Retrospective revaluation— learning about implied but unpresented cues— poses one of the greatest challenges to classical learning theories. Whereas theorists have revised their models to accommodate revaluation, the empirical reliability of the phenomenon remains contentious. I present two sets of experiments that examine revaluative learning under different but analogous experimental protocols. Results provided mixed empirical evidence that is difficult to interpret in isolation. To address the issue, I apply two computational models to the experiments. An instance-based model of associative learning (Jamieson et al., 2012) predicts retrospective revaluation and anticipates participant behaviour in one set of experiments. An updated classical learning model (Ghirlanda, 2005) fails to predict retrospective revaluation, but anticipates participant behaviour in the other set of experiments. I argue that retrospective revaluation emerges as a corollary of basic memorial processes and discuss the empirical and theoretical implications.

Retrospective revaluation— learning about implied but unpresented cues— poses one of the greatest challenges to classical learning theories. Whereas theorists have revised their models to accommodate revaluation, the empirical reliability of the phenomenon remains contentious. I present two sets of experiments that examine revaluative learning under different but analogous experimental protocols. Results provided mixed empirical evidence that is difficult to interpret in isolation. To address the issue, I apply two computational models to the experiments. An instance-based model of associative learning (Jamieson et al., 2012) predicts retrospective revaluation and anticipates participant behaviour in one set of experiments. An updated classical learning model (Ghirlanda, 2005) fails to predict retrospective revaluation, but anticipates participant behaviour in the other set of experiments. I argue that retrospective revaluation emerges as a corollary of basic memorial processes and discuss the empirical and theoretical implications.

A system for generative rhythmic modeling is presented. The work aims to explore computational models of creativity, realizing them in a system designed for realtime generation of semi-improvisational music. This is envisioned as an attempt to develop musical intelligence in the context of structured improvisation, and by doing so to enable and encourage new forms of musical control and performance; the systems described in this work, already capable of realtime creation, have been designed with the explicit intention of embedding them in a variety of performance-based systems. A model of qaida, a solo tabla form, is presented, along with the results of an online survey comparing it to a professional tabla player's recording on dimensions of musicality, creativity, and novelty. The qaida model generates a bank of rhythmic variations by reordering subphrases. Selections from this bank are sequenced using a feature-based approach. An experimental extension into modeling layer- and loop-based forms of electronic music is presented, in which the initial modeling approach is generalized. Starting from a seed track, the layer-based model utilizes audio analysis techniques such as blind source separation and onset-based segmentation to generate layers which are shuffled and recombined to generate novel music in a manner analogous to the qaida model.

Doctor of Philosophy / The motivation for the research presented in this thesis stems from the recent availability of high frequency limit order book data, relative scarcity of studies employing such data, economic significance of transaction costs management, and a perceived potential of data mining for uncovering patterns and relationships not identified by the traditional top-down modelling approach. We analyse and build computational models for order submissions on the Australian Stock Exchange, an order-driven market with a public electronic limit order book. The focus of the thesis is on the trade implementation problem faced by a trader who wants to transact a buy or sell order of a certain size. We use two approaches to build our models, top-down and bottom-up. The traditional, top-down approach is applied to develop an optimal order submission plan for an order which is too large to be traded immediately without a prohibitive price impact. We present an optimisation framework and some solutions for non-stationary and non-linear price impact and price impact risk. We find that our proposed transaction costs model produces fairly good forecasts of the variance of the execution shortfall. The second, bottom-up, or data mining, approach is employed for trade sign inference, where trade sign is defined as the side which initiates both a trade and the market order that triggered the trade. We are interested in an endogenous component of the order flow, as evidenced by the predictable relationship between trade sign and the variables used to infer it. We want to discover the rules which govern the trade sign, and establish a connection between them and two empirically observed regularities in market order submissions, competition for order execution and transaction cost minimisation. To achieve the above aims we first use exploratory analysis of trade and limit order book data. In particular, we conduct unsupervised clustering with the self-organising map technique. The visualisation of the transformed data reveals that buyer-initiated and seller-initiated trades form two distinct clusters. We then propose a local non-parametric trade sign inference model based on the k-nearest-neighbour classifier. The best k-nearest-neighbour classifier constructed by us requires only three predictor variables and achieves an average out-of-sample accuracy of 71.40% (SD=4.01%)1, across all of the tested stocks. The best set of predictor variables found for the non-parametric model is subsequently used to develop a piecewise linear trade sign model. That model proves superior to the k-nearest-neighbour classifier, and achieves an average out-of-sample classification accuracy of 74.38% (SD=4.25%). The result is statistically significant, after adjusting for multiple comparisons. The overall classification performance of the piecewise linear model indicates a strong dependence between trade sign and the three predictor variables, and provides evidence for the endogenous component in the order flow. Moreover, the rules for trade sign classification derived from the structure of the piecewise linear model reflect the two regularities observed in market order submissions, competition for order execution and transaction cost minimisation, and offer new insights into the relationship between them. The obtained results confirm the applicability and relevance of data mining for the analysis and modelling of stock market order submissions.

