Computational models are often employed in systems biology to study the dynamic behaviours of complex systems. With the rise in the number of computational models, finding ways to improve the reusability of these models and their ability to reproduce virtual experiments becomes critical. Correct and effective model annotation in community-supported and standardised formats is necessary for this improvement. Here, we present recent efforts toward a common framework for annotated, accessible, reproducible and interoperable computational models in biology, and discuss key challenges of the field.

Abstract Summary The Community of Special Interest (COSI) in Computational Modelling of Biological Systems (SysMod) brings together interdisciplinary scientists interested in combining data-driven computational modelling, multi-scale mechanistic frameworks, large-scale -omics data and bioinformatics. SysMod’s main activity is an annual meeting at the Intelligent Systems for Molecular Biology (ISMB) conference, a meeting for computer scientists, biologists, mathematicians, engineers and computational and systems biologists. The 2021 SysMod meeting was conducted virtually due to the ongoing COVID-19 pandemic (coronavirus disease 2019). During the 2-day meeting, the development of computational tools, approaches and predictive models was discussed, along with their application to biological systems, emphasizing disease mechanisms. This report summarizes the meeting. Availability and implementation All resources and further information are freely accessible at https://sysmod.info.

Rheumatoid Arthritis (RA) is an autoimmune disease characterized by a highly invasive pannus formation consisting mainly of Synovial Fibroblasts (RASFs). This pannus leads to cartilage, bone, and soft tissue destruction in the affected joint. RASFs' activation is associated with metabolic alterations resulting from dysregulation of extracellular signals' transduction and gene regulation. Deciphering the intricate mechanisms at the origin of this metabolic reprogramming may provide significant insight into RASFs' involvement in RA's pathogenesis and offer new therapeutic strategies. Qualitative and quantitative dynamic modeling can address some of these features, but hybrid models represent a real asset in their ability to span multiple layers of biological machinery. This work presents the first hybrid RASF model: the combination of a cell-specific qualitative regulatory network with a global metabolic network. The automated framework for hybrid modeling exploits the regulatory network's trap-spaces as additional constraints on the metabolic network. Subsequent flux balance analysis allows assessment of RASFs' regulatory outcomes' impact on their metabolic flux distribution. The hybrid RASF model reproduces the experimentally observed metabolic reprogramming induced by signaling and gene regulation in RASFs. Simulations also enable further hypotheses on the potential reverse Warburg effect in RA. RASFs may undergo metabolic reprogramming to turn into "metabolic factories", producing high levels of energy-rich fuels and nutrients for neighboring demanding cells through the crucial role of HIF1.

Mechanistic computational models enable the study of regulatory mechanisms implicated in various biological processes. These models provide a means to analyze the dynamics of the systems they describe, and to study and interrogate their properties, and provide insights about the emerging behavior of the system in the presence of single or combined perturbations. Aimed at those who are new to computational modeling, we present here a practical hands-on protocol breaking down the process of mechanistic modeling of biological systems in a succession of precise steps. The protocol provides a framework that includes defining the model scope, choosing validation criteria, selecting the appropriate modeling approach, constructing a model and simulating the model. To ensure broad accessibility of the protocol, we use a logical modeling framework, which presents a lower mathematical barrier of entry, and two easy-to-use and popular modeling software tools: Cell Collective and GINsim. The complete modeling workflow is applied to a well-studied and familiar biological process-the lac operon regulatory system. The protocol can be completed by users with little to no prior computational modeling experience approximately within 3 h.

The fast accumulation of biological data calls for their integration, analysis and exploitation through more systematic approaches. The generation of novel, relevant hypotheses from this enormous quantity of data remains challenging. Logical models have long been used to answer a variety of questions regarding the dynamical behaviours of regulatory networks. As the number of published logical models increases, there is a pressing need for systematic model annotation, referencing and curation in community-supported and standardised formats. This article summarises the key topics and future directions of a meeting entitled 'Annotation and curation of computational models in biology', organised as part of the 2019 [BC]2 conference. The purpose of the meeting was to develop and drive forward a plan towards the standardised annotation of logical models, review and connect various ongoing projects of experts from different communities involved in the modelling and annotation of molecular biological entities, interactions, pathways and models. This article defines a roadmap towards the annotation and curation of logical models, including milestones for best practices and minimum standard requirements.

