262 research outputs found

    Search based software engineering: Trends, techniques and applications

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    © ACM, 2012. This is the author's version of the work. It is posted here by permission of ACM for your personal use. Not for redistribution. The definitive version is available from the link below.In the past five years there has been a dramatic increase in work on Search-Based Software Engineering (SBSE), an approach to Software Engineering (SE) in which Search-Based Optimization (SBO) algorithms are used to address problems in SE. SBSE has been applied to problems throughout the SE lifecycle, from requirements and project planning to maintenance and reengineering. The approach is attractive because it offers a suite of adaptive automated and semiautomated solutions in situations typified by large complex problem spaces with multiple competing and conflicting objectives. This article provides a review and classification of literature on SBSE. The work identifies research trends and relationships between the techniques applied and the applications to which they have been applied and highlights gaps in the literature and avenues for further research.EPSRC and E

    Multidisciplinary Design Optimization for Space Applications

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    Multidisciplinary Design Optimization (MDO) has been increasingly studied in aerospace engineering with the main purpose of reducing monetary and schedule costs. The traditional design approach of optimizing each discipline separately and manually iterating to achieve good solutions is substituted by exploiting the interactions between the disciplines and concurrently optimizing every subsystem. The target of the research was the development of a flexible software suite capable of concurrently optimizing the design of a rocket propellant launch vehicle for multiple objectives. The possibility of combining the advantages of global and local searches have been exploited in both the MDO architecture and in the selected and self developed optimization methodologies. Those have been compared according to computational efficiency and performance criteria. Results have been critically analyzed to identify the most suitable optimization approach for the targeted MDO problem

    Statistical risk estimation for communication system design

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    Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Aeronautics and Astronautics, 2012.Cataloged from PDF version of thesis.Includes bibliographical references (p. 281-295).Spacecraft are complex systems that involve many subsystems and multiple relationships among them. The design of a spacecraft is an evolutionary process that starts from requirements and evolves over time. During this process, changes can affect mass and power at component, subsystem, and system level. Each spacecraft has to respect overall constraints in terms of mass and power. The current practice in system design deals with this problem by allocating margins to individual components and to individual subsystems. However, a statistical characterization of the fluctuations in mass and power of the overall system (i.e. the spacecraft) is missing. This lack can result in a risky spacecraft design that might not fit the mission constraints and requirements, or in a conservative design that might not fully utilize the available resources. This problem is especially challenging at the initial stage of the design, when high levels of uncertainty due to lack of knowledge are unavoidable. This research proposes a statistical approach to quantify the likelihood that the design of a spacecraft would meet the mission constraints in mass and power consumption, focusing on the initial stage of the design. Due to the complexity of the problem and the different expertise required to develop a complete risk model for a spacecraft design, the scope of this research is focused on risk estimation for a specific spacecraft subsystem: the communication subsystem. The current research aims to be a "proof of concept" of a risk-based design approach, which can then be further expanded to the design of other subsystems as well as to the whole spacecraft. The approach presented in this thesis includes a baseline communication system design tool, and a statistical characterization of the design risks through a combination of historical mission data and expert opinion. Different statistical techniques are explored to ensure that the amount of information extracted from data and expert opinion is maximized. Specifically, for statistics based on data, Kernel Density Estimator is selected as the preferred technique to extract probability densities from a database of previous space missions' components. Expert elicitation is generated through a four-part model which quantifies experts' sensitivity to biases, and uses this measurement to compose properly the assessments from different experts. Finally, an optimization framework is developed to compare multiple possible design architectures, and to select the one that minimizes design objectives, like mass and power consumption, while minimizing the risk associated with the same metrics. Examples of missions are applied to validate the model. Results show that the statistical approach recognizes whether the initial estimate of the system is an overestimation or an underestimation, providing a valuable tool to measure the risk of a communication system at the initial state of the design. Specifically, statistics based on historical data and on expert elicitation allow the designer to size contingency properly, providing a reliable estimation of mass and power in the initial stage of the design. Thanks to this method, the communication system designers will be able to evaluate and compare different communication architectures in a risk trade-off prospective across the evolution of the design. Extensions to different subsystems and to additional metrics (like cost) make this model applicable to a wider range of problems.by Alessandra Babuscia.Ph.D

