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ВКР (магистерская диссертация) состоит из введения, трех глав, заключения, библиографического списка, включающего 70 наименований. Работа включает 18 таблиц и 4 рисунка. Общий объем ВКР (магистерской диссертации) – 72 страницы. Цель исследования: оценка наличия взаимосвязи между качеством внешнего аудита и финансовыми результатами деятельности компаний, котирующихся на Амманской фондовой бирже и разработка рекомендаций по политике выбора и организации внешнего аудита для коммерческих организаций. Объектом исследования выступают компании, котирующиеся на Амманском фондовом рынке. Научная новизна исследования состоит в проверке гипотез по влиянию отдельных факторов, характеризующих качество аудита на финансовые результаты аудируемой компании. Практическая значимость исследования заключается в формулировании на основе построенной модели и выдвинутых гипотез алгоритма выбора внешнего финансового аудитора для компаний различных сфер деятельности. / The master's thesis (master's thesis) consists of an introduction, three chapters, a conclusion, and a bibliography that includes 70 titles. The work includes 18 tables and 4 figures. The total volume of the master's thesis (master's thesis) is 72 pages. The purpose of the study: to assess the relationship between the quality of external audit and the financial performance of companies listed on the Amman Stock Exchange and to develop recommendations on the policy for selecting and organizing external audit for commercial organizations. The object of the study is companies listed on the Amman stock market. The scientific novelty of the study lies in testing hypotheses on the influence of individual factors characterizing the quality of the audit on the financial results of the audited company. The practical significance of the study lies in the formulation, based on the constructed model and put forward hypotheses, of an algorithm for selecting an external financial auditor for companies in various fields of activity.

[pt] É constante o desafio das refinarias de petróleo na busca pela maximização da rentabilidade diante da natureza dinâmica das variáveis que afetam seus processos, como: demanda e especificações de produtos, qualidade de carga e preços de matéria-prima e derivados. Com a expectativa de mudanças nestas variáveis, um planejamento estratégico integrado para definir as necessidades de investimento em novas unidades de processo e ampliação de capacidade de unidades existentes pode contribuir para os melhores resultados do negócio de refino. Em face destas oportunidades e desafios, este trabalho propõe uma análise do planejamento de investimentos em refino, considerando o crescimento da demanda de diesel com ultra baixo teor de enxofre (S10) e também o crescimento plurianual da demanda de derivados, tendo como estudo de caso uma das maiores refinarias brasileiras. Como ferramenta de análise, foi utilizado um modelo matemático para planejamento integrado de refino de petróleo, que considera a otimização do planejamento operacional para definir as necessidades de investimento na refinaria, uma integração temporal, resultando em um modelo não linear inteiro misto (MINLP), cuja resolução utiliza uma lógica de decomposição em dois problemas integrados. Foi analisado o planejamento estratégico de refino, no horizonte de 19 anos e foram feitos vários cenários de demanda, com análises de sensibilidade para preços de petróleo e produtos, limite de importação e restrição de investimentos. Os resultados mostraram alinhamento com situação atual do mercado de derivados, com importação favorecida e com a expectativa de investimento mínimo em refino. / [en] It is a constant challenge for oil refineries the profitability maximization considering the dynamic nature of variables that affect their processes, such as demand and product specifications, feed quality and prices of raw materials and products. Expecting changes in such variables, an integrated strategic planning to define the needs for investment in new process units and capacity expansion of existing units can contribute to better results of the refining business. Given these opportunities and challenges, this dissertation proposes an analysis of refining investment planning, considering the increasing demand for ultralow sulfur diesel (S10) and also the multi-year growth of demand for oil products, performing a case study for one of the largest Brazilian refineries. As an analysis tool, it was used a mathematical model for integrated planning of oil refining, which considers the optimization of operational planning to set the investment needs in the refinery, a temporal integration, resulting in a mixed integer nonlinear model (MINLP), which resolution is based on a logic decomposition in two integrated problems. The strategic refining planning was analyzed on the 19 years horizon for different demand scenarios and some sensitivity analyses were carried out for oil and product prices, import limit and investment restrictions. The results were consistent with the current situation of the Brazilian derivatives market, characterized by favorable import and the minimum investment expected for refining.