Causal molecular interactions represent key building blocks used in computational modeling, where they facilitate the assembly of regulatory networks. Logical regulatory networks can be used to predict biological and cellular behaviors by system perturbations and in silico simulations. Today, broad sets of causal interactions are available in a variety of biological knowledge resources. However, different visions, based on distinct biological interests, have led to the development of multiple ways to describe and annotate causal molecular interactions. It can therefore be challenging to efficiently explore various resources of causal interaction and maintain an overview of recorded contextual information that ensures valid use of the data. This review lists the different types of public resources with causal interactions, the different views on biological processes that they represent, the various data formats they use for data representation and storage, and the data exchange and conversion procedures that are available to extract and download these interactions. This may further raise awareness among the targeted audience, i.e. logical modelers and other scientists interested in molecular causal interactions, but also database managers and curators, about the abundance and variety of causal molecular interaction data, and the variety of tools and approaches to convert them into one interoperable resource.

Computational models of biological systems can exploit a broad range of rapidly developing approaches, including novel experimental approaches, bioinformatics data analysis, emerging modelling paradigms, data standards and algorithms. A discussion about the most recent advances among experts from various domains is crucial to foster data-driven computational modelling and its growing use in assessing and predicting the behaviour of biological systems. Intending to encourage the development of tools, approaches and predictive models, and to deepen our understanding of biological systems, the Community of Special Interest (COSI) was launched in Computational Modelling of Biological Systems (SysMod) in 2016. SysMod's main activity is an annual meeting at the Intelligent Systems for Molecular Biology (ISMB) conference, which brings together computer scientists, biologists, mathematicians, engineers, computational and systems biologists. In the five years since its inception, SysMod has evolved into a dynamic and expanding community, as the increasing number of contributions and participants illustrate. SysMod maintains several online resources to facilitate interaction among the community members, including an online forum, a calendar of relevant meetings and a YouTube channel with talks and lectures of interest for the modelling community. For more than half a decade, the growing interest in computational systems modelling and multi-scale data integration has inspired and supported the SysMod community. Its members get progressively more involved and actively contribute to the annual COSI meeting and several related community workshops and meetings, focusing on specific topics, including particular techniques for computational modelling or standardisation efforts.

MOTIVATION: Molecular interaction maps have emerged as a meaningful way of representing biological mechanisms in a comprehensive and systematic manner. However, their static nature provides limited insights to the emerging behaviour of the described biological system under different conditions. Computational modelling provides the means to study dynamic properties through in silico simulations and perturbations. We aim to bridge the gap between static and dynamic representations of biological systems with CaSQ, a software tool that infers Boolean rules based on the topology and semantics of molecular interaction maps built with CellDesigner. RESULTS: We developed CaSQ by defining conversion rules and logical formulas for inferred Boolean models according to the topology and the annotations of the starting molecular interaction maps. We used CaSQ to produce executable files of existing molecular maps that differ in size, complexity and the use of Systems Biology Graphical Notation (SBGN) standards. We also compared, where possible, the manually built logical models corresponding to a molecular map to the ones inferred by CaSQ. The tool is able to process large and complex maps built with CellDesigner (either following SBGN standards or not) and produce Boolean models in a standard output format, Systems Biology Marked Up Language-qualitative (SBML-qual), that can be further analyzed using popular modelling tools. References, annotations and layout of the CellDesigner molecular map are retained in the obtained model, facilitating interoperability and model reusability. AVAILABILITY AND IMPLEMENTATION: The present tool is available online: https://lifeware.inria.fr/∼soliman/post/casq/ and distributed as a Python package under the GNU GPLv3 license. The code can be accessed here: https://gitlab.inria.fr/soliman/casq. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

The Disease Maps Project builds on a network of scientific and clinical groups that exchange best practices, share information and develop systems biomedicine tools. The project aims for an integrated, highly curated and user-friendly platform for disease-related knowledge. The primary focus of disease maps is on interconnected signaling, metabolic and gene regulatory network pathways represented in standard formats. The involvement of domain experts ensures that the key disease hallmarks are covered and relevant, up-to-date knowledge is adequately represented. Expert-curated and computer readable, disease maps may serve as a compendium of knowledge, allow for data-supported hypothesis generation or serve as a scaffold for the generation of predictive mathematical models. This article summarizes the 2nd Disease Maps Community meeting, highlighting its important topics and outcomes. We outline milestones on the roadmap for the future development of disease maps, including creating and maintaining standardized disease maps; sharing parts of maps that encode common human disease mechanisms; providing technical solutions for complexity management of maps; and Web tools for in-depth exploration of such maps. A dedicated discussion was focused on mathematical modeling approaches, as one of the main goals of disease map development is the generation of mathematically interpretable representations to predict disease comorbidity or drug response and to suggest drug repositioning, altogether supporting clinical decisions.