    Genetic Algorithms in Software Architecture Synthesis

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    Ohjelmistoarkkitehtuurien suunnittelu on kriittinen vaihe ohjelmistokehitystä, sillä arkkitehtuuri määrittelee ohjelmiston rungon: miten ohjelma jaetaan eri komponentteihin, ja miten komponentit ovat yhteydessä toisiinsa. Ohjelmisto voidaan yleensä toteuttaa toimivasti monella eri tavalla, mutta toimiva toteutus ei aina takaa, että ohjelmisto on myös toteutettu laadukkaasti. Laadun takeena onkin huolella ja taidolla suunniteltu arkkitehtuuri. Ohjelmistoarkkitehtuurin suunnittelu on haastavaa. Suunnitelmaa tehdessä tulee ottaa huomioon monen eri sidosryhmän (esim. käyttäjä, toteuttaja, markkinoija) vaatimukset ja miettiä, miten mahdollisimman suuri osa vaatimuksista voidaan toteuttaa arkkitehtuurissa. Arkkitehtuurisuunnittelu vaatiikin kokeneen ohjelmistoarkkitehdin, joka on hankkinut tietotaitonsa vuosien ajalta eri ohjelmistoprojekteista. Kokemukseen perustuvan tiedon lisäksi ohjelmistoarkkitehtuurisuunnittelun käytäntöjä on koottu eräänlaisiksi katalogeiksi, joissa esitellään hyväksi havaittuja ratkaisuja, ns. suunnittelutyylejä ja -malleja, yleisiin arkkitehtuurisuunnitteluongelmiin. Voidaankin ajatella, että arkkitehtuuri tuotetaan etsimällä (kokemukseen nojaten) paras mahdollinen kombinaatio suunnittelumalleja ja -tyylejä. Arkkitehtuurin suunnittelu onkin siis eräänlainen optimointiongelma. Ohjelmistoista tulee jatkuvasti yhä monimutkaisempia. Sovelluksien monimutkaistuessa myös arkkitehtuurisuunnittelu muuttuu entistä vaikeammaksi ja vie yhä enemmän aikaa. Suunnittelun perustuminen hiljaiseen tietoon ja arkkitehtien kokemukseen tekee prosessista yhä hitaamman ja läpinäkymättömämmän. Arkkitehtuurisuunnittelun automatisointi toisikin suuria säästöjä. Henkilöstövaihdosten yhteydessä ei myöskään tarvitsisi pelätä tietotaidon katoamista, kun arkkitehtuurisuunnittelu olisi helposti toistettavissa aina alusta lähtien. Tässä väitöskirjassa on tutkittu, miten parhaan mahdollisen ratkaisun etsintäprosessin (eli suunnittelumallien ja -tyylien soveltamisen) voisi automatisoida. Monimutkaisissa optimointiongelmissa käytetään etsintäalgoritmeja, jotka haravoivat hakuavaruutta jollain satunnaistetulla menetelmällä. Yksi suosituimmista etsintäalgoritmeista on geneettinen algoritmi. Geneettiset algoritmit tarkastelevat aina pientä ratkaisujoukkoa kerrallaan ja etsivät parasta ratkaisua yhdistelemällä osia löydetyistä ratkaisuista sekä muuntelemalla ratkaisuja. Jokaiselle ratkaisulle lasketaan laatuarvo, ja luonnonvalintaa jäljitellen jatketaan parhaiden vaihtoehtojen tarkastelua sekä kehittelyä ja hylätään huonoimmat ratkaisut. Etsintäalgoritmien käyttämistä ohjelmistokehityksen ongelmiin, esim. ohjelmistosuunnitteluun, testaukseen ja projektinhallintaan, kutsutaan etsintäperustaiseksi ohjelmistokehitykseksi. Väitöskirja kuuluu etsintäperustaisen ohjelmistosuunnittelun alaan, ja siinä tutkitaan ns. ohjelmistoarkkitehtuurisynteesiä geneettisten algoritmien avulla. Ohjelmistoarkkitehtuurisynteesi lähtee ns. nolla-arkkitehtuurista , joka toteuttaa järjestelmän toiminnalliset vaatimukset, mutta ei ota kantaa laatuvaatimuksiin. Laatua pyritään parantamaan lisäämällä lähtöarkkitehtuuriin suunnittelutyylejä ja -malleja. Väitöskirjassa laatuarviointiin on käytetty muunneltavuutta, tehokkuutta ja ymmärrettävyyttä. Lopputuloksena saadaan