The Swedish Sea Rescue Society (SSRS) is exploring how small, remotely launched drones can help in making the rescue work safer and more efficient. The planned drone to be used for such purposes is a 1 kg, 1 m wide, foam constructed, flying wing drone. Aviation regulatory authorities are however struggling with the problem posed by balancing the benefits of unmanned aerial vehicles (UASs) with the safety risk posed to manned aircraft, people and structures on the ground. A risk assessment framework called Specific Operations Risk Assessment (SORA) states specifications on risks that a certain operation can generate. An impact study was requested from SSRS as the purpose of this master thesis, to make sure the drones will not cause danger to other aircraft in the same airspace. SSRS needs to know how dangerous their drone is according to the regulations and how they can improve the design. A literature study was made to determine the critical scenarios for the UAVs area of application. A mathematical collision model was developed where the properties of the flying wing were considered to determine the energies involved. The results provide limits for when a small flying wing poses danger in its area of operation. The results also shows the effects of having a crumple zone included in the construction. A crumple zone only makes a difference when colliding at lower speeds. For the future, a combined model for the UAV to be used with the collision object would provide more accurate results since they affect each other in the collision. / Sjöräddningssällskapet (SSRS) undersöker hur små, fjärrstyrda drönare kan göra deras räddningsarbete säkrare och effektivare. Den planerade drönaren som ska användas för sådana ändamål är en 1 kg, 1 m bred, skumkonstruerad, drönare av typen flygande vinge. Luftfartsmyndigheterna strävar efter att balansera fördelarna med obemannade flygfordon (UAS) med säkerhetsrisken för bemannade flygplan, människor och byggnader. En riskbedömningsram som benämns Specific Operations Risk Assessment (SORA) anger specifikationer för risker som en viss tillämning kan generera. En konsekvensstudie vid kollision med drönare begärdes från SSRS som syfte med detta examensarbete. Detta för att säkerställa att drönarna inte kommer att orsaka fara för andra flygfarkoster i samma luftrum som deras UAV ska användas. SSRS behöver veta hur riskfylld deras drönare är enligt riskspecifikationerna och hur de kan förbättra sin design. En litteraturstudie gjordes för att bestämma de kritiska scenarierna för deras drönares tillämpningsområde. En matematisk kollisionsmodell har utveklats som tar hänsyn till drönarens material och konstruktion och hur det påverkar de involverade energierna. Resultaten sätter gränser för när en liten fjärrstyrd drönare kan utgöra fara i sitt användningsområde. Resultaten visar också effekten av att ha en deformationszon på drönaren. En deformationzon visar sig, bara göra skillnad i kollisioner vid låga hastigheter. För framtiden skulle en kombinerad modell för den UAV som ska användas med kollisionsobjektet ge mer exakta resultat, eftersom de påverkar varandra i kollisionen.

The paper examines the impact of fees on the return of a fund investment using different simulation and fee structure models. The results show that fees have a significant expected impact, particularly for well-performing funds. Two simulation models were used, the Geometric Brownian Motion (GBM) model and Merton Jump Diffusion (MJD) model. Two fee structures were also analysed for each simulation, a High-water mark fee structure and a Hurdle fee structure. Comparing the GBM and MJD models, the two tend to generate very similar fee statistics even though the MJD model's day-to-day returns fit better with empirical data. When comparing the HWM and Hurdle fee models, larger differences are observed. While overall average fee statistics are similar, the performance fee statistics are significantly higher in the Hurdle fee structure for assets achieving higher returns, e.g. at least an 8% annual return. However, the HWM fee structure tends to generate higher performance fees for assets with low returns. Regression models are also developed for each combination of the simulation model and fee structure. The regression models reflect the above conclusions and can for investors serve as simple key indicators to estimate expected fund fee payments. The GBM regression results are likely more useful than the MJD regression results, as the parameters of the former are easier to calculate based on historical return data. / Uppsatsen undersöker effekten av avgifter på avkastningen av en fondinvestering med hjälp av olika simuleringar och avgiftsmodeller. Resultaten visar att avgifter förväntas ha en betydande påverkan, särskilt för fonder som genererar hög avkastning. Två simuleringar användes, Geometric Brownian Motion (GBM) och Merton Jump Diffusion (MJD). Två avgiftsstrukturer analyserades också för varje simulering, en High-water mark avgiftsstruktur och en Hurdle avgiftsstruktur. Jämförelse mellan GBM och MJD-modellerna visar att de två tenderar att generera mycket liknande avgiftsstatistik trots att MJD-modellens dagliga avkastning passar bättre med empiriska data. Vid jämförelse av HWM- och Hurdle avgiftsmodellerna observeras större skillnader. Medan den övergripande genomsnittliga avgiftsstatistiken är liknande för avgiftsmodellerna, är resultatbaserade avgifterna betydligt högre i Hurdle avgiftsstrukturen för tillgångar som uppnår högre avkastning, t.ex. minst 8% årlig avkastning. Däremot tenderar HWM-avgiftsstrukturen att generera högre resultatbaserade avgifter för tillgångar med låg avkastning. Regressionsmodeller utvecklades också för varje kombination av simulering och avgiftsstruktur. Regressionmodellerna återspeglar ovanstående slutsatser och kan för investerare fungera som enkla nyckeltal för att uppskatta förväntad kostnad av fondavgifter. GBM-regressionsresultaten är sannolikt mer användbara än MJD-regressionsresultaten, eftersom parametrarna för den förra är lättare att beräkna baserat på historisk avkastningsdata.

