Deterministic and stochastic P systems for modelling cellular processes

This paper presents two approaches based on metabolic and stochastic P systems, together with their associated analysis methods, for modelling biological sys- tems and illustrates their use through two case studies.Kingdom's Engineering and Physical Sciences Research Council EP/ E017215/1Biotechnology and Biological Sciences Research Council/United Kingdom BB/D019613/1Biotechnology and Biological Sciences Research Council/United Kingdom BB/F01855X/

Probabilistic Guarded P Systems, A New Formal Modelling Framework

Multienvironment P systems constitute a general, formal framework for modelling the dynamics of population biology, which consists of two main approaches: stochastic and probabilistic. The framework has been successfully used to model biologic systems at both micro (e.g. bacteria colony) and macro (e.g. real ecosystems) levels, respectively. In this paper, we extend the general framework in order to include a new case study related to P. Oleracea species. The extension is made by a new variant within the probabilistic approach, called Probabilistic Guarded P systems (in short, PGP systems). We provide a formal definition, a simulation algorithm to capture the dynamics, and a survey of the associated software.Ministerio de Economía y Competitividad TIN2012- 37434Junta de Andalucía P08-TIC-0420

Process Algebra with Layers: Multi-scale Integration Modelling applied to Cancer Therapy

We present a novel Process Algebra designed for multi-scale integration modelling: Process Algebra with Layers (PAL). The unique feature of PAL is the modularisation of scale into integrated layers: Object and Population. An Object can represent a molecule, organelle, cell, tissue, organ or any organism. Populations hold specific types of Object, for example, life stages, cell phases and infectious states. The syntax and semantics of this novel language are presented. A PAL model of the multi-scale system of cell growth and damage from cancer treatment is given. This model allows the analysis of different scales of the system. The Object and Population levels give insight into the length of a cell cycle and cell population growth respectively. The PAL model results are compared to wet laboratory survival fractions of cells given different doses of radiation treatment [1]. This comparison shows how PAL can be used to aid in investigations of cancer treatment in systems biology

Evolving cell models for systems and synthetic biology

This paper proposes a new methodology for the automated design of cell models for systems and synthetic biology. Our modelling framework is based on P systems, a discrete, stochastic and modular formal modelling language. The automated design of biological models comprising the optimization of the model structure and its stochastic kinetic constants is performed using an evolutionary algorithm. The evolutionary algorithm evolves model structures by combining different modules taken from a predefined module library and then it fine-tunes the associated stochastic kinetic constants. We investigate four alternative objective functions for the fitness calculation within the evolutionary algorithm: (1) equally weighted sum method, (2) normalization method, (3) randomly weighted sum method, and (4) equally weighted product method. The effectiveness of the methodology is tested on four case studies of increasing complexity including negative and positive autoregulation as well as two gene networks implementing a pulse generator and a bandwidth detector. We provide a systematic analysis of the evolutionary algorithm’s results as well as of the resulting evolved cell models

Membrane Computing as a Modelling Tool: Looking Back and Forward from Sevilla

This paper is a tribute to Prof. Mario de Jesús Pérez- Jiménez. An overview of modelling applications in membrane computing has been compiled, trying to narrate it from a historical perspective and including numerous bibliographical references. Since being exhaustive was obviously out of scope, this quick tour on almost two decades of applications is biased, paying special attention to the contributions in which Prof. Pérez-Jiménez and members of his research group were involved.Ministerio de Economía y Competitividad TIN2017-89842-

A membrane computing simulator of trans-hierarchical antibiotic resistance evolution dynamics in nested ecological compartments (ARES)

