Modeling, analyzing and controlling hybrid systems by Guarded Flexible Nets

A number of artificial and natural systems can be modeled as hybrid models in which continuous and discrete variables interact. Such hybrid models are usually challenging to analyze and control due to the computational complexity associated with existing methods. In this paper, the novel modeling formalism of Guarded Flexible Nets (GFNs) is proposed for the modeling, analysis and control of hybrid system. A GFN consists of an event net that determines how the state changes as processes execute, and an intensity net that determines the speeds of the processes. In a GFN, the continuous state is given by the value of its state variables, and the discrete state is given by the region within which such variables lie. GFNs are shown to possess a high modeling power while offering appealing analysis and control possibilities.European Commission through a 7th Framework Program BIOLEDGE Contract No: 289126 to SGO Marie Curie Intra European Fellowship to JJ (FormalBio Contract No: 623995, Call reference: FP7-PEOPLE-2013-IEF). Biotechnology & Biological Sciences Research Council (UK) grant no. BB/N02348X/1 as part of the IBiotech Program, and by the Indus- trial Biotechnology Catalyst (Innovate UK, BBSRC, EPSRC) to support the translation, development and commercialisation of innovative Industrial Biotechnology processes

Modeling, analyzing and controlling hybrid systems by Guarded Flexible Nets

A number of artificial and natural systems can be modeled as hybrid models in which continuous and discrete variables interact. Such hybrid models are usually challenging to analyze and control due to the computational complexity associated with existing methods. In this paper, the novel modeling formalism of Guarded Flexible Nets (GFNs) is proposed for the modeling, analysis and control of hybrid system. A GFN consists of an event net that determines how the state changes as processes execute, and an intensity net that determines the speeds of the processes. In a GFN, the continuous state is given by the value of its state variables, and the discrete state is given by the region within which such variables lie. GFNs are shown to possess a high modeling power while offering appealing analysis and control possibilities

Quantification and compensation of the impact of faults in system throughput

Performability relates the performance (throughput) and reliability of software systems whose normal behaviour may degrade owing to the existence of faults. These systems, naturally modelled as discrete event systems using shared resources, can incorporate fault-tolerant techniques to mitigate such a degradation. In this article, compositional faulttolerant models based on Petri nets, which make its sensitive performability analysis easier, are proposed. Besides, two methods to compensate existence of faults are provided: an iterative algorithm to compute the number of extra resources needed, and an integer-linear programming problem that minimises the cost of incrementing resources and/or decrementing fault-tolerant activities. The applicability of the developed methods is shown on a Petri net that models a secure database system. Keywords Performability, fault-tolerant techniques, Petri nets, integer-linear programmin

Hybrid adaptive Petri nets: a conceptual framework for partial fluidization of Petri nets

Petri nets (PNs) constitute a well known family of formalisms for the modeling and analysis ofDiscrete Event Dynamic Systems (DEDS). As most formalisms for discrete event systems, PNssuffer from the state explosion problem, which renders enumerative analysis techniquesunfeasible for large systems. A technique to overcome the problem is to relax integralitycontraints of the discrete PN model, leading to continuous PN. This relaxation highly reducesthe complexity of analysis techniques but may not preserve important properties of theoriginal PN system such as deadlock‐freeness, liveness, reversibility, etc. This work focuses onHybrid Adaptive Petri nets (HAPNs), a Petri net based formalism in which the firing oftransitions is partially relaxed. The transitions of a HAPN can behave in two different modes:continuous mode for high transition workload, and discrete in other case. This way, a HAPN isable to adapt its behaviour to the net workload, it offers the possibility to represent morefaithfully the discrete model and use efficient analysis techniques by behaving as continuouswhen the load is high. Reachability space and the deadlock‐freeness property of hybridadaptive nets is studied in this work

On the Performance Estimation and Resource Optimisation in Process Petri Nets

Many artificial systems can be modeled as discrete dynamic systems in which resources are shared among different tasks. The performance of such systems, which is usually a system requirement, heavily relies on the number and distribution of such resources. The goal of this paper is twofold: first, to design a technique to estimate the steady-state performance of a given system with shared resources, and second, to propose a heuristic strategy to distribute shared resources so that the system performance is enhanced as much as possible. The systems under consideration are assumed to be large systems, such as service-oriented architecture (SOA) systems, and modeled by a particular class of Petri nets (PNs) called process PNs. In order to avoid the state explosion problem inherent to discrete models, the proposed techniques make intensive use of linear programming (LP) problems

