Canonical WNT/β-catenin signaling is a central pathway in embryonic development, but it is also connected to a number of cancers and developmental disorders. Here we apply a combined in-vitro and in-silico approach to investigate the spatio-temporal regulation of WNT/β-catenin signaling during the early neural differentiation process of human neural progenitors cells (hNPCs), which form a new prospect for replacement therapies in the context of neurodegenerative diseases. Experimental measurements indicate a second signal mechanism, in addition to canonical WNT signaling, being involved in the regulation of nuclear β-catenin levels during the cell fate commitment phase of neural differentiation. We find that the biphasic activation of β-catenin signaling observed experimentally can only be explained through a model that combines Reactive Oxygen Species (ROS) and raft dependent WNT/β-catenin signaling. Accordingly after initiation of differentiation endogenous ROS activates DVL in a redox-dependent manner leading to a transient activation of down-stream β-catenin signaling, followed by continuous auto/paracrine WNT signaling, which crucially depends on lipid rafts. Our simulation studies further illustrate the elaborate spatio-temporal regulation of DVL, which, depending on its concentration and localization, may either act as direct inducer of the transient ROS/β-catenin signal or as amplifier during continuous auto-/parcrine WNT/β-catenin signaling. In addition we provide the first stochastic computational model of WNT/β-catenin signaling that combines membrane-related and intracellular processes, including lipid rafts/receptor dynamics as well as WNT- and ROS-dependent β-catenin activation. The model’s predictive ability is demonstrated under a wide range of varying conditions for in-vitro and in-silico reference data sets. Our in-silico approach is realized in a multi-level rule-based language, that facilitates the extension and modification of the model. Thus, our results provide both new insights and means to further our understanding of canonical WNT/β-catenin signaling and the role of ROS as intracellular signaling mediator.

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Unambiguous experiment descriptions are increasingly required for model publication, as they contain information important for reproducing simulation results. In the context of model composition, this information can be used to generate experiments for the composed model. If the original experiment descriptions specify which model property they refer to, we can then execute the generated experiments and assess the validity of the composed model by evaluating their results. Thereby, we move the attention to describing properties of a model's behavior and the conditions under which these hold, i.e., its semantics. We illuminate the potential of this concept by considering the composition of Lotka-Volterra models. In a first prototype realized for JAMES II, we use ML-Rules to describe and execute the Lotka-Volterra models and SESSL for specifying the original experiments. Model properties are described in continuous stochastic logic, and we use statistical model checking for their evaluation. Based on this, experiments to check whether these properties hold for the composed model are automatically generated and executed.

Simulation replication is a necessity for all stochastic simulations. Its efficient execution is particularly important when additional techniques are used on top, such as optimization or sensitivity analysis. One way to improve replication efficiency is to ensure that the best configuration of the simulation system is used for execution. A selection of the best configuration is possible when the number of required replications is sufficiently high, even without any prior knowledge on simulator performance or problem instance. We present an adaptive replication mechanism that combines portfolio theory with reinforcement learning: it adapts itself to the given problem instance at runtime and can be restricted to an efficient algorithm portfolio.