3,753 research outputs found

    Elasticity sampling links thermodynamics to metabolic control

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    Metabolic networks can be turned into kinetic models in a predefined steady state by sampling the reaction elasticities in this state. Elasticities for many reversible rate laws can be computed from the reaction Gibbs free energies, which are determined by the state, and from physically unconstrained saturation values. Starting from a network structure with allosteric regulation and consistent metabolic fluxes and concentrations, one can sample the elasticities, compute the control coefficients, and reconstruct a kinetic model with consistent reversible rate laws. Some of the model variables are manually chosen, fitted to data, or optimised, while the others are computed from them. The resulting model ensemble allows for probabilistic predictions, for instance, about possible dynamic behaviour. By adding more data or tighter constraints, the predictions can be made more precise. Model variants differing in network structure, flux distributions, thermodynamic forces, regulation, or rate laws can be realised by different model ensembles and compared by significance tests. The thermodynamic forces have specific effects on flux control, on the synergisms between enzymes, and on the emergence and propagation of metabolite fluctuations. Large kinetic models could help to simulate global metabolic dynamics and to predict the effects of enzyme inhibition, differential expression, genetic modifications, and their combinations on metabolic fluxes. MATLAB code for elasticity sampling is freely available

    Extending the linear-noise approximation to biochemical systems influenced by intrinsic noise and slow lognormally distributed extrinsic noise

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    It is well known that the kinetics of an intracellular biochemical network is stochastic. This is due to intrinsic noise arising from the random timing of biochemical reactions in the network as well as due to extrinsic noise stemming from the interaction of unknown molecular components with the network and from the cell's changing environment. While there are many methods to study the effect of intrinsic noise on the system dynamics, few exist to study the influence of both types of noise. Here we show how one can extend the conventional linear-noise approximation to allow for the rapid evaluation of the molecule numbers statistics of a biochemical network influenced by intrinsic noise and by slow lognormally distributed extrinsic noise. The theory is applied to simple models of gene regulatory networks and its validity confirmed by comparison with exact stochastic simulations. In particular we show how extrinsic noise modifies the dependence of the variance of the molecule number fluctuations on the rate constants, the mutual information between input and output signalling molecules and the robustness of feed-forward loop motifs.Comment: 43 pages, 4 figure

    Forward Flux Sampling for rare event simulations

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    Rare events are ubiquitous in many different fields, yet they are notoriously difficult to simulate because few, if any, events are observed in a conventiona l simulation run. Over the past several decades, specialised simulation methods have been developed to overcome this problem. We review one recently-developed class of such methods, known as Forward Flux Sampling. Forward Flux Sampling uses a series of interfaces between the initial and final states to calculate rate constants and generate transition paths, for rare events in equilibrium or nonequilibrium systems with stochastic dynamics. This review draws together a number of recent advances, summarizes several applications of the method and highlights challenges that remain to be overcome.Comment: minor typos in the manuscript. J.Phys.:Condensed Matter (accepted for publication

    Asymptotic analysis of noisy fitness maximization, applied to metabolism and growth

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    We consider a population dynamics model coupling cell growth to a diffusion in the space of metabolic phenotypes as it can be obtained from realistic constraints-based modelling. In the asymptotic regime of slow diffusion, that coincides with the relevant experimental range, the resulting non-linear Fokker-Planck equation is solved for the steady state in the WKB approximation that maps it into the ground state of a quantum particle in an Airy potential plus a centrifugal term. We retrieve scaling laws for growth rate fluctuations and time response with respect to the distance from the maximum growth rate suggesting that suboptimal populations can have a faster response to perturbations.Comment: 24 pages, 6 figure

