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BackgroundComputational support is essential in order to reason on the dynamics of biological systems. We have developed the software tool ANIMO (Analysis of Networks with Interactive MOdeling) to provide such computational support and allow insight into the complex networks of signaling events occurring in living cells. ANIMO makes use of timed automata as an underlying model, thereby enabling analysis techniques from computer science like model checking. Biology experts are able to use ANIMO via a user interface specifically tailored for biological applications. In this paper we compare the use of ANIMO with some established formalisms on two case studies.ResultsANIMO is a powerful and user-friendly tool that can compete with existing continuous and discrete paradigms. We show this by presenting ANIMO models for two case studies: Drosophila melanogaster circadian clock, and signal transduction events downstream of TNF α and EGF in HT-29 human colon carcinoma cells. The models were originally developed with ODEs and fuzzy logic, respectively.ConclusionsTwo biological case studies that have been modeled with respectively ODE and fuzzy logic models can be conveniently modeled using ANIMO. The ANIMO models require less parameters than ODEs and are more precise than fuzzy logic. For this reason we position the modelling paradigm of ANIMO between ODEs and fuzzy logic.Electronic supplementary materialThe online version of this article (doi:10.1186/s12918-016-0286-z) contains supplementary material, which is available to authorized users.

Attack trees (ATs) are a popular formalism for security analysis, and numerous variations and tools have been developed around them. These were mostly developed independently, and offer little interoperability or ability to combine various AT features. We present ATTop, a software bridging tool that enables automated analysis of ATs using a model-driven engineering approach. ATTop fulfills two purposes: 1. It facilitates interoperation between several AT analysis methodologies and resulting tools (e.g., ATE, ATCalc, ADTool 2.0), 2. it can perform a comprehensive analysis of attack trees by translating them into timed automata and analyzing them using the popular model checker Uppaal, and translating the analysis results back to the original ATs. Technically, our approach uses various metamodels to provide a unified description of AT variants. Based on these metamodels, we perform model transformations that allow to apply various analysis methods to an AT and trace the results back to the AT domain. We illustrate our approach on the basis of a case study from the AT literature.

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Interleukin 1 beta (IL1β) and Wingless-Type MMTV Integration Site Family (WNT) signaling are major players in Osteoarthritis (OA) pathogenesis. Despite having a large functional overlap in OA onset and development, the mechanism of IL1β and WNT crosstalk has remained largely unknown. In this study, we have used a combination of computational modeling and molecular biology to reveal direct or indirect crosstalk between these pathways. Specifically, we revealed a mechanism by which IL1β upregulates WNT signaling via downregulating WNT antagonists, DKK1 and FRZB. In human chondrocytes, IL1β decreased the expression of Dickkopf-1 (DKK1) and Frizzled related protein (FRZB) through upregulation of nitric oxide synthase (iNOS), thereby activating the transcription of WNT target genes. This effect could be reversed by iNOS inhibitor 1400W, which restored DKK1 and FRZB expression and their inhibitory effect on WNT signaling. In addition, 1400W also inhibited both the matrix metalloproteinase (MMP) expression and cytokine-induced apoptosis. We concluded that iNOS/NO play a pivotal role in the inflammatory response of human OA through indirect upregulation of WNT signaling. Blocking NO production may inhibit the loss of the articular phenotype in OA by preventing downregulation of the expression of DKK1 and FRZB.

Living cells are constantly subjected to a plethora of environmental stimuli that require integration into an appropriate cellular response. This integration takes place through signal transduction events that form tightly interconnected networks. The understanding of these networks requires capturing their dynamics through computational support and models. ANIMO (analysis of Networks with Interactive Modeling) is a tool that enables the construction and exploration of executable models of biological networks, helping to derive hypotheses and to plan wet-lab experiments. The tool is based on the formalism of Timed Automata, which can be analyzed via the UPPAAL model checker. Thanks to Timed Automata, we can provide a formal semantics for the domain-specific language used to represent signaling networks. This enforces precision and uniformity in the definition of signaling pathways, contributing to the integration of isolated signaling events into complex network models. We propose an approach to discretization of reaction kinetics that allows us to efficiently use UPPAAL as the computational engine to explore the dynamic behavior of the network of interest. A user-friendly interface hides the use of Timed Automata from the user, while keeping the expressive power intact. Abstraction to single-parameter kinetics speeds up construction of models that remain faithful enough to provide meaningful insight. The resulting dynamic behavior of the network components is displayed graphically, allowing for an intuitive and interactive modeling experience.

We propose a model-driven engineering approach that facilitates the production of tool chains that use the popular model checker Uppaal as a back-end analysis tool. In this approach, we introduce a metamodel for Uppaal's input model, containing both timed-automata concepts and syntax-related elements for C-like expressions. We also introduce a metamodel for Uppaal's query language to specify temporal properties; as well as a metamodel for traces to interpret Uppaal's counterexamples and witnesses. The approach provides a systematic way to build software bridging tools (i.e., tools that translate from a domainspecific language to Uppaal's input language) such that these tools become easier to debug, extend, reuse and maintain. We demonstrate our approach on five different domains: cyber-physical systems, hardwaresoftware co-design, cyber-security, reliability engineering and software timing analysis. IntroductionUppaal [3] is a leading model checker for real-time systems, allowing one to verify automatically whether a system meets its timing requirements. Uppaal and its extensions have been applied to a large number of domains, ranging from communication protocols [28], over planning [4] to systems biology [31]. As such, Uppaal is a popular back-end for various other real-time analysis tools, such as ANIMO [31], sdf2ta [13] and STATE [19]. Typically such tools take their inputs in a domain-specific language (DSL) and translate these inputs into timed automata, which are then fed into Uppaal to perform the analysis. In this way, domain experts can write their models in a DSL that they are familiar with, while still using Uppaal's powerful analysis algorithms behind the scenes.A disadvantage of this approach is, however, that the tools that translate from a DSL to Uppaal's input language, i.e., software bridging tools, are often implemented ad hoc, and hence difficult to debug, reuse, extend and maintain.

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