In Silico Biology - Volume 5, issue 2

Authors: Hofestädt, Ralf

Article Type: Other

Citation: In Silico Biology, vol. 5, no. 2, pp. 81-82, 2005

Authors: Voit, Eberhard O. | Marino, Simeone | Lall, Raman

Article Type: Research Article

Abstract: Modern methods of high-throughput molecular biology render it possible to generate time series of metabolite concentrations and the expression of genes and proteins in vivo. These time profiles contain valuable information about the structure and dynamics of the underlying biological system. This information is implicit and its extraction is a challenging but ultimately very rewarding task for the mathematical modeler. Using a well-suited modeling framework, such as Biochemical Systems Theory (BST), it is …possible to formulate the extraction of information as an inverse problem that in principle may be solved with a genetic algorithm or nonlinear regression. However, two types of issues associated with this inverse problem make the extraction task difficult. One type pertains to the algorithmic difficulties encountered in nonlinear regressions with moderate and large systems. The other type is of an entirely different nature. It is a consequence of assumptions that are often taken for granted in the design and analysis of mathematical models of biological systems and that need to be revisited in the context of inverse analyses. The article describes the extraction process and some of its challenges and proposes partial solutions. Show more

Keywords: Biochemical Systems Theory, metabolic profile, network identification, pathway analysis, proteomics, S-system, time series

Citation: In Silico Biology, vol. 5, no. 2, pp. 83-92, 2005

Authors: Borisjuk, Ljudmilla | Hajirezaei, Mohammad-Reza | Klukas, Christian | Rolletschek, Hardy | Schreiber, Falk

Article Type: Research Article

Abstract: Modern 'omics'-technologies result in huge amounts of data about life processes. For analysis and data mining purposes this data has to be considered in the context of the underlying biological networks. This work presents an approach for integrating data from biological experiments into metabolic networks by mapping the data onto network elements and visualising the data enriched networks automatically. This methodology is implemented in DBE, an information system that supports the analysis and visualisation …of experimental data in the context of metabolic networks. It consists of five parts: (1) the DBE-Database for consistent data storage, (2) the Excel-Importer application for the data import, (3) the DBE-Website as the interface for the system, (4) the DBE-Pictures application for the up- and download of binary (e.g. image) files, and (5) DBE-Gravisto, a network analysis and graph visualisation system. The usability of this approach is demonstrated in two examples. Show more

Keywords: metabolic networks, visualisation, metabolic profiling, information system, data integration

Citation: In Silico Biology, vol. 5, no. 2, pp. 93-102, 2005

Authors: Dandekar, Thomas | Schmidt, Steffen

Article Type: Research Article

Abstract: Flexibility of metabolites and enzymes is investigated (i) on the level of the individual molecule, (ii) on the pathway level and (iii) combined effects on the systems and network level. Tools and results from our current research are summarized including data from our metabolite enzyme database. Including our latest census we find frequently used metabolites stimulate evolutionary flexibility in specific enzyme superfamilies. Furthermore, simultaneous changes of reactions and metabolites are observed in these …flexible enzyme superfamilies. Both effects provide a strong source for resistance in parasites and pathogens. Specific adaptations scenarios and some counter strategies are discussed. Show more

Keywords: flexibility, metabolites, enzyme family, resistance, adaptation, pathway, network

Citation: In Silico Biology, vol. 5, no. 2, pp. 103-110, 2005

Authors: Chen, Ming | Hofestädt, Ralf

Article Type: Research Article

Abstract: Metabolic pathway alignment represents one of the most powerful tools for comparative analysis of metabolism. It involves recognition of metabolites common to a set of functionally-related metabolic pathways, interpretation of biological evolution processes and determination of alternative metabolic pathways. Moreover, it is of assistance in function prediction and metabolism modeling. Although research on genomic sequence alignment is extensive, the problem of aligning metabolic pathways has received less attention. We are motivated to …develop an algorithm of metabolic pathway alignment to reveal the similarities between metabolic pathways. A new definition of the metabolic pathway is introduced. The algorithm has been implemented into the PathAligner system; its web-based interface is available at http://bibiserv.techfak.uni-bielefeld.de/pathaligner/. Show more

Keywords: metabolic pathways, alignment, algorithm, PathAligner

Citation: In Silico Biology, vol. 5, no. 2, pp. 111-128, 2005

Authors: Koch, Ina | Schüler, Markus | Heiner, Monika

Article Type: Research Article

Abstract: To understand biochemical processes caused by, e.g., mutations or deletions in the genome, the knowledge of possible alternative paths between two arbitrary chemical compounds is of increasing interest for biotechnology, pharmacology, medicine, and drug design. With the steadily increasing amount of data from high-throughput experiments new biochemical networks can be constructed and existing ones can be extended, which results in many large metabolic, signal transduction, and gene regulatory networks. The search for …alternative paths within these complex and large networks can provide a huge amount of solutions, which can not be handled manually. Moreover, not all of the alternative paths are generally of interest. Therefore, we have developed and implemented a method, which allows us to define constraints to reduce the set of all structurally possible paths to the truly interesting path set. The paper describes the search algorithm and the constraints definition language. We give examples for path searches using this dedicated special language for a Petri net model of the sucrose-to-starch breakdown in the potato tuber. Availability: http://sanaga.tfh-berlin.de/~stepp/ Show more