Τα κυψελικά αυτόματα (ΚΑ) αποτελούν την εξιδανίκευση ενός φυσικού συστήματος όπου ο χώρος και ο χρόνος είναι διακριτοί και οι φυσικές ποσότητες λαμβάνουν μόνο ένα πεπερασμένο σύνολο τιμών. Τα κυψελικά αυτόματα αποτελούνται από ένα πλέγμα με διακριτούς πανομοιότυπους κόμβους. Κάθε σημείο-κόμβος του πλέγματος χαρακτηρίζεται από μία τιμή η οποία δεν είναι αυθαίρετη, αλλά λαμβάνεται από ένα συγκεκριμένο σύνολο ‘επιτρεπτών’ ακέραιων τιμών. Οι τιμές αυτών των κόμβων του πλέγματος εξελίσσονται από τη μία χρονική στιγμή στην άλλη σύμφωνα με προκαθορισμένους τοπικούς κανόνες. Η συνολική δομή αποτελεί ένα μοντέλο παράλληλου υπολογισμού. ΄Οταν η απλή δομή του μοντέλου επαναλαμβάνεται, προκύπτουν πολύπλοκα πρότυπα που μπορούν να προσομοιώσουν ποικίλα πολύπλοκα φυσικά φαινόμενα και συστήματα. Χρησιμοποιούμε τα κυψελικά αυτόματα για να προσομοιώσουμε έναν αλγόριθμο ελέγχου τοπολογίας για ασύρματα δίκτυα αισθητήρων. Τα ασύρματα δίκτυα αισθητήρων αποτελούνται από ένα μεγάλο αριθμό διασκορπισμένων αισθητήρων-κόμβων που λειτουργούν με μπαταρίες. Σκοπός του προβλήματος ελέγχου τοπολογίας σε ασύρματα δίκτυα αισθητήρων είναι η επιλογή κατάλληλου υποσυνόλου κόμβων ικανών να παρακολουθούν μια περιοχή με στόχο τη μικρότερη δυνατή κατανάλωση ενέργειας και ως εκ τούτου την επέκταση της διάρκειας ζωής του δικτύου. / Cellular automata (CA) are an idealization of a physical system where space and time are discrete and the physical quantities take only a finite set of values. Cellular automata consist of a regular grid of identical cells-nodes. Each node is characterized by a non arbitrary value selected by a specific set of appropriate integers. The values of the nodes change over time according to predefined localized rules. The overall structure can be viewed as a parallel processing device. This simple structure when iterated several times produces complex patterns displaying the potential to simulate different sophisticated natural phenomena. We use cellular automata for simulating a topology control algorithm in Wireless Sensor Networks (WSNs). WSNs are composed of a large number of distributed sensor nodes operating on batteries; the objective of the topology control problem in WSNs is to select an appropriate subset of nodes able to monitor a region at a minimum energy consumption cost thus extending the network lifetime.

