Computational models for inferring biochemical networks

Biochemical networks are of great practical importance. The interaction of biological compounds in cells has been enforced to a proper understanding by the numerous bioinformatics projects, which contributed to a vast amount of biological information. The construction of biochemical systems (systems of chemical reactions), which include both topology and kinetic constants of the chemical reactions, is NP-hard and is a well-studied system biology problem. In this paper, we propose a hybrid architecture, which combines genetic programming and simulated annealing in order to generate and optimize both the topology (the network) and the reaction rates of a biochemical system. Simulations and analysis of an artificial model and three real models (two models and the noisy version of one of them) show promising results for the proposed method.The Romanian National Authority for Scientific Research, CNDI–UEFISCDI, Project No. PN-II-PT-PCCA-2011-3.2-0917

Process Calculi Abstractions for Biology

Several approaches have been proposed to model biological systems by means of the formal techniques and tools available in computer science. To mention just a few of them, some representations are inspired by Petri Nets theory, and some other by stochastic processes. A most recent approach consists in interpreting the living entities as terms of process calculi where the behavior of the represented systems can be inferred by applying syntax-driven rules. A comprehensive picture of the state of the art of the process calculi approach to biological modeling is still missing. This paper goes in the direction of providing such a picture by presenting a comparative survey of the process calculi that have been used and proposed to describe the behavior of living entities. This is the preliminary version of a paper that was published in Algorithmic Bioprocesses. The original publication is available at http://www.springer.com/computer/foundations/book/978-3-540-88868-

Modeling formalisms in systems biology

Systems Biology has taken advantage of computational tools and high-throughput experimental data to model several biological processes. These include signaling, gene regulatory, and metabolic networks. However, most of these models are specific to each kind of network. Their interconnection demands a whole-cell modeling framework for a complete understanding of cellular systems. We describe the features required by an integrated framework for modeling, analyzing and simulating biological processes, and review several modeling formalisms that have been used in Systems Biology including Boolean networks, Bayesian networks, Petri nets, process algebras, constraint-based models, differential equations, rule-based models, interacting state machines, cellular automata, and agent-based models. We compare the features provided by different formalisms, and discuss recent approaches in the integration of these formalisms, as well as possible directions for the future.Research supported by grants SFRH/BD/35215/2007 and SFRH/BD/25506/2005 from the Fundacao para a Ciencia e a Tecnologia (FCT) and the MIT-Portugal Program through the project "Bridging Systems and Synthetic Biology for the development of improved microbial cell factories" (MIT-Pt/BS-BB/0082/2008)

Modularization of biochemical networks based on classification of Petri net t-invariants

<p>Abstract</p> <p>Background</p> <p>Structural analysis of biochemical networks is a growing field in bioinformatics and systems biology. The availability of an increasing amount of biological data from molecular biological networks promises a deeper understanding but confronts researchers with the problem of combinatorial explosion. The amount of qualitative network data is growing much faster than the amount of quantitative data, such as enzyme kinetics. In many cases it is even impossible to measure quantitative data because of limitations of experimental methods, or for ethical reasons. Thus, a huge amount of qualitative data, such as interaction data, is available, but it was not sufficiently used for modeling purposes, until now. New approaches have been developed, but the complexity of data often limits the application of many of the methods. Biochemical Petri nets make it possible to explore static and dynamic qualitative system properties. One Petri net approach is model validation based on the computation of the system's invariant properties, focusing on t-invariants. T-invariants correspond to subnetworks, which describe the basic system behavior.</p> <p>With increasing system complexity, the basic behavior can only be expressed by a huge number of t-invariants. According to our validation criteria for biochemical Petri nets, the necessary verification of the biological meaning, by interpreting each subnetwork (t-invariant) manually, is not possible anymore. Thus, an automated, biologically meaningful classification would be helpful in analyzing t-invariants, and supporting the understanding of the basic behavior of the considered biological system.</p> <p>Methods</p> <p>Here, we introduce a new approach to automatically classify t-invariants to cope with network complexity. We apply clustering techniques such as UPGMA, Complete Linkage, Single Linkage, and Neighbor Joining in combination with different distance measures to get biologically meaningful clusters (t-clusters), which can be interpreted as modules. To find the optimal number of t-clusters to consider for interpretation, the cluster validity measure, Silhouette Width, is applied.</p> <p>Results</p> <p>We considered two different case studies as examples: a small signal transduction pathway (pheromone response pathway in <it>Saccharomyces cerevisiae</it>) and a medium-sized gene regulatory network (gene regulation of Duchenne muscular dystrophy). We automatically classified the t-invariants into functionally distinct t-clusters, which could be interpreted biologically as functional modules in the network. We found differences in the suitability of the various distance measures as well as the clustering methods. In terms of a biologically meaningful classification of t-invariants, the best results are obtained using the Tanimoto distance measure. Considering clustering methods, the obtained results suggest that UPGMA and Complete Linkage are suitable for clustering t-invariants with respect to the biological interpretability.</p> <p>Conclusion</p> <p>We propose a new approach for the biological classification of Petri net t-invariants based on cluster analysis. Due to the biologically meaningful data reduction and structuring of network processes, large sets of t-invariants can be evaluated, allowing for model validation of qualitative biochemical Petri nets. This approach can also be applied to elementary mode analysis.</p

On Modeling Signal Transduction Networks

Signal transduction networks are very complex processes employed by the living cell to suitably react to environmental stimuli. Qualitative and quantitative computational models play an increasingly important role in the representation of these networks and in the search of new insights about these phenomena. In this work we analyze some graph-based models used to discover qualitative properties of such networks. In turn, we show that MP systems can naturally extend these graph-based models by adding some qualitative elements. The case study of integrins activation during the lymphocyte recruitment, a crucial phenomenon in inflammatory processes, is described, and a first MP graph for this network is designed. Finally, we discuss some open problems related to the qualitative modeling of signaling networks

Computational Modeling, Formal Analysis, and Tools for Systems Biology.

As the amount of biological data in the public domain grows, so does the range of modeling and analysis techniques employed in systems biology. In recent years, a number of theoretical computer science developments have enabled modeling methodology to keep pace. The growing interest in systems biology in executable models and their analysis has necessitated the borrowing of terms and methods from computer science, such as formal analysis, model checking, static analysis, and runtime verification. Here, we discuss the most important and exciting computational methods and tools currently available to systems biologists. We believe that a deeper understanding of the concepts and theory highlighted in this review will produce better software practice, improved investigation of complex biological processes, and even new ideas and better feedback into computer science

A diversity-aware computational framework for systems biology

L'abstract è presente nell'allegato / the abstract is in the attachmen

Toward Accessible Multilevel Modeling in Systems Biology: A Rule-based Language Concept

Promoted by advanced experimental techniques for obtaining high-quality data and the steadily accumulating knowledge about the complexity of life, modeling biological systems at multiple interrelated levels of organization attracts more and more attention recently. Current approaches for modeling multilevel systems typically lack an accessible formal modeling language or have major limitations with respect to expressiveness. The aim of this thesis is to provide a comprehensive discussion on associated problems and needs and to propose a concrete solution addressing them