[pt] A logística humanitária visa salvar vidas e aliviar o sofrimento em desastres. Além disso, suprimentos humanitários são itens essenciais para a sobrevivência humana (como exemplo, água e alimentos) e sua falta pode causar grande impacto. No entanto, os recursos disponíveis podem não ser suficientes para atender a demanda dos beneficiários. O custo de privação quantifica o sofrimento causado as vítimas de desastres pela falta desses itens. Assim, este trabalho objetiva analisar o efeito da inclusão dele na gestão de estoque de suprimentos de alívio a desastres. Para alcançar o objetivo proposto, a pesquisa analisa o estado da arte da modelagem deste custo por meio de uma revisão sistemática da literatura acadêmica. Um modelo de gestão de estoque considerando custos de privação é então formulado como um modelo estocástico de dois estágios. Ademais, as diversas funções de custo de privação encontradas na literatura são analisadas. Finalmente, o modelo é validado empiricamente através de dois estudos de caso. Os resultados sugerem que a escolha da função de privação pode impactar em até 99,9 por cento de diferença nos custos totais da gestão de estoques. O nível de atendimento gerado também possui uma alta amplitude quando as diferentes funções de privação encontradas na literatura são comparadas. Conclui-se que as funções geram níveis de atendimentos distintos, cabendo aos tomadores de decisão escolher qual se adequa melhor ao problema estudado. Como contribuição prática, destaca-se que o modelo de gestão de estoque considerando o custo de privação proposto pode auxiliar os tomadores de decisão e reduzir o sofrimento das pessoas atingidas por desastres. Como contribuição acadêmica, o estudo analisa e compara as principais funções de privação propostas na literatura, o que pode auxiliar a proposição de novas modelagens. / [en] Humanitarian logistics aims to save lives and alleviate human suffering in disasters. Furthermore, humanitarian supplies are essential items for humanity (such as water and food), and their lack can have a great impact. However, the available resources may not be enough to meet the beneficiaries needs. The deprivation cost quantifies the suffering caused to disaster victims by the lack of these items. Thus, this paper aims to analyze the effect of including deprivation costs in disaster relief supplies inventory management. To reach the proposed goal, the research analyzes the state of the art of its modeling through a systematic review of the academic literature. An inventory management model considering deprivation costs is then formulated as a two-stage stochastic model. Furthermore, the various deprivation cost functions found in the literature are analyzed. Finally, the model is empirically validated through a two case studies. The results suggest that the choice of the deprivation function can impact up to a 99.9 per cent difference in the total costs of inventory management. The service level generated also has a high amplitude when the different functions are compared. It is concluded that the functions generate different service levels, and it is up to the decision-makers to choose which one best suits the studied problem. As a practical contribution, we highlight that the proposed inventory management model considering the cost of deprivation may help decision-makers and reduce the suffering of people affected by disasters. As an academic contribution, the study analyzes and compares the main deprivation functions proposed in the literature, which can help to propose new models.

