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Deciphering the functioning of biological networks is one of the central tasks in systems biology. In particular, signal transduction networks are crucial for the understanding of the cellular response to external and internal perturbations. Importantly, in order to cope with the complexity of these networks, mathematical and computational modeling is required. We propose a computational modeling framework in order to achieve more robust discoveries in the context of logical signaling networks. More precisely, we focus on modeling the response of logical signaling networks by means of automated reasoning using Answer Set Programming (ASP). ASP provides a declarative language for modeling various knowledge representation and reasoning problems. Moreover, available ASP solvers provide several reasoning modes for assessing the multitude of answer sets. Therefore, leveraging its rich modeling language and its highly efficient solving capacities, we use ASP to address three challenging problems in the context of logical signaling networks: learning of (Boolean) logical networks, experimental design, and identification of intervention strategies. Overall, the contribution of this thesis is three-fold. Firstly, we introduce a mathematical framework for characterizing and reasoning on the response of logical signaling networks. Secondly, we contribute to a growing list of successful applications of ASP in systems biology. Thirdly, we present a software providing a complete pipeline for automated reasoning on the response of logical signaling networks.

Biology has made great progress in identifying and measuring the building blocks of life. The availability of high-throughput methods in molecular biology has dramatically accelerated the growth of biological knowledge for various organisms. The advancements in genomic, proteomic and metabolomic technologies allow for constructing complex models of biological systems. An increasing number of biological repositories is available on the web, incorporating thousands of biochemical reactions and genetic regulations. Systems Biology is a recent research trend in life science, which fosters a systemic view on biology. In Systems Biology one is interested in integrating the knowledge from all these different sources into models that capture the interaction of these entities. By studying these models one wants to understand the emerging properties of the whole system, such as robustness. However, both measurements as well as biological networks are prone to considerable incompleteness, heterogeneity and mutual inconsistency, which makes it highly non-trivial to draw biologically meaningful conclusions in an automated way. Therefore, we want to promote Answer Set Programming (ASP) as a tool for discrete modeling in Systems Biology. ASP is a declarative problem solving paradigm, in which a problem is encoded as a logic program such that its answer sets represent solutions to the problem. ASP has intrinsic features to cope with incompleteness, offers a rich modeling language and highly efficient solving technology. We present ASP solutions, for the analysis of genetic regulatory networks, determining consistency with observed measurements and identifying minimal causes for inconsistency. We extend this approach for computing minimal repairs on model and data that restore consistency. This method allows for predicting unobserved data even in case of inconsistency. Further, we present an ASP approach to metabolic network expansion. This approach exploits the easy characterization of reachability in ASP and its various reasoning methods, to explore the biosynthetic capabilities of metabolic reaction networks and generate hypotheses for extending the network. Finally, we present the BioASP library, a Python library which encapsulates our ASP solutions into the imperative programming paradigm. The library allows for an easy integration of ASP solution into system rich environments, as they exist in Systems Biology.

Answer Set Programming (ASP) emerged in the late 1990s as a new logic programming paradigm, having its roots in nonmonotonic reasoning, deductive databases, and logic programming with negation as failure. The basic idea of ASP is to represent a computational problem as a logic program whose answer sets correspond to solutions, and then to use an answer set solver for finding answer sets of the program. ASP is particularly suited for solving NP-complete search problems. Among these, we find applications to product configuration, diagnosis, and graph-theoretical problems, e.g. finding Hamiltonian cycles. On different lines of ASP research, many extensions of the basic formalism have been proposed. The most intensively studied one is the modelling of preferences in ASP. They constitute a natural and effective way of selecting preferred solutions among a plethora of solutions for a problem. For example, preferences have been successfully used for timetabling, auctioning, and product configuration. In this thesis, we concentrate on preferences within answer set programming. Among several formalisms and semantics for preference handling in ASP, we concentrate on ordered logic programs with the underlying D-, W-, and B-semantics. In this setting, preferences are defined among rules of a logic program. They select preferred answer sets among (standard) answer sets of the underlying logic program. Up to now, those preferred answer sets have been computed either via a compilation method or by meta-interpretation. Hence, the question comes up, whether and how preferences can be integrated into an existing ASP solver. To solve this question, we develop an operational graph-based framework for the computation of answer sets of logic programs. Then, we integrate preferences into this operational approach. We empirically observe that our integrative approach performs in most cases better than the compilation method or meta-interpretation. Another research issue in ASP are optimization methods that remove redundancies, as also found in database query optimizers. For these purposes, the rather recently suggested notion of strong equivalence for ASP can be used. If a program is strongly equivalent to a subprogram of itself, then one can always use the subprogram instead of the original program, a technique which serves as an effective optimization method. Up to now, strong equivalence has not been considered for logic programs with preferences. In this thesis, we tackle this issue and generalize the notion of strong equivalence to ordered logic programs. We give necessary and sufficient conditions for the strong equivalence of two ordered logic programs. Furthermore, we provide program transformations for ordered logic programs and show in how far preferences can be simplified. Finally, we present two new applications for preferences within answer set programming. First, we define new procedures for group decision making, which we apply to the problem of scheduling a group meeting. As a second new application, we reconstruct a linguistic problem appearing in German dialects within ASP. Regarding linguistic studies, there is an ongoing debate about how unique the rule systems of language are in human cognition. The reconstruction of grammatical regularities with tools from computer science has consequences for this debate: if grammars can be modelled this way, then they share core properties with other non-linguistic rule systems.