A flexible architecture for modeling and simulation of diffusional association

Up to now, it is not possible to obtain analytical solutions for complex molecular association processes (e.g. Molecule recognition in Signaling or catalysis). Instead Brownian Dynamics (BD) simulations are commonly used to estimate the rate of diffusional association, e.g. to be later used in mesoscopic simulations. Meanwhile a portfolio of diffusional association (DA) methods have been developed that exploit BD. However, DA methods do not clearly distinguish between modeling, simulation, and experiment settings. This hampers to classify and compare the existing methods with respect to, for instance model assumptions, simulation approximations or specific optimization strategies for steering the computation of trajectories. To address this deficiency we propose FADA (Flexible Architecture for Diffusional Association) - an architecture that allows the flexible definition of the experiment comprising a formal description of the model in SpacePi, different simulators, as well as validation and analysis methods. Based on the NAM (Northrup-Allison-McCammon) method, which forms the basis of many existing DA methods, we illustrate the structure and functioning of FADA. A discussion of future validation experiments illuminates how the FADA can be exploited in order to estimate reaction rates and how validation techniques may be applied to validate additional features of the model

Exploring the spatio-temporal dynamics of lipid rafts and their role in Signal transduction: a modeling and simulation approach

The aim of this thesis is to elucidate the biological as well as methodological implications that arise from modeling the spatio-temporal dynamics of lipid rafts. Therefore the effect of raft-dependent receptors dynamics on both, individual signaling events as well as the canonical Wnt signaling pathway, is thoroughly analyzed. To explore the effect of lipid rafts on individual signaling events, a Cellular-Automata based membrane model is developed. The specific involvement of lipid rafts in Wnt/β-catenin signaling is explored by means of an integrated in silico and in vitro approach

Supporting the Integrated Visual Analysis of Input Parameters and Simulation Trajectories

The visualization of simulation trajectories is a well-established approach to analyze simulated processes. Likewise, the visualization of the parameter space that configures a simulation is a well-known method to get an overview of possible parameter combinations. This paper follows the premise that both of these approaches are actually two sides of the same coin: Since the input parameters influence the simulation outcome, it is desirable to visualize and explore both in a combined manner. The main challenge posed by such an integrated visualization is the combinatorial explosion of possible parameter combinations. It leads to insurmountably high simulation runtimes and screen space requirements for their visualization. The Visual Analytics approach presented in this paper targets this issue by providing a visualization of a coarsely sampled subspace of the parameter space and its corresponding simulation outcome. In this visual representation, the analyst can identify regions for further drill-down and thus finer subsampling. We aid this identification by providing visual cues based on heterogeneity metrics. These indicate in which regions of the parameter space deviating behavior occurs at a more fine-grained scale and thus warrants further investigation and possible re-computation. We demonstrate our approach in the domain of systems biology by a visual analysis of a rule-based model of the canonical Wnt signaling pathway that plays a major role in embryonic development. In this case, the aim of the domain experts was to systematically explore the parameter space to determine those parameter configurations that match experimental data sufficiently well

Broadening the miRNA Catalogue in Livestock Species

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Genetically regulated hepatic transcripts and pathways orchestrate haematological, biochemical and body composition traits

The liver is the central metabolic organ and exhibits fundamental functions in haematological traits. Hepatic expression, haematological, plasma biochemical, and body composition traits were assessed in a porcine model (n = 297) to establish tissue-specific genetic variations that influence the function of immune-metabolism-correlated expression networks. At FDR (false discovery rate) <1%, more than 3,600 transcripts were jointly correlated (r = |0.22–0.48|) with the traits. Functional enrichment analysis demonstrated common links of metabolic and immune traits. To understand how immune and metabolic traits are affected via genetic regulation of gene expression, eQTLs were assessed. 20517 significant (FDR < 5%) eQTLs for 1401 transcripts were identified, among which 443 transcripts were associated with at least one of the examined traits and had cis-eQTL (such as ACO1 (6.52 × 10−7) and SOD1 (6.41 × 10−30). The present study establishes a comprehensive view of hepatic gene activity which links together metabolic and immune traits in a porcine model for medical research