[ES] Una vía para conseguir un cambio de modelo de negocio hacia modelos más sostenibles es transformar el modelo empresarial tradicional lineal hacia modelos más circulares, priorizando el aprovechamiento de los recursos y la reducción del consumo de materias primas. De hecho, uno de los diecisiete Objetivos de Desarrollo Sostenible, hace referencia a la producción y al consumo responsables, incluyendo, como una de sus metas, "reducir considerablemente la generación de desechos mediante actividades de prevención, reducción, reciclado y reutilización". En este contexto de expansión del concepto de desarrollo sostenible y de la economía circular, la gestión de los productos recuperados ha convertido la Logística Inversa (LI) en una competencia clave de las Cadenas de Suministro (CdS) modernas. Otra de las causas que sitúan a la LI en la primera línea de las preocupaciones de las empresas son las devoluciones de los productos adquiridos y el elevado flujo inverso que generan, debido al incremento exponencial del comercio electrónico y su permisiva política de devoluciones. Ante este vertiginoso crecimiento de las operaciones de LI, surge la necesidad de actualizar los tradicionales procesos logísticos de las empresas, integrando en ellos el Proceso de Logística Inversa (PLI), lo cual permite controlar todo el ciclo de vida del producto. Sin embargo, debido fundamentalmente a que los flujos inversos son menos predecibles y más variables que los directos, la gestión de la LI no es una tarea fácil. En este contexto, muchas empresas han comenzado a trabajar duramente por estandarizar y formalizar sus PLI, estableciendo una serie de reglas, procedimientos y comunicaciones, que faciliten la comprensión del proceso a todos los interesados y les ayude a saber cómo actuar en cada momento. Disponer de un PLI estandarizado y formalizado permite una mejor comprensión y gestión de los productos devueltos o recuperados y una LI más eficiente, que puede a su vez proporcionar una ventaja competitiva a la empresa. Otro aspecto vital para conseguir una mayor eficiencia y rentabilidad de los PLI es facilitar la toma de decisiones en dicho proceso. En definitiva, una toma de decisiones ágil y acertada aumentará la eficiencia, permitiendo reducir costes, mejorar el servicio al cliente e incrementar los beneficios de la compañía. En este sentido, de entre todas las decisiones relacionadas con el PLI, la decisión sobre la alternativa de disposición (DD) puede destacarse como la más determinante. Precisamente, la importancia del PLI y la complejidad de la DD en el contexto descrito, justifican el desarrollo de herramientas de ayuda a la toma de decisiones. Sin embargo, los trabajos hallados en la literatura, si bien se centran en aportar modelos de ayuda a la toma de decisiones, no trabajan el PLI en su conjunto, y no llegan a estandarizar las operaciones que se realizan a lo largo del proceso, sin mostrar claramente cómo se construyen dichos modelos ni la composición de los distintos elementos del modelo. La presente tesis desarrolla un Marco de Referencia para el Desarrollo Integrado de Modelos de Procesos y Matemáticos en un contexto de LI (MR-DIMPM-LI), aportando una solución integrada que aborde el PLI en su conjunto y facilite la formalización del proceso y la toma de decisiones eficiente y sostenible en cada caso concreto. Mediante el Marco de Referencia planteado se promueve el desarrollo de modelos sostenibles, no solo favoreciendo el entendimiento y la incorporación del PLI en las empresas sino, además, haciendo que este sea realmente sostenible. Este Marco de Referencia se ha aplicado en una red de LI de bucle cerrado de un fabricante de sillones de relax y, por otro lado, en una red de LI de bucle abierto de neumáticos usados. Como resultado, se ha podido comprobar la idoneidad del Marco de Referencia propuesto en cuanto a la formalización del PLI y a la toma de decisiones de la DD, haciéndola más e / [CAT] Una via per aconseguir un canvi de model de negoci cap a models més sostenibles és transformar el model empresarial tradicional lineal cap a models més circulars, prioritzant l'aprofitament dels recursos i la reducció del consum de matèries primeres. De fet, un dels disset Objectius de Desenvolupament Sostenible, fa referència a la producció i al consum responsables, incloent-hi, com un dels seus objectius, "reduir considerablement la generació de residus mitjançant activitats de prevenció, reducció, reciclatge i reutilització". En aquest context d'expansió del concepte de desenvolupament sostenible i de l'economia circular, la gestió dels productes recuperats ha convertit la Logística Inversa (LI) en una competència clau de les Cadenes de Subministrament (CdS) modernes. Una altra de les causes que situen la LI en la primera línia de les preocupacions de les empreses són les devolucions dels productes adquirits i l'elevat flux invers que generen, a causa de l'increment exponencial del comerç electrònic i la seua permissiva política de devolucions. Davant d'aquest vertiginós creixement de les operacions de LI, sorgeix