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As a preliminary overview, this work provides first a broad tutorial on the fluidization of discrete event dynamic models, an efficient technique for dealing with the classical state explosion problem. Even if named as continuous or fluid, the relaxed models obtained are frequently hybrid in a technical sense. Thus, there is plenty of room for using discrete, hybrid and continuous model techniques for logical verification, performance evaluation and control studies. Moreover, the possibilities for transferring concepts and techniques from one modeling paradigm to others are very significant, so there is much space for synergy. As a central modeling paradigm for parallel and synchronized discrete event systems, Petri nets (PNs) are then considered in much more detail. In this sense, this paper is somewhat complementary to David and Alla (2010). Our presentation of fluid views or approximations of PNs has sometimes a flavor of a survey, but also introduces some new ideas or techniques. Among the aspects that distinguish the adopted approach are: the focus on the relationships between discrete and continuous PN models, both for untimed, i.e., fully non-deterministic abstractions, and timed versions; the use of structure theory of (discrete) PNs, algebraic and graph based concepts and results; and the bridge to Automatic Control Theory. After discussing observability and controllability issues, the most technical part in this work, the paper concludes with some remarks and possible directions for future research.

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In this paper we introduce a class of continuous-time hybrid dynamical systems called integral continuous-time hybrid automata (icHA) for which we propose an event-driven optimization-based control strategy. Events include both external actions applied to the system and changes of continuous dynamics (mode switches). The icHA formalism subsumes a number of hybrid dynamical systems with practical interest, e.g., linear hybrid automata. Different cost functions, including minimum-time and minimum-effort criteria, and constraints are examined in the event-driven optimal control formulation. This is translated into a finite-dimensional mixed-integer optimization problem, in which the event instants and the corresponding values of the control input are the optimization variables. As a consequence, the proposed approach has the advantage of automatically adjusting the attention of the controller to the frequency of event occurrence in the hybrid process. A receding horizon control scheme exploiting the event-based optimal control formulation is proposed as a feedback control strategy and proved to ensure either finite-time or asymptotic convergence of the closed-loop.

Mathematical models that combine predictive accuracy with explanatory power are central to the progress of systems and synthetic biology, but the heterogeneity and incompleteness of biological data impede our ability to construct such models. Furthermore, the robustness displayed by many biological systems means that they have the flexibility to operate under a range of physiological conditions and this is difficult for many modeling formalisms to handle. Flexible nets (FNs) address these challenges and represent a paradigm shift in model-based analysis of biological systems. FNs can: (i) handle uncertainties, ranges and missing information in concentrations, stoichiometry, network topology, and transition rates without having to resort to statistical approaches; (ii) accommodate different types of data in a unified model that integrates various cellular mechanisms; and (iii) be employed for system optimization and model predictive control. We present FNs and illustrate their capabilities by modeling a well-established system, the dynamics of glucose consumption by a microbial population. We further demonstrate the ability of FNs to take control actions in response to genetic or metabolic perturbations. Having bench-marked the system, we then construct the first quantitative model for Wilson disease—a rare genetic disorder that impairs copper utilization in the liver. We used this model to investigate the feasibility of using vitamin E supplementation therapy for symptomatic improvement. Our results indicate that hepatocytic inflammation caused by copper accumulation was not aggravated by limitations on endogenous antioxidant supplies, which means that treating patients with antioxidants is unlikely to be effective.

The coronavirus disease 2019 (COVID-19) pandemic caused by the new coronavirus (SARS-CoV-2) is currently responsible for more than 3 million deaths in 219 countries across the world and with more than 140 million cases. The absence of FDA-approved drugs against SARS-CoV-2 has highlighted an urgent need to design new drugs. We developed an integrated model of the human cell and SARS-CoV-2 to provide insight into the virus’ pathogenic mechanism and support current therapeutic strategies. We show the biochemical reactions required for the growth and general maintenance of the human cell, first, in its healthy state. We then demonstrate how the entry of SARS-CoV-2 into the human cell causes biochemical and structural changes, leading to a change of cell functions or cell death. A new computational method that predicts 20 unique reactions as drug targets from our models and provides a platform for future studies on viral entry inhibition, immune regulation, and drug optimisation strategies. The model is available in BioModels (https://www.ebi.ac.uk/biomodels/MODEL2007210001) and the software tool, findCPcli, that implements the computational method is available at https://github.com/findCP/findCPcli.

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