We need to effectively combine the knowledge from surging literature with complex datasets to propose mechanistic models of SARS-CoV-2 infection, improving data interpretation and predicting key targets of intervention. Here, we describe a large-scale community effort to build an open access, interoperable and computable repository of COVID-19 molecular mechanisms. The COVID-19 Disease Map (C19DMap) is a graphical, interactive representation of disease-relevant molecular mechanisms linking many knowledge sources. Notably, it is a computational resource for graph-based analyses and disease modelling. To this end, we established a framework of tools, platforms and guidelines necessary for a multifaceted community of biocurators, domain experts, bioinformaticians and computational biologists. The diagrams of the C19DMap, curated from the literature, are integrated with relevant interaction and text mining databases. We demonstrate the application of network analysis and modelling approaches by concrete examples to highlight new testable hypotheses. This framework helps to find signatures of SARS-CoV-2 predisposition, treatment response or prioritisation of drug candidates. Such an approach may help deal with new waves of COVID-19 or similar pandemics in the long-term perspective.

Computational modeling constitutes a crucial step toward the functional understanding of complex cellular networks. In particular, logical modeling has proven suitable for the dynamical analysis of large signaling and transcriptional regulatory networks. In this context, signaling input components are generally meant to convey external stimuli, or environmental cues. In response to such external signals, cells acquire specific gene expression patterns modeled in terms of attractors (e.g., stable states).The capacity for cells to alter or reprogram their differentiated states upon changes in environmental conditions is referred to as cell plasticity. In this article, we present a multivalued logical framework along with computational methods recently developed to efficiently analyze large models. We mainly focus on a symbolic model checking approach to investigate switches between attractors subsequent to changes of input conditions. As a case study, we consider the cellular network regulating the differentiation of T-helper (Th) cells, which orchestrate many physiological and pathological immune responses. To account for novel cellular subtypes, we present an extended version of a published model of Th cell differentiation. We then use symbolic model checking to analyze reachability properties between Th subtypes upon changes of environmental cues. This allows for the construction of a synthetic view of Th cell plasticity in terms of a graph connecting subtypes with arcs labeled by input conditions. Finally, we explore novel strategies enabling specificTh cell polarizing or reprograming events.

The logical formalism is well adapted to model large cellular networks, for which detailed kinetic data are scarce. This tutorial focuses on this well-established qualitative framework. Relying on GINsim (release 3.0), a software implementing this formalism, we guide the reader step by step towards the definition, the analysis and the simulation of a four-node model of the mammalian p53-Mdm2 network.

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High-dimensional multi-omics data are now standard in biology. They can greatly enhance our understanding of biological systems when effectively integrated. To achieve this multi-omics data integration, Joint Dimensionality Reduction (jDR) methods are among the most efficient approaches. However, several jDR methods are available, urging the need for a comprehensive benchmark with practical guidelines.We performed a systematic evaluation of nine representative jDR methods using three complementary benchmarks. First, we evaluated their performances in retrieving ground-truth sample clustering from simulated multi-omics datasets. Second, we used TCGA cancer data to assess their strengths in predicting survival, clinical annotations and known pathways/biological processes. Finally, we assessed their classification of multi-omics singlecell data.From these in-depth comparisons, we observed that intNMF performs best in clustering, while MCIA offers a consistent and effective behavior across many contexts. The full code of this benchmark is implemented in a Jupyter notebook -multi-omics mix (momix) -to foster reproducibility, and support data producers, users and future developers.

Summary Quantitative methods for modelling biological networks require an in-depth knowledge of the biochemical reactions and their stoichiometric and kinetic parameters. In many practical cases, this knowledge is missing. This has led to the development of several qualitative modelling methods using information such as, for example, gene expression data coming from functional genomic experiments. The SBML Level 3 Version 1 Core specification does not provide a mechanism for explicitly encoding qualitative models, but it does provide a mechanism for SBML packages to extend the Core specification and add additional syntactical constructs.The SBML Qualitative Models package for SBML Level 3 adds features so that qualitative models can be directly and explicitly encoded. The approach taken in this package is essentially based on the definition of regulatory or influence graphs. The SBML Qualitative Models package defines the structure and syntax necessary to describe qualitative models that associate discrete levels of activities with entity pools and the transitions between states that describe the processes involved. This is particularly suited to logical models (Boolean or multi-valued) and some classes of Petri net models can be encoded with the approach.

Mathematical modeling aims at understanding the effects of biological perturbations, suggesting ways to intervene and to reestablish proper cell functioning in diseases such as cancer or in autoimmune disorders. This is a difficult task for obvious reasons: the level of details needed to describe the intra-cellular processes involved, the numerous interactions between cells and cell types, and the complex dynamical properties of such populations where cells die, divide and interact constantly, to cite a few. Another important difficulty comes from the spatial distribution of these cells, their diffusion and motility. All of these aspects cannot be easily resolved in a unique mathematical model or with a unique formalism. To cope with some of these issues, we introduce here a novel framework, UPMaBoSS (for Update Population MaBoSS), dedicated to modeling dynamic populations of interacting cells. We rely on the preexisting tool MaBoSS, which enables probabilistic simulations of cellular networks. A novel software layer is added to account for cell interactions and population dynamics, but without considering the spatial dimension. This modeling approach can be seen as an intermediate step towards more complex spatial descriptions. We illustrate our methodology by means of a case study dealing with TNF-induced cell death. Interestingly, the simulation of cell population dynamics with UPMaBoSS reveals a mechanism of resistance triggered by TNF treatment. Relatively easy to encode, UPMaBoSS simulations require only moderate computational power and execution time. To ease the reproduction of simulations, we provide several Jupyter notebooks that can be accessed within the CoLoMoTo Docker image, which contains all software and models used for this study.

Here we introduce bioLQM, a new Java software toolkit for the conversion, modification, and analysis of Logical Qualitative Models of biological regulatory networks, aiming to foster the development of novel complementary tools by providing core modelling operations. Based on the definition of multi-valued logical models, it implements import and export facilities, notably for the recent SBML-qual exchange format, as well as for formats used by several popular tools, facilitating the design of workflows combining these tools. Model modifications enable the definition of various perturbations, as well as model reduction, easing the analysis of large models. Another modification enables the study of multi-valued models with tools limited to the Boolean case. Finally, bioLQM provides a framework for the development of novel analysis tools. The current version implements the usual updating modes for model simulation (notably synchronous, asynchronous, and random asynchronous), as well as some static analysis features for the identification of attractors. The bioLQM software can be integrated into analysis workflows through command line and scripting interfaces. As a Java library, it further provides core data structures to the GINsim and EpiLog interactive tools, which supply graphical interfaces and additional analysis methods for cellular and multi-cellular qualitative models.