In this article, we introduce ARES (Antibiotic Resistance Evolution Simulator) a software device that simulates P-system model scenarios with five types of nested computing membranes oriented to emulate a hierarchy of eco-biological compartments, i.e. a) peripheral ecosystem; b) local environment; c) reservoir of supplies; d) animal host; and e) host's associated bacterial organisms (microbiome). Computational objects emulating molecular entities such as plasmids, antibiotic resistance genes, antimicrobials, and/or other substances can be introduced into this framework and may interact and evolve together with the membranes, according to a set of pre-established rules and specifications. ARES has been implemented as an online server and offers additional tools for storage and model editing and downstream analysisThis work has also been supported by grants BFU2012-39816-C02-01 (co-financed by FEDER funds and the Ministry of Economy and Competitiveness, Spain) to AL and Prometeo/2009/092 (Ministry of Education, Government of Valencia, Spain) and Explora Ciencia y Explora Tecnologia/SAF2013-49788-EXP (Spanish Ministry of Economy and Competitiveness) to AM. IRF is recipient of a "Sara Borrell" postdoctoral fellowship (Ref. CD12/00492) from the Ministry of Economy and Competitiveness (Spain). We are also grateful to the Spanish Network for the Study of Plasmids and Extrachromosomal Elements (REDEEX) for encouraging and funding cooperation among Spanish microbiologists working on the biology of mobile genetic elements (Spanish Ministry of Science and Innovation, reference number BFU2011-14145-E).Campos Frances, M.; Llorens, C.; Sempere Luna, JM.; Futami, R.; Rodríguez, I.; Carrasco, P.; Capilla, R.... (2015). A membrane computing simulator of trans-hierarchical antibiotic resistance evolution dynamics in nested ecological compartments (ARES). Biology Direct. 10(41):1-13. https://doi.org/10.1186/s13062-015-0070-9S1131041Baquero F, Coque TM, Canton R. Counteracting antibiotic resistance: breaking barriers among antibacterial strategies. Expert Opin Ther Targets. 2014;18:851–61.Baquero F, Lanza VF, Canton R, Coque TM. Public health evolutionary biology of antimicrobial resistance: priorities for intervention. Evol Appl. 2014;8:223–39.Baquero F, Coque TM, de la Cruz F. Ecology and evolution as targets: the need for novel eco-evo drugs and strategies to fight antibiotic resistance. Antimicrob Agents Chemother. 2011;55:3649–60.Carlet J, Jarlier V, Harbarth S, Voss A, Goossens H, Pittet D, et al. Ready for a world without antibiotics? The pensieres antibiotic resistance call to action. Antimicrob Resist Infect Control. 2012;1:11.Laxminarayan R, Duse A, Wattal C, Zaidi AK, Wertheim HF, Sumpradit N, et al. Antibiotic resistance-the need for global solutions. Lancet Infect Dis. 2013;13:1057–98.G8-Science-Ministers-Statement. 2013. https://www.gov.uk/government/news/g8-science-ministers-statement .Levy SB, Marshall B. Antibacterial resistance worldwide: causes, challenges and responses. Nat Med. 2004;10:S122–9.Wellington EM, Boxall AB, Cross P, Feil EJ, Gaze WH, Hawkey PM, et al. The role of the natural environment in the emergence of antibiotic resistance in gram-negative bacteria. Lancet Infect Dis. 2013;13:155–65.Marshall BM, Levy SB. Food animals and antimicrobials: impacts on human health. Clin Microbiol Rev. 2011;24:718–33.Marshall BM, Ochieng DJ, Levy SB. Commensals: underappreciated reservoir of antibiotic resistance. Microbe. 2009;4:231–8.Forsberg KJ, Reyes A, Wang B, Selleck EM, Sommer MO, Dantas G. The shared antibiotic resistome of soil bacteria and human pathogens. Science. 2012;337:1107–11.Heuer H, Schmitt H, Smalla K. Antibiotic resistance gene spread due to manure application on agricultural fields. Curr Opin Microbiol. 2011;14:236–43.Teillant A, Laxminarayan R. Economics of Antibiotic Use in U.S. Swine and Poultry Production. Choices. 2015;30:1. 1st Quarter 2015.ANTIBIOTIC RESISTANCE THREATS in the United States. http://www.cdc.gov/drugresistance/threat-report-2013/pdf/ar-threats-2013-508.pdf .Gillings MR. Evolutionary consequences of antibiotic use for the resistome, mobilome and microbial pangenome. Front Microbiol. 2013;4:4.Davies J, Davies D. Origins and evolution of antibiotic resistance. Microbiol Mol Biol Rev. 2010;74:417–33.Palmer AC, Kishony R. Understanding, predicting and manipulating the genotypic evolution of antibiotic resistance. Nat Rev Genet. 2013;14:243–8.Baquero F, Tedim AP, Coque TM. Antibiotic resistance shaping multi-level population biology of bacteria. Front Microbiol. 2013;4:15.Partridge SR. Analysis of antibiotic resistance regions in Gram-negative bacteria. FEMS Microbiol Rev. 2011;35:820–55.Baquero F, Coque TM. Multilevel population genetics in antibiotic resistance. FEMS Microbiol Rev. 2011;35:705–6.Martinez JL, Baquero F, Andersson DI. Predicting antibiotic resistance. Nat Rev Microbiol. 2007;5:958–65.Martinez JL, Baquero F. Emergence and spread of antibiotic resistance: setting a parameter space. Upsala Journal of Medical Sciences. Upsala J Med Sci. 2014, Early Online: 1–10, doi: 10.3109/03009734.2014.901444 ).Baquero F, Nombela C. The microbiome as a human organ. Clin Microbiol Infect. 