Made available in DSpace on 2017-07-21T19:59:58Z (GMT). No. of bitstreams: 1 Bruna Steckling.pdf: 1617437 bytes, checksum: a310841fa34ee2fb3a59be3ff493fbe8 (MD5) Previous issue date: 2013-03-13 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Agrochemicals have become necessary to improve crops yields and provide the increasing demand for foods. Nevertheless, pesticides can persist in the environment and be harmful to non target organisms. Mesotrione, the active ingredient of Callisto, is a selective herbicide recommended for pre and post-emergent weed control in corn culture, with high leaching potential, and it has the ability to inhibit the activity of HPPD enzyme, interfering with the synthesis of carotenoids in target plants. The aim of this work was to evaluate the strategies used by the strain Bacillus megaterium Mes13 to avoid toxic effects of Callisto and its active substance, mesotrione, by analyzing the differential expression of antioxidative enzymes, mesotrione degradation, and changes in membrane structure. There were no specific responses from isozymes to herbicides. Catalase activity at Callisto treatment was lower than control, suggestingother mechanisms affecting cellular defense. Lipid peroxidation (MDA), which depends on saturation degree of membrane fatty acids, was lower at Callisto treatment, and changes in bacterial membrane were observed at Callisto treatment, probably protecting membrane against lipid peroxidation. Mesotrione was used neither as C nor N source for growing of Bacillus megaterium, although degradation of mesotrione was higher at minimal medium with no N source, suggesting that herbicide degradation occurs as a cometabolism. Probably the membrane modifications and mesotrione degradation made this bacteria able to tolerate the herbicides at experimental conditions. / O uso de agroquímicos se faz necessário para aumentar a produtividade e suprir a crescente demanda por alimentos. Entretanto, estes químicos podem persistir no meio ambiente e serem danosos aos organismos não-alvo. O mesotrione é um herbicida seletivo indicado para o controle pré e pós-emergente de plantas daninhas na cultura do milho com alto potencial de lixiviação, que apresenta a capacidade de inibir a atividade da enzima 4-hidroxifenil-piruvato-dioxigenase (HPPD), interferindo na síntese de carotenóides. Neste trabalho analisamos três possíveis estratégias utilizadas pela linhagem Bacillus megaterium Mes13 para tolerar o herbicida Callisto e seu princípio ativo, mesotrione: expressão de enzimas antioxidativas, degradação do princípio ativo e modificações na estrutura de lipídeos da célula. Avaliações de atividade e perfil proteico de catalase (CAT) e superóxido dismutase (SOD) foram realizadas para avaliar os possíveis danos gerados pelo contato da bactéria com o herbicida. Nenhuma isoforma específica foi observada em resposta aos tratamentos contendo os xenobióticos e a atividade de CAT foi mais baixa no tratamento contendo Callisto indicando outros possíveis mecanismos de defesa celular. Corroborando estes resultados, as análises de peroxidação lipídica (MDA), que dependem do estado de saturação de lipídeos de membrana, mostraram taxas mais baixas no tratamento com Callisto. Modificações na membrana bacteriana foram observadas nos tratamentos contendo Callisto, o que, possivelmente diminuíram as taxas de peroxidação lipídica. Esta linhagem não utiliza mesotrione como fonte de nitrogênio e carbono, contudo, o processo de degradação do herbicida foi mais eficiente na ausência de Nitrato de Sódio em meio de cultura. A degradação provavelmente se dá por uma enzima inespecífica. Na ausência da fonte primária de nitrogênio, esta linhagem degrada o mesotrione por cometabolismo. Provavelmente as modificações na membrana plasmática aliada a degradação da molécula do xenobiótico conferiram a linhagem capacidade de tolerar a presença dos herbicidas nas condições experimentais testadas. Palavras-chave: SOD, CAT, MDA, Biodegradação de herbicidas, Fonte de nitrogênio, modificações na membrana plasmática.

