Corrado Priami - Böcker

Modeling is fast becoming fundamental to understanding the processes that define biological systems. High-throughput technologies are producing increasing quantities of data that require an ever-expanding toolset for their effective analysis and interpretation. Analysis of high-throughput data in the context of a molecular interaction network is particularly informative as it has the potential to reveal the most relevant network modules with respect to a phenotype or biological process of interest.Analysis of Biological Systems collects classical material on analysis, modeling and simulation, thereby acting as a unique point of reference. The joint application of statistical techniques to extract knowledge from big data and map it into mechanistic models is a current challenge of the field, and the reader will learn how to build and use models even if they have no computing or math background. An in-depth analysis of the currently available technologies, and a comparison between them, is also included. Unlike other reference books, this in-depth analysis is extended even to the field of language-based modeling. The overall result is an indispensable, self-contained and systematic approach to a rapidly expanding field of science.

This Festschrift volume is published in honor of Pierpaolo Degano on the occasion of his 65th birthday and is the outcome of a colloquium held in Pisa, Italy, in June 2015. Pierpaolo Degano has worked on a large variety of topics including formal program semantics, concurrency theory, systems biology and security.The volume contains 22 refereed papers and one extended abstract, including personal memoirs and regular research papers by close collaborators and friends and a laudatio illustrating his distinguished career and his main scientific contributions. The papers deal with the main research topics explored by Pierpaolo Degano and those still under his investigation.

Starting from basic simulation algorithms, the book also introduces more advanced techniques that support delays, diffusion in space, or that are based on hybrid simulation strategies.This is a valuable self-contained resource for graduate students and practitioners in computer science, biology and bioinformatics.

Starting from basic simulation algorithms, the book also introduces more advanced techniques that support delays, diffusion in space, or that are based on hybrid simulation strategies.This is a valuable self-contained resource for graduate students and practitioners in computer science, biology and bioinformatics.

