Anti-tumoral effect of the non-nucleoside DNMT inhibitor RG108 in human prostate cancer cells

Background: Current therapeutic strategies for advanced prostate cancer (PCa) are largely ineffective. Because aberrant DNA methylation associated with inappropriate gene-silencing is a common feature of PCa, DNA methylation inhibitors might constitute an alternative therapy. In this study we aimed to evaluate the anti-cancer properties of RG108, a novel non-nucleoside inhibitor of DNA methyltransferases (DNMT), in PCa cell lines. Methods: The anti-tumoral impact of RG108 in LNCaP, 22Rv1, DU145 and PC-3 cell lines was assessed through standard cell viability, apoptosis and cell cycle assays. Likewise, DNMT activity, DNMT1 expression and global levels of DNA methylation were evaluated in the same cell lines. The effectiveness of DNA demethylation was further assessed through the determination of promoter methylation and transcript levels of GSTP1, APC and RAR-β2, by quantitative methylation-specific PCR and RT-PCR, respectively. Results: RG108 led to a significant dose and time dependent growth inhibition and apoptosis induction in LNCaP, 22Rv1 and DU145. LNCaP and 22Rv1 also displayed decreased DNMT activity, DNMT1 expression and global DNA methylation. Interestingly, chronic treatment with RG108 significantly decreased GSTP1, APC and RAR-β2 promoter hypermethylation levels, although mRNA re-expression was only attained GSTP1 and APC. Conclusions: RG108 is an effective tumor growth suppressor in most PCa cell lines tested. This effect is likely mediated by reversion of aberrant DNA methylation affecting cancer related-genes epigenetically silenced in PCa. However, additional mechanism might underlie the anti-tumor effects of RG108. In vivo studies are now mandatory to confirm these promising results and evaluate the potential of this compound for PCa therapy.

A influência do acompanhamento em suporte digital na motivação dos alunos de saxofone: relatório de estágio

I (Prática pedagógica)- Esta secção do Relatório de Estágio pretende apresentar elementos referentes ao Estágio do Ensino Especializado da Música no ensino do saxofone, efectuado na Escola de Música Luís António Maldonado Rodrigues, no ano lectivo 2012/2013. Neste estágio foram envolvidos e analisados três alunos, em níveis distintos de desenvolvimento, mas com orientações semelhantes no que respeita à organização do trabalho. Para cada aluno foram realizados trinta planos de aula, uma planificação anual e três gravações vídeo/áudio em contexto de sala de aula, permitindo uma análise e reflexão mais profunda do trabalho docente. A secção é composta pela caracterização da escola onde se realizou o estágio, através da sua contextualização/funcionamento, dos seus espaços e equipamentos, recursos humanos existentes e organização pedagógica. Posteriormente é efectuada a caracterização dos três alunos envolvidos no estágio, baseada na experiência docente e nos conhecimentos fornecidos pelas Unidades Curriculares do Mestrado em Ensino da Música. Seguidamente descrevem-se as práticas lectivas desenvolvidas ao longo do ano lectivo por parte do docente, incorporando linhas orientadoras da docência aplicadas na prática pedagógica. É feita uma análise crítica da actividade docente no âmbito do estágio do Ensino Especializado da Música, e, por último, uma conclusão desta primeira secção. .