Le récepteur de la progestérone (PR) est un acteur majeur du développement de la glande mammaire. Dans les cellules épithéliales normales, PR est exprimé sous deux isoformes PRA (94 kDa) et PRB (116 kDa) de façon équimolaire. Il est établi que celles-ci ont un impact important sur le développement des cancers du sein, mais leurs rôles dans l’évolution métastatique reste très mal connus. Le ratio d’expression PRA/PRB étant souvent déséquilibré dans les tumeurs mammaires, nous avons analysé le turnover des deux isoformes. Nous avons démontré que PRA et PRB sont les cibles de modifications post-traductionnelles dirigées par les MAPK qui tendent à stabiliser l’une ou l’autre isoforme de manière sélective. Ainsi, Erk1/2 (p42/44) inhibe la dégradation de PRB tandis que la p38 stabilise PRA. Il en résulte que le ratio PRA/PRB varie de façon importante en fonction des signalisations extracellulaires impliquant les facteurs de croissance et les cytokines inflammatoires souvent exacerbés dans les cancers. Pour mieux étudier les effets différentiels de PRA et PRB, nous avons établi un modèle cellulaire original exprimant de manière bi-inductible l’une ou l’autre isoforme de PR, à partir de la lignée cellulaire MDA-MB 231 provenant d’une métastase de cancer du sein. En étudiant les variations induites par PRA ou PRB sur le transcriptome de ces cellules, nous avons identifié les gènes cibles spécifiques de ces isoformes. Parmi-eux se trouvent de nombreux gènes impliqués dans les cancers, notamment agissant sur la prolifération, la survie et la motilité cellulaires comme uPA et PAI-1. De plus, en analysant la migration cellulaire, nous avons mis en évidence un effet pro-migratoire de PRB particulièrement important en absence d’hormone. En recherchant la cause de ces effets, nous avons découvert que PRB était colocalisé et interagissait avec la kinase d’adhésion focale (FAK) qu’il active au niveau des points d’adhésion focaux. Ces travaux soulignent l’incidence du ratio PRA/PRB et du statut du ligand sur les métastases du cancer du sein, aussi bien au niveau de la sélectivité transcriptionnelle que celui des régulations non génomiques impactant la migration cellulaire. Nous suggérons la possibilité de cibler les tumeurs mammaires par des antagonistes sélectifs de PR et des inhibiteurs des voies de signalisation des MAPK ou de FAK. / Progesterone receptor (PR) is a major actor of mammary gland development. PR is equally expressed as two main isoforms PRA (94 kDa) and PRB (116kDa) in the mammary gland epithelium. However, breast cancer progression has been associated with abnormalities of their expression ratio through undefined mechanisms. In this study, using a stably transfected cell line, we showed that PRA and PRB stabilizations are differentially regulated by Erk1/2 (p42/44) and p38 MAPKs respectively, leading to strongly influence PRA/PRB ratio. These results highlight the impact of growth factors and inflammatory cytokines on PRA/PRB imbalance in cancer cells. To study the differential effect of PR isoforms, we established an original bi-inducible cell line expressing either PRA and/or PRB. By analyzing variations induced by PRA and PRB on such cell transcriptomes, we identified the isoform-specific targets genes by DNA microarrays. Most of them are implicated in cancers, notably acting on cell proliferation, survival and motility. Furthermore, focusing our studies on cell migration, we showed that PRB acts as a pro-migratory factor particularly powerful in the absence of ligand. We discovered that PRB colocalized and interacted with the focal adhesion kinase (FAK) that was activated in focal adhesion points. Our results highlight the impacts of both PRA/PRB ratio and ligand status on metastatic evolution, in the contexts of transcriptional regulation as well as non-genomic events. We suggest the possibility to target mammary tumors by PR-selective antagonists and/or inhibitors of MAPK and FAK signalings.