Molecularbiologyhasuntilnowmainlyfocussedonindividualmolecules,on theirpropertiesasisolatedentitiesorascomplexesinverysimplemodelsystems. However,biologicalmoleculesinlivingsystemsparticipateinverycomplexn- works,includingregulatorynetworksforgeneexpression,intracellularmetabolic networksandbothintra-andintercellularcommunicationnetworks. Suchn- worksareinvolvedinthemaintenance(homeostasis)aswellasthedi?erentiation ofcellularsystemsofwhichwehaveaveryincompleteunderstanding. Nevertheless,theprogressinmolecularbiologyhasmadepossiblethedetailed descriptionofthecomponentsthatconstitutelivingsystems,notablygenesand proteins. Large-scalegenomesequencingmeansthatwecan(atleastinpr- ciple)delineateallmacromolecularcomponentsofagivencellularsystem,and microarrayexperimentsaswellaslarge-scaleproteomicswillsoongiveuslarge amountsofexperimentaldataongeneregulation,molecularinteractionsand cellularnetworks. Thechallengeofthe21stcenturywillbetounderstandhow theseindividualcomponentsintegrateintocomplexsystemsandthefunction andevolutionofthesesystems,thusscalingupfrommolecularbiologytos- temsbiology.Bycombiningexperimentaldatawithadvancedformaltheories fromcomputerscience,"theformallanguageforbiologicalsystems"tospecify dynamicmodelsofinteractingmolecularentitieswouldbeessentialfor:(i)- derstandingthenormalbehaviourofcellularprocesses,andhowchangesmay a?ecttheprocessesandcausedisease-itmaybepossibletocorrelategenetic propertiesandsymptomsinnewandmoree?cientways,basedonanactual- derstandingofhowvariousprocessesinteract;(ii)providingpredictabilityand ?exibilitytoacademic,pharmaceutical,biotechnologyandmedicalresearchers studyinggeneorproteinfunctions. Inparticular,itmaysavetimebyreducing thenumberofexperimentsneeded,ifinadequatehypothesescanbeexcludedby computersimulation. Inresponsetothecallforpapers39weresubmittedtoCMSB2003. Allthe submittedpaperswerereviewedandtheprogrammecommittee(listedbelow) selected11high-qualitypapersforpublicationinthisvolume. Thecareofthe reviewersandoftheprogrammecommitteemembersinreviewingthepapers wassurelyvaluable. Afurther11paperswereselectedonlyforpresentationat theworkshopinordertostimulatediscussions(anabstractisincluded). AttheworkshopEhudShapiroandMichaelSterngavetwoinvited talks whosetopicsaredescribedinpapersincludedinthisvolume.Theprogramme committeedecidedtoacceptforpublicationinthisvolumealsosomeposition papers that highlight the research trends in this new ?eld of computational methodsinsystemsbiology. Thereasonisthatbecausethisisthe?rstedition ofaworkshopinthisfast-growing?eldalargeviewofpotentialtopicsofresearch wasconsideredextremelyimportant. Rovereto,December2002 CorradoPriami ProgrammeCommitteeofCMSB 2003 CorradoPriami(Chair),UniversityofTrento(Italy), CharlesAu?ray,CNRS,Villejuif(France), CosimaBaldari,Universit'adiSiena(Italy), AlexanderBockmayr,Universit'eHenriPoincar'e(France), LucaCardelli,MicrosoftResearchCambridge(UK), VincentDanos,Universit'eParisVII(France), PierpaoloDegano,Universitad ' iPisa(Italy), Francois , Fages,INRIA,Rocquencourt(France), DrablosFinn,NorwegianUniversityofScienceandTechnology,Trondheim(N- way), MonikaHeiner,BrandenburgUniversityofTechnologyatCottbus(Germany), InaKoch,UniversityofAppliedSciencesBerlin,(Germany), JohnE.Ladbury,UniversityCollegeLondon(UK), PatrickLincoln,SRI(USA), SatoruMiyano,UniversityofTokyo(Japan), GordonPlotkin,UniversityofEdinburgh(UK), SimonPlyte,PharmaciaCorporation(Italy), AvivRegev,WeizmannInstituteofScience(Israel), MagaliRoux-Rouqui'e,BSMIPasteurInstitute(France), VincentSchachter,HybrigenicsParis(France), MasaruTomita,KeioUniversity(Japan), AdelindeUhrmacher,UniversityofRostock(Germany), AlfonsoValencia,CNB-CSIC,CentroNacionaldeBiotecnologia(Spain), OlafWolkenhauer,UMIST,Manchester(UK) Local Organizing Committee Corrado Priami, Linda Brodo, Michela de Concini, Debora Schuch da Rosa Machado,andtheUniversityofTrentoEventsandMeetingsO?ce. List ofReferees F. Abascal,N. Chabrier,A. Cimatti,M. Curti,M. D. Devignes,S. Gnesi, J. Guijarro,K. Hafez,E. Klipp,C. Laneve,P. LopezRomero,F. Luccio, R. Marangoni,M. Padron,M. C. Pinotti,R. Rizzi,S. Tini. Acknowledgement TheworkshopwassponsoredandpartiallysupportedbytheUniversityofTrento, ComunediRovereto,APT,andtheEUprojectIST-32072-DEGAS. Table of Contents IInvitedPapers CellsasComputation...1 AmitaiRegevandEhudShapiro FormalModelingofC. elegansDevelopment:AScenario-BasedApproach ...4Na'aman Kam,David Harel,Hillel Kugler, RamiMarelly, AmirPnueli, E. JaneAlbertHubbard, andMichael J. Stern IIRegularPapers Causal?-CalculusforBiochemicalModelling ...21 Michele Curti,Pierpaolo Degano, andCosima Tatiana Baldari GraphsforCoreMolecularBiology ...34 Vincent Danos and Cosimo Laneve ContributionofComputationalTreeLogic toBiologicalRegulatoryNetworks: ExamplefromPseudomonasAeruginosa...47 SabinePeresandJean-PaulComet ModelingCellularBehaviorwithHybridAutomata: BisimulationandCollapsing...57 Marco Antoniotti, Bhubaneswar Mishra, Carla Piazza, Alberto Policriti, andMarta Simeoni MultiscaleModelingofAlternativeSplicingRegulation...75 Damien Eveillard, Delphine Ropers,Hidde deJong,Christiane Branlant, andAlexanderBockmayr AMethodforEstimatingMetabolicFluxes fromIncompleteIsotopomerInformation...88 JuhoRousu,AriRantanen,HannuMaaheimo, Esa Pitk. anen, KatjaSaarela, andEsko Ukkonen DynamicBayesianNetworkandNonparametricRegression forNonlinearModelingofGeneNetworks fromTimeSeriesGeneExpressionData...104 SunYongKim, SeiyaImoto, andSatoru Miyano VIII Table ofContents DiscreteEventSimulationforaBetterUnderstanding ofMetaboliteChanneling-ASystemTheoreticApproach...114 Daniela Degenring,Mathias Rohl, .. andAdelinde M. Uhrmacher MathematicalModelingoftheIn?uenceofRKIP ontheERKSignalingPathway...127 Kwang-HyunCho, Sung-YoungShin, Hyun-WooKim,Olaf Wolkenhauer, Brian McFerran,and WalterKolch AMethodtoIdentifyEssentialEnzymesintheMetabolism: ApplicationtoEscherichia Coli...

This book constitutes the revised refereed summary of the results presented during the European IST/FET proactive initiative's Global Computing workshop, GC 2003, held in Rovereto, Italy, in February 2003.The eight revised full papers and survey articles presented together with a detailed introductory overview assess the state of the art in global computing. Global computing attempts to develop models, frameworks, methods, and algorithms to build systems that are flexible, dependable, secure, robust, and efficient. The dominant technical issues are coordination, interaction, security, safety, scalability, robustness, mobility, risk management, performance analysis, etc.