Relatório de estágio

I (Prática Pedagógica) - O estágio foi realizado na Academia de Música de Almada (AMA) com três alunos de níveis diferentes: Aluno x, Iniciação Musical; Aluna y, 2º grau; e Aluna z, 5º grau. A planificação do trabalho foi feita com a colaboração do professor Vasco Broco e sob a supervisão do professor Pedro Saglimbeni Muñoz, tendo por base o programa da AMA e procurando corresponder às necessidades individuais de cada aluno, bem como respeitar os diferentes ritmos de aprendizagem. Dadas as diferenças de idade e de nível, os objectivos que procurei atingir com cada aluno durante o ano lectivo são naturalmente díspares, bem como a perspectiva de cada um em relação ao próprio instrumento e ao ensino da música. Enquanto que os mais novos encaram a aprendizagem musical como uma actividade meramente recreativa, pelo menos por enquanto, a Aluna z ambiciona fazer uma carreira como instrumentista. Mesmo entre os mais novos há diferenças, pois apesar de o Aluno x ainda estar a frequentar a Iniciação Musical, já iniciou a sua aprendizagem há mais tempo do que a Aluna y, encarando o ensino com mais seriedade. A AMA tem a vantagem de ter um pianista acompanhador disponível para cada dia da semana, o que tornou possível desenvolver um trabalho consistente com os alunos em termos de ensaios e audições. As audições e momentos de avaliação foram marcados em reuniões de Departamento Curricular, à excepção da calendarização das Provas Globais que foi feita em reunião de Conselho Pedagógico. O aproveitamento foi positivo para os três alunos no final do estágio, tendo todos transitado para o nível de ensino seguinte.

Avaliação e a Qualidade das Práticas de Inclusão para Alunos com PEA: Escala LAQI (Louisiana Autism Quality Indicators)

Dissertação apresentada à Escola Superior de Educação de Lisboa para obtenção de grau de mestre em Educação Especial, domínio Cognição e Multideficiência

Concurrent tabling

In the past few years Tabling has emerged as a powerful logic programming model. The integration of concurrent features into the implementation of Tabling systems is demanded by need to use recently developed tabling applications within distributed systems, where a process has to respond concurrently to several requests. The support for sharing of tables among the concurrent threads of a Tabling process is a desirable feature, to allow one of Tabling’s virtues, the re-use of computations by other threads and to allow efficient usage of available memory. However, the incremental completion of tables which are evaluated concurrently is not a trivial problem. In this dissertation we describe the integration of concurrency mechanisms, by the way of multi-threading, in a state of the art Tabling and Prolog system, XSB. We begin by reviewing the main concepts for a formal description of tabled computations, called SLG resolution and for the implementation of Tabling under the SLG-WAM, the abstract machine supported by XSB. We describe the different scheduling strategies provided by XSB and introduce some new properties of local scheduling, a scheduling strategy for SLG resolution. We proceed to describe our implementation work by describing the process of integrating multi-threading in a Prolog system supporting Tabling, without addressing the problem of shared tables. We describe the trade-offs and implementation decisions involved. We then describe an optimistic algorithm for the concurrent sharing of completed tables, Shared Completed Tables, which allows the sharing of tables without incurring in deadlocks, under local scheduling. This method relies on the execution properties of local scheduling and includes full support for negation. We provide a theoretical framework and discuss the implementation’s correctness and complexity. After that, we describe amethod for the sharing of tables among threads that allows parallelism in the computation of inter-dependent subgoals, which we name Concurrent Completion. We informally argue for the correctness of Concurrent Completion. We give detailed performance measurements of the multi-threaded XSB systems over a variety of machines and operating systems, for both the Shared Completed Tables and the Concurrent Completion implementations. We focus our measurements inthe overhead over the sequential engine and the scalability of the system. We finish with a comparison of XSB with other multi-threaded Prolog systems and we compare our approach to concurrent tabling with parallel and distributed methods for the evaluation of tabling. Finally, we identify future research directions.

Energy-conscious tasks partitioning onto a heterogeneous multi-core platform

Modern multicore processors for the embedded market are often heterogeneous in nature. One feature often available are multiple sleep states with varying transition cost for entering and leaving said sleep states. This research effort explores the energy efficient task-mapping on such a heterogeneous multicore platform to reduce overall energy consumption of the system. This is performed in the context of a partitioned scheduling approach and a very realistic power model, which improves over some of the simplifying assumptions often made in the state-of-the-art. The developed heuristic consists of two phases, in the first phase, tasks are allocated to minimise their active energy consumption, while the second phase trades off a higher active energy consumption for an increased ability to exploit savings through more efficient sleep states. Extensive simulations demonstrate the effectiveness of the approach.