Fluid approximation of Petri net models with relatively small populations

Fluidization is an appealing relaxation technique based on the removal of integrality constraints in order to ease the analysis of discrete Petri nets. The result of fluidifying discrete Petri nets are the so called Fluid or Continuous Petri nets. As with any relaxation technique, discrepancies among the behaviours of the discrete and the relaxed model may appear. Moreover, such discrepancies may have a comparatively bigger effect when the population of the system, the marking in Petri net terms, is “relatively” small. This paper proposes two complementary approaches to obtain a better fluid approximation of discrete Petri nets. The first one focuses on untimed systems and is based on the addition of places that are implicit in the untimed discrete system but not in the continuous. The idea is to cut undesired spurious solutions whose existence worsens the fluidization. The second one focuses on a particular situation that can severely affect the quality of fluidization in timed systems. Namely, such a situation arises when the enabling degree of a transition is equal to 1. This last approach aims to alleviate such a state of affairs, which is termed the bound reaching problem, on systems under infinite servers semantics

Integrated human/SARS-CoV-2 metabolic models present novel treatment strategies against COVID-19

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. © 2021 Bannerman et al

Identification of inhibitors targeting ferredoxin-NADP+ reductase from the xanthomonas citri subsp. Citri phytopathogenic bacteria

Ferredoxin-NADP(H) reductases (FNRs) deliver NADPH or low potential one-electron donors to redox-based metabolism in plastids and bacteria. Xanthomonas citri subsp. citri (Xcc) is a Gram-negative bacterium responsible for citrus canker disease that affects commercial citrus crops worldwide. The Xcc fpr gene encodes a bacterial type FNR (XccFPR) that contributes to the bacterial response to oxidative stress conditions, usually found during plant colonization. Therefore, XccFPR is relevant for the pathogen survival and its inhibition might represent a strategy to treat citrus canker. Because of mechanistic and structural differences from plastidic FNRs, XccFPR is also a potential antibacterial target. We have optimized an activity-based high-throughput screening (HTS) assay that identifies XccFPR inhibitors. We selected 43 hits from a chemical library and narrowed them down to the four most promising inhibitors. The antimicrobial effect of these compounds was evaluated on Xcc cultures, finding one with antimicrobial properties. Based on the functional groups of this compound and their geometric arrangement, we identified another three XccFPR inhibitors. Inhibition mechanisms and constants were determined for these four XccFPR inhibitors. Their specificity was also evaluated by studying their effect on the plastidic Anabaena PCC 7119 FNR, finding differences that can become interesting tools to discover Xcc antimicrobials

Proline dehydrogenase from Thermus thermophilus does not discriminate between FAD and FMN as cofactor

Flavoenzymes are versatile biocatalysts containing either FAD or FMN as cofactor. FAD often binds to a Rossmann fold, while FMN prefers a TIM-barrel or flavodoxin-like fold. Proline dehydrogenase is denoted as an exception: it possesses a TIM barrel-like fold while binding FAD. Using a riboflavin auxotrophic Escherichia coli strain and maltose-binding protein as solubility tag, we produced the apoprotein of Thermus thermophilus ProDH (MBP-TtProDH). Remarkably, reconstitution with FAD or FMN revealed that MBP-TtProDH has no preference for either of the two prosthetic groups. Kinetic parameters of both holo forms are similar, as are the dissociation constants for FAD and FMN release. Furthermore, we show that the holo form of MBP-TtProDH, as produced in E. coli TOP10 cells, contains about three times more FMN than FAD. In line with this flavin content, the crystal structure of TtProDH variant ¿ABC, which lacks helices aA, aB and aC, shows no electron density for an AMP moiety of the cofactor. To the best of our knowledge, this is the first example of a flavoenzyme that does not discriminate between FAD and FMN as cofactor. Therefore, classification of TtProDH as an FAD-binding enzyme should be reconsidered

Current perspectives on the use of anti-VEGF drugs as adjuvant therapy in glaucoma

The approval of one of the first anti-vascular endothelial growth factor (VEGF) agents for the treatment of neovascular age-related macular degeneration one decade ago marked the beginning of a new era in the management of several sight-threatening retinal diseases. Since then, emerging evidence has demonstrated the utility of these therapies for the treatment of other ocular conditions characterized by elevated VEGF levels. In this article we review current perspectives on the use of anti-VEGF drugs as adjuvant therapy in the management of neovascular glaucoma (NVG). The use of anti-VEGFs for modifying wound healing in glaucoma filtration surgery (GFS) is also reviewed. Selected studies investigating the use of anti-VEGF agents or antimetabolites in GFS or the management of NVG have demonstrated that these agents can improve surgical outcomes. However, anti-VEGF agents have yet to demonstrate specific advantages over the more established agents commonly used today. Further studies are needed to evaluate the duration of action, dosing intervals, and toxicity profile of these treatments