Keywords: Petri nets, systems biology, biochemical networks, metabolic networks, signal transduction networks, path search with constraints, graph theory, sucrose-to-starch breakdown, potato tuber

Citation: In Silico Biology, vol. 5, no. 2, pp. 129-137, 2005

Authors: Wishart, David S. | Yang, Robert | Arndt, David | Tang, Peter | Cruz, Joseph

Article Type: Research Article

Abstract: A wide variety of approaches, ranging from Petri nets to systems of partial differential equations, have been used to model very specific aspects of cellular or biochemical functions. Here we describe how an agent-based or dynamic cellular automata (DCA) approach can be used as a very simple, yet very general method to model many different kinds of cellular or biochemical processes. Specifically, using simple pairwise interaction rules coupled with random object moves to simulate Brownian motion, …we show how the DCA approach can be used to easily and accurately model diffusion, viscous drag, enzyme rate processes, metabolism (the Kreb's cycle), and complex genetic circuits (the repressilator). We also demonstrate how DCA approaches are able to accurately capture the stochasticity of many biological processes. The success and simplicity of this technique suggests that many other physical properties and significantly more complicated aspects of cellular behavior could be modeled using DCA methods. An easy-to-use, graphically-based computer program, called SimCell, was developed to perform the DCA simulations described here. It is available at http://wishart.biology.ualberta.ca/SimCell/. Show more

Keywords: cellular simulation, cellular automata, E. coli, genetic circuit

Citation: In Silico Biology, vol. 5, no. 2, pp. 139-161, 2005

Authors: Broderick, Gordon | Ru'aini, Melania | Chan, Eugene | Ellison, Michael J.

Article Type: Research Article

Abstract: A framework is presented that captures the discrete and probabilistic nature of molecular transport and reaction kinetics found in a living cell as well as formally representing the spatial distribution of these phenomena. This particle or agent-based approach is computationally robust and complements established methods. Namely it provides a higher level of spatial resolution than formulations based on ordinary differential equations (ODE) while offering significant advantages in computational efficiency over molecular dynamics …(MD). Using this framework, a model cell membrane has been constructed with discrete particle agents that respond to local component interactions that resemble flocking or herding behavioural cues in animals. Results from simulation experiments are presented where this model cell exhibits many of the characteristic behaviours associated with its biological counterpart such as lateral diffusion, response to osmotic pressure gradients, membrane growth and cell division. Lateral diffusion rates and estimates for the membrane modulus of elasticity derived from these simple experiments fall well within a biologically relevant range of values. More importantly, these estimates were obtained by applying a simple qualitative tuning of the model membrane. Membrane growth was simulated by injecting precursor molecules into the proto-cell at different rates and produced a variety of morphologies ranging from a single large cell to a cluster of cells. The computational scalability of this methodology has been tested and results from benchmarking experiments indicate that real-time simulation of a complete bacterial cell will be possible within 10 years. Show more

Keywords: mathematical model, agents, flocking, lipid bilayer, cell membrane, discrete automata, stochastic simulation, virtual cell

Citation: In Silico Biology, vol. 5, no. 2, pp. 163-178, 2005

Authors: Pruess, Manuela | Kersey, Paul | Apweiler, Rolf

Article Type: Research Article

Abstract: Integr8 (http://www.ebi.ac.uk/integr8/) is providing an integration layer for the exploitation of genomic and proteomic data by drawing on databases maintained at major bioinformatics centres in Europe. Main aims are to store the relationships of biological entities to each other and to entries in other databases, to provide a framework that allows for new kinds of data to be integrated, and to offer an entity-centric view of complete genomes and proteomes. Basic tools for data integration comprise …the Proteome Analysis database, the International Protein Index (IPI), the Universal Protein sequence archive (UniParc) and the Genome Reviews. Entry points for the Integr8 portal depend on the users entity of interest: from browsing the taxonomy or with a predetermined species of interest, the species page can be used, and a simple search page leads to different applications when looking for certain protein sequences or genes. Customisable statistics data are available from the BioMart application, and pre-prepared data can be downloaded from the FTP site. Show more

Keywords: bioinformatics, proteomics, genomes, molecular biology databases, database integration, protein sequences, nucleotide sequences

Citation: In Silico Biology, vol. 5, no. 2, pp. 179-185, 2005

Authors: Turinsky, Andrei L. | Ah-Seng, Andrew C. | Gordon, Paul M.K. | Stromer, Julie N. | Taschuk, Morgan L. | Xu, Emily W. | Sensen, Christoph W.

