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In vertebrate oocytes, meiotic progression is driven by the sequential translational activation of maternal messenger RNAs stored in the cytoplasm. This activation is mainly induced by the cytoplasmic elongation of their poly(A) tails, which is mediated by the cytoplasmic polyadenylation element (CPE) present in their 3’ untranslated regions (3´ UTRs). Sequential, phase-specific translation of these maternal mRNAs is required to complete the two meiotic divisions. Although the earlier polyadenylation events in prophase I and metaphase I are driven by the CPE-binding protein 1 (CPEB1), 90% of this protein is degraded by the anaphase promoting complex in the first meiotic division. The low levels of CPEB1 during interkinesis and in metaphase II raise the question of how the cytoplasmic polyadenylation required for the second meiotic division is achieved. In this work, we demonstrate that CPEB1 activates the translation of the maternal mRNA encoding CPEB4, which, in turn, recruits the cytoplasmic poly(A) polymerase GLD2 to “late” CPE-regulated mRNAs driving the transition from metaphase I to metaphase II, and, therefore, replacing CPEB1 for “late” meiosis polyadenylation.

Modern software systems are increasingly characterized by uncertainties in the operating context and user requirements. These uncertainties are difficult to predict at design time. Achieving the quality goals of such systems depends on the ability of the software to deal with these uncertainties at runtime. A self-adaptive system employs a feedback loop to continuously monitor and adapt itself to achieve particular quality goals (i.e., adaptation goals) regardless of uncertainties. Current research applies formal techniques to provide guarantees for adaptation goals, typically using exhaustive verification techniques. Although these techniques offer strong guarantees for the goals, they suffer from well-known state explosion problem. In this thesis, we take a broader perspective and focus on two types of guarantees: (1) functional correctness of the feedback loop, and (2) guaranteeing the adaptation goals in an efficient manner. To that end, we present ActivFORMS (Active FORmal Models for Self-adaptation), a formally founded model-driven approach for engineering self-adaptive systems with guarantees. ActivFORMS achieves functional correctness by direct execution of formally verified models of the feedback loop using a reusable virtual machine. To efficiently provide guarantees for the adaptation goals with a required level of confidence, ActivFORMS applies statistical model checking at runtime. ActivFORMS supports on the fly changes of adaptation goals and updates of the verified feedback loop models that meet the changed goals. To demonstrate the applicability and effectiveness of the approach, we applied ActivFORMS in several domains: warehouse transportation, oceanic surveillance, tele assistance, and IoT building security monitoring. / Marie Curie CIG, FP7-PEOPLE-2011-CIG, Project ID: 303791

Increasingly complex dynamics in the software operations pose formidable software evolution challenges to the software industry. Examples of these dynamics include the globalization of software markets, the massive increase of interconnected devices worldwide with the internet of things, and the digital transformation to large-scale cyber-physical systems. To tackle these challenges, researchers and practitioners have developed impressive bodies of knowledge, including adaptive and autonomic systems, run-time models, continuous software engineering, and the practice of combining software development and operations (i.e., DevOps). Despite the tremendous strides the software engineering community has made toward managing highly dynamic systems, software-intensive industries face major challenges to match the ever-increasing pace. To cope with this rapid rate at which operational contexts for software systems change, organizations are required to automate and expedite software evolution on both the development and operations sides. The aim of our research is to develop continuous and autonomic methods, infrastructures, and tools to realize software evolution holistically. In this dissertation, we shift the prevalent autonomic computing paradigm and provide new perspectives and foci on integrating autonomic computing techniques into continuous software engineering practices, such as DevOps. Our methods and approaches are based on online experimentation and evolutionary optimization. Experimentation allows autonomic managers to make in- formed data-driven and explainable decisions and present evidence to stakeholders. As a result, autonomic managers contribute to the continuous and holistic evolution of design, configuration and deployment artifacts, providing guarantees on the validity, quality and effectiveness of enacted changes. Ultimately, our approach turns autonomic managers into online stakeholders whose contributions are subject to quality control. Our contributions are threefold. We focus on effecting