ehdotus arkkitehtuurista, joka toteuttaa toiminnalliset vaatimukset ja on myös laadukas. Geneettisiä algoritmeja ei ole aiemmin sovellettu vastaavantasoisiin suunnitteluongelmiin, joten toteutuksessa on kehitetty uusi tapa mallintaa arkkitehtuuri geneettiselle algoritmille sekä laskukaava arkkitehtuurin laadulle. Perustoteutuksen lisäksi myös geneettisen algoritmin eri ominaisuuksia, ns. risteytysoperaatiota ja laatufunktiota on tutkittu tarkemmin, ja niille on kehitetty vaihtoehtoisia toteutuksia. Tapaustarkasteluista saadut tulokset osoittavat, että tällä hetkellä geneettisiin algoritmeihin perustuvaa arkkitehtuurisynteesi tuottaa suunnilleen samantasoisia ratkaisuja kuin kolmannen vuosikurssin ohjelmistotekniikan opiskelija.This thesis presents an approach for synthesizing software architectures with genetic algorithms. Previously in the literature, genetic algorithms have been mostly used to improve existing architectures. The method presented here, however, focuses on upstream design. The chosen genetic construction of software architectures is based on a model which contains information on functional requirements only. Architecture styles and design patterns are used to transform the initial high-level model to a more detailed design. Quality attributes, here modifiability, efficiency and complexity, are encoded in the algorithm s fitness function for evaluating the produced solutions. The final solution is given as a UML class diagram. While the main contribution is introducing the method for architecture synthesis, basic tool support for the implementation is also presented. Two case studies are used for evaluation. One case study uses the sketch for an electronic home control system, which is a typical embedded system. The other case study is based on a robot war game simulator, which is a typical framework system. Evaluation is mostly based on fitness graphs and (subjective) evaluation of produced class diagrams. In addition to the basic approach, variations and extensions regarding crossover and fitness function have been made. While the standard algorithm uses a random crossover, asexual reproduction and complementary crossover are also studied. Asexual crossover corresponds to real-life design situations, where two architectures are rarely combined. Complementary crossover, in turn, attempts to purposefully combine good parts of two architectures. The fitness function is extended with the option to include modifiability scenarios, which enables more targeted design decisions as critical parts of the architecture can be evaluated individually. In order to achieve a wider range of solutions that answer to competing quality demands, a multi-objective approach using Pareto optimality is given as an alternative for the single weighted fitness function. The multi-objective approach evaluates modifiability and efficiency, and gives as output the class diagrams of the whole Pareto front of the last generation. Thus, extremes for both quality attributes as well as solutions in the middle ground can be compared. An experimental study is also conducted where independent experts evaluate produced solutions for the electronic home control. Results show that genetic software architecture synthesis is indeed feasible, and the quality of solutions at this stage is roughly at the level of third year software engineering students