Este trabalho define um modelo de execução para cláusulas Prolog, a partir do modelo abstrato de Máquinas de Cláusulas, e o Projeto de uma arquitetura paralela que suporte o modelo proposto. São também introduzidos alguns aspectos sobre as linguagens Lógicas e as máquinas Prolog visto que estes elementos estão relacionados intimamente tanto com o modelo quanto com a arquitetura propostos. Na proposta do modelo de execução são definidos uma representação para os elementos do modelo abstrato (predicados, arcos e clausulas) e um conjunto de algoritmos que permitem a operacionalização do modelo de forma a que tanto o paralelismo como a concorrência inerentes ao modelo abstrato sejam exploradas de forma integral. Na proposta da arquitetura são, primeiramente, discutidas algumas opções de arquitetura básica e, posteriormente, descrita a arquitetura escolhida tanto a nível de blocos bem como dos seus componentes principais, a saber: interface de mem6ria, processador e rede de interconexão. Para cada um destes componentes são descritas as principais instruções e são apresentados os algoritmos que as implementam. Junto com a descrição da arquitetura é definida uma estrutura de dados que permite a implementação da representação descrita no modelo de execuqao e é definido também o algoritmo de unificação que percorre a estrutura proposta. Na validação é feito o cálculo da largura de banda máxima alcançada pela arquitetura proposta, calculo este baseado no algoritmo de unificação descrito. E também feita uma avaliação do ganho de performance da arquitetura proposta em relação a um processador bem como é justificado o numero de processadores escolhidos comparando a performance alcançada na arquitetura proposta com a performance alcançada por conjuntos maiores e menores de processadores. Por fim na conclusa o são feitos comentários sobre os objetivos atingidos e sobre possíveis extensões a este trabalho. / The present work defines a execution model for Prolog clauses based on the clause machines abstract model and then proposes a parallel architecture for the execution model. Some topics about Logic languages and Prolog machines were therefore introduced because they are closely related with, both, the model and the architecture proposed. In the execution model the representation of the abstract model elements (predicates, arcs and clauses) and the set of algoritms that allow the operation of the model were defined so that the parallelism of the model can be integraly achieved. In the architecture proposal, first some options for the basic architecture were discussed and then the chosen architecture is describeb at block level as much as at its components level. The most importants components reported are the memory interface, the processor and the interconection net, for each one of them the possible instructions were describeb as well as their algoritms. Together with the especification of the architecture, the data estructure that allows the implementation of the execution model representation and the concerning unification algorit that scans the proposed representation were especified too. In the validation the thoughtput permited by the proposal architecture is calculated based on the unification algoritm earlier described. Besides that the performance gain compared with an architecture with only one processor was estimated, as much as the confrontation of the performance of lesser and greater sets of processors elements were made in order to validate the chossen number. At last, in the conclusion, some coments about the fulfilled goals and about eventual extends for the work.

