Distributed Web Service Coordination for Collaboration Applications and Biological Workflows

In this dissertation work, we have investigated the main research thrust of decentralized coordination of workflows over web services. To address distributed workflow coordination, first we have developed “Web Coordination Bonds” as a capable set of dependency modeling primitives that enable each web service to manage its own dependencies. Web bond primitives are as powerful as extended Petri nets and have sufficient modeling and expressive capabilities to model workflow dependencies. We have designed and prototyped our “Web Service Coordination Management Middleware” (WSCMM) system that enhances current web services infrastructure to accommodate web bond enabled web services. Finally, based on core concepts of web coordination bonds and WSCMM, we have developed the “BondFlow” system that allows easy configuration distributed coordination of workflows. The footprint of the BonFlow runtime is 24KB and the additional third party software packages, SOAP client and XML parser, account for 115KB

Evolution from the ground up with Amee – From basic concepts to explorative modeling

Evolutionary theory has been the foundation of biological research for about a century now, yet over the past few decades, new discoveries and theoretical advances have rapidly transformed our understanding of the evolutionary process. Foremost among them are evolutionary developmental biology, epigenetic inheritance, and various forms of evolu- tionarily relevant phenotypic plasticity, as well as cultural evolution, which ultimately led to the conceptualization of an extended evolutionary synthesis. Starting from abstract principles rooted in complexity theory, this thesis aims to provide a unified conceptual understanding of any kind of evolution, biological or otherwise. This is used in the second part to develop Amee, an agent-based model that unifies development, niche construction, and phenotypic plasticity with natural selection based on a simulated ecology. Amee is implemented in Utopia, which allows performant, integrated implementation and simulation of arbitrary agent-based models. A phenomenological overview over Amee’s capabilities is provided, ranging from the evolution of ecospecies down to the evolution of metabolic networks and up to beyond-species-level biological organization, all of which emerges autonomously from the basic dynamics. The interaction of development, plasticity, and niche construction has been investigated, and it has been shown that while expected natural phenomena can, in principle, arise, the accessible simulation time and system size are too small to produce natural evo-devo phenomena and –structures. Amee thus can be used to simulate the evolution of a wide variety of processes

Ontology-based instance data validation for high-quality curated biological pathways

<p>Abstract</p> <p>Background</p> <p>Modeling in systems biology is vital for understanding the complexity of biological systems across scales and predicting system-level behaviors. To obtain high-quality pathway databases, it is essential to improve the efficiency of model validation and model update based on appropriate feedback.</p> <p>Results</p> <p>We have developed a new method to guide creating novel high-quality biological pathways, using a rule-based validation. Rules are defined to correct models against biological semantics and improve models for dynamic simulation. In this work, we have defined 40 rules which constrain event-specific participants and the related features and adding missing processes based on biological events. This approach is applied to data in Cell System Ontology which is a comprehensive ontology that represents complex biological pathways with dynamics and visualization. The experimental results show that the relatively simple rules can efficiently detect errors made during curation, such as misassignment and misuse of ontology concepts and terms in curated models.</p> <p>Conclusions</p> <p>A new rule-based approach has been developed to facilitate model validation and model complementation. Our rule-based validation embedding biological semantics enables us to provide high-quality curated biological pathways. This approach can serve as a preprocessing step for model integration, exchange and extraction data, and simulation.</p

Computational Techniques for the Structural and Dynamic Analysis of Biological Networks

The analysis of biological systems involves the study of networks from different omics such as genomics, transcriptomics, metabolomics and proteomics. In general, the computational techniques used in the analysis of biological networks can be divided into those that perform (i) structural analysis, (ii) dynamic analysis of structural prop- erties and (iii) dynamic simulation. Structural analysis is related to the study of the topology or stoichiometry of the biological network such as important nodes of the net- work, network motifs and the analysis of the flux distribution within the network. Dy- namic analysis of structural properties, generally, takes advantage from the availability of interaction and expression datasets in order to analyze the structural properties of a biological network in different conditions or time points. Dynamic simulation is useful to study those changes of the biological system in time that cannot be derived from a structural analysis because it is required to have additional information on the dynamics of the system. This thesis addresses each of these topics proposing three computational techniques useful to study different types of biological networks in which the structural and dynamic analysis is crucial to answer to specific biological questions. In particu- lar, the thesis proposes computational techniques for the analysis of the network motifs of a biological network through the design of heuristics useful to efficiently solve the subgraph isomorphism problem, the construction of a new analysis workflow able to integrate interaction and expression datasets to extract information about the chromo- somal connectivity of miRNA-mRNA interaction networks and, finally, the design of a methodology that applies techniques coming from the Electronic Design Automation (EDA) field that allows the dynamic simulation of biochemical interaction networks and the parameter estimation