la necessitat d'actualitzar els tradicionals processos logístics de les empreses, integrant en ells el Procés de Logística Inversa (PLI), la qual cosa permet controlar tot el cicle de vida del producte. Tanmateix, a causa del fet que els fluxos inversos són menys predictibles i més variables que els directes, la gestió de la LI no és una tasca fàcil. En aquest context, moltes empreses han començat a treballar durament per estandarditzar i formalitzar els seus PLI, establint una sèrie de regles, procediments i comunicacions, que faciliten la comprensió del procés a tots els interessats i els ajude a saber com actuar en cada moment.Un altre aspecte vital per tal d'aconseguir una major eficiència i rendibilitat dels PLI és facilitar la presa de decisions en aquest procés. La identificació, estudi, descripció i modelatge de les decisions ajudarà els gestors o decisors a tenir una visió integrada de les mateixes i a entendre millor els aspectes a considerar en aquestes decisions i el seu impacte. En definitiva, una presa de decisions àgil i encertada augmentarà l'eficiència, permetent reduir costos, millorar el servei al client i incrementar els beneficis de la companyia. En aquest sentit, d'entre totes les decisions relacionades amb el PLI, la decisió sobre l'alternativa de disposició (DD) pot destacar-se com la més determinant, pel fet que ha de ser única per cada producte, condiciona a la resta de decisions, està influenciada per una elevada incertesa, repercuteix en el grau de sostenibilitat de l'empresa, està condicionada per molts factors la condicionen i generalment precisa d'agilitat i rapidesa per proporcionar una resposta a client. Precisament, la importància del PLI i la complexitat de la DD en el context descrit, justifiquen el desenvolupament d'eines d'ajuda a la presa de decisions. No obstant això, els treballs trobats a la literatura, tot i que se centren en aportar models d'ajuda a la presa de decisions, no treballen el PLI en el seu conjunt, i no arriben a estandarditzar les operacions que es realitzen al llarg de el procés. La present tesi desenvolupa un Marc de Referència (MR) per al Desenvolupament Integrat de Models de Processos i Matemàtics en un context de LI, aportant una solució integrada que aborde el PLI en el seu conjunt i facilite la formalització del procés i la presa de decisions eficient i sostenible en cada cas concret. El MR plantejat promou els models sostenibles, no només afavorint l'enteniment i la incorporació del PLI a les empreses sinó, a més, fent que aquest siga realment sostenible. Aquest MR s'ha aplicat a una xarxa de LI d'un fabricant de butaques de relax i a una xarxa de LI de pneumàtics usats. Com a resultat, s'ha pogut comprovar la idoneïtat del MR proposat pel que fa a la formalització del PLI i a la presa / [EN] One way to achieve a change in the business model towards more sustainable ones is to transform the traditional linear business models to more circular ones, prioritizing the use of resources and reducing the consumption of raw materials. In fact, one of the seventeen Sustainable Development Goals, refers to responsible production and consumption, including, as one of its goals, "considerably reduce the generation of waste through prevention, reduction, recycling and reuse activities". In this context of expanding the sustainable development and the circular economy concepts, recovered product's management has made Reverse Logistics (RL) a key competence of modern Supply Chains (SC). Another reason why RL is a major concern for companies is the returns of purchased products and the high reverse flow generated, due to the exponential e-commerce increase and its permissive return policy. Because of this vertiginous growth of RL operations, the companies must update the traditional logistics processes, integrating the Reverse Logistics Process (RLP) into them, which allows controlling the entire life cycle of the product. However, RL management is not an easy task, mainly because reverse flows are less predictable and more variable than direct ones. In this context, many companies have begun to work hard to standardize and formalize their RLP, establishing a set of rules, procedures and communications, which facilitate the understanding of the process for all interested stakeholders and help them to know how to act at any time. Having a standardized and formalized RLP enables better understanding and management of returned or recovered products and a more efficient RL, which can in turn provide a competitive advantage to the company. Another vital aspect to achieve greater efficiency and profitability of the RLP is to facilitate decision making in this process. The identification, study, description and modeling of decisions will help managers or decision-makers to have an integrated vision of them and to better understand the aspects to be considered in such decisions and their impact. In fact, agile and accurate decision making will increase efficiency, reducing costs, improving customer service and increasing company profits. In this sense, among all the