Este trabalho define um modelo de execução para cláusulas Prolog, a partir do modelo abstrato de Máquinas de Cláusulas, e o Projeto de uma arquitetura paralela que suporte o modelo proposto. São também introduzidos alguns aspectos sobre as linguagens Lógicas e as máquinas Prolog visto que estes elementos estão relacionados intimamente tanto com o modelo quanto com a arquitetura propostos. Na proposta do modelo de execução são definidos uma representação para os elementos do modelo abstrato (predicados, arcos e clausulas) e um conjunto de algoritmos que permitem a operacionalização do modelo de forma a que tanto o paralelismo como a concorrência inerentes ao modelo abstrato sejam exploradas de forma integral. Na proposta da arquitetura são, primeiramente, discutidas algumas opções de arquitetura básica e, posteriormente, descrita a arquitetura escolhida tanto a nível de blocos bem como dos seus componentes principais, a saber: interface de mem6ria, processador e rede de interconexão. Para cada um destes componentes são descritas as principais instruções e são apresentados os algoritmos que as implementam. Junto com a descrição da arquitetura é definida uma estrutura de dados que permite a implementação da representação descrita no modelo de execuqao e é definido também o algoritmo de unificação que percorre a estrutura proposta. Na validação é feito o cálculo da largura de banda máxima alcançada pela arquitetura proposta, calculo este baseado no algoritmo de unificação descrito. E também feita uma avaliação do ganho de performance da arquitetura proposta em relação a um processador bem como é justificado o numero de processadores escolhidos comparando a performance alcançada na arquitetura proposta com a performance alcançada por conjuntos maiores e menores de processadores. Por fim na conclusa o são feitos comentários sobre os objetivos atingidos e sobre possíveis extensões a este trabalho. / The present work defines a execution model for Prolog clauses based on the clause machines abstract model and then proposes a parallel architecture for the execution model. Some topics about Logic languages and Prolog machines were therefore introduced because they are closely related with, both, the model and the architecture proposed. In the execution model the representation of the abstract model elements (predicates, arcs and clauses) and the set of algoritms that allow the operation of the model were defined so that the parallelism of the model can be integraly achieved. In the architecture proposal, first some options for the basic architecture were discussed and then the chosen architecture is describeb at block level as much as at its components level. The most importants components reported are the memory interface, the processor and the interconection net, for each one of them the possible instructions were describeb as well as their algoritms. Together with the especification of the architecture, the data estructure that allows the implementation of the execution model representation and the concerning unification algorit that scans the proposed representation were especified too. In the validation the thoughtput permited by the proposal architecture is calculated based on the unification algoritm earlier described. Besides that the performance gain compared with an architecture with only one processor was estimated, as much as the confrontation of the performance of lesser and greater sets of processors elements were made in order to validate the chossen number. At last, in the conclusion, some coments about the fulfilled goals and about eventual extends for the work.

Os aspectos quantitativos regem as práticas de engenharia visando o gerenciamento de reservatórios. Entretanto, a preocupação em relação aos aspectos qualitativos da água tem aumentado, já que um número cada vez maior de reservatórios estão sendo utilizados para vários tipos de usos. No processo de gerenciamento de reservatórios é necessário que se leve em consideração todos os usos que serão beneficiados pelo sistema em questão. Nesse sentido, o objetivo do trabalho foi o emprego de técnicas computacionais para análise quanti-qualitativa dos usos múltiplos do reservatório de Barra Bonita - SP, realizando simulações computacionais através do modelo MIKE BASIN; propondo e testando um modelo de otimização com programação não-linear baseado no método das restrições e incorporando o uso de geotecnologias para análise espacial (distribuição horizontal) e temporal (sazonalidade) da qualidade da água do reservatório. Selecionou-se o reservatório de Barra Bonita para análise, devido aos usos múltiplos da água (geração de energia, navegação, recreação, turismo e pesca) e a presença de uma eclusa para transposição do desnível entre a jusante da barragem e o reservatório de acumulação da hidrelétrica, o que torna o reservatório uma área de estudo diferenciada. Os resultados das simulações realizadas no modelo MIKE BASIN para avaliar os usos múltiplos do reservatório, demonstraram que o melhor