Dans le cycle de vie logiciel nous avons principalement les activités (1) de pré-développement (l’analyse des besoins, les spécifications, la conception architecturale et la conception détaillée), (2) de développement (l’implémentation, le prototypage, les tests unitaires et les tests d’intégration) et (3) de post-développement (déploiement). Le déploiement de logiciel couvre l’ensemble des activités post-développement. Les activités de déploiement permettent de rendre une application utilisable. Elles sont identifiées comme cycle de vie de déploiement couvrant l'archivage des logiciels, leur chargement, leur installation sur les sites clients, leur configuration, leur activation ainsi que leur mise à jour. Le développement de systèmes à composants a permis de mieux identifier cette partie du cycle de vie global du logiciel, comme le montrent de nombreux travaux industriels et académiques. Cependant ces travaux sont en général développés de manière ad’ hoc, spécifiques à une plate-forme donnée. Peu flexibles, ils s'adaptent difficilement aux stratégies des entreprises. Les systèmes de déploiement comme le montrent ceux supportés par les environnements de type intergiciel CCM, .Net, EJB développent de manière spécifique les mécanismes et outils de déploiement et introduisent des choix prédéfinis et figés de stratégies de déploiement. Nos travaux se situent dans le contexte de logiciels à base de composants distribués et portent sur la proposition d'un environnement générique pour supporter leur déploiement. C'est une nouvelle génération de systèmes proposée essentiellement par le monde académique de génie logiciel qui s'est approprié la problématique de déploiement à large échelle. Dans ce contexte, nous proposons une approche basée sur l’ingénierie dirigée par les modèles où nous introduisons les abstractions nécessaires pour décrire les logiciels à déployer, les infrastructures de déploiement, les stratégies de déploiement ainsi que le processus de déploiement avec l’identification et l’ordonnancement des activités à accomplir et le support pour leur exécution. / In the software life cycle we have mainly (1) the pre-development (requirements, specification and design), (2) the development (implementation, prototyping, testing) and (3) the post-development (deployment) activities. Software deployment encompasses all post-development activities that make an application operational. These activities, identified as deployment life cycle, include: i) software packaging, ii) loading and installation of software on client sites, iii) instance creation, iv) configuration and v) updating. The development of system-based components made it possible to better highlight this part of the global software lifecycle, as illustrated by numerous industrial and academic studies. However these are generally developed ad hoc, and consequently platform-dependent. Deployment systems, such as supported by middleware environments (CCM, .Net and EJB), specifically develop mechanisms and tools related to pre-specified deployment strategies. Our work, related to the topic of distributed component-based software applications, aims at specifying a generic deployment framework independent of the target environments. Driven by the meta-model approach, we first describe the abstractions used to characterize the deployed software. We then specify the deployment infrastructure and processes, highlighting the activities to be carried out and the support for their execution.Keywords

Este trabalho tem por objetivo propor a utilização de soluções pré-definidas e comprovadas na abordagem MDA, auxiliando o desenvolvedor na resolução de problemas recorrentes ao desenvolvimento de software. A utilização destas soluções pré-definidas leva a um aumento de produtividade no contexto MDA e na geração de software baseado em boas práticas. Para que este objetivo seja cumprido, é empreendida uma análise sobre o MDA e sobre como operacionalizar as transformações entre modelos. Também é empreendida uma análise sobre o suporte fornecido pela UML e sobre reutilização em desenvolvimento orientado a modelos. Por fim este trabalho apresenta partes de uma aplicação protótipo, construída para ser uma prova de conceito de código gerado através da combinação de UML e soluções pré-definidas. / The goal of this work is to propose the use of pre-defined solutions on MDA approach, supporting the developer in solving recurrent problems of software development. The use of these pre-defined solutions leads to an increase of productivity in MDA context, and in the generation of software based on best practices. To reach this goal, an analysis of MDA is undertaken, as well as an analysis of how to enable the transformations between models. It is also undertaken an analysis about the use of UML and the reuse in model driven development. Finally this work presents portions of a prototype application, constructed to be a proof-of-concept of generated code, combining UML and the pre-defined solutions.