Infection and childhood leukemia: review of evidence

OBJECTIVE : To analyze studies that evaluated the role of infections as well as indirect measures of exposure to infection in the risk of childhood leukemia, particularly acute lymphoblastic leukemia. METHODS : A search in Medline, Lilacs, and SciELO scientific publication databases initially using the descriptors “childhood leukemia” and “infection” and later searching for the words “childhood leukemia” and “maternal infection or disease” or “breastfeeding” or “daycare attendance” or “vaccination” resulted in 62 publications that met the following inclusion criteria: subject aged ≤ 15 years; specific analysis of cases diagnosed with acute lymphoblastic leukemia or total leukemia; exposure assessment of mothers’ or infants’ to infections (or proxy of infection), and risk of leukemia. RESULTS : Overall, 23 studies that assessed infections in children support the hypothesis that occurrence of infection during early childhood reduces the risk of leukemia, but there are disagreements within and between studies. The evaluation of exposure to infection by indirect measures showed evidence of reduced risk of leukemia associated mainly with daycare attendance. More than 50.0% of the 16 studies that assessed maternal exposure to infection observed increased risk of leukemia associated with episodes of influenza, pneumonia, chickenpox, herpes zoster, lower genital tract infection, skin disease, sexually transmitted diseases, Epstein-Barr virus, and Helicobacter pylori . CONCLUSIONS : Although no specific infectious agent has been identified, scientific evidence suggests that exposure to infections has some effect on childhood leukemia etiology.

Contratos de futuros sobre taxas de juro : estudo de caso sobre a Euribor a 3 meses

Mestrado em Contabilidade e Análise Financeira

Evaluating Android OS for embedded real-time systems

Since its official public release, Android has captured the interest from companies, developers and the general audience. From that time up to now, this software platform has been constantly improved either in terms of features or supported hardware and, at the same time, extended to new types of devices different from the originally intended mobile ones. However, there is a feature that has not been explored yet - its real-time capabilities. This paper intends to explore this gap and provide a basis for discussion on the suitability of Android in order to be used in Open Real-Time environments. By analysing the software platform, with the main focus on the virtual machine and its underlying operating system environments, we are able to point out its current limitations and, therefore, provide a hint on different perspectives of directions in order to make Android suitable for these environments. It is our position that Android may provide a suitable architecture for real-time embedded systems, but the real-time community should address its limitations in a joint effort at all of the platform layers.

Isolation and characterisation of metallothionein from the clam Ruditapes decussatus

Aquatic Toxicology 63 (2003) 307-318

An implicit GTS allocation mechanism in IEEE 802.15.4 for time-sensitive wireless sensor networks: theory and practice

Timeliness guarantee is an important feature of the recently standardized IEEE 802.15.4 protocol, turning it quite appealing for Wireless Sensor Network (WSN) applications under timing constraints. When operating in beacon-enabled mode, this protocol allows nodes with real-time requirements to allocate Guaranteed Time Slots (GTS) in the contention-free period. The protocol natively supports explicit GTS allocation, i.e. a node allocates a number of time slots in each superframe for exclusive use. The limitation of this explicit GTS allocation is that GTS resources may quickly disappear, since a maximum of seven GTSs can be allocated in each superframe, preventing other nodes to benefit from guaranteed service. Moreover, the GTS may be underutilized, resulting in wasted bandwidth. To overcome these limitations, this paper proposes i-GAME, an implicit GTS Allocation Mechanism in beacon-enabled IEEE 802.15.4 networks. The allocation is based on implicit GTS allocation requests, taking into account the traffic specifications and the delay requirements of the flows. The i-GAME approach enables the use of one GTS by multiple nodes, still guaranteeing that all their (delay, bandwidth) requirements are satisfied. For that purpose, we propose an admission control algorithm that enables to decide whether to accept a new GTS allocation request or not, based not only on the remaining time slots, but also on the traffic specifications of the flows, their delay requirements and the available bandwidth resources. We show that our approach improves the bandwidth utilization as compared to the native explicit allocation mechanism defined in the IEEE 802.15.4 standard. We also present some practical considerations for the implementation of i-GAME, ensuring backward compatibility with the IEEE 801.5.4 standard with only minor add-ons. Finally, an experimental evaluation on a real system that validates our theoretical analysis and demonstrates the implementation of i-GAME is also presented