long-lasting software changes through self-management, self-improvement, and self-regulation. First, we propose a framework for continuous software evolution pipelines for bridging offline and online evolution processes. Our framework’s infrastructure captures run-time changes and turns them into configuration and deployment code updates. Our functional validation on cloud infrastructure management demonstrates its feasibility and soundness. It effectively contributes to eliminate technical debt from the Infrastructure-as-Code (IAC) life cycle, allowing development teams to embrace the benefits of IAC without sacrificing existing automation. Second, we provide a comprehensive implementation for the continuous IAC evolution pipeline. Third, we design a feedback loop to conduct experimentation-driven continuous exploration of design, configuration and deployment alternatives. Our experimental validation demonstrates its capacity to enrich the software architecture with additional components, and to optimize the computing cluster’s configuration, both aiming to reduce service latency. Our feedback loop frees DevOps engineers from incremental improvements, and allows them to focus on long-term mission-critical software evolution changes. Fourth, we define a reference architecture to support short-lived and long-lasting evolution actions at run-time. Our architecture incorporates short-term and long-term evolution as alternating autonomic operational modes. This approach keeps internal models relevant over prolonged system operation, thus reducing the need for additional maintenance. We demonstrate the usefulness of our research in case studies that guide the designs of cloud management systems and a Colombian city transportation system with historical data. In summary, this dissertation presents a new approach on how to manage software continuity and continuous software improvement effectively. Our methods, infrastructures, and tools constitute a new platform for short-term and long-term continuous integration and software evolution strategies and processes for large-scale intelligent cyber-physical systems. This research is a significant contribution to the long-standing challenges of easing continuous integration and evolution tasks across the development-time and run-time boundary. Thus, we expand the vision of autonomic computing to support software engineering processes from development to production and back. This dissertation constitutes a new holistic approach to the challenges of continuous integration and evolution that strengthens the causalities in current processes and practices, especially from execution back to planning, design, and development. / Graduate

This dissertation examines the assessment and mitigation of airborne noise from power generation equipment. The first half of the dissertation investigates the diagnosis and treatment of combustion oscillations in boilers. Sound is produced by the flame and is reflected downstream from the combustion chamber. The reflected sound waves perturb the mixture flow or equivalence ratio increasing the heat release pulsations and the accompanying sound produced by the flame. A feedback loop model for determining the likelihood of and diagnosing combustion oscillations was reviewed, enhanced, and then validated. The current work applies the feedback loop stability model to two boilers, which exhibited combustion oscillations. Additionally, a feedback loop model was developed for equivalence ratio fluctuations and validated. For the first boiler, the combustion oscillation problem is primarily related to the geometry of the burner and the intake system. For the second boiler, the model indicated that the combustion oscillations were due to equivalence ratio fluctuations. Principles for both measuring and simulating the acoustic impedance are summarized. An approach for including the effect of structural-acoustic coupling was developed. Additionally, a method for determining the impedance above the plane wave cut-off frequency, using the acoustic FEM, of the boiler was proposed. The second half of the dissertation examines the modeling of bar silencers. Bar silencers are used to mitigate the airborne noise from large power generation equipment (especially gas turbines). Due to the large dimensions of the full cross section, a small representative cell is isolated from the entire array for analysis purposes. To predict the acoustical performance of the isolated cell for different geometric configurations, a numerical method based on the direct mixed-body boundary element method (BEM) was used. An analytical solution for a simplified circular geometry was also derived to serve as a comparison tool for the BEM. Additionally, a parametric study focusing on the effects of flow resistivity, perforate porosity, length of bars, and cross-sectional area ratio was performed. A new approach was proposed to evaluate the transmission loss based on a reciprocal work identity. Moreover, extension of the transmission loss computation above the plane wave cut-off frequency was demonstrated.

