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Systems of Systems (SoS) have received a lot of attention recently. In this thesis we will focus on SoS that are built atop the techniques of Service-Oriented Architectures and thus combine the benefits and challenges of both paradigms. For this thesis we will understand SoS as ensembles of single autonomous systems that are integrated to a larger system, the SoS. The interesting fact about these systems is that the previously isolated systems are still maintained, improved and developed on their own. Structural dynamics is an issue in SoS, as at every point in time systems can join and leave the ensemble. This and the fact that the cooperation among the constituent systems is not necessarily observable means that we will consider these systems as open systems. Of course, the system has a clear boundary at each point in time, but this can only be identified by halting the complete SoS. However, halting a system of that size is practically impossible. Often SoS are combinations of software systems and physical systems. Hence a failure in the software system can have a serious physical impact what makes an SoS of this kind easily a safety-critical system. The contribution of this thesis is a modelling approach that extends OMG's SoaML and basically relies on collaborations and roles as an abstraction layer above the components. This will allow us to describe SoS at an architectural level. We will also give a formal semantics for our modelling approach which employs hybrid graph-transformation systems. The modelling approach is accompanied by a modular verification scheme that will be able to cope with the complexity constraints implied by the SoS' structural dynamics and size. Building such autonomous systems as SoS without evolution at the architectural level --- i. e. adding and removing of components and services --- is inadequate. Therefore our approach directly supports the modelling and verification of evolution. / Systems of Systems (SoS) sind ein seit längerem bekanntes Konzept, das jedoch in letzter Zeit vermehrt Aufmerksamkeit erhielt. Das Hauptaugenmerk dieser Arbeit wird auf SoS liegen, die mit Hilfe von Techniken aus Service-Orientierten Architekturen erstellt werden. Somit vereinen die hier betrachteten SoS die Vorteile und Herausforderungen beider Paradigmen. SoS können definiert werden als Zusammenschlüsse einzelner, autonomer Systeme, die zu einem größeren System integriert werden. In diesem Zusammenhang interessant ist, dass die ehemals isolierten Systeme nach wie vor isoliert voneinander weiterentwickelt und gewartet werden. Desweiteren kommt der Strukturdynamik innerhalb des SoS eine beachtliche Bedeutung zu, da jederzeit Systeme dem SoS beitreten und es verlassen können. Zusammen mit der Tatsache, dass die Kooperationen zwischen den konstituierenden Systemen nicht immer beobachtbar sind, führt dies dazu, dass wir diese Systeme als offene Systeme bezeichnen. Wobei das System natürlich jederzeit eine klar definierte Grenze besitzt, diese aber nur durch ein Anhalten des Systems zu bestimmen ist. Dies jedoch ist, von einer praktischen Perspektive aus betrachtet, unmöglich. Häufig stellen SoS eine Kombination aus Softwaresystemen und pyhsikalischen Systemen dar mit der Folge, dass ein Fehler in der Software eine SoS schnell eine immense physikalische Wirkung entwickeln kann. Von daher fallen SoS leicht in die Klasse der sicherheitskritischen Systeme. In dieser Arbeit werden wir einen Modellierungsansatz vorstellen, der die Sprache SoaML der OMG erweitert. Die grundlegenden Konzepte dieses Ansatzes sind die Modellierung mit Kollaborationen und Rollen als Abstraktionsebene über Komponenten. Der vorgestellte Ansatz erlaubt es uns SoS auf einer architekturellen Ebene zu betrachten. Die formale Semantik unseres Modellierungsansatzes ist durch hybride Graphtransformationssysteme gegeben. Abgestimmt auf die Modellierung werden wir ebenfalls ein Verfahren zu Verifikation von SoS vorstellen, welches trotz der inhärenten Komplexität von SoS, diese zu verifizieren. Die Modellierung und Verifikation von Evolution wird von unserem Ansatz direkt unterstützt.

Our bodies contain a vast number and diversity of microbes. These microbes interact, and these interactions can define how microbes affect us. Microbial ecology and evolution, therefore, are important for both microbiology and human health. However, our understanding of microbial communities remains limited. There is a need for theory that dissects the complexity and identifies the key factors and processes affecting microbial groups. Here I develop realistic computer simulations and population models of microbial communities. My first project seeks to explain microbial communication (quorum sensing) and argues that quorum sensing is a way to infer when competing genotypes are no longer a threat. The second project proposes an evolutionary explanation for another major microbial trait: adhesion. I argue that adhesion is a weapon allowing cells to compete within microbial groups and push competitors out, particularly when growing on a host epithelium. The third project moves from microbes to the host and asks whether a host can control which microbes grow and persist inside it. I develop a model of the human gut epithelium and show that the gut architecture amplifies the ability of hosts to select helpful microbes over harmful ones using nutrient secretion. In addition to selecting particular microbial strains, a host will also benefit from stable symbiotic communities that behave in a predictable manner. But what determines whether host-associated communities are ecologically stable? My final project uses ecological network theory to show that ecological stability is likely to be a problem for gut communities that are diverse and contain species that cooperate with each other. However, I argue that the host should function as an ecosystem engineer that increases ecological stability by weakening the strong dependence of cooperating species upon one another. While host-associated communities are complex ecological systems, my thesis identifies key factors that affect their form and function.

Antibiotic resistance in bacteria is acquired through spontaneous chromosomal mutations or horizontal gene transfer. In the absence of antibiotics, resistant mutants generally show reduced fitness due to compromised growth rate, competitive ability and virulence compared to their antibiotic-sensitive ancestors. The focus of my research is to dissect the molecular underpinnings of the variations in the fitness cost of chromosomal antibiotic resistance using a systems-level approach. From an evolutionary perspective, my research aims are to understand how the fitness cost influences adaptation in resistant populations in an antibiotic-free environment. Using rifampicin resistance in Pseudomonas aeruginosa as a model, my work shows that most of the variation in the fitness cost of rifampicin resistance can be attributed to the direct effect of rifampicin resistance mutations on transcriptional efficiency. Through RNA-Seq transcriptome profiling, I demonstrate that global changes in gene expression levels associated with resistance mutations are surprisingly subtle, suggesting that the transcriptional regulatory network of P. aeruginosa is robust against compromised transcriptional efficiency. Using experimental evolution and whole-genome sequencing, my work reveals a systematic difference in the genetic basis of adaptation in mutants that were propagated in the absence of antibiotics. During compensatory adaptation, resistant mutants can recover the fitness cost of resistance by fixing second-site mutations that directly offset the deleterious effects of resistance mutations. Amongst resistant mutant populations with low fitness costs, general adaptation limits compensatory adaptation, which is most likely to be due to the rarity of compensatory mutations and clonal interference. Far from being the most ubiquitous mechanism in the evolution of resistance, compensatory adaptation is the exception that is more likely to be observed in resistant mutants with high fitness costs. In addition, I applied key elements of the integrative experimental approach developed in this work to dissect the molecular basis of the fitness cost associated with carriage of the pNUK73 small plasmid in P. aeruginosa, which carries the rep gene encoding a plasmid replication protein. My results confirmed that rep expression generates a significant fitness cost in P. aeruginosa and demonstrate how the molecular origins of the fitness cost of resistance can be dissected in a different biological context.

科学研究費補助金 研究種目:基盤研究(A)(1) 課題番号: 研究代表者:三井 斌友 研究期間:1996-1998年度