism is an important tool in the study of this disorder. Prenatal exposure to VPA reproduces symptoms similar to those found in the human condition of autism. The VPA is known as a potential teratogen in humans and its mechanisms of action is not well understood. VPA appears to influence the zinc metabolism during the prenatal period, compromising normal fetal development. This study was done into two parts: (1st) obtain an autism model induced by prenatal VPA (400 mg/kg 12.5 GD) and (2nd) evaluate whether prenatal administration of zinc (2 mg/kg after 1h) prevents or reverses the behavioral impairments and protein striatal TH-expression associated with autism caused by prenatal exposure to VPA in rats. It was evaluated the reproductive parameters, abnormal behavior in the communication (ultrasonic vocalization test), repetitive behavior and cognitive capacity (T-maze test) and social interaction (play behavior test), and the evaluation of the dopaminergic system by quantification of TH-striatal expression in male and female offspring of rats. The VPA was able to cause reproductive damage, impairment in ultrasonic vocalization, repetitive/restricted behavior and cognitive inflexibility, impairment in socialization with decreased play behavior and reduction in striatal TH levels in male offspring. The zinc administration has not been able to prevent reproductive damage caused by VPA, but ameliorates the cognitive inflexibility and attenuated the social play behavior, without restoring TH-striatal levels. The offspring females were less affected as males, with alterations into ultrasonic vocalization only and zinc reestablished this damage. The reduction in striatal TH-male offspring suggests that the autistic-like phenotype, investigated in this study is, may be is related to functional modifications in the dopaminergic system.

Submitted by Automa??o e Estat?stica (sst@bczm.ufrn.br) on 2016-08-16T23:02:45Z No. of bitstreams: 1 AnaMariaAraujoSoares_DISSERT.pdf: 3132164 bytes, checksum: 1d26fedd574b389db008072f0a9d4fcb (MD5) / Approved for entry into archive by Arlan Eloi Leite Silva (eloihistoriador@yahoo.com.br) on 2016-08-24T00:27:46Z (GMT) No. of bitstreams: 1 AnaMariaAraujoSoares_DISSERT.pdf: 3132164 bytes, checksum: 1d26fedd574b389db008072f0a9d4fcb (MD5) / Made available in DSpace on 2016-08-24T00:27:46Z (GMT). No. of bitstreams: 1 AnaMariaAraujoSoares_DISSERT.pdf: 3132164 bytes, checksum: 1d26fedd574b389db008072f0a9d4fcb (MD5) Previous issue date: 2015-10-30 / O autismo ? um transtorno do desenvolvimento que se manifesta nos primeiros anos de vida e apresenta semiologia heterog?nea. Esta patologia afeta a matura??o do enc?falo e produz altera??es sensoriais, de linguagem e de intera??o social no in?cio na inf?ncia. O modelo experimental de autismo utilizando ?cido valproico (VPA) durante o per?odo gestacional tem sido demonstrado ter alta validade de face e permitir estudos tanto das bases neuropatol?gicas quanto neuro-funcionais durante o desenvolvimento. A despeito do recente interesse por este modelo como instrumento de compreens?o dos aspectos b?sicos da fisiopatologia do autismo, a maioria dos estudos experimentais t?m se concentrado nos aspectos comportamentais, histol?gicos e celulares. Neste trabalho, foram propostas estrat?gias experimentais de avalia??o comportamental associadas a eletrofisiologia \textit{in vivo}, uma t?cnica que nunca fora utilizada para avalia??o desse modelo. Animais controles e experimentais, submetidos previamente a um procedimento cir?rgico para implante de eletrodos cr?nicos, participaram de experimentos de livre explora??o, intera??o social e condicionamento ao medo. / O autismo ? um transtorno do desenvolvimento que se manifesta nos primeiros anos de vida e apresenta semiologia heterog?nea. Esta patologia afeta a matura??o do enc?falo e produz altera??es sensoriais, de linguagem e de intera??o social no in?cio na inf?ncia. O modelo experimental de autismo utilizando ?cido valproico (VPA) durante o per?odo gestacional tem sido demonstrado ter alta validade de face e permitir estudos tanto das bases neuropatol?gicas quanto neuro-funcionais durante o desenvolvimento. A despeito do recente interesse por este modelo como instrumento de compreens?o dos aspectos b?sicos da fisiopatologia do autismo, a maioria dos estudos experimentais t?m se concentrado nos aspectos comportamentais, histol?gicos e celulares. Neste trabalho, foram propostas estrat?gias experimentais de avalia??o comportamental associadas a eletrofisiologia \textit{in vivo}, uma t?cnica que nunca fora utilizada para avalia??o desse modelo. Animais controles e experimentais, submetidos previamente a um procedimento cir?rgico para implante de eletrodos cr?nicos, participaram de experimentos de livre explora??o, intera??o social e condicionamento ao medo.