An approach to health and safety in E.U. forestry operations – Hazards and preventive measures

Forestry in general and logging in particular continue to be among the three most hazardous sectors in European countries. The aim of this article is to characterize health and safety problems and solutions in E.U. forestry operations, and particularly in Portuguese operations. Forest types, production, employment and ownership are used to characterize the forest sector. Forestry accidents and health problems data are mentioned. Typical hazards associated to the nature of logging operations are systematized. Preventive measures, focused on a wide spectrum of measures, making safety considerations an integral feature of all operational activities from planning to organization to execution and supervision of work are emphasized in this article.

Fazer, dançar, de dentro : a fusão entre os processos do fazer e do sentir na prática diária da Técnica de Dança Clássica

Relatório Final de Estágio apresentado à Escola Superior de Dança com vista à obtenção do Grau de Mestre em Ensino de Dança.

Automatic learning for the classification of chemical reactions and in statistical thermodynamics

This Thesis describes the application of automatic learning methods for a) the classification of organic and metabolic reactions, and b) the mapping of Potential Energy Surfaces(PES). The classification of reactions was approached with two distinct methodologies: a representation of chemical reactions based on NMR data, and a representation of chemical reactions from the reaction equation based on the physico-chemical and topological features of chemical bonds. NMR-based classification of photochemical and enzymatic reactions. Photochemical and metabolic reactions were classified by Kohonen Self-Organizing Maps (Kohonen SOMs) and Random Forests (RFs) taking as input the difference between the 1H NMR spectra of the products and the reactants. The development of such a representation can be applied in automatic analysis of changes in the 1H NMR spectrum of a mixture and their interpretation in terms of the chemical reactions taking place. Examples of possible applications are the monitoring of reaction processes, evaluation of the stability of chemicals, or even the interpretation of metabonomic data. A Kohonen SOM trained with a data set of metabolic reactions catalysed by transferases was able to correctly classify 75% of an independent test set in terms of the EC number subclass. Random Forests improved the correct predictions to 79%. With photochemical reactions classified into 7 groups, an independent test set was classified with 86-93% accuracy. The data set of photochemical reactions was also used to simulate mixtures with two reactions occurring simultaneously. Kohonen SOMs and Feed-Forward Neural Networks (FFNNs) were trained to classify the reactions occurring in a mixture based on the 1H NMR spectra of the products and reactants. Kohonen SOMs allowed the correct assignment of 53-63% of the mixtures (in a test set). Counter-Propagation Neural Networks (CPNNs) gave origin to similar results. The use of supervised learning techniques allowed an improvement in the results. They were improved to 77% of correct assignments when an ensemble of ten FFNNs were used and to 80% when Random Forests were used. This study was performed with NMR data simulated from the molecular structure by the SPINUS program. In the design of one test set, simulated data was combined with experimental data. The results support the proposal of linking databases of chemical reactions to experimental or simulated NMR data for automatic classification of reactions and mixtures of reactions. Genome-scale classification of enzymatic reactions from their reaction equation. The MOLMAP descriptor relies on a Kohonen SOM that defines types of bonds on the basis of their physico-chemical and topological properties. The MOLMAP descriptor of a molecule represents the types of bonds available in that molecule. The MOLMAP descriptor of a reaction is defined as the difference between the MOLMAPs of the products and the reactants, and numerically encodes the pattern of bonds that are broken, changed, and made during a chemical reaction. The automatic perception of chemical similarities between metabolic reactions is required for a variety of applications ranging from the computer validation of classification systems, genome-scale reconstruction (or comparison) of metabolic pathways, to the classification of enzymatic mechanisms. Catalytic functions of proteins are generally described by the EC numbers that are simultaneously employed as identifiers of reactions, enzymes, and enzyme genes, thus linking metabolic and genomic information. Different methods should be