cenário foi o que estabeleceu prioridades iguais para a geração de energia e a navegação. A maximização da geração de energia hidroelétrica, através do modelo de otimização, não prejudicou os outros usos do reservatório (principalmente a navegação) e, mesmo no período seco, a energia média gerada pelo modelo registrou valores acima da energia média real gerada pela Usina Hidrelétrica de Barra Bonita-SP (período de 2001 a 2005). O emprego de geotecnologias (software Surfer) proporcionou boas condições para análise espaço-temporal da qualidade da água, quando aliado ao conhecimento sobre as características e condições do ambiente de estudo. Os dados obtidos em campo, demonstraram que algumas variáveis analisadas, como a condutividade elétrica e a turbidez aumentam significativamente do período seco para o chuvoso, pois estão diretamente relacionados com o aporte de material orgânico e inorgânico. O potencial hidrogeniônico (pH) sofre uma variação muito pequena do período seco para o chuvoso, mas seus valores variam espacialmente, sendo encontrados valores maiores no compartimento da barragem para o período seco, e no final do braço do rio Piracicaba para o período chuvoso. Quanto ao oxigênio dissolvido, este aumenta bastante do período chuvoso para o seco, mas em ambos os períodos as maiores concentrações são encontradas no final do braço do rio Piracicaba - SP. Ressalta-se, que apenas o oxigênio dissolvido (estação seca) não se enquadrou no padrão da Resolução CONAMA nº 357/2005, para águas de classe II. / The quantitative aspects rule the engineering practices aimed at reservoirs management. However, the concern about the qualitative aspects of water has increased, since a growing number of reservoirs are being used for many kinds of applications. In the process of reservoir management it is necessary to take into consideration all the uses that will benefit from the system itself. Hence, the objective of this study was the use of computational techniques for quantitative and qualitative analysis of the multiple applications of the reservoir of Barra Bonita - SP, performing computer simulations using the model MIKE BASIN, proposing and testing an optimization model with non-linear programming based on the constraint method and incorporating the use of geotechnologies for spatial (horizontal distribution) and time (seasonal distribution) analysis of the reservoir water quality. It was selected the reservoir of Barra Bonita for analysis because of the multiple applications of the water (power generation, navigation, recreation, tourism and fishing) and the presence of a lock for transposition of the gap between the dam downstream and the power plant accumulation reservoir, which makes the reservoir a different area of study. The results of the simulations performed in MIKE BASIN model to evaluate the multiple applications of the reservoir showed that the best scenario was the one in which the priorities were the same for power generation and navigation. The maximization of the hydropower generation through the optimization model, did not impair other uses of the reservoir (mainly navigation) and even in the dry season, the average power generated by the model registered values above the average real power generated by the Hydroelectric Power Plant of Barra Bonita-SP (from 2001 to 2005). The use of geotechnologies (Surfer software) provided good conditions for space-time analysis of water quality when coupled with the knowledge about the characteristics and conditions of the studied environment. The data obtained showed that some variables, such as electrical conductivity and turbidity significantly increase from the dry season to the rainy season, since they are directly related to the supply of organic and inorganic materials. The hydrogen potential (pH) undergoes a very small variation from the dry season to the rainy season, but its values vary spatially, with higher values found in the compartment of the dam during the dry season, and at the end of the arm of the Piracicaba river during the wet season. The dissolved oxygen greatly increases from the rainy season to the dry one, but in both periods the highest concentrations are found at the end of the arm of the river Piracicaba - SP. It is emphasized that only the dissolved oxygen (dry season) did not fit the pattern of CONAMA Resolution nº 357/2005, to class II waters.

