BioModels—15 years of sharing computational models in life science

Computational modelling has become increasingly common in life science research. To provide a platform to support universal sharing, easy accessibility and model reproducibility, BioModels (https://www.ebi.ac.uk/biomodels/), a repository for mathematical models, was established in 2005. The current BioModels platform allows submission of models encoded in diverse modelling formats, including SBML, CellML, PharmML, COMBINE archive, MATLAB, Mathematica, R, Python or C++. The models submitted to BioModels are curated to verify the computational representation of the biological process and the reproducibility of the simulation results in the reference publication. The curation also involves encoding models in standard formats and annotation with controlled vocabularies following MIRIAM (minimal information required in the annotation of biochemical models) guidelines. BioModels now accepts large-scale submission of auto-generated computational models. With gradual growth in content over 15 years, BioModels currently hosts about 2000 models from the published literature. With about 800 curated models, BioModels has become the world’s largest repository of curated models and emerged as the third most used data resource after PubMed and Google Scholar among the scientists who use modelling in their research. Thus, BioModels benefits modellers by providing access to reliable and semantically enriched curated models in standard formats that are easy to share, reproduce and reuse

The Scientific Foundations of Forecasting Magnetospheric Space Weather

The magnetosphere is the lens through which solar space weather phenomena are focused and directed towards the Earth. In particular, the non-linear interaction of the solar wind with the Earth's magnetic field leads to the formation of highly inhomogenous electrical currents in the ionosphere which can ultimately result in damage to and problems with the operation of power distribution networks. Since electric power is the fundamental cornerstone of modern life, the interruption of power is the primary pathway by which space weather has impact on human activity and technology. Consequently, in the context of space weather, it is the ability to predict geomagnetic activity that is of key importance. This is usually stated in terms of geomagnetic storms, but we argue that in fact it is the substorm phenomenon which contains the crucial physics, and therefore prediction of substorm occurrence, severity and duration, either within the context of a longer-lasting geomagnetic storm, but potentially also as an isolated event, is of critical importance. Here we review the physics of the magnetosphere in the frame of space weather forecasting, focusing on recent results, current understanding, and an assessment of probable future developments.Peer reviewe

BNC1 IS A KEY REGULATOR OF HUMAN EPICARDIAL HETEROGENEITY AND FUNCTION

The epicardium is a transcriptionally heterogeneous cell layer covering the heart, crucial to correct cardiovascular development. Following epithelial-to-mesenchymal transition (EMT), epicardial cells migrate into myocardium, form coronary smooth muscle cells and cardiac fibroblasts, and instruct cardiomyocytes to proliferate and mature. Adult mammalian epicardium is quiescent, but reactivates post-injury with limited effect. However, in zebrafish and in neonatal mouse, epicardial signalling enables robust cardiac regeneration after myocardial infarction. We hypothesise that manipulating human epicardial function could facilitate heart regeneration, via reactivation of embryonic processes. However, epicardial regulation remains incompletely understood; although understanding epicardial mechanisms could be key to potentially manipulating epicardium for therapeutic benefit. This PhD investigates a candidate transcription factor, Basonuclin 1 (BNC1), in functional regulation of human epicardial models, and identifies this gene as a potential key human epicardial regulator. Epicardial-like cells derived from human pluripotent stem cells (hPSC-epi) were previously used for single-cell RNA sequencing (scRNA-seq) in order to investigate possible human epicardial heterogeneity. This identified two distinct hPSC-epi subpopulations: one high in WT1 expression, the other high in TCF21. Bioinformatic analyses identified BNC1 as a potential key node in the hPSC-epi signalling network, via network inference modelling. BNC1 is a transcription factor known to regulate migration and proliferation in other epithelia. Given our network inference analyses and the literature evidence, I hypothesised that BNC1 would have functional relevance in human epicardium, so aimed to investigate its function in hPSC-epi differentiation and epicardial cell migration, as well as identify its putative epicardial targets. Firstly, scRNA-seq data describing hPSC-epi heterogeneity were validated in primary human foetal epicardium and BNC1 expression was confirmed in human epicardial models. BNC1 was subsequently investigated, both by siRNA-knockdown in hPSC-epi and foetal epicardial explants and inducible knockdown cell lines (siKD). siKD hPSC-epi had over 90% BNC1 reduction and displayed significantly altered expression of canonical epicardial genes WT1 and TCF21: hPSC-epi heterogeneity was thereby lost. Altered hPSC-epi proliferation and viability were also observed. siKD hPSC-epi was subsequently used in a simple epicardial EMT model (epi-EMT). siKD epi-EMT displayed impaired migration and pronounced cortical actin localisation. ChIP sequencing and bulk RNA sequencing identified potentially promising BNC1 targets, such as actin-binding protein supervillin, for future investigation. We conclude that BNC1 is a key functional epicardial regulator in vitro, paving the way for in vivo characterisation. The knowledge that manipulating BNC1 regulates epicardial heterogeneity and function may instruct efforts to harness epicardial potential for future therapeutic benefit.The British Heart Foundation fully funded this doctorat

Toward Community Standards and Software for Whole-Cell Modeling

OBJECTIVE: Whole-cell (WC) modeling is a promising tool for biological research, bioengineering, and medicine. However, substantial work remains to create accurate comprehensive models of complex cells. METHODS: We organized the 2015 Whole-Cell Modeling Summer School to teach WC modeling and evaluate the need for new WC modeling standards and software by recoding a recently published WC model in the Systems Biology Markup Language. RESULTS: Our analysis revealed several challenges to representing WC models using the current standards. CONCLUSION: We, therefore, propose several new WC modeling standards, software, and databases. SIGNIFICANCE: We anticipate that these new standards and software will enable more comprehensive models