    Integrated design optimization methods for optimal sensor placement and cooling system architecture design for electro-thermal systems

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    Dynamic thermal management plays a very important role in the design and development of electro-thermal systems as these become more active and complex in terms of their functionalities. In highly power dense electronic systems, the heat is concentrated over small spatial domains. Thermal energy dissipation in any electrified system increases the temperature and might cause component failure, degradation of heat sensitive materials, thermal burnouts and failure of active devices. So thermal management needs to be done both accurately (by thermal monitoring using sensors) and efficiently (by applying fluid-based cooling techniques). In this work, two important aspects of dynamic thermal management of a highly dense power electronic system have been investigated. The first aspect is the problem of optimal temperature sensor placement for accurate thermal monitoring aimed toward achieving thermally-aware electrified systems. Strategic placement of temperature sensors can improve the accuracy of real-time temperature distribution estimates. Enhanced temperature estimation supports increased power throughput and density because Power Electronic Systems (PESs) can be operated in a less conservative manner while still preventing thermal failure. This work presents new methods for temperature sensor placement for 2- and 3-dimensional PESs that 1) improve computational efficiency (by orders of magnitude in at least one case), 2) support use of more accurate evaluation metrics, and 3) are scalable to high-dimension sensor placement problems. These new methods are tested via sensor placement studies based on a 2-kW, 60Hz, single-phase, Flying Capacitor Multi-Level (FCML) prototype inverter. Information-based metrics are derived from a reduced-order Resistance-Capacitance (RC) lumped parameter thermal model. Other more general metrics and system models are possible through application of a new continuous relaxation strategy introduced here for placement representation. A new linear Programming (LP) formulation is presented that is compatible with a particular type of information-based metric. This LP strategy is demonstrated to support the efficient solution of finely-discretized large-scale placement problems. The optimal sensor locations obtained from these methods were tested via physical experiments. The new methods and results presented here may aid the development of thermally-aware PESs with significantly enhanced capabilities. The second aspect is to design optimal fluid-based thermal management architectures through enumerative methods that help operate the system efficiently within its operating temperature limits using the minimum feasible coolant flow level. Expert intuition based on physics knowledge and vast experience may not be adequate to identify optimal thermal management designs as systems increase in size and complexity. This work also presents a design framework supporting comprehensive exploration of a class of single-phase fluid-based cooling architectures. The candidate cooling system architectures are represented using labeled rooted tree graphs. Dynamic models are automatically generated from these trees using a graph-based thermal modeling framework. Optimal performance is determined by solving an appropriate fluid flow distribution problem, handling temperature constraints in the presence of exogenous heat loads. Rigorous case studies are performed in simulation, with components having variable sets of heat loads and temperature constraints. Results include optimization of thermal endurance for an enumerated set of 4,051 architectures. In addition, cooling system architectures capable of steady-state operation under a given loading are identified. Optimization of the cooling system design has been done subject to a representative mission, consisting of multiple time-varying loads. Work presented in this thesis clearly shows that the transient effects of heat loads are expected to have important impacts on design decisions when compared to steady-state operating conditions

    A RISK-INFORMED DECISION-MAKING METHODOLOGY TO IMPROVE LIQUID ROCKET ENGINE PROGRAM TRADEOFFS

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    This work provides a risk-informed decision-making methodology to improve liquid rocket engine program tradeoffs with the conflicting areas of concern affordability, reliability, and initial operational capability (IOC) by taking into account psychological and economic theories in combination with reliability engineering. Technical program risks are associated with the number of predicted failures of the test-analyze-and-fix (TAAF) cycle that is based on the maturity of the engine components. Financial and schedule program risks are associated with the epistemic uncertainty of the models that determine the measures of effectiveness in the three areas of concern. The affordability and IOC models' inputs reflect non-technical and technical factors such as team experience, design scope, technology readiness level, and manufacturing readiness level. The reliability model introduces the Reliability- As-an-Independent-Variable (RAIV) strategy that aggregates fictitious or actual hotfire tests of testing profiles that differ from the actual mission profile to estimate the system reliability. The main RAIV strategy inputs are the physical or functional architecture of the system, the principal test plan strategy, a stated reliability-bycredibility requirement, and the failure mechanisms that define the reliable life of the system components. The results of the RAIV strategy, which are the number of hardware sets and number of hot-fire tests, are used as inputs to the affordability and the IOC models. Satisficing within each tradeoff is attained by maximizing the weighted sum of the normalized areas of concern subject to constraints that are based on the decision-maker's targets and uncertainty about the affordability, reliability, and IOC using genetic algorithms. In the planning stage of an engine program, the decision variables of the genetic algorithm correspond to fictitious hot-fire tests that include TAAF cycle failures. In the program execution stage, the RAIV strategy is used as reliability growth planning, tracking, and projection model. The main contributions of this work are the development of a comprehensible and consistent risk-informed tradeoff framework, the RAIV strategy that links affordability and reliability, a strategy to define an industry or government standard or guideline for liquid rocket engine hot-fire test plans, and an alternative to the U.S. Crow/AMSAA reliability growth model applying the RAIV strategy