Este trabalho define um modelo de execução para cláusulas Prolog, a partir do modelo abstrato de Máquinas de Cláusulas, e o Projeto de uma arquitetura paralela que suporte o modelo proposto. São também introduzidos alguns aspectos sobre as linguagens Lógicas e as máquinas Prolog visto que estes elementos estão relacionados intimamente tanto com o modelo quanto com a arquitetura propostos. Na proposta do modelo de execução são definidos uma representação para os elementos do modelo abstrato (predicados, arcos e clausulas) e um conjunto de algoritmos que permitem a operacionalização do modelo de forma a que tanto o paralelismo como a concorrência inerentes ao modelo abstrato sejam exploradas de forma integral. Na proposta da arquitetura são, primeiramente, discutidas algumas opções de arquitetura básica e, posteriormente, descrita a arquitetura escolhida tanto a nível de blocos bem como dos seus componentes principais, a saber: interface de mem6ria, processador e rede de interconexão. Para cada um destes componentes são descritas as principais instruções e são apresentados os algoritmos que as implementam. Junto com a descrição da arquitetura é definida uma estrutura de dados que permite a implementação da representação descrita no modelo de execuqao e é definido também o algoritmo de unificação que percorre a estrutura proposta. Na validação é feito o cálculo da largura de banda máxima alcançada pela arquitetura proposta, calculo este baseado no algoritmo de unificação descrito. E também feita uma avaliação do ganho de performance da arquitetura proposta em relação a um processador bem como é justificado o numero de processadores escolhidos comparando a performance alcançada na arquitetura proposta com a performance alcançada por conjuntos maiores e menores de processadores. Por fim na conclusa o são feitos comentários sobre os objetivos atingidos e sobre possíveis extensões a este trabalho. / The present work defines a execution model for Prolog clauses based on the clause machines abstract model and then proposes a parallel architecture for the execution model. Some topics about Logic languages and Prolog machines were therefore introduced because they are closely related with, both, the model and the architecture proposed. In the execution model the representation of the abstract model elements (predicates, arcs and clauses) and the set of algoritms that allow the operation of the model were defined so that the parallelism of the model can be integraly achieved. In the architecture proposal, first some options for the basic architecture were discussed and then the chosen architecture is describeb at block level as much as at its components level. The most importants components reported are the memory interface, the processor and the interconection net, for each one of them the possible instructions were describeb as well as their algoritms. Together with the especification of the architecture, the data estructure that allows the implementation of the execution model representation and the concerning unification algorit that scans the proposed representation were especified too. In the validation the thoughtput permited by the proposal architecture is calculated based on the unification algoritm earlier described. Besides that the performance gain compared with an architecture with only one processor was estimated, as much as the confrontation of the performance of lesser and greater sets of processors elements were made in order to validate the chossen number. At last, in the conclusion, some coments about the fulfilled goals and about eventual extends for the work.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / The enzyme acetylcholinesterase (EC 3.1.1.7, AChE) is responsible to terminate acetylcholine activity in the terminal nervous junctions with its effector organs or post-synaptic sites. The activity of this enzyme could be inhibited by organophosphorus (OP) compounds, and this inactivation leads to an accumulation of acetylcholine in the cholinergic receptors, leading to a cholinergic crisis that may result in death. In this way, the OP compound methamidophos has been related to its broad use in various agriculture cultures in Brazil, with high intoxication rate. Actually, the only compounds able to revert the AChE inhibition by OP, are the oxime, such compounds may reactive the enzyme activity due its high nuclephilic power, attacking the phosphoryl group of the inhibited enzyme and displacing it. However, such compounds show toxic effects, and its use is limited by the high specificity, with each oxime acting only in the reactivation of AChE induced by specific OP coumponds. These limitations raise the need of development of new compounds with AChE reactivator potency, with minor side effects. In this way, have been utilized a series of computational tools (in silico models), with the aim of understand the interaction occurring at a molecular level and, so, rationalize the new compounds development. Thus, the aim of this thesis is to evaluate the activity of three new compounds in reactivate the AChE inhibited by methamidophos, in comparison with two others oximes used in clinical (obidoxime and pralidoxime), both in in silico and in vitro models. Our work demonstrate that the newly synthesized compounds are able to reactivate human erythrocyte AChE, however less efficiently than pralidoxime and obidoxime, and reactivate human plasma butyrylcholinesterase (BChE), where the classical oximes failed. We also show that pralidoxime, which obtained the best reactivation constant among all tested compounds, attack the phosphorus-oxygen moiety (formed between the