Automatic Reuse, Adaption, and Execution of Simulation Experiments via Provenance Patterns

Simulation experiments are typically conducted repeatedly during the model development process, for example, to re-validate if a behavioral property still holds after several model changes.Approaches for automatically reusing and generating simulation experiments can support modelers in conducting simulation studies in a more systematic and effective manner.They rely on explicit experiment specifications and, so far, on user interaction for initiating the reuse. Thereby, they are constrained to support the reuse of simulation experiments in a specific setting. Our approach now goes one step further by automatically identifying and adapting the experiments to be reused for a variety of scenarios.To achieve this, we exploit provenance graphs of simulation studies, which provide valuable information about the previous modeling and experimenting activities, and contain meta-information about the different entities that were used or produced during the simulation study. We define provenance patterns and associate them with a semantics, which allows us to interpret the different activities, and construct transformation rules for provenance graphs.Our approach is implemented in a Reuse and Adapt framework for Simulation Experiments (RASE) which can interface with various modeling and simulation tools. In the case studies, we demonstrate the utility of our framework for a) the repeated sensitivity analysis of an agent-based model of migration routes, and b) the cross-validation of two models of a cell signaling pathway

Spatio-temporal Model of Endogenous ROS and Raft-Dependent WNT/Beta-Catenin Signaling Driving Cell Fate Commitment in Human Neural Progenitor Cells

<div><p>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.</p></div

Wnt signaling related transcripts and their relationship to energy metabolism in C2C12 myoblasts under temperature stress

Temperature stress is one of the main environmental stressors affecting the welfare, health and productivity of livestock. Temperature changes can modify cell membrane components, disrupting the crosstalk between the cell and its surroundings by affecting signaling pathways including Wnt signaling pathway, which subsequently disrupts cell energy metabolism. The present study aims to understand the effect of temperature stress on the expression of genes involved in Wnt signaling pathways, and their interaction with energy metabolism in C2C12 myoblasts cells. The C2C12 cells were exposed to cold stress (35 °C), mild heat stress (39 °C) and severe heat stress (41 °C), whereas 37 °C was used as control temperature. Transcript levels of important genes involved in Wnt signaling including Axin2, Tnks2, Sfrp1, Dkk1, Dact1, Cby1, Wnt5a, Wnt7a, Wnt11, Porcn, Ror2, Daam1, and Ppp3ca were significantly altered under severe heat stress (41 °C), whereas eight Wnt signaling-related transcripts (Daam1, Ppp3ca, Fzd7, Wnt5a, Porcn, Tnks2, Lrp6, and Aes) were significantly altered under cold stress (35 °C) compared to control. Under heat stress transcripts of the Wnt/β-catenin inhibitors (Sfrp1, Dkk1, and Cby1) and negative regulators (Dact1 and Axin2) are activated. A positive correlation between oxidative phosphorylation and Wnt-related transcripts was found under high temperatures. Transcripts of the cell membrane receptors, including Lrp6 and Fzd7, and the members of Wnt/Ca+2 signaling pathway, including Ppp3ca and Porcn were downregulated under cold stress. Many Wnt signaling-related transcripts were positively correlated with glycolysis under cold stress. These findings indicate a cross-talk between Wnt signaling and energy metabolism under thermal stress

Confocal Microscopy of mitochondrial ROS level.

<p>Confocal microscopy of mito-ROS levels for untreated (control) cells and MbCD-treated cells. Proliferating cells have been treated with H₂O₂ as positive control and MbCD for 1 hour (first column). 1 hour after induction of differentiation cells show a marked increase of mito-ROS levels, and subsequent decrease after 3 hours. Images further confirm that neither proliferating nor differentiating cells are subject to crucial changes in mitochondrial ROS level due to raft disruption through MbCD treatment. Scale bar 20 <i>μ</i>m.</p