    Systems Engineering: Availability and Reliability

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    Current trends in Industry 4.0 are largely related to issues of reliability and availability. As a result of these trends and the complexity of engineering systems, research and development in this area needs to focus on new solutions in the integration of intelligent machines or systems, with an emphasis on changes in production processes aimed at increasing production efficiency or equipment reliability. The emergence of innovative technologies and new business models based on innovation, cooperation networks, and the enhancement of endogenous resources is assumed to be a strong contribution to the development of competitive economies all around the world. Innovation and engineering, focused on sustainability, reliability, and availability of resources, have a key role in this context. The scope of this Special Issue is closely associated to that of the ICIE’2020 conference. This conference and journal’s Special Issue is to present current innovations and engineering achievements of top world scientists and industrial practitioners in the thematic areas related to reliability and risk assessment, innovations in maintenance strategies, production process scheduling, management and maintenance or systems analysis, simulation, design and modelling

    Tradespace and Affordability – Phase 2

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    MOTIVATION AND CONTEXT: One of the key elements of the SERC’s research strategy is transforming the practice of systems engineering – “SE Transformation.” The Grand Challenge goal for SE Transformation is to transform the DoD community’s current systems engineering and management methods, processes, and tools (MPTs) and practices away from sequential, single stovepipe system, hardware-first, outside-in, document-driven, point-solution, acquisition-oriented approaches; and toward concurrent, portfolio and enterprise-oriented, hardware-software-human engineered, balanced outside-in and inside-out, model-driven, set-based, full life cycle approaches.This material is based upon work supported, in whole or in part, by the U.S. Department of Defense through the Office of the Assistant Secretary of Defense for Research and Engineering (ASD(R&E)) under Contract H98230-08- D-0171 (Task Order 0031, RT 046).This material is based upon work supported, in whole or in part, by the U.S. Department of Defense through the Office of the Assistant Secretary of Defense for Research and Engineering (ASD(R&E)) under Contract H98230-08- D-0171 (Task Order 0031, RT 046)

    A methodology for rapid vehicle scaling and configuration space exploration

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    Drastic changes in aircraft operational requirements and the emergence of new enabling technologies often occur symbiotically with advances in technology inducing new requirements and vice versa. These changes sometimes lead to the design of vehicle concepts for which no prior art exists. They lead to revolutionary concepts. In such cases the basic form of the vehicle geometry can no longer be determined through an ex ante survey of prior art as depicted by aircraft concepts in the historical domain. Ideally, baseline geometries for revolutionary concepts would be the result of exhaustive configuration space exploration and optimization. Numerous component layouts and their implications for the minimum external dimensions of the resultant vehicle would be evaluated. The dimensions of the minimum enclosing envelope for the best component layout(s) (as per the design need) would then be used as a basis for the selection of a baseline geometry. Unfortunately layout design spaces are inherently large and the key contributing analysis i.e. collision detection, can be very expensive as well. Even when an appropriate baseline geometry has been identified, another hurdle i.e. vehicle scaling has to be overcome. Through the design of a notional Cessna C-172R powered by a liquid hydrogen Proton Exchange Membrane (PEM) fuel cell, it has been demonstrated that the various forms of vehicle scaling i.e. photographic and historical-data-based scaling can result in highly sub-optimal results even for very small O(10-3) scale factors. There is therefore a need for higher fidelity vehicle scaling laws especially since emergent technologies tend to be volumetrically and/or gravimetrically constrained when compared to incumbents. The Configuration-space Exploration and Scaling Methodology (CESM) is postulated herein as a solution to the above-mentioned challenges. This bottom-up methodology entails the representation of component or sub-system geometries as matrices of points in 3D space. These typically large matrices are reduced using minimal convex sets or convex hulls. This reduction leads to significant gains in collision detection speed at minimal approximation expense. (The Gilbert-Johnson-Keerthi algorithm is used for collision detection purposes in this methodology.) Once the components are laid out, their collective convex hull (from here on out referred to as the super-hull) is used to approximate the inner mold line of the minimum enclosing envelope of the vehicle concept. A sectional slicing algorithm is used to extract the sectional dimensions of this envelope. An offset is added to these dimensions in order to come up with the sectional fuselage dimensions. Once the lift and control surfaces are added, vehicle level objective functions can be evaluated and compared to other designs. For each design, changes in the super-hull dimensions in response to perturbations in requirements can be tracked and regressed to create custom geometric scaling laws. The regressions are based on dimensionally consistent parameter groups in order to come up with dimensionally consistent and thus physically meaningful laws. CESM enables the designer to maintain design freedom by portably carrying multiple designs deeper into the design process. Also since CESM is a bottom-up approach, all proposed baseline concepts are implicitly volumetrically feasible. Furthermore the scaling laws developed from custom data for each concept are subject to less design noise than say, regression based approaches. Through these laws, key physics-based characteristics of vehicle subsystems such as energy density can be mapped onto key system level metrics such as fuselage volume or take-off gross weight. These laws can then substitute some historical-data based analyses thereby improving the fidelity of the analyses and reducing design time.Ph.D.Committee Chair: Dr. Dimitri Mavris; Committee Member: Dean Ward; Committee Member: Dr. Daniel Schrage; Committee Member: Dr. Danielle Soban; Committee Member: Dr. Sriram Rallabhandi; Committee Member: Mathias Emenet