methamidophos and the AChE catalytic triad residue Ser203) via a region known as oxyanion-hole , composed by the residues Gly120, Gly121 and Ala204. Such found may help in the development of new compounds with better reactivatory activity on AChE inhibited by OP compounds. Furthermore, we show for the first time the individual contribution of each amino acid of AChE, in a radii of 14 Å from the ligand, to the oxime bonding to its active site, using quantum chemistry methods. Here, we demonstrate the important of a quaternary nitrogen to the stabilization of the oximes into the active site; as well as, we obtained evidences that the active form of oximes should be the unprotonated one, instead the protonated, which has been target of debate in the scientific society. Particularly important, we show the critical contribution of amino acids that lies distant from the ligand to the adopted conformation and stabilization of the compounds into the active site of AChE, which has been neglected until far. Finally, our study also evaluates the toxic effects of the compound isatin-3-N4-benzilthiosemicarbazone (IBTC) in mice, which presented low toxicity, with median lethal dose superior at 500 mg/kg. Concluding, this study contributes significantly to the development of new drugs able to restore the AChE activity with minor toxic effects. / A enzima acetilcolinesterase (EC 3.1.1.7, AChE) é responsável por terminar a ação da acetilcolina nas junções das terminações nervosas com seus órgãos efetores ou sítios pós-sinaptícos. A atividade desta enzima pode ser inibida por compostos organofosforados (OP), e sua inativação resulta em um acúmulo de acetilcolina nos receptores colinérgicos, levando a crise colinérgica que pode levar a morte. No Brasil, se destaca o uso do composto OP metamidofós, que é largamente utilizado no controle de pragas em culturas agrícolas e tem sido relacionado com altas taxas de intoxicação. Atualmente, os únicos compostos capazes de reverter a inibição da AChE por OP são as oximas, tais compostos podem reativar a enzima devido a seu alto poder nucleofílico, podendo atacar e retirar o grupamento fosforil da enzima inibida. Porém, tais compostos apresentam efeitos tóxicos, e tem seu uso limitado pela alta especificidade, com cada oxima atuando na AChE inibida por apenas alguns compostos OP. Tais limitações criam a necessidade do desenvolvimento de novos fármacos com potencial reativador da AChE com menores efeitos colaterais. Neste sentido, se tem utilizado uma série de ferramentas computacionais (modelos in silico), com o objetivo de entender as interações que ocorrem em nível molecular e, desta forma, racionalizar o desenvolvimento de novos compostos. Sendo assim, o objetivo desta tese consiste em avaliar a atividade de três novos compostos, em comparação com duas oximas já utilizadas na clínica (obidoxima e pralidoxima), sobre a atividade da AChE inibida por metamidofós, tanto em modelos in silico como in vitro. Como resultados, observamos que os três novos compostos foram capazes de reativar a AChE de eritrócitos humanos inibida por metamidofós, contudo com menor eficiência que as oximas já utilizadas na clínica. Porém, todos os novos compostos foram capazes de reativar a enzima butirilcolinesterase (BChE), uma enzima acessória à AChE no sistema colinérgico, inibida por metamidofós, enquanto nenhumas das oximas clássicas tiveram qualquer atividade reativadora nesta enzima. Nosso trabalho também demonstrou que a pralidoxima, que obteve a melhor constante de reativação entre todos os compostos testados, ataca a ligação fosforo-oxigênio (formada entre o metamidofós e o resíduo Ser203, da tríade catalítica da AChE) via uma região conhecida como oxyanion-hole , que compreende os resíduos Gly120, Gly121 e Ala204. Tal achado pode ajudar no desenvolvimento de novos compostos com melhor atividade reativatória na AChE inibida por OPs. Além disso, mostramos aqui pela primeira vez, a contribuição de cada resíduo de aminoácido da AChE, num raio de 14 Å do ligante, para a ligação das oximas no seu sítio ativo, usando métodos de química quântica. Tais achados mostraram a importância da presença de um nitrogênio quaternário para a estabilização das oximas no sítio ativo; assim como colheu evidências que a forma ativa das oximas seria a sua forma desprotonada, ao invés da forma protonada, o que tem sido alvo de algum debate no meio cientifico. Particularmente importante, foi demonstrado a contribuição fundamental de aminoácidos que se encontram distantes do ligante, para a estabilização e conformação adotada pelos compostos, e que até o momento tem sido negligenciados em estudos in silico. Por fim, nosso estudo também avaliou os efeitos tóxicos do composto isatina-3-N4-benziltiosemicarbazona (IBTC) em camundongos, o qual apresentando baixa toxicidade, com valores de dose letal mediana (LD50) superiores a 500 mg/kg. Desta forma, este estudo contribui para a desenvolvimento de novos fármacos capazes de reativar a AChE e que apresentem menos efeitos tóxicos.