The enhanced expression of histone deacetylases (HDACs) in a variety of malignancies drew attention to investigate a new category of anti-cancer drugs that are based on the inhibition of those enzymes. Valproic acid (VPA) is a well-known antiepileptic drug that exhibits antitumor activities through inhibition of HDACs class I and IIa. Cancer stem cells (CSCs) have been recognized to drive the tumor growth and progression hence; attention has been given to target this small subpopulation of CSCs rather than the whole bulk tumor cells. CD133 is considered to be a CSC marker in several tumors and its transcription is strongly influenced by epigenetic changes that will be altered upon administration of histone deacetylase inhibitors (HDACi) in cancer treatment. Therefore, we evaluated the epigenetic and cytotoxic effects of treatment with 1 mM VPA in combination with other chemotherapeutics and its influence on the expression of CD133 in human neuroblastoma (NB) cell lines. Our results revealed that addition of VPA to DNA-damaging chemotherapeutics induced a synergistic anti-tumor effect that was associated with caspase-3 dependent induction of apoptosis in UKF-NB-4 cells. This synergism was related to the increase of the acetylation status of histones H3 and H4 and was only produced either by...

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This research delves into the complex nexus between sustainable development and the participation of Indigenous Peoples (IPs), with a specific emphasis on Amerindians in Guyana. While sustainable development increasingly integrates into global policy, IPs have historically faced marginalisation, often finding their rights overlooked in discussions on climate change and sustainability. The inherent connection of IPs to their territories, marked by their role as stewards of the environment, showcases their critical importance in global sustainable practices. However, mainstream development often disregards the rich mosaic of Indigenous cultures, experiences, and worldviews. Utilising the Guyana-European Union Forest Law Enforcement, Governance, and Trade Voluntary Partnership Agreements (FLEGT VPA) as a case study, this research probes the intricate dynamics of a solution acclaimed for addressing deforestation and illegal logging. Central to the study is the exploration of participatory communication within this development intervention. By highlighting the potential of this communication approach, the study posits that IPs can actively engage, empowering them to reclaim their narrative and enhance their self-determination. Theoretical insights, which include postcolonial and subaltern studies, are complemented by several frameworks such as Communication for Development (C4D) and Communication for Social Change (CSC), among others. By employing a mixed-method approach encompassing individual interviews and focus group discussions, the research presents a comprehensive portrayal of IPs' perspectives on communication processes. The findings aim to augment academic discourse on the communication dynamics around sustainable initiatives, spotlighting avenues for more inclusive, patient, and equitable strategies in support of IPs and local communities. In essence, this thesis calls for an enduring commitment to bridge the chasm between vision and reality in sustainable development.

[pt] O presente estudo tem como objetivo testar a possibilidade de obtenção de retornos anormais de capital entre jan/2003 e dez/2012 para o mercado acionário brasileiro no curtíssimo prazo. Investigou-se, para tanto, a hipótese de reversão à média de curto prazo associada a uma seleção de ativos (ações) com base no critério de ordenamento decrescente do múltiplo P/VPA. Os ativos integrantes das carteiras vigentes do IBrX-100 foram ordenados de forma decrescente e em seguida estratégias contrárias com carteiras compradas em ações perdedoras e vendidas em ganhadoras foram montadas e testadas nos períodos subseqüentes. Evidências empíricas foram encontradas a favor da combinação de estratégias de valor e momento e, consequentemente, a favor da possibilidade de retornos anormais. Entretanto, o teste estatístico realizado felha em rejeitar a hipótese da significância dos resultados. Por fim, o trabalho investigou a existência de retornos residuais, expressos pelos Coeficientes de Jensen. Contudo, novamente o teste estatístico realizado não foi capaz de confirmar a significância dos resultados. / [en] The goal of this study is to test the possibility of obtaining abnormal capital returns between Jan/2003 and Dec/2012 for the Brazilian stock market in the very short run. We investigated, therefore, the hypothesis of mean reversion of returns associated with a selection of assets (shares) based on the criteria of descending order of P/BV ratio. Assets present in IBrX – 100 existing portfolios were ranked in decreasing order of P/BV ratio and then contrarian strategies were used with portfolios built by winner and loser stocks to test the abnormal returns in subsequent periods. Empirical evidences were found for the combination of Value and Momentum strategies and therefore for the possibility of abnormal returns. However, the statistical test performed fail to reject the hypothesis of significance of the results. Finally, the study investigated the existence of residua returns, expressed by Jensen Coeficients. However, once again the statistical test performed was not able to confirm the significance of the results.

Schizophrenia is a mental illness with early adult onset. Prophylactic treatments would be clinically important and therefore we investigated the effect of two interventions: influenza vaccination of pregnant mothers and valproate treatment during late adolescence. Maternal immune response during pregnancy is thought to adversely affect brain development. We sought to assess whether immune activation by influenza vaccine could itself cause behavioural abnormalities in a mouse model. Our data suggest that further work is needed to make firm conclusions about the behavioural effects of the influenza vaccine. The second part of this thesis describes an analysis of valproate treatment on cortical neuron morphology in Disc1 L100P mice, a model for schizophrenia. Valproate was previously shown to prevent the onset of abnormal behaviours in Disc1 L100P mice. Contrary to expectations, valproate decreased apical spine density and the number of dendritic processes rather than reversing the dendritic deficits seen in Disc1 L100P mice.