2012;18 Suppl 4:2–4.Kumsa B, Socolovschi C, Parola P, Rolain JM, Raoult D. Molecular detection of Acinetobacter species in lice and keds of domestic animals in Oromia Regional State. Ethiopia PLoS One. 2012;7:e52377.Ahmad A, Ghosh A, Schal C, Zurek L. Insects in confined swine operations carry a large antibiotic resistant and potentially virulent enterococcal community. BMC Microbiol. 2011;11:23.Graczyk TK, Knight R, Gilman RH, Cranfield MR. The role of non-biting flies in the epidemiology of human infectious diseases. Microbes Infect. 2001;3:231–5.Limoee M, Enayati AA, Khassi K, Salimi M, Ladonni H. Insecticide resistance and synergism of three field-collected strains of the German cockroach Blattella germanica (L.) (Dictyoptera: Blattellidae) from hospitals in Kermanshah, Iran. Trop Biomed. 2011;28:111–8.Salehzadeha A, Tavacolb P, Mahjubc H. Bacterial, fungal and parasitic contamination of cockroaches in public hospitals of Hamadan, Iran. J Vect Borne Dis. 2007;44:105–10.Akinjogunla OJ, Odeyemi AT, Udoinyang EP. Cockroaches (periplaneta americana and blattella germanica): reservoirs of multi drug resistant (MDR) bacteria in Uyo, Akwa Ibom State. Scientific J Biol Sci. 2012;1:19–30.Mideo N, Alizon S, Day T. Linking within- and between-host dynamics in the evolutionary epidemiology of infectious diseases. Trends Ecol Evol. 2008;23:511–7.Gillings MR, Stokes HW. Are humans increasing bacterial evolvability? Trends EcolEvol. 2012;27:346–52.Baquero F. Environmental stress and evolvability in microbial systems. Clin Microbiol Infect. 2009;15 Suppl 1:5–10.Paun G, Rozemberg G, Salomaa A. The Oxford Handbook of Membrane Computing. Oxford, London. Oxford University Press. 2010.Paun G. Membrane Computing. An Introduction. Berlin, Heidelberg. Springer-Verlag GmbH. 2002.Paun G. Computing with membranes. J Comput Syst Sci. 2000;61:108–43.Fontana F, Biancom L, Manca V. P systems and the modeling of biochemical oscillations. Lect Notes Comput Sci. 2006;3850:199–208.Cheruku S, Paun A, Romero-Campero FJ, Perez-Jimenez MJ, Ibarra OH. Simulating FAS-induced apoptosis by using P systems. Prog Nat Sci. 2007;4:424–31.Perez-Jimenez MJ, Romero-Campero FJ. P systems, a new computational modelling tool for systems biology. Transactions on computational systems. Lect N Bioinformat. 2006;Biology VI:176–97.Romero-Campero FJ, Perez-Jimenez MJ. Modelling gene expression control using P systems: The Lac Operon, a case study. Biosystems. 2008;91:438–57.Romero-Campero FJ, Perez-Jimenez MJ. A model of the quorum sensing system in Vibrio fischeri using P systems. Artif Life. 2008;14:95–109.Besozzi D, Cazzaniga P, Pescini D, Mauri G. Modelling metapopulations with stochastic membrane systems. Biosystems. 2008;91:499–514.Cardona M, Colomer MA, Perez-Jimenez MJ, Sanuy D, Margalida A. Modelling ecosystems using P Systems: The Bearded Vulture, a case of study. Lect Notes Comput Sci. 2009;5391:137–56.Cardona M, Colomer MA, Margalida A, Perez-Hurtado I, Perez-Jimenez MJ, Sanuy D. A P system based model of an ecosystem of some scavenger birds. Lect Notes Comput Sci. 2010;5957:182–95.Frisco P, Gheorghe M, Perez-Jimenez M. Applications of Membrane Computing in Systems and Synthetic biology. Cham. Springer International Publishing. 2014.Membrane Computing Community. http://ppage.psystems.eu .P-Lingua. http://www.p-lingua.org/wiki/index.php/Main_Page .Llorens C, Futami R, Covelli L, Dominguez-Escriba L, Viu JM, Tamarit D, et al. The Gypsy Database (GyDB) of mobile genetic elements: release 2.0. Nucleic Acids Res. 2011;39:D70–4.Baquero F. From pieces to patterns: evolutionary engineering in bacterial pathogens. Nat Rev Microbiol. 2004;2:510–8.Java. http://www.java.com .Garcia-Quismondo M, Gutierrez-Escudero R, Martinez-del-Amor MA, Orejuela-Pinedo E, Pérez-Hurtado I. P-Lingua 2.0: a software framework for cell-like P systems. Int J Comput Commun. 2009;IV:234.R programming language. http://www.r-project.org .Maciel A, Sankaranarayanan G, Halic T, Arikatla VS, Lu Z, De S. Surgical model-view-controller simulation software framework for local and collaborative applications. Int J Comput Assist Radiol Surg. 2011;6:457–71.Dethlefsen L, McFall-Ngai M, Relman DA. An ecological and evolutionary perspective on human-microbe mutualism and disease. Nature. 2007;449:811–8.Ley RE, Lozupone CA, Hamady M, Knight R, Gordon JI. Worlds within worlds: evolution of the vertebrate gut microbiota. Nat Rev Microbiol. 2008;6:776–88.Pallen MJ, Wren BW. Bacterial pathogenomics. Nature. 2007;449:835–42.Carrasco P, Perez-Cobas AE, Van de Pol C, Baixeras J, Moya A, Latorre A. Succession of the gut microbiota in the cockroach Blattella germanica. Int Microbiol. 2014;17:99–109

Extended simulation and verification platform for kernel P systems

NoKernel P systems integrate in a coherent and elegant manner many of the features of different P system variants, successfully used for modelling various applications. In this paper, we present our initial attempt to extend the software framework developed to support kernel P systems: a formal verification tool based on the NuSMV model checker and a large scale simulation environment based on FLAME. The use of these two tools for modelling and analysis of biological systems is illustrated with a synthetic biology example