Table 1.
Wnt simulation models (as of Feb. 1, 2021) with those included in this study printed in bold.
Fig 1.
Combined overview of all qualitative Wnt (sub-)models found within the 19 Wnt simulation studies.
Depicted are the components (species, compartments, and reactions) of the canonical Wnt signaling pathway (a) and its crosstalk with other signaling pathways (b) found within the 19 Wnt simulation studies. Note that the overview is a simplified and condensed representation. Interactions are simplified and some components of the submodels that do not directly affect the Wnt signaling pathway are omitted. Activated/phosphorylated proteins are indicated by (*). Inactive/unphosphorylated states of proteins have been omitted when possible. Submodels involving membrane-mediated processes, such as receptor/ligand interactions, destruction complex recruitment and endocytosis [31, 45, 51, 56], or cadherin-mediated cell adhesion [34, 39, 49] are incorporated in (a). Submodels involving crosstalk with ERK/FGF/PI3K/Akt [32, 36, 53], Notch [33, 36, 48], and ROS/Dvl-mediated pathways [51, 57] are shown in the lower panels of (b), respectively.
Fig 2.
UML class diagram of provenance entities in WebProv.
We have identified the following entities to be useful for providing provenance information from simulation studies in the field of systems biology: Research Question, Assumption, Requirement, Qualitative Model, Simulation Model, Simulation Experiment, Simulation Data, and Wet-lab Data. The requested information for each entity type is kept minimal for demonstration purposes and can easily be extended. The Study (Reference) contains information of the publication, for instance, “Lee et al. (2003)” and determines which study an entity belongs to. The Description contains a brief explanation of a particular entity and may be a cited text from the publication. Furthermore, entity references should ideally consist of a digital object identifier (DOI) to make the artifact associated with the particular entity unambiguously accessible. Additional information can always be entered in the “Further Information” part of WebProv.
Table 2.
Entities, activities and allowed relations in our PROV-DM specialization.
Fig 3.
Provenance graph of the study by Lee et al. (2003) [28].
Besides the entities and activities that make up the provenance information from the study (see legend), additional entities from three other studies [64–66], which were used by Lee et al. (2003), are shown. The colors of the ellipses show different entity types, the borders of the rectangles visualize different activity types. The gray areas separate the individual studies. The graph displays, for example, that the Building Simulation Model activity BSM1 used, among others, the entity WD1 of type Wet-lab Data from Lee et al. 2001 [64]. This activity then generated the Simulation Model SM1.
Fig 4.
This screenshot shows the provenance graph of the study by Lee et al. (2003) [28] with additional entities from three other studies [64–66], which are automatically colored differently. The node SD2 has been clicked on, which opens a box on the right with the stored and editable metadata.
Fig 5.
Categories of the simulation experiments conducted within the analyzed 19 Wnt signaling studies.
All of these simulation experiments have been categorized. Most simulation experiments were parameter scans.
Fig 6.
Provenance graph of all Wnt/β-catenin simulation studies considered here (black outlines) as well as additionally used studies (gray outlines).
The colors indicate the cell lines used in wet-lab experiments of that study (see legend below graph). Gray boxes represent pure Wnt/β-catenin simulation studies without acquiring wet-lab data. White boxes display publications used by some of the Wnt/β-catenin simulation studies that are either text books or simulation studies without published wet-lab data. The figure was created using the R package DiagrammeR [103]. The references to the additionally used studies are found in S1 Appendix.
Table 3.
Cell lines and organisms used building the simulation models.