Modelling and simulating in systems biology: an approach based on multi-agent systems

Systems Biology is an innovative way of doing biology recently raised in bio-informatics contexts, characterised by the study of biological systems as complex systems with a strong focus on the system level and on the interaction dimension. In other words, the objective is to understand biological systems as a whole, putting on the foreground not only the study of the individual parts as standalone parts, but also of their interaction and of the global properties that emerge at the system level by means of the interaction among the parts. This thesis focuses on the adoption of multi-agent systems (MAS) as a suitable paradigm for Systems Biology, for developing models and simulation of complex biological systems. Multi-agent system have been recently introduced in informatics context as a suitabe paradigm for modelling and engineering complex systems. Roughly speaking, a MAS can be conceived as a set of autonomous and interacting entities, called agents, situated in some kind of nvironment, where they fruitfully interact and coordinate so as to obtain a coherent global system behaviour. The claim of this work is that the general properties of MAS make them an effective approach for modelling and building simulations of complex biological systems, following the methodological principles identified by Systems Biology. In particular, the thesis focuses on cell populations as biological systems. In order to support the claim, the thesis introduces and describes (i) a MAS-based model conceived for modelling the dynamics of systems of cells interacting inside cell environment called niches. (ii) a computational tool, developed for implementing the models and executing the simulations. The tool is meant to work as a kind of virtual laboratory, on top of which kinds of virtual experiments can be performed, characterised by the definition and execution of specific models implemented as MASs, so as to support the validation, falsification and improvement of the models through the observation and analysis of the simulations. A hematopoietic stem cell system is taken as reference case study for formulating a specific model and executing virtual experiments

Systematic reconstruction of TRANSPATH data into Cell System Markup Language

<p>Abstract</p> <p>Background</p> <p>Many biological repositories store information based on experimental study of the biological processes within a cell, such as protein-protein interactions, metabolic pathways, signal transduction pathways, or regulations of transcription factors and miRNA. Unfortunately, it is difficult to directly use such information when generating simulation-based models. Thus, modeling rules for encoding biological knowledge into system-dynamics-oriented standardized formats would be very useful for fully understanding cellular dynamics at the system level.</p> <p>Results</p> <p>We selected the TRANSPATH database, a manually curated high-quality pathway database, which provides a plentiful source of cellular events in humans, mice, and rats, collected from over 31,500 publications. In this work, we have developed 16 modeling rules based on hybrid functional Petri net with extension (HFPNe), which is suitable for graphical representing and simulating biological processes. In the modeling rules, each Petri net element is incorporated with Cell System Ontology to enable semantic interoperability of models. As a formal ontology for biological pathway modeling with dynamics, CSO also defines biological terminology and corresponding icons. By combining HFPNe with the CSO features, it is possible to make TRANSPATH data to simulation-based and semantically valid models. The results are encoded into a biological pathway format, Cell System Markup Language (CSML), which eases the exchange and integration of biological data and models.</p> <p>Conclusion</p> <p>By using the 16 modeling rules, 97% of the reactions in TRANSPATH are converted into simulation-based models represented in CSML. This reconstruction demonstrates that it is possible to use our rules to generate quantitative models from static pathway descriptions.</p