Das triple-negative Mammakarzinom exprimiert weder Östrogen- noch Progesteronrezeptoren und es kommt zu keiner Überexprimierung des HER2-neu Gens. Daher haben bei diesem Subtyp des Mammakarzinoms spezifische Therapien, welche gezielt an diesen Rezeptoren wirken, keinerlei Nutzen. Etwa 60% aller Mammakarzinome exprimieren GnRH-Rezeptoren, welche als Ziel genutzt werden könnten. Der GnRH-Rezeptor kann für eine gezielte Chemotherapie mit zytotoxischen GnRH-Agonisten wie AN-152, bei welchem Doxorubicin an [D-Lys6]GnRH gebunden ist, genutzt werden. In der vorliegenden Arbeit habe ich in vitro als auch in vivo analysiert ob der zytotoxische GnRH-Agonist AN-152 Apoptose in triple-negativen Mammakarzinomzellen, welche GnRH-Rezeptoren exprimieren, induziert. Die GnRH-Rezeptorexpression in Tumorbiopsien triple-negativer Mammakarzinome wurde immunhistochemisch getestet. Die Zellproliferation wurde unter Verwendung des AlamarBlue®-Proliferationsassays analysiert. Die Apoptoseinduktion wurde durch die Bestimmung des mitochondrialen Membranpotentialverlustes quantifiziert. Die in vivo Experimente wurden mit Nackmäusen nach Xenotransplantation von humanen Brustkrebszellen durchgeführt. Wir konnten zeigen das die Behandlung triple-negativer aber GnRH-positiver MDA¬ MB 231, HCC 1806 und HCC 1937 Mammakarzinomzellen mit AN-152 in vitro zum apoptotischen Zelltod durch Aktivierung der Caspase-3 führt. Diese Antitumoreffekte konnten im Nacktmausmodell bestätigt werden. AN-152 inhibierte das Wachstum triple-negativer Mammakarzinomxenotransplantate in den Nacktmäusen komplett, ohne offensichtliche Nebenwirkungen. Der zytotoxische GnRH-Agonist AN-152 scheint ein passendes Medikament mit niedriger Toxizität für eine effiziente Therapie des triple-negativen Mammakarzinoms zu sein. (Föst C, Duwe F, Hellriegel M, Schweyer S, Emons G, Gründker C (2011). Targeted chemotherapy for triple-negative breast cancers via LHRH receptor. Oncol Rep, 25, 1481-7.)

Detta kandidatarbete undersöker och skapar en djupare förståelse för olika narrativa strukturer och tekniker som finns i litteratur, film och digitala spel. Detta har gjorts genom att besvara frågan hur man kan applicera narrativa strukturer och tekniker från litteratur och film i ett digitalt spel. För att svara på denna fråga har vi utvecklat en gestaltning som består av ett digitalt spel som använder sig av olika narrativa strukturer och tekniker som är mer vanliga inom litteratur och filmer. Till hjälp för detta har vi använt oss av metodologin MDA-ramverket samt berättelseskrivarmetoderna Snöflingemetoden och The Fantasy Fiction Formula. Undersökningen visar hur en berättelse i ett digitalt spel, med hjälp av ett antal narratologiska begrepp, kan använda sig av narrativa strukturer och tekniker från litteratur och film. Snöflingemetoden visade sig vara användbar, men inte anpassad för denna typ av skrivande. På grund av tidsbrist kunde vi inte använda oss av så många tekniker och strukturer från film som vi ville. / This Bachelor Thesis aims to explore and create a deeper understanding of various narrative structures and techniques found in literature, film and digital games. This has been done by answering the question how one can apply narrative structures and techniques from literature and film in a digital game. To answer this question, we have developed a digital game that uses different narrative structures and techniques that are more common in literature and films. For this, we used the MDA-framework methodology as well as the story writing methods The Snowflake Method and The Fantasy Fiction Formula. This thesis shows how a story in a digital game, using a number of narratological concepts, can make use of narrative structures and techniques from literature and film. The Snowflake Method proved useful, but not adapted for this type of writing. Due to time limitations we were not able to use as many structures and techniques from films as we wanted to.