    A systems engineering approach to model, tune and test synthetic gene circuits

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    La biología sintética se define como la ingeniería de la biología: el (re)diseño y construcción de nuevas partes, dispositivos y sistemas biológicos para realizar nuevas funciones con fines útiles, que se basan en principios elucidados de la biología y la ingeniería. Para facilitar la construcción rápida, reproducible y predecible de estos sistemas biológicos a partir de conjuntos de componentes es necesario desarrollar nuevos métodos y herramientas. La tesis plantea la optimización multiobjetivo como el marco adecuado para tratar los problemas comunes que surgen en el diseño racional y el ajuste óptimo de los circuitos genéticos sintéticos. Utilizando un enfoque clásico de ingeniería de sistemas, la tesis se centra principalmente en: i) el modelado de circuitos genéticos sintéticos basado en los primeros principios, ii) la estimación de parámetros de modelos a partir de datos experimentales y iii) el ajuste basado en modelos para lograr el desempeño deseado de los circuitos. Se han utilizado dos circuitos genéticos sintéticos de diferente naturaleza y con diferentes objetivos y problemas: un circuito de realimentación de tipo 1 incoherente (I1-FFL) que exhibe la importante propiedad biológica de adaptación, y un circuito de detección de quorum sensing y realimentación (QS/Fb) que comprende dos bucles de realimentación entrelazados -uno intracelular y uno basado en la comunicación de célula a célula- diseñado para regular el nivel medio de expresión de una proteína de interés mientras se minimiza su varianza a través de la población de células. Ambos circuitos han sido analizados in silico e implementados in vivo. En ambos casos, se han desarrollado modelos de estos circuitos basado en primeros principios. Se presta especial atención a ilustrar cómo obtener modelos de orden reducido susceptibles de estimación de parámetros, pero manteniendo el significado biológico. La estimación de los parámetros del modelo a partir de los datos experimentales se considera en diferentes escenarios, tanto utilizando modelos determinísticos como estocásticos. Para el circuito I1-FFL se consideran modelos determinísticos. Aquí, la tesis plantea la utilización de modelos locales utilizando la optimización multiobjetivo para realizar la estimación de parámetros del modelo bajo escenarios con estructura de modelo incompleta. Para el circuito QS/Fb, una estructura controlada por realimentación, el problema tratado es la falta de excitabilidad de las señales. La tesis propone una metodología de estimación en dos etapas utilizando modelos estocásticos. La metodología permite utilizar datos de curso temporal promediados de la población y mediciones de distribución en estado estacionario para una sola célula. El ajuste de circuitos basado en modelos para lograr un desempeño deseado también se aborda mediante la optimización multiobjetivo. Para el circuito QS/Fb se realiza un análisis estocástico completo. La tesis aborda cómo tener en cuenta correctamente tanto el ruido intrínseco como el extrínseco, las dos principales fuentes de ruido en los circuitos genéticos. Se analiza el equilibrio entre ambas fuentes de ruido y el papel que desempeñan en el bucle de realimentación intracelular, y en la realimentación extracelular de toda la población. La principal conclusión es que la compleja interacción entre ambos canales de realimentación obliga al uso de la optimización multiobjetivo para el adecuado ajuste del circuito. En esta tesis además del uso adecuado de herramientas de optimización multiobjetivo, la principal preocupación es cómo derivar directrices para el ajuste in silico de parámetros de circuitos que puedan aplicarse de forma realista in vivo en un laboratorio estándar. Como alternativa al análisis de sensibilidad de parámetros clásico, la tesis propone el uso de técnicas de clustering a lo largo de los frentes de Pareto, relacionando el comprLa biologia sintètica es defineix com l'enginyeria de la biologia: el (re) disseny i construcció de noves parts, dispositius i sistemes biològics