[pt] O objetivo deste trabalho é compreender as características da dinâmica da família em que um ou mais de seus componentes é adicto a substâncias psicoativas. Utilizamos, para este fim, o referencial sistêmico. Entendemos que a dependência por substâncias seja tanto uma patologia em si, quanto um sintoma de um sistema familiar. Nas relações que se estabelecem entre o dependente e os outros membros da família, vai-se construindo uma teia relacional que, muitas vezes, perpetua os padrões disfuncionais que ajudam a manter a dependência. É indispensável, no tratamento da dependência, abordar os vínculos familiares, para que o sistema familiar possa encontrar alternativas mais saudáveis de relacionamento, a fim de promover uma progressiva mudança nos padrões de interação que são facilitadores da manutenção do comportamento adictivo. / [en] The purpose of this exertion is to understand the caracteristics of the family dynamics in the way that one or more of their components is addicted to alcohol and other drugs. To get to this outcome will use the systemic referencial. We understand that the substance dependence is a much a patology itself as a symptom related to a family system. In the individual´s relationship with the family and the same with the individual that is a drug user, it goes on establishing a tangled relational that the most of the times perpetuate the disfuncionals patterns that helps to sustain the dependence in the family. It is indispensable, in the treatment of the dependence, to come to grips with the family ties so that family system can find healthier alternatives in the relationship, in order to promote a progressive change in the interaction patterns that are facilitators for the maintenance of the addictive behavior.

Das Kernstueck der vorliegenden Arbeit ist die Betonung von kleinen Modulen als Schluesselkomponenten von biologischen Netzwerken. Unter den zahlreichen moeglichen Modulen scheinen besondere diejenigen interessant zu sein, welche die Rueckkopplungen realisieren und in regulatorischen Einheiten auftreten. Prozesse wie Genregulation, Differentiation oder Homeostasis benoetigen haeufig Autoregulation. Auf Grund dessen ist die detaillierte Kenntnis der dynamischen Eigenschaften von kleinen Modulen von groesserem Interesse. Es werden zwei biologische Systeme analysiert. Das erste beschaftigt sich mit dem Zellzyklus, das zweite Beispiel kommt aus der Immunologie und betrifft die Aktivierung von T-Zellen. Beide Modelle, d.h. ihre zugrundeliegende Netzwerke, lassen sich in Untereinheiten mit wohldefinierten Funktionen zerlegen. Diese Module entscheiden ueber das Verhalten des gesamten Netzwerkes. Mit anderen Worten, die von den Modulen getroffenen Entscheidungen, werden von dem gesamten System uebernommen. Bei der Analyse des Modells zum Zellzyklus wurde eine interessante Eigenschaft von gekoppelten Modulen deutlich, die wir dann getrennt behandelt haben. Seriell geschaltete Module mit positiver Rueckkopplung liefern ueberraschende Konstruktionsmoeglichkeiten fuer Systeme mit mehreren stabilen Gleichgewichtslagen. Obwohl nicht alle hier aufgestellten Hypothesen derzeit experimentell ueberpruefbar sind, es kann eine wichtige Aussage getroffen werden. Uebereinstimmende Strukturen und Mechanismen, die in verschiedenen biologischen Systemen vorkommen, bieten uns die Moeglichkeit einer Klassifizierung von biologischen Systemen bezueglich ihrer strukturellen Aehnlichkeiten. / The thesis emphasizes the importance of small modules as key components of biological networks. Especially, those which perform positive feedbacks seem to be involved in a number of regulatory units. Processes like gene regulation, differentiation and homeostasis often require autoregulation. Therefore, detailed knowledge of dynamics of small modules becomes nowadays an important subject of study. We analyze two biological systems: one regarding cell cycle regulation and one immunological example related to T-cell activation. Their underlying networks can be dissected into subunits with well defined functions. These modules decide about the behavior of the global network. In other words, they have decision taking function, which is inherited by the whole system. Stimulated by the cell cycle model and its interesting dynamics resulting from coupled modules, we analyzed the switching issue separately. Serial coupling of positive feedback circuits provides astonishing possibilities to construct systems with multiple stable steady states. Even though, in current stage, no exact experimental proof of all hypotheses is possible, one important observation can be made. Common structures and mechanisms found in different biological systems allow to classify biological systems with respect to their structural similarities.