Gamification har börjat integreras mer och mer i våra liv varje år inom diverse områden såsom shopping, sport och undervisning. Gamification används per definition för att öka motivation hos användare genom att introducera spelmoment i en icke-spel kontext. Denna studie syftar till att utvärdera hur bra de designprinciper och designriktlinjer, som är formade utifrån ett ramverk som kallas för MDA-ramverket (ett ramverk inom gamification), kan tillämpas vid utformningen av en gamificationapplikation inom kontexten av ett biobesök eller om det krävs en modifiering av dessa. Studien syftar även till att ta reda på huruvida den här typen av applikation skulle kunna öka det generella intresset för att bli medlem hos en bioverksamhet likt Filmstaden. För att ta reda på detta gjordes en intervju som en del av förstudien för att kontrollera den generella attityden och intresset för en applikation som denna. MDA-ramverket användes sedan till att utveckla en Lo-Fi prototyp utifrån principerna och riktlinjerna inom MDA-ramverket. Denna prototyp testades genom att observera totalt tio användare som fick interagera fritt med prototypens olika funktioner. Observationen följdes upp av en intervju med samma användare som fick uttrycka sina känslor gentemot applikationen och de potentiella problem som uppkom med den. Analysen av observationen samt svaren från respondenterna jämfördes sedan med principerna och riktlinjerna som användes under designfasen för att se hur väl dessa kunde tillämpas i kontexten av ett biobesök eller om de kunde ses som felaktiga. Resultatet av studien visade på att de flesta riktlinjer var essentiella för kvalitén av prototypen men att några av dem borde ses över vid utvecklingen av en gamificationapplikation i kontexten av ett biobesök. Slutligen visade också studien, baserat på intervjusvaren som samlades in, att en applikation som denna skulle kunna öka motivation bland biobesökare att bli medlem i Filmstadens bioklubb. / Gamification has been increasingly integrated into our lives every year within different areas such as shopping, sports and education. It focuses by definition on increasing the motivation in users by introducing gaming elements into a non-gaming context. This paper aims to investigate how well current design principles and design guidelines, that have been shaped from the so-called MDA-framework (a framework within gamification), can be used for designing a gamification application within the context of a cinematic experience or if modification is required. It also investigates whether this sort of application would be able to increase the general interest of becoming a member at a cinema enterprise such as Filmstaden, Sweden. First of all, an interview was constructed as part of the pre-study to check the general attitude and interest toward an application like this. An existing framework for gamification called the MDA-framework was then used to create a Lo-Fi prototype that practices the principles and guidelines of MDA for an optimal design. This prototype was then tested by observing a total of 10 users who got to interact freely with the different functions. This observation was followed by an interview with the same users where they got to express their feelings toward the application and the potential issues that were presented with it. This result was then compared to the principles and guidelines used during the design to see whether any of the guidelines could be seen as faulty or if any potential guidelines were missing. The analysis of the research showed that most principles and guidelines were very helpful and brought the quality of the prototype to a satisfactory level on most accounts. The attitude towards some of the guidelines was proven to have changed since their emergence though. Finally, the paper also discovered, based on the applicant’s answers, that an application like this could increase the motivation of becoming a member in the “Cinema Club”.