per a realitzar noves funcions útils que es basen a principis elucidats de la biologia i l'enginyeria. Per facilitar la construcció ràpida, reproduïble i predictible de aquests sistemes biològics a partir de conjunts de components és necessari desenvolupar nous mètodes i eines. La tesi planteja la optimització multiobjectiu com el marc adequat per a tractar els problemes comuns que apareixen en el disseny racional i l' ajust òptim dels circuits genètics sintètics. Utilitzant un enfocament clàssic d'enginyeria de sistemes, la tesi es centra principalment en: i) el modelatge de circuits genètics sintètics basat en primers principis, ii) l' estimació de paràmetres de models a partir de dades experimentals i iii) l' ajust basat en models per aconseguir el rendiment desitjat dels circuits. S'han utilitzat dos circuits genètics sintètics de diferent naturalesa i amb diferents objectius i problemes: un circuit de prealimentació de tipus 1 incoherent (I1-FFL) que exhibeix la important propietat biològica d'adaptació, i un circuit de quorum sensing i realimentació (QS/Fb) que comprèn dos bucles de realimentació entrellaçats -un intracel·lular i un basat en la comunicació de cèl·lula a cèl·lula- dis-senyat per regular el nivell mitjà d'expressió normal d'una proteïna d'interès mentre es minimitza la seua variació al llarg de la població de cèl·lules. Els dos circuits han estat analitzats in silico i implementats in vivo. En tots dos casos, s'han desenvolupat models basats en primers principis d'aquests circuits. Després es presta especial atenció a delinear com obtenir models d'ordre reduït susceptibles de estimació de paràmetres, però mantenint el significat biològic. L' estimació dels paràmetres del model a partir de les dades experimentals es considera en diferents escenaris, tant utilitzant models determinístics com estocàstics. Per al circuit I1-FFL es consideren models determinístics. La tesi planteja la utilització de models locals utilitzant la optimització multiobjectiu per realitzar l'estimació de parametres del model sota escenaris amb estructura de model incompleta (dinàmica no modelada). Per al circuit de QS/Fb, una estructura controlada per realimentació, el problema tractat és la manca d'excitabilitat dels senyals. La tesi proposa una metodologia de estimació en dues etapes utilitzant models estocàstics. La metodologia permet utilitzar dades de curs temporal promediats de la població i mesures de distribució en estat estacionari d'una sola una cèl·lula. L' ajust de circuits basat en models per aconseguir el rendiment desitjat dels circuits també s' aborda mitjançant la optimització multiobjectiu. Per al circuit QS/Fb, es fa un anàlisi estocàstic complet. La tesi aborda com tenir en compte correctament tant el soroll intrínsec com l' extrínsec, les dues principals fonts de soroll en els circuits genètics sintètics. S' analitza l'equilibri entre dues fonts de soroll i el paper que exerceixen en el bucle de realimentació intracel·lular, les i en la realimentació extracel·lular de tota la població. La principal conclusió es que la complexa interacció entre els dos canals de realimentació fa necessari l' ús de la optimització multiobjectiu per al adequat ajust del circuit. En aquesta tesi, a més de l'ús adequat d'eines d'optimització multiobjectiu, la principal preocupació és com derivar directives per al ajust in silico de paràmetres de circuits que puguin aplicar-se de forma realista en viu en un laboratori estàndard. Així, com a alternativa a l'anàlisi de sensibilitat de paràmetres clàssic, la tesi proposa l'ús de l' tècniques de l'agrupació al llarg dels fronts de Pareto, relacionant el compromís de dessempeny amb les regions en l'espai d'paràmetres.Synthetic biology is defined as the engineering of biology: the deliberate (re)design and construction of novel biological and biologically based parts, devices and systems to perform new functions for useful purposes, that draws on principles elucidated from biology and engineering. Methods and tools are needed to facilitate fast, reproducible and predictable construction of biological systems from sets of biological components. This thesis raises