[pt] Esta dissertação estuda um meio de apoiar a elicitação de requisitos, utilizando reuniões. Para isso utiliza a gerência de conflitos, que através do estímulo aos conflitos funcionais e do controle e tratamento dos conflitos não funcionais, visa à criação de idéias e o dinamismo da reunião, aumentando o volume de conhecimento elicitado. Tudo isso é realizado através de um trabalho cooperativo entre os interessados no sistema a ser desenvolvido. O método proposto é uma evolução de um trabalho anterior e baseia- se na gerência de conflitos em um ciclo de reuniões. Essa gerência é levada adiante por meio de um processo de retroalimentação de responsabilidade dos participantes das reuniões, que utilizam um questionário para fornecimento destas informações. Uma ferramenta Web foi construída para a coleta das respostas ao questionário, bem como para apoiar à análise dos conflitos. / [en] This work reports research on the automation support for requirements elicitation performed by means of meetings. In order to provide this support, we ground our work on conflict management, stimulating functional conflicts and controlling non-functional conflicts in order to increase the volume of elicited knowledge. This is based on cooperative work among the stakeholders of the demanded system or demanded changes on an existing system. The method is an evolution of a previous work on the topic and is based on conflict management over a cycle of meetings. This management is performed by a feedback process enacted by the meeting participants by means of a questionnaire for the provision of information. A Web tool to support the method was built to collect the information and analyze the conflicts.

Dans l’objectif de limiter les effets destructeurs de l’implosion de bulles de cavitation ultrasonore, un régime d’oscillations stables de bulles doit potentiellement être visé pour des applications thérapeutiques sensibles comme l’ouverture de la barrière hémato-encéphalique. Cependant, garantir une activité d’oscillations stables est difficile de par le caractère stochastique de la cavitation ultrasonore, et de la coexistence de bulles oscillantes (cavitation stable) et implosantes (cavitation inertielle) au sein d’un nuage de bulles. Il est donc nécessaire de contrôler spatialement et temporellement le phénomène de cavitation en discriminant les régimes de cavitation stable ou inertielle, au cours de la durée d’un tir ultrasonore, et ce en régime pulsé. Dans une première étude, la dynamique d’un nuage de bulles monodisperses et uniformément réparties dans l’espace met en évidence l’effet de l’interaction entre bulles sur le seuil de cavitation stable : il s’abaisse en pression et la fréquence de résonance des bulles se décale en fonction de la densité de bulle. Il est ainsi montré qu’il existe une densité de bulle optimale pour l’émission de la composante sous-harmonique. Ensuite, une stratégie de contrôle est développée, basée sur une boucle de rétroaction régulant la signature acoustique d’un régime donné de cavitation. L’utilisation de la stratégie d’asservissement permet de discriminer les régimes de cavitation stable et inertielle au cours du temps, mais aussi de garantir une activité de cavitation plus stable temporellement, plus reproductible, et ce pour des énergies acoustiques moyennes délivrées inférieures. Enfin, le processus de contrôle est utilisé expérimentalement pour des applications in-vitro de sonoporation cellulaire. Tout d’abord, une étude de sonoporation en cavitation inertielle régulée met en évidence l’amélioration de la reproductibilité des taux de sonoporation obtenus, et la possibilité de s’affranchir de l’utilisation d’agents de contraste comme agents de nucléation. Ensuite, une étude en cavitation stable régulée met en évidence la possibilité de sonoporer des cellules en limitant les activités de cavitation inertielle, et donc potentiellement en limitant la lyse cellulaire / In the aim of limiting the destructive behavior of collapsing cavitation bubbles, an exclusively stable cavitation state is targeted for sensitive therapeutics applications like blood-brain barrier opening. Ensuring a stable cavitation regime is complex because of (i) the coexistence of stably oscillating bubbles