decisions related to the RLP, the disposition decision (DD) can be highlighted as the most decisive, since it must be unique for each product, it determines the rest of the decisions, it is influenced by high uncertainty and affects the degree of sustainability of the company, it is conditioned by multiple factors and generally requires agility and speed to respond to the costumer. Precisely, the importance of RLP and the complexity of DD in the context described, justify the development of tools as an aid to decision-making. However, the studies found in the literature, although they focus on providing models for decision-making, do not work on the PLI as a whole, and do not come to standardize the operations carried out throughout the process, hardly showing how these models are built or the composition of the different elements of the model.This thesis develops a Reference Framework for the Integrated Development of Mathematical and Process Models in an RL context, providing an integrated solution that addresses the RLP as a whole and facilitates the formalization of the process and the efficient and sustainable decision making in each specific case. Through this, the development of sustainable models is promoted, not only favoring the understanding and incorporation of the RLP in companies but also making it truly sustainable. This framework has been applied to two real examples: a RL network of the manufacturer of relaxing chairs and a network of used tires. As a result, it has been possible to verify the suitability of the proposed Reference Framework regarding the formalization of the RLP and the decision-making of the DD, making it more efficient and sustainable. / Cortés Pellicer, P. (2020). Marco de Referencia para el Desarrollo Integrado de Modelos de Procesos y Matemáticos de Ayuda a la Toma de Decisiones en un Contexto de Logística Inversa [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/159265

Mathematical models of a nitritation: anaerobic ammonia oxidation (anammox)-coupled biofilm in a counter-diffusion hollow fiber membrane bioreactor (HFMBR) and a nitritation: anammox-coupled biofilm in a co-diffusion rotating biological contactor (RBC) were developed and implemented using AQUASIM. Four different start-up scenarios on the nitritation: anammox-coupled biofilm in an HFMBR were investigated. The supply of oxygen was simulated with the flow through the lumen of the hollow fiber membrane. For the four scenarios, two scenarios investigated the start-up when nitrite was supplied in the feed while the other two scenarios investigated when the source of nitrite was through nitritation only. The results showed that the presence of nitrite in the feed facilitated the start-up of the reactor. In addition, the results also showed that increasing oxygen flux through the membrane up to a certain ratio of ammonia flux with oxygen flux affected reactor performance by improving nitrogen removal and reducing start up time. For the nitritation: anammox-coupled biofilm in an RBC, four different process options were investigated: the number of reactors, the initial anammox (AnAOB) biomass fraction, the bulk oxygen concentration and the maximum biofilm thickness. Modeling results revealed that the steady state total nitrogen removal in RBC reactors in series occurred primarily in the first and second reactors. It is concluded that the number of reactors in series dictates the effluent performance and, therefore, this number can be selected depending upon the desired total nitrogen removal. Simulation results also revealed that increasing the initial AnAOB biomass fraction from 0.01% to 1.0% had no effect in the steady state nitrogen removal but had an effect in the required time to reach the steady state total nitrogen removal and the maximum biofilm thickness. Modeling results of the third process option showed that increasing the bulk oxygen concentration in the reactor from 0.2 g/m3 to 5 g/m3 linearly increased the steady state total nitrogen removal and reduced the time to reach the maximum biofilm thickness. Beyond 5 g/m3, steady state total nitrogen removal decreased. In addition, simulation results revealed that the thicker biofilm clearly showed a more linear correlation between the increase in bulk oxygen concentration and the increase in the steady state total nitrogen removal within a range of bulk oxygen concentrations. The results showed that RBC performance could be controlled by several process options: the number of reactors in series, initial biomass fraction, the bulk oxygen concentration and the maximum biofilm thickness. The mathematical modeling results for the HFMBR and RBC have shown that both have potential as carriers for nitritation: anammox-coupled biofilms targeted at the removal of nitrogen in the wastewater. / Master of Science