Article Type: Research Article

Abstract: We have created a new Java™-based integrated computational environment for the exploration of genomic data, called Bluejay. The system is capable of using almost any XML file related to genomic data. Non-XML data sources can be accessed via a proxy server. Bluejay has several features, which are new to Bioinformatics, including an unlimited semantic zoom capability, coupled with Scalable Vector Graphics (SVG) outputs; an implementation of the XLink standard, which features access to MAGPIE Genecards as …well as any BioMOBY service accessible over the Internet; and the integration of gene chip analysis tools with the functional assignments. The system can be used as a signed web applet, Web Start, and a local stand-alone application, with or without connection to the Internet. It is available free of charge and as open source via http://bluejay.ucalgary.ca. Show more

Keywords: bioinformatics, visualization, open standards, eXtensible Markup Language (XML), Scalable Vector Graphics (SVG), Java™, BioMOBY web services, Bluejay

Citation: In Silico Biology, vol. 5, no. 2, pp. 187-198, 2005

Authors: Fattore, Matteo | Arrigo, Patrizio

Article Type: Research Article

Abstract: The possibility to study an organism in terms of system theory has been proposed in the past, but only the advancement of molecular biology techniques allow us to investigate the dynamical properties of a biological system in a more quantitative and rational way than before. These new techniques can gave only the basic level view of an organisms functionality. The comprehension of its dynamical behaviour depends on the possibility to perform a multiple level analysis. …Functional genomics has stimulated the interest in the investigation the dynamical behaviour of an organism as a whole. These activities are commonly known as System Biology, and its interests ranges from molecules to organs. One of the more promising applications is the 'disease modeling'. The use of experimental models is a common procedure in pharmacological and clinical researches; today this approach is supported by 'in silico' predictive methods. This investigation can be improved by a combination of experimental and computational tools. The Machine Learning (ML) tools are able to process different heterogeneous data sources, taking into account this peculiarity, they could be fruitfully applied to support a multilevel data processing (molecular, cellular and morphological) that is the prerequisite for the formal model design; these techniques can allow us to extract the knowledge for mathematical model development. The aim of our work is the development and implementation of a system that combines ML and dynamical models simulations. The program is addressed to the virtual analysis of the pathways involved in neurodegenerative diseases. These pathologies are multifactorial diseases and the relevance of the different factors has not yet been well elucidated. This is a very complex task; in order to test the integrative approach our program has been limited to the analysis of the effects of a specific protein, the Cyclin Dependent Kinase 5 (CDK5) which relies on the induction of neuronal apoptosis. The system has a modular structure centred on a textual knowledge discovery approach. The text mining is the only way to enhance the capability to extract ,from multiple data sources, the information required for the dynamical simulator. The user may access the publically available modules through the following site: http://biocomp.ge.ismac.cnr.it. Show more

Keywords: System Biology, Knowledge Discovery, integrative bioinformatics, molecular medicine, Alzheimer's diseases, CDK5, virtual screening, drug design

Citation: In Silico Biology, vol. 5, no. 2, pp. 199-208, 2005

Authors: Guía, Marylens Hernández | Pérez, Abel González | Angarica, Vladimir Espinosa | Vasconcelos, Ana T. | Collado-Vides, Julio

Article Type: Research Article

Abstract: Prokaryotic genomes annotation has focused on genes location and function. The lack of regulatory information has limited the knowledge on cellular transcriptional regulatory networks. However, as more phylogenetically close genomes are sequenced and annotated, the implementation of phylogenetic footprinting strategies for the recognition of regulators and their regulons becomes more important. In this paper we describe a comparative genomics approach to the prediction of new gamma-proteobacterial regulon members. We take advantage of …the phylogenetic proximity of Escherichia coli and other 16 organisms of this subdivision and the intensive search of the space sequence provided by a pattern-matching strategy. Using this approach we complement predictions of regulatory sites made using statistical models currently stored in Tractor_DB, and increase the number of transcriptional regulators with predicted binding sites up to 86. All these computational predictions may be reached at Tractor_DB (www.bioinfo.cu/Tractor_DB, www.tractor.lncc.br, www.ccg.unam.mx/Computational_Genomics/tractorDB/). We also take a first step in this paper towards the assessment of the conservation of the architecture of the regulatory network in the gamma-proteobacteria through evaluating the conservation of the overall connectivity of the network. Show more

Keywords: transcriptional regulatory networks, comparative genomics, gamma-proteobacterial regulons

Citation: In Silico Biology, vol. 5, no. 2, pp. 209-219, 2005