Identification of Piecewise Linear Models of Complex Dynamical Systems

The paper addresses the realization and identification problem or a subclass of piecewise-affine hybrid systems. The paper provides necessary and sufficient conditions for existence of a realization, a characterization of minimality, and an identification algorithm for this subclass of hybrid systems. The considered system class and the identification problem are motivated by applications in systems biology

Statistical Model Checking for Stochastic Hybrid Systems

This paper presents novel extensions and applications of the UPPAAL-SMC model checker. The extensions allow for statistical model checking of stochastic hybrid systems. We show how our race-based stochastic semantics extends to networks of hybrid systems, and indicate the integration technique applied for implementing this semantics in the UPPAAL-SMC simulation engine. We report on two applications of the resulting tool-set coming from systems biology and energy aware buildings.Comment: In Proceedings HSB 2012, arXiv:1208.315

Natural Variation and Neuromechanical Systems

Natural variation plays an important but subtle and often ignored role in neuromechanical systems. This is especially important when designing for living or hybrid systems \ud which involve a biological or self-assembling component. Accounting for natural variation can be accomplished by taking a population phenomics approach to modeling and analyzing such systems. I will advocate the position that noise in neuromechanical systems is partially represented by natural variation inherent in user physiology. Furthermore, this noise can be augmentative in systems that couple physiological systems with technology. There are several tools and approaches that can be borrowed from computational biology to characterize the populations of users as they interact with the technology. In addition to transplanted approaches, the potential of natural variation can be understood as having a range of effects on both the individual's physiology and function of the living/hybrid system over time. Finally, accounting for natural variation can be put to good use in human-machine system design, as three prescriptions for exploiting variation in design are proposed

Dynamical Properties of a Two-gene Network with Hysteresis

A mathematical model for a two-gene regulatory network is derived and several of their properties analyzed. Due to the presence of mixed continuous/discrete dynamics and hysteresis, we employ a hybrid systems model to capture the dynamics of the system. The proposed model incorporates binary hysteresis with different thresholds capturing the interaction between the genes. We analyze properties of the solutions and asymptotic stability of equilibria in the system as a function of its parameters. Our analysis reveals the presence of limit cycles for a certain range of parameters, behavior that is associated with hysteresis. The set of points defining the limit cycle is characterized and its asymptotic stability properties are studied. Furthermore, the stability property of the limit cycle is robust to small perturbations. Numerical simulations are presented to illustrate the results.Comment: 55 pages, 31 figures.Expanded version of paper in Special Issue on Hybrid Systems and Biology, Elsevier Information and Computation, 201

Hybrid systems biology: application to Escherichia coli

Dissertation presented to obtain a Master degree in BiotechnologyIn complex biological systems, it is unlikely that all relevant cellular functions can be fully described either by a mechanistic (parametric) or by a statistic (nonparametric) modelling approach. Quite often, hybrid semiparametric models are the most appropriate to handle such problems. Hybrid semiparametric systems make simultaneous use of the parametric and nonparametric systems analysis paradigms to solve complex problems. The main advantage of the semiparametric over the parametric or nonparametric frameworks lies in that it broadens the knowledge base that can be used to solve a particular problem, thus avoiding reductionism. In this M.Sc. thesis, a hybrid modelling method was adopted to describe in silico Escherichia coli cells. The method consists in a modified projection to latent structures model that explores elementary flux modes (EFMs) as metabolic network principal components. It maximizes the covariance between measured fluxome and any input “omic” dataset. Additionally this method provides the ranking of EFMs in increasing order of explained flux variance and the identification of correlations between EFMs weighting factors and input variables. When applied to a subset of E. coli transcriptome, metabolome, proteome and envirome (and combinations thereof) datasets from different E. coli strains (both wild-type and single gene knockout strains) the model is able, in general, to make accurate flux predictions. More particularly, the results show that envirome and the combination of envirome and transcriptome are the most appropriate datasets to make an accurate flux prediction (with 88.5% and 85.2% of explained flux variance in the validation partition, respectively). Furthermore, the correlations between EFMs weighting factors and input variables are consistent with previously described regulatory patterns, supporting the idea that the regulation of metabolic functions is conserved among distinct envirome and genotype variants, denoting a high level of modularity of cellular functions

A General Hybrid Modeling Framework for Systems Biology Applications: Combining Mechanistic Knowledge with Deep Neural Networks under the SBML Standard

This work was supported by the Associate Laboratory for Green Chemistry—LAQV which is financed by national funds from FCT/MCTES (UIDB/50006/2020 and UIDP/50006/2020). This work has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement number 870292 (BioICEP project). J.P. acknowledges a PhD grant (SFRD/BD14610472019), Fundação para a Ciência e Tecnologia (FCT) and R.S.C. the contract CEECIND/01399/2017In this paper, a computational framework is proposed that merges mechanistic modeling with deep neural networks obeying the Systems Biology Markup Language (SBML) standard. Over the last 20 years, the systems biology community has developed a large number of mechanistic models that are currently stored in public databases in SBML. With the proposed framework, existing SBML models may be redesigned into hybrid systems through the incorporation of deep neural networks into the model core, using a freely available python tool. The so-formed hybrid mechanistic/neural network models are trained with a deep learning algorithm based on the adaptive moment estimation method (ADAM), stochastic regularization and semidirect sensitivity equations. The trained hybrid models are encoded in SBML and uploaded in model databases, where they may be further analyzed as regular SBML models. This approach is illustrated with three well-known case studies: the Escherichia coli threonine synthesis model, the P58IPK signal transduction model, and the Yeast glycolytic oscillations model. The proposed framework is expected to greatly facilitate the widespread use of hybrid modeling techniques for systems biology applications.publishersversionpublishe

Quantifying cancer epithelial-mesenchymal plasticity and its association with stemness and immune response

Cancer cells can acquire a spectrum of stable hybrid epithelial/mesenchymal (E/M) states during epithelial-mesenchymal transition (EMT). Cells in these hybrid E/M phenotypes often combine epithelial and mesenchymal features and tend to migrate collectively commonly as small clusters. Such collectively migrating cancer cells play a pivotal role in seeding metastases and their presence in cancer patients indicates an adverse prognostic factor. Moreover, cancer cells in hybrid E/M phenotypes tend to be more associated with stemness which endows them with tumor-initiation ability and therapy resistance. Most recently, cells undergoing EMT have been shown to promote immune suppression for better survival. A systematic understanding of the emergence of hybrid E/M phenotypes and the connection of EMT with stemness and immune suppression would contribute to more effective therapeutic strategies. In this review, we first discuss recent efforts combining theoretical and experimental approaches to elucidate mechanisms underlying EMT multi-stability (i.e. the existence of multiple stable phenotypes during EMT) and the properties of hybrid E/M phenotypes. Following we discuss non-cell-autonomous regulation of EMT by cell cooperation and extracellular matrix. Afterwards, we discuss various metrics that can be used to quantify EMT spectrum. We further describe possible mechanisms underlying the formation of clusters of circulating tumor cells. Last but not least, we summarize recent systems biology analysis of the role of EMT in the acquisition of stemness and immune suppression.Comment: 50 pages, 6 figure