Die Durchführung von Experimenten und das mathematische Modellieren von zellulären Prozessen gehören in der Systembiologie untrennbar zusammen. Das gemeinsame Ziel ist die Aufklärung des Zusammenspiels intrazellulärer Prozesse wie Metabolismus, Genexpression oder Signaltransduktion. Während sich molekularbiologische Untersuchungen mit den molekularen Mechanismen einzelner isolierter Systeme beschäftigen, zielt die Systembiologie auf die Aufklärung der Zusammenhänge ganzer Prozesse und schließlich auch ganzer Zellen ab. Die Verfügbarkeit von umfangreichen Datensätzen und die steigenden Möglichkeiten im Bereich der Computersimulation haben in den letzten Jahren den Weg geebnet, um auch Ganzzellsimulationen nicht mehr unmöglich erscheinen zu lassen. Diese Arbeit stellt das erste eukaryotische Ganzzellmodell der Bäckerhefe Saccharomyces cerevisiae vor. Hefe als eukaryotischer Modellorganismus ist hierbei der perfekte Kandidat für die Erstellung eines solchen Modells. Er bietet, als wohl meist erforschter eukaryotischer Einzeller in Verbindung mit der Verfügbarkeit einer großen Menge experimenteller Daten, beste Voraussetzungen zur Erstellung eines solchen Modells. Das Projekt ist hierbei in drei Teile gegliedert: i) Die Erstellung eines modularen Ganzzellmodells das alle zellulären Funktionen wie Zellzyklus, Genexpression, Metabolismus, Transport und Wachstum abbildet. ii) Die Implementation einer spezialisierten Simulationsumgebung in Verbindung mit einer Datenbank, um die Erstellung, Simulation und Parametrisierung von Modulen zu ermöglichen. iii) Die Durchführung von Experimenten, um einen ganzheitlichen Datensatz zu erlangen, der Wachstum, Genexpression und Metabolismus abbildet. Die hier vorgestellte Arbeit liefert nicht nur ein mathematisches Modell, sondern benennt auch die Herausforderungen, die während der Arbeit an einem Ganzzellmodell auftreten und stellt mögliche Lösungsansätze vor. / In systems biology experiments and mathematical modeling are going hand in hand to gain and increase understanding of cellular processes like metabolism, gene expression, or signaling pathways. While molecular biology investigates single isolated parts and molecular mechanisms of cellular processes, systems biology aims at unraveling the whole process and ultimately whole organisms. Today the availability of comprehensive high-throughput data and computational power paved the way to increase the size of analyzed systems to reach the cellular level. This thesis presents the first whole-cell model (WCM) of a eukaryotic cell, the yeast Saccharomyces cerevisiae. This established model organism is the perfect candidate for the implementation of a holistic model based on the available experimental data and the accumulated biological knowledge. The project is split into three parts: i) The creation of a modular functional-complete whole-cell model, combining the processes cell cycle, gene expression, metabolism, transport, and growth. ii) The implementation of a specialized simulation environment and a database to support module creation, simulation, and parameterization. iii) The elicitation of experimental data by conducting an experiment to achieve a comprehensive data set for parameterization, combining growth, metabolic, proteomic, and transcriptomic data. The presented work provides not only a simple mathematical model but also addresses challenges occurring during the development of whole-cell models and names possible solutions and new methodologies required for the creation of WCMs.

Krebs und Infektionskrankheiten, wie z.B. Influenza, stellen zwei der großen Bedrohungen für die Menschheit dar. Gerade durch den demographischen Wandel sind immer mehr Menschen gefährdet. Mathematische Modelle von Krankheiten decken verschiedene Detailebenen ab -- von epidemologischen Modellen der Virusinfektion bis zu intrazellulären Modellen der Signaltransduktion in einzelnen Krebszellen. Diese Modelle, sofern sie anhand von biologische Daten kalibriert wurden, können sich als sehr nützlich erweisen um Hypothesen zu bisher unbekannten Wechselwirkungen zu generieren, Wirkstoffkandidaten vorherzusagen, und die Funktionsweise von existierenden Wirkstoffen besser zu verstehen. Im Rahmen dieser Arbeit möchte ich mehrere Projekte vorstellen, in denen prädiktive mathematische Modelle dazu benutzt wurden, tiefere Einblicke in die biologischen Prozesse zu gewinnen und die Therapieansätze bei Krebserkrankungen und den damit verbundenen Gesundheitsproblemen zu verbessern. Im ersten Teil geht es um die Bedeutung von gemeinschaftlich entwickelter Software für die Systembiologie. Eine offene und erweiterbare Modellierungssoftware ermöglicht es ständig verbessert zu werden und an die Bedürfnisse der Nutzer angepasst zu werden. Im zweiten Projekt wurden die intrazellulären Prozesse während der frühen Influenza A Infektion untersucht. Durch eine Kombination von biologischen Messungen und mathematischer Modellierung konnte der Abbau von viraler RNA wähernd des Transportes durch das Wirtszellzytoplasma als limitierender Faktor für die erfolgreiche Infektion identifiziert werden. Mit Hilfe eines experimentell modifizierten viralen Hämagglutintin-Proteins mit veränderter pH-Abhängigkeit konnte gezeigt werden, dass sich der Abstand zum Zellkern, in dem das virale Genom freigesetzt wird, vergrößert. Die