available to automatically compare metabolic reactions and for the automatic assignment of EC numbers to reactions still not officially classified. In this study, the genome-scale data set of enzymatic reactions available in the KEGG database was encoded by the MOLMAP descriptors, and was submitted to Kohonen SOMs to compare the resulting map with the official EC number classification, to explore the possibility of predicting EC numbers from the reaction equation, and to assess the internal consistency of the EC classification at the class level. A general agreement with the EC classification was observed, i.e. a relationship between the similarity of MOLMAPs and the similarity of EC numbers. At the same time, MOLMAPs were able to discriminate between EC sub-subclasses. EC numbers could be assigned at the class, subclass, and sub-subclass levels with accuracies up to 92%, 80%, and 70% for independent test sets. The correspondence between chemical similarity of metabolic reactions and their MOLMAP descriptors was applied to the identification of a number of reactions mapped into the same neuron but belonging to different EC classes, which demonstrated the ability of the MOLMAP/SOM approach to verify the internal consistency of classifications in databases of metabolic reactions. RFs were also used to assign the four levels of the EC hierarchy from the reaction equation. EC numbers were correctly assigned in 95%, 90%, 85% and 86% of the cases (for independent test sets) at the class, subclass, sub-subclass and full EC number level,respectively. Experiments for the classification of reactions from the main reactants and products were performed with RFs - EC numbers were assigned at the class, subclass and sub-subclass level with accuracies of 78%, 74% and 63%, respectively. In the course of the experiments with metabolic reactions we suggested that the MOLMAP / SOM concept could be extended to the representation of other levels of metabolic information such as metabolic pathways. Following the MOLMAP idea, the pattern of neurons activated by the reactions of a metabolic pathway is a representation of the reactions involved in that pathway - a descriptor of the metabolic pathway. This reasoning enabled the comparison of different pathways, the automatic classification of pathways, and a classification of organisms based on their biochemical machinery. The three levels of classification (from bonds to metabolic pathways) allowed to map and perceive chemical similarities between metabolic pathways even for pathways of different types of metabolism and pathways that do not share similarities in terms of EC numbers. Mapping of PES by neural networks (NNs). In a first series of experiments, ensembles of Feed-Forward NNs (EnsFFNNs) and Associative Neural Networks (ASNNs) were trained to reproduce PES represented by the Lennard-Jones (LJ) analytical potential function. The accuracy of the method was assessed by comparing the results of molecular dynamics simulations (thermal, structural, and dynamic properties) obtained from the NNs-PES and from the LJ function. The results indicated that for LJ-type potentials, NNs can be trained to generate accurate PES to be used in molecular simulations. EnsFFNNs and ASNNs gave better results than single FFNNs. A remarkable ability of the NNs models to interpolate between distant curves and accurately reproduce potentials to be used in molecular simulations is shown. The purpose of the first study was to systematically analyse the accuracy of different NNs. Our main motivation, however, is reflected in the next study: the mapping of multidimensional PES by NNs to simulate, by Molecular Dynamics or Monte Carlo, the adsorption and self-assembly of solvated organic molecules on noble-metal electrodes. Indeed, for such complex and heterogeneous systems the development of suitable analytical functions that fit quantum mechanical interaction energies is a non-trivial or even impossible task. The data consisted of energy values, from Density Functional Theory (DFT) calculations, at different distances, for several molecular orientations and three electrode adsorption sites. The results indicate that NNs require a data set large enough to cover well the diversity of possible interaction sites, distances, and orientations. NNs trained with such data sets can perform equally well or even better than analytical functions. Therefore, they can be used in molecular simulations, particularly for the ethanol/Au (111) interface which is the case studied in the present Thesis. Once properly trained, the networks are able to produce, as output, any required number of energy points for accurate interpolations.

Aspect-oriented domain analysis

Dissertação de Mestrado em Engenharia Informática