Semantic Multi-Classifier Systems Identify Predictive Processes in Heart Failure Models across Species.

Genetic model organisms have the potential of removing blind spots from the underlying gene regulatory networks of human diseases. Allowing analyses under experimental conditions they complement the insights gained from observational data. An inevitable requirement for a successful trans-species transfer is an abstract but precise high-level characterization of experimental findings. In this work, we provide a large-scale analysis of seven weak contractility/heart failure genotypes of the model organism zebrafish which all share a weak contractility phenotype. In supervised classification experiments, we screen for discriminative patterns that distinguish between observable phenotypes (homozygous mutant individuals) as well as wild-type (homozygous wild-types) and carriers (heterozygous individuals). As the method of choice we use semantic multi-classifier systems, a knowledge-based approach which constructs hypotheses from a predefined vocabulary of high-level terms (e.g., Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways or Gene Ontology (GO) terms). Evaluating these models leads to a compact description of the underlying processes and guides the screening for new molecular markers of heart failure. Furthermore, we were able to independently corroborate the identified processes in Wistar rats.

A Boolean network of the crosstalk between IGF and Wnt signaling in aging satellite cells.

Aging is a complex biological process, which determines the life span of an organism. Insulin-like growth factor (IGF) and Wnt signaling pathways govern the process of aging. Both pathways share common downstream targets that allow competitive crosstalk between these branches. Of note, a shift from IGF to Wnt signaling has been observed during aging of satellite cells. Biological regulatory networks necessary to recreate aging have not yet been discovered. Here, we established a mathematical in silico model that robustly recapitulates the crosstalk between IGF and Wnt signaling. Strikingly, it predicts critical nodes following a shift from IGF to Wnt signaling. These findings indicate that this shift might cause age-related diseases.

Stability of Signaling Pathways during Aging-A Boolean Network Approach.

Biological pathways are thought to be robust against a variety of internal and external perturbations. Fail-safe mechanisms allow for compensation of perturbations to maintain the characteristic function of a pathway. Pathways can undergo changes during aging, which may lead to changes in their stability. Less stable or less robust pathways may be consequential to or increase the susceptibility of the development of diseases. Among others, NF- κ B signaling is a crucial pathway in the process of aging. The NF- κ B system is involved in the immune response and dealing with various internal and external stresses. Boolean networks as models of biological pathways allow for simulation of signaling behavior. They can help to identify which proposed mechanisms are biologically representative and which ones function but do not mirror physical processes-for instance, changes of signaling pathways during the aging process. Boolean networks can be inferred from time-series of gene expression data. This allows us to get insights into the changes of behavior of pathways such as NF- κ B signaling in aged organisms in comparison to young ones.

ViSiBooL-visualization and simulation of Boolean networks with temporal constraints.

Summary: Mathematical models and their simulation are increasingly used to gain insights into cellular pathways and regulatory networks. Dynamics of regulatory factors can be modeled using Boolean networks (BNs), among others. Text-based representations of models are precise descriptions, but hard to understand and interpret. ViSiBooL aims at providing a graphical way of modeling and simulating networks. By providing visualizations of static and dynamic network properties simultaneously, it is possible to directly observe the effects of changes in the network structure on the behavior. In order to address the challenges of clear design and a user-friendly graphical user interface (GUI), ViSiBooL implements visual representations of BNs. Additionally temporal extensions of the BNs for the modeling of regulatory time delays are incorporated. The GUI of ViSiBooL allows to model, organize, simulate and visualize BNs as well as corresponding simulation results such as attractors. Attractor searches are performed in parallel to the modeling process. Hence, changes in the network behavior are visualized at the same time. Availability and Implementation: ViSiBooL (Java 8) is freely available at http://sysbio.uni-ulm.de/?Software:ViSiBooL . Contact: hans.kestler@uni-ulm.de.