Modellvorhersage, dass die Infektion dadurch weniger effektiv wird, konnte experimentell bestätigt werden. Im dritten Projekt beschäftigte ich mich mit gesundheitlichen Problemen, die im Zusammenhang mit einer Krebserkrankung und deren Behandlung auftreten können. Chemotherapie oder die Krebserkrankung selbst führt bei vielen Patienten zu einer Blutarmut (Anämie). Diese wird aktuell entweder durch regelmäßige Bluttransfusionen oder durch Verabreichung von sogenannten Erythropoiesis-Stimulating Agents (kurz: ESA, zu Deutsch: Erythropoese-stimulierende Substanzen) behandelt. Mithilfe eines publizierten mathematischen Modells zur ESA-EpoR Interaktion konnten die Bindungseigenschaften verschiedener ESAs charakterisiert und zudem die Anzahl der Bindungsstellen auf unterschiedlichen Zelllinien bestimmt werden. Durch eine Erweiterung des Modells mit einem pharmakokinetischen und -dynamischen Teil konnte die Dosierung für Anämiepatienten retrospektiv verbessert werden. Das letzte Projekt stellt eine computerbasierte Methode zur Analyse und Entschlüsselung der zellulären Zusammensetzung von Tumorproben dar. In den vergangenen Jahren wurde vermehrt eine neue Klasse von Krebsmedikamenten entwickelt, die sich das körpereigene Immunsystem zunutze macht, um den Krebs zu bekämpfen. Das Funktionieren dieser Medikamente hängt jedoch davon ab, ob bestimmte Immunzellen in der Umgebung des Tumors vorhanden sind. Auf Grundlage von Einzelzell RNA-Sequenzierungsdaten konnte eine existierende Methode so erweitert werden, dass nunmehr auch Proben von soliden Tumoren entschlüsselt werden können. Zudem wurden die Einflüsse von verschiedenen Faktoren, wie etwa der Gewebeherkunft oder dem verwendeten Algorithmus, systematisch ausgewertet. Zusammengefasst habe ich in dieser Arbeit dargestellt, wie prädiktive Computermodelle dazu verwendet werden können bestehende Behandlungsansätze zu verbessern und neue Wirkstoffkandidaten zu identifizieren. / Cancer and infectious diseases, such as influenza infection, represent major threats to the human population, especially since demographic change makes more and more people vulnerable. Mathematical modeling of disease covers several layers of detail ranging from epidemiological models for infection spread to cancer-associated signaling within individual cells. These models, when being calibrated to biological data, can provide useful means for generating hypothesis of priorly unknown interactions, predicting drug targets for novel therapeutic substances and for improving the understanding and efficient functioning of existing treatment strategies. In this thesis, I present several projects in which predictive computational models are utilized to gain deeper insights into the biological processes and to improve therapy of cancer and associated health problems. The first part highlights the importance of community-driven software development for systems biology applications. Efficient, yet expandable and open software continuously improves, driven by an active community of users and developers. In the second project, the intracellular processes during the early influenza A infection are investigated. Using a combination of experimental measurements and mathematical modeling, degradation of the viral genome during its diffusion through the cytoplasm could be identified as a limiting factor for a successful infection. By experimentally increasing the pH sensitivity of the viral hemagglutinin protein, the distance of diffusion was increased and the computationally predicted decrease in infectivity could be validated in experiment. The third project deals with cancer-associated health issues and their treatment. Patients suffering from anemia, caused by the cancer itself or as a side-effect of chemotherapy, are treated either with blood transfusions or with an erythropoiesis stimulating agent (ESA). By adapting a published model of ESA-EpoR interaction, not only the biochemical properties of different ESAs could be characterized in silico but also the number of binding sites (i.e. Epo receptors on the cell surface) in different cell lines was accurately determined. The model was extended by a pharmaco-kinetic and -dynamic part. The combined ESA-EpoR-PK/PD model could be utilized to retrospectively optimize the dosing regimen of patients suffering from anemia. In the last project, a computational method for analyzing and deciphering the cellular composition of bulk tumor samples is presented. Only recently, a new class of anti-cancer drugs was introduced recruiting the body’s own immune system to combat malignant tissue. However, the efficient functioning of these immunotherapeutical drugs heavily depends on the presence of specific immune cells in the tumor micro-environment. Based on single-cell RNA sequencing data, an existing method for computational deconvolution could be adapted for data from solid tumor tissue and its performance was benchmarked. Taken together, in this thesis I present approaches how predictive computational models can be utilized to render more efficient existing treatment strategies.