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      Origins of Stochasticity and Burstiness in High-Dimensional Biochemical Networks

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      EURASIP Journal on Bioinformatics and Systems Biology
      BioMed Central

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          Abstract

          Two major approaches are known in the field of stochastic dynamics of intracellular biochemical networks. The first one places the focus of attention on the fact that many biochemical constituents vitally important for the network functionality may be present only in small quantities within the cell, and therefore the regulatory process is essentially discrete and prone to relatively big fluctuations. The second approach treats the regulatory process as essentially continuous. Complex pseudostochastic behavior in such processes may occur due to multistability and oscillatory motions within limit cycles. In this paper we outline the third scenario of stochasticity in the regulatory process. This scenario is only conceivable in high-dimensional highly nonlinear systems. In particular, we show that burstiness, a well-known phenomenon in the biology of gene expression, is a natural consequence of high dimensionality coupled with high nonlinearity. In mathematical terms, burstiness is associated with heavy-tailed probability distributions of stochastic processes describing the dynamics of the system. We demonstrate how the "shot" noise originates from purely deterministic behavior of the underlying dynamical system. We conclude that the limiting stochastic process may be accurately approximated by the "heavy-tailed" generalized Pareto process which is a direct mathematical expression of burstiness.

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          Metabolomics--the link between genotypes and phenotypes.

          Metabolites are the end products of cellular regulatory processes, and their levels can be regarded as the ultimate response of biological systems to genetic or environmental changes. In parallel to the terms 'transcriptome' and proteome', the set of metabolites synthesized by a biological system constitute its 'metabolome'. Yet, unlike other functional genomics approaches, the unbiased simultaneous identification and quantification of plant metabolomes has been largely neglected. Until recently, most analyses were restricted to profiling selected classes of compounds, or to fingerprinting metabolic changes without sufficient analytical resolution to determine metabolite levels and identities individually. As a prerequisite for metabolomic analysis, careful consideration of the methods employed for tissue extraction, sample preparation, data acquisition, and data mining must be taken. In this review, the differences among metabolite target analysis, metabolite profiling, and metabolic fingerprinting are clarified, and terms are defined. Current approaches are examined, and potential applications are summarized with a special emphasis on data mining and mathematical modelling of metabolism.
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            Stochastic mechanisms in gene expression.

            In cellular regulatory networks, genetic activity is controlled by molecular signals that determine when and how often a given gene is transcribed. In genetically controlled pathways, the protein product encoded by one gene often regulates expression of other genes. The time delay, after activation of the first promoter, to reach an effective level to control the next promoter depends on the rate of protein accumulation. We have analyzed the chemical reactions controlling transcript initiation and translation termination in a single such "genetically coupled" link as a precursor to modeling networks constructed from many such links. Simulation of the processes of gene expression shows that proteins are produced from an activated promoter in short bursts of variable numbers of proteins that occur at random time intervals. As a result, there can be large differences in the time between successive events in regulatory cascades across a cell population. In addition, the random pattern of expression of competitive effectors can produce probabilistic outcomes in switching mechanisms that select between alternative regulatory paths. The result can be a partitioning of the cell population into different phenotypes as the cells follow different paths. There are numerous unexplained examples of phenotypic variations in isogenic populations of both prokaryotic and eukaryotic cells that may be the result of these stochastic gene expression mechanisms.
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              It's a noisy business! Genetic regulation at the nanomolar scale.

              Many molecules that control genetic regulatory circuits act at extremely low intracellular concentrations. Resultant fluctuations (noise) in reaction rates cause large random variation in rates of development, morphology and the instantaneous concentration of each molecular species in each cell. To achieve regulatory reliability in spite of this noise, cells use redundancy in genes as well as redundancy and extensive feedback in regulatory pathways. However, some regulatory mechanisms exploit this noise to randomize outcomes where variability is advantageous.
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                Author and article information

                Journal
                EURASIP J Bioinform Syst Biol
                EURASIP Journal on Bioinformatics and Systems Biology
                BioMed Central
                1687-4145
                1687-4153
                2009
                14 May 2008
                : 2009
                : 1
                : 362309
                Affiliations
                [1 ]Division of Cancer Prevention (DCP), National Cancer Institute, EPN 3108, 6130 Executive Blvd, Bethesda, MO 20892, USA
                Article
                1687-4153-2009-362309
                10.1155/2009/362309
                3171425
                18946549
                c2f00f21-6d1d-4dbb-9b6a-75982ecf9547
                Copyright ©2009 Simon Rosenfeld.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 5 February 2008
                : 24 April 2008
                Categories
                Research Article

                Bioinformatics & Computational biology
                Bioinformatics & Computational biology

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