and collapsing bubbles in the same bubble cloud, and (ii) the stochastic behavior of the phenomenon during time. Therefore, it is necessary to control spatially and temporally the cavitation activity, by discriminating the stable from the inertial regime. Firstly, the theoretical study of the dynamics of a monodisperse and homogeneous cloud shows a modification of the stable cavitation threshold as a function of the bubble density: the subharmonics emission threshold is lowered and the resonance frequency is shifted. The study leads also to the expression of a particular microbubbles density leading to optimized subharmonics emission. Secondly, a real-time control strategy based on a feedback loop process on subharmonics emission is designed. The use of this strategy allows discriminating the two cavitation states during time, and ensures a better reproducibility, time-stability and an acoustic energy gain. The control device is used for cells sonoporation in-vitro. In a first study, the sonoporation by inertial cavitation control is performed in a stationary ultrasonic field configuration. This leads to high sonoporation efficiency coupled to the possibility of counterbalancing the use of supplementary nuclei (encapsulated microbubbles). In a second one, the stable cavitation control applied in a focused ultrasound configuration field pinpoints the possibility of sonoporating cells without inertial cavitation, and then to limit cell lysis

La plupart des êtres vivants possèdent une horloge circadienne (période de 24heures). Elle leur permet notamment d’anticiper les changements quotidiens (lumière,température) imposés par la rotation de la terre et d’y adapter leur comportement et leurphysiologie. L’horloge est présente dans la plupart des cellules et repose sur deux boucles derégulation transcriptionnelle négative qui génèrent des oscillations d’ARNm des gènesd’horloge. Un délai entre l’accumulation des ARNm et celle des protéines assure lefonctionnement de la boucle de rétroaction. Ce délai est dû à des modifications posttraductionnellesdes protéines PERIOD et TIMELESS. Les oscillations protéiques sontnotamment contrôlées par leur phosphorylation, l’ubiquitination et la dégradation via leprotéasome. L’ubiquitine ligase SCFSlmb induit la dégradation circadienne de PER et de TIM.SCFJetlag contrôle la dégradation de TIM par la lumière, cette dernière intervenant dans lasynchronisation de l’oscillateur.Au cours de notre étude, nous avons identifié une nouvelle ubiquitine ligase, uncomplexe Cul-3, qui contrôle principalement la stabilité de TIM. Nos résultats indiquent queCul-3 contrôle surtout la stabilité de TIM peu phosphorylé, de façon indépendante de PER,tandis que Slmb contrôle principalement la stabilité de TIM phosphorylé. Nous proposons unmodèle dans l'oscillation de TIM régie par deux systèmes d'ubiquitination: Cul-3 pourretarder l'accumulation nocturne de la protéine, et Slmb pour précipiter sa disparition en finde nuit. / Most living organisms possess a circadian clock (24 hours period). This internal clockallows them to anticipate the daily changes (light, temperature) due to the rotation of theearth and consequently adapt their behavior and physiology. The molecular clock relies ontwo negative feedback loops that generate oscillations of the clock gene mRNA. A delaybetween the accumulation of the mRNAs and the proteins is required for the feedback loop,and is generated by post-translational modifications of PERIOD and TIMELESS. The proteinoscillations are controlled by their phosphorylation, ubiquitination and proteasomedependentdegradation. The ubiquitin ligase SCFSlmb induces the circadian degradation ofPER and TIM. SCFJetlag controls the light-dependent degradation of TIM, which is involved inthe resetting of the clock.In our study, we have identified Cul-3, as a new clock ubiquitin ligase that controlsTIM stability. Our results indicate that Cul-3 mostly controls the stability ofhypophosphorylated TIM, independently of PER, whereas SLMB controls the stability ofphosphorylated TIM. We propose a model where TIM oscillations are regulated by twoubiquitination process. Cul-3 delays the night accumulation of TIM, whereas Slmbprecipitates its degradation at the end of the night.