multi-objective optimization as the proper framework to deal with common problems arising in rational design and optimal tuning of synthetic gene circuits. Using a classical systems engineering approach, the thesis mainly addresses: i) synthetic gene circuit modeling based on first principles, ii) model parameters estimation from experimental data and iii) model-based tuning to achieve desired circuit performance. Two gene synthetic circuits of different nature and with different goals and inherent problems have been used throughout the thesis: an Incoherent type 1 feedforward circuit (I1-FFL) that exhibits the important biological property of adaptation, and a Quorum sensing/Feedback circuit (QS/Fb) comprising two intertwined feedback loops -an intracellular one and a cell-to-cell communication-based one-- designed to regulate the mean expression level of a protein of interest while minimizing its variance across the population of cells. Both circuits have been analyzed in silico and implemented in vivo. In both cases, circuit modeling based on first principles has been carried out. Then, special attention is paid to illustrate how to obtain reduced order models amenable for parameters estimation yet keeping biological significance. Model parameters estimation from experimental data is considered in different scenarios, both using deterministic and stochastic models. For the I1-FFL circuit, deterministic models are considered. In this case, the thesis raises ensemble modeling using multi-objective optimization to perform model parameters estimation under scenarios with incomplete model structure (unmodeled dynamics). For the QS/Fb gene circuit, a feedback controlled structure, the lack of excitability of the signals is the problem addressed. The thesis proposes a two-stage estimation methodology using stochastic models. The methodology allows using population averaged time-course data and steady state distribution measurements at the single-cell level. Model-based circuit tuning to achieve desired circuit performance is also addressed using multi-objective optimization. First, for the QS/Fb feedback control circuit, a complete stochastic analysis is performed. Here, the thesis addresses how to correctly take into account both intrinsic and extrinsic noise, the two main sources of noise in gene synthetic circuits. The trade-off between both sources of noise, and the role played by in the intracellular single-cell feedback loop and the extracellular population-wide feedback is analyzed. The main conclusion being that the complex interplay between both feedback channels compel the use of multi-objective optimization for proper tuning of the circuit to achieve desired performance. Thus, the thesis wraps up all the previous results and uses them to address circuit tuning for desired performance. Here, besides the proper use of multi-objective optimization tools, the main concern is how to derive guidelines for circuit parameters tuning in silico that can realistically be applied in vivo in a standard laboratory. Thus, as an alternative to classical parameters sensitivity analysis, the thesis proposes the use of clustering techniques along the optimal Pareto fronts relating the performance trade-offs with regions in the circuits parameters space.This work has been partially supported by the Spanish Government (CICYT DPI2014- 55276-C5-1) and the European Union (FEDER). The author was recipient of the grant Formación de Personal Investigador by the Universitat Politècnica de València, subprogram 1 (FPI/2013-3242). She was also recipient of the competitive grants for pre-doctoral stays Erasmus Student Placement-European Programme 2015, and FPI Mobility program 2016 of the Universitat Politècnica de València. She also received the competitive grant for a pre-doctoral stay Becas de movilidad para Jóvenes Profesores e Investigadores 2016, Programa de Becas Iberoamérica of the Santander Bank.Boada Acosta, YF. (2018). A systems engineering approach to model, tune and test synthetic gene circuits [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/112725TESI
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