In-silico-Systemanalyse von Biopathways

Chen M. In silico systems analysis of biopathways. Bielefeld (Germany): Bielefeld University; 2004.In the past decade with the advent of high-throughput technologies, biology has migrated from a descriptive science to a predictive one. A vast amount of information on the metabolism have been produced; a number of specific genetic/metabolic databases and computational systems have been developed, which makes it possible for biologists to perform in silico analysis of metabolism. With experimental data from laboratory, biologists wish to systematically conduct their analysis with an easy-to-use computational system. One major task is to implement molecular information systems that will allow to integrate different molecular database systems, and to design analysis tools (e.g. simulators of complex metabolic reactions). Three key problems are involved: 1) Modeling and simulation of biological processes; 2) Reconstruction of metabolic pathways, leading to predictions about the integrated function of the network; and 3) Comparison of metabolism, providing an important way to reveal the functional relationship between a set of metabolic pathways. This dissertation addresses these problems of in silico systems analysis of biopathways. We developed a software system to integrate the access to different databases, and exploited the Petri net methodology to model and simulate metabolic networks in cells. It develops a computer modeling and simulation technique based on Petri net methodology; investigates metabolic networks at a system level; proposes a markup language for biological data interchange among diverse biological simulators and Petri net tools; establishes a web-based information retrieval system for metabolic pathway prediction; presents an algorithm for metabolic pathway alignment; recommends a nomenclature of cellular signal transduction; and attempts to standardize the representation of biological pathways. Hybrid Petri net methodology is exploited to model metabolic networks. Kinetic modeling strategy and Petri net modeling algorithm are applied to perform the processes of elements functioning and model analysis. The proposed methodology can be used for all other metabolic networks or the virtual cell metabolism. Moreover, perspectives of Petri net modeling and simulation of metabolic networks are outlined. A proposal for the Biology Petri Net Markup Language (BioPNML) is presented. The concepts and terminology of the interchange format, as well as its syntax (which is based on XML) are introduced. BioPNML is designed to provide a starting point for the development of a standard interchange format for Bioinformatics and Petri nets. The language makes it possible to exchange biology Petri net diagrams between all supported hardware platforms and versions. It is also designed to associate Petri net models and other known metabolic simulators. A web-based metabolic information retrieval system, PathAligner, is developed in order to predict metabolic pathways from rudimentary elements of pathways. It extracts metabolic information from biological databases via the Internet, and builds metabolic pathways with data sources of genes, sequences, enzymes, metabolites, etc. The system also provides a navigation platform to investigate metabolic related information, and transforms the output data into XML files for further modeling and simulation of the reconstructed pathway. An alignment algorithm to compare the similarity between metabolic pathways is presented. A new definition of the metabolic pathway is proposed. The pathway defined as a linear event sequence is practical for our alignment algorithm. The algorithm is based on strip scoring the similarity of 4-hierarchical EC numbers involved in the pathways. The algorithm described has been implemented and is in current use in the context of the PathAligner system. Furthermore, new methods for the classification and nomenclature of cellular signal transductions are recommended. For each type of characterized signal transduction, a unique ST number is provided. The Signal Transduction Classification Database (STCDB), based on the proposed classification and nomenclature, has been established. By merging the ST numbers with EC numbers, alignments of biopathways are possible. Finally, a detailed model of urea cycle that includes gene regulatory networks, metabolic pathways and signal transduction is demonstrated by using our approaches. A system biological interpretation of the observed behavior of the urea cycle and its related transcriptomics information is proposed to provide new insights for metabolic engineering and medical care

Modular Verification of Biological Systems

Systems of interest in systems biology (such as metabolic pathways, signalling pathways and gene regulatory networks) often consist of a huge number of components interacting in different ways, thus exhibiting very complex behaviours. In biology, such behaviours are usually explored by means of simulation techniques applied to models defined on the basis of system observation and of hypotheses on its functioning. Model checking has also been recently applied to the analysis of biological systems. This analysis technique typically relies on a state space representation whose size, unfortunately, makes the analysis often intractable for realistic models. A method for trying to avoid the state space explosion problem is to consider a decomposition of the system, and to apply a modular verification technique. In particular, properties to be verified often concern only a small portion of the modelled system rather than the system as a whole. Hence, for each property it would be useful to be able to isolate a minimal fragment of the model that is necessary to verify such a property. In this thesis we introduce a modular verification technique in which the system of interest is described by means of an automata-based formalism, called sync-programs, that supports modular construction. Our modular verification technique is based on results of Grumberg et al.~and on their application to the theory of concurrent systems proposed by Attie and Emerson. In particular, we adapt Attie and Emerson's approach to deal with biological systems by allowing automata to synchronise by performing transitions simultaneously. Modular verification allows qualitative aspects of systems to be analysed with the guarantee that properties proved to hold in a suitable model fragment also hold in the whole model. The correctness of the verification technique is proved. The class of properties preserved is ACTL$^{-}$, the universal fragment of temporal logic CTL. The preservation holds only for positive answers and negative answers are not necessarily preserved. In order to verify properties we use the NuSMV model checker, which is a well-established and efficient instrument. We provide a formal translation of sync-programs to simpler automata, which can be given as input to NuSMV. We prove the correspondence of the verification problems. We show the application of our verification technique in some biological case studies. We compare the time required to verify the property on the whole model with the time needed to verify the same property by only considering those modules which are involved in the behaviour of the system related to the property. In order to handle modelling and verification of more realistic biological scenarios, we propose also a dynamic version of our formalism. It allows entities to be created dynamically, in particular by other already running entities, as it often happens in biological systems. Moreover, multiple copies of the same entities can be present at the same time in a system. We show a correspondence of our model with Petri Nets. This has a consequence that tools developed for Petri Nets could be used also for dynamic sync-programs. Modular verification allows properties expressed as DACTL- formulae (dynamic version of ACTL-) to be verified on a portion of the model. The results of analysis of the case study of the MAP kinase cascade activated by surface and internalised EGF receptors, which consists of 143 species and 80 reactions, suggest applicability and scalability of the approach. The results raise the prospect of rendering tractable problems that are currently intractable in the verification of biological systems. In addition, we expect that the techniques developed in the thesis could be applied with profit not only to models of biological systems, but more generally to models of concurrent systems