This volume collects revised versions of some of the papers presented at the S- ond IST/FET International Workshop on Global Computing held in Rovereto, Italy (9-12 March, 2004). The workshop involved all the thirteen projects funded under the IST/FET proactive initiative on GLOBAL COMPUTING: AGILE; CRESCCO; DART; DBGLOBE;DEGAS;FLAGS;MIKADO;MRG;MYTHS;PEPITO;PROFUN- DIS; SECURE; SOCS. The ?rst aim of the GLOBAL COMPUTING initiative is the development of paradigms for building ?exible, dependable, secure, robust and e?cient systems. Primaryresearchconcernsaretheco-ordination,interaction,security,reliability, robustness, and risk control of the entities in the global system. The ultimate goaloftheresearchactionistoprovideasolidscienti?cfoundationforthedesign of such systems, and to lay the groundwork for achieving e?ective principles for building and analysing them. Theworkshopcoveredtopicsrelatedtoprogrammingenvironments,dynamic recon?guration, resource guarantees, peer-to-peer networks, analysis of systems and resources, resource sharing, and security, as well as foundational calculi for mobility. The present collection o?ers a rich sample of research results on the above subjects.We acknowledge the Dipartimento di Informatica e Telecomunicazioni of the University of Trento for partially funding the workshop, and the Events and Meetings O?ce of the University of Trento for the valuable collaboration.

In the last few decades, advances in molecular biology and in the research - frastructure in this ?eld has given rise to the "omics" revolution in molecular biology,alongwiththeexplosionofdatabases:fromgenomicstotranscriptomics, proteomics, interactomics,and metabolomics. However,the huge amount of b- logicalinformationavailablehasleftabottleneckindataprocessing:information over?ow has called for innovative techniques for their visualization, modelling, interpretationandanalysis.The manyresultsfromthe ?eldsofcomputerscience andengineeringhavethenmetwithbiology,leadingto new,emergingdisciplines such as bioinformatics and systems biology. So, for instance, as the result of - plicationoftechniquessuchasmachinelearning,self-organizingmaps,statistical algorithms,clusteringalgorithmsandmulti-agentsystemstomodernbiology,we can actually model and simulate some functions of the cell (e.g., protein inter- tion, gene expression and gene regulation), make inferences from the molecular biology database, make connections among biological data, and derive useful predictions. Today, and more generally, two di?erent scenarios characterize the po- genomic era.On the one hand, the huge amount of datasets made available by biological research all over the world mandates for suitable techniques, tools and methods meant at modelling biological processes and analyzing biological sequences. On the other hand, biological systems work as the sources of a wide range of new computational models and paradigms, which are now ready to be applied in the context of computer-based systems.

This book constitutes the refereed proceedings of the International Conference on Computational Methods in Systems Biology, CMSB 2006, held in Trento, Italy, in October 2006. The 22 fully revised papers presented together with 2 invited talks were carefully reviewed and selected from 68 submissions. The papers present a variety of techniques from computer sciences, such as language design, concurrency theory, software engineering, and formal methods.

The LNCS journal Transactions on Computational Systems Biology is devoted to inter- and multidisciplinary research in the fields of computer science and life sciences. It supports a paradigmatic shift in the techniques from computer and information science to cope with the new challenges arising from the systems oriented point of view of biological phenomena. The six papers selected for this special issue cover a broad range of topics.

The LNCS journal Transactions on Computational Systems Biology is devoted to inter- and multidisciplinary research in the fields of computer science and life sciences and supports a paradigmatic shift in the techniques from computer and information science to cope with the new challenges arising from the systems oriented point of view of biological phenomena. This issue contains four highly detailed papers. The first paper focuses on quantitative aspects of the bgl operon for E.coli. The second contribution deals with ecosystem transitions affecting phenotype expressions and selection mechanisms. The third paper presents the Stochastic Calculus of Looping Sequences (SCLS) suitable for the description of microbiological systems, such as cellular pathways, and their evolution. The final contribution describes the use of biological transactions to make atomic sequences of interactions in the BlenX language.

Technology is taking us to a world where myriads of heavily networked devices interact with the physical world in multiple ways, and at many levels, from the globalInternetdowntomicroandnanodevices. Manyofthesedevicesarehighly mobile and autonomous and must adapt to the surrounding environment in a totally unsupervised way. A fundamental research challenge is the design of robust decentralized c- puting systemsthat arecapableofoperating in changing environmentsandwith noisy input, and yet exhibit the desired behavior and response time, under c- straints such as energy consumption, size, and processing power. These systems should be able to adapt and learn how to react to unforeseen scenarios as well as to display properties comparable to social entities. The observation of nature has brought us many great and unforeseen concepts. Biological systems are able to handle many of these challenges with an elegance and e?ciency far beyond currenthumanartifacts. Basedonthisobservation,bio-inspiredapproacheshave been proposed as a means of handling the complexity of such systems. The goal is to obtain methods to engineer technical systems, which are of a stability and e?ciency comparable to those found in biological entities. This Special Issue on Biological and Biologically-inspired Communication contains the best papers from the Second International Conference on Bio- Inspired Models of Network, Information, and Computing Systems (BIONET- ICS 2007). The BIONETICS conference aims to bring together researchers and scientistsfromseveraldisciplines incomputerscienceandengineeringwhereb- inspired methods are investigated, as well as from bioinformatics, to deepen the information exchange and collaboration among the di?erent communities.