Based on the increasing complexity of modern avionics, the associated system design processes moved towards Model Driven Architecture (MDA) based processes. Additionally, the demand for higher system autonomy features requires means to further modularise mission systems and to define and establish interactions among the systems’ individual components. Therefore, the ideas of service-oriented computing are currently adapted to established, model driven design processes. With respect to modelling interactions for service components, current approaches are limited to only a fixed set of communication primitives, restricting a service designer’s expressiveness to specify service interaction. In consequence, interaction patterns not included in this basic set have to be reflected in application code, mangling application and communication logic. Furthermore, when service functionality relies on communication semantics which are not provided by the underlying set of primitives, additional emulation behaviour has to be added to the service which makes this mangling even worse. Platform independence is reduced as services can not easily be ported to platforms not natively supporting the selected primitives which contradicts the ideas of model-driven development. Addressing these limitations, this thesis proposes a new model-driven service development process based on Interaction Templates (ITs), promoting interactions among service participants to first class modelling entities. The process focuses on modelling the interactions among service participants. Interaction semantics are explicitly specified in models, beyond pure stereotyping, and gain increased platform independence for services with respect to communication. The process exploits automated Model-to-Model (M2M) and Model-to-Text (M2T) transformations to assist service implementation and to automatically derive interaction realisations on concrete target platforms. This allows for easy replacement and inter-mixing of communication middleware to realise a service’s interactions. This way, services become independent of the underlying communication primitives by only relying on ITs and not platform primitives which are hidden behind ITs. In turn, realising ITs on concrete platforms is not affected by their utilisation for service interaction. Beside the novel modelling process itself, the presented work defines a Unified Modeling Language (UML) profile, referred to as UML Profile for Interaction-centric Services (UP4IS), which directly supports the adaptation of standard UML language constructs and tools for the proposed modelling approach. The whole development process is demonstrated via the specification of a simple video recording systems consisting of two services. The services themselves are based on a representative IT library which forms an essential part of the presented case study. Using these service and IT models, the thesis emphasises the necessary model transformation and code generation steps to derive service implementations based on the abstract models.

Diese Diplomarbeit behandelt das Themengebiet der automatischen Erzeugung von grafischen Benutzeroberflächen (GUIs) im Kontext von Webservices. Es geht dabei konkret um einen Editor, mit dem Hinweise zur Generierung von Dialogen erstellt werden können. Diese Hinweise sollen dann von den dialogerzeugenden Anwendungen einbezogen werden, um eine dynamische Interaktion mit Webservices durch beliebige Nutzer ohne dienstspezifische Software zu ermöglichen. Die Arbeit führt in die aktuellen Techniken zur GUI-Generierung ein und stellt Transformationsprinzipien vor, die eine Generierung ausgehend von einem formalen Datenmodell ermöglichen. Dabei müssen mangelnde Modellparameter in Beschreibungen von Webservices manuell ausgeglichen werden (WSGUI-Konzepte). Diese Zielstellung führt zum Entwurf des WSGUI-Editors. Die anschließende Implementierung berücksichtigt darüber hinaus Integrationsaspekte wie die Publizierung von WSGUI-Hinweisen, Einbindung von GUI-Übersetzungen und eine Vorschau auf die zu generierenden Dialoge. Abgeschlossen wird die Arbeit mit einer Bewertung des Editors, aber auch einer Reihe von Vorschlägen zur Vereinfachung ähnlich gelagerter zukünftiger Projekte im Umfeld von Webservices.

Unter dem Terminus der MDA (Model Driven Architecture)versteht man eine Methode, Anwendungen im Rahmen der UML zu spezifizieren und ablauffähigen Programm-Code durch automatische Generierung zu erzeugen. Am Lehrstuhl für Datenbanken existiert in diesem Zusammenhang das GignoMDA-Projekt, daß sich mit der modellgetriebenen Entwicklung von Datenbankenanwendungen beschäftigt. Als wesentlicher Bestandteil der jeweiligen Anwendung sind Datenmodelle jedoch, genau wie die Anwendungsarchitektur selbst, Anpassungen an sich veränderte Zielstellungen und Umgebungsbedingungen unterworfen. Es stellt sich also die Notwendigkeit der Überführung von Datenbeständen in neu generierte Zielsysteme, als Bestandteil eines vollständig modellgetriebenen Ansatzes dar. Diese Arbeit stellt ein Konzept zur Schema- und Datenmigration bei der Weiterentwicklung der Anwendungs-Datenbankmodelle vor. Dabei werden Datenmigrationen, gemäß dem MDA-Ansatz, als Modell in UML ausgedrückt und anschließend zur automatischen Erzeugung von plattformabhängigen Migrationsmodellen genutzt. Aus diesen Migrationsmodellen können so, Datenbanktechnik basierte Programme (ETL, Stored Procedures) zur effizienten Ausführung von Migrationen generiert werden.