    Learning and Designing Stochastic Processes from Logical Constraints

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    Stochastic processes offer a flexible mathematical formalism to model and reason about systems. Most analysis tools, however, start from the premises that models are fully specified, so that any parameters controlling the system's dynamics must be known exactly. As this is seldom the case, many methods have been devised over the last decade to infer (learn) such parameters from observations of the state of the system. In this paper, we depart from this approach by assuming that our observations are {\it qualitative} properties encoded as satisfaction of linear temporal logic formulae, as opposed to quantitative observations of the state of the system. An important feature of this approach is that it unifies naturally the system identification and the system design problems, where the properties, instead of observations, represent requirements to be satisfied. We develop a principled statistical estimation procedure based on maximising the likelihood of the system's parameters, using recent ideas from statistical machine learning. We demonstrate the efficacy and broad applicability of our method on a range of simple but non-trivial examples, including rumour spreading in social networks and hybrid models of gene regulation

    Identifying stochastic oscillations in single-cell live imaging time series using Gaussian processes

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    Multiple biological processes are driven by oscillatory gene expression at different time scales. Pulsatile dynamics are thought to be widespread, and single-cell live imaging of gene expression has lead to a surge of dynamic, possibly oscillatory, data for different gene networks. However, the regulation of gene expression at the level of an individual cell involves reactions between finite numbers of molecules, and this can result in inherent randomness in expression dynamics, which blurs the boundaries between aperiodic fluctuations and noisy oscillators. Thus, there is an acute need for an objective statistical method for classifying whether an experimentally derived noisy time series is periodic. Here we present a new data analysis method that combines mechanistic stochastic modelling with the powerful methods of non-parametric regression with Gaussian processes. Our method can distinguish oscillatory gene expression from random fluctuations of non-oscillatory expression in single-cell time series, despite peak-to-peak variability in period and amplitude of single-cell oscillations. We show that our method outperforms the Lomb-Scargle periodogram in successfully classifying cells as oscillatory or non-oscillatory in data simulated from a simple genetic oscillator model and in experimental data. Analysis of bioluminescent live cell imaging shows a significantly greater number of oscillatory cells when luciferase is driven by a {\it Hes1} promoter (10/19), which has previously been reported to oscillate, than the constitutive MoMuLV 5' LTR (MMLV) promoter (0/25). The method can be applied to data from any gene network to both quantify the proportion of oscillating cells within a population and to measure the period and quality of oscillations. It is publicly available as a MATLAB package.Comment: 36 pages, 17 figure

    Towards Understanding the Origin of Genetic Languages

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    Molecular biology is a nanotechnology that works--it has worked for billions of years and in an amazing variety of circumstances. At its core is a system for acquiring, processing and communicating information that is universal, from viruses and bacteria to human beings. Advances in genetics and experience in designing computers have taken us to a stage where we can understand the optimisation principles at the root of this system, from the availability of basic building blocks to the execution of tasks. The languages of DNA and proteins are argued to be the optimal solutions to the information processing tasks they carry out. The analysis also suggests simpler predecessors to these languages, and provides fascinating clues about their origin. Obviously, a comprehensive unraveling of the puzzle of life would have a lot to say about what we may design or convert ourselves into.Comment: (v1) 33 pages, contributed chapter to "Quantum Aspects of Life", edited by D. Abbott, P. Davies and A. Pati, (v2) published version with some editin

    Information theoretic framework for stochastic sensitivity and specificity analysis in biochemical networks

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    Biochemical reaction networks involve many chemical species and are inherently stochastic and complex in nature. Reliable and organised functioning of such systems in varied environments requires that their behaviour is robust with respect to certain parameters while sensitive to other variations, and that they exhibit specific responses to various stimuli. There is a continuous need for improved models and methodologies to unravel the complex behaviour of the dynamics of such systems. In this thesis, we apply ideas from information theory to develop novel methods to study properties of biochemical networks. In the first part of the thesis, a framework for the study of parametric sensitivity in stochastic models of biochemical networks using entropies and mutual information is developed. The concept of noise entropy is introduced and its interplay with parametric sensitivity is studied as the system becomes more stochastic. Using the methodology for gene expression models, it is shown that noise can change the sensitivities of the system at var- ious orders of parameter interaction. An approximate and computationally more efficient way of calculating the sensitivities is also developed using unscented transform. Finally, the methodology is applied to a circadian clock model, illustrating the applicability of the approach to more complex systems. In the second part of the thesis, a novel method for specificity quantification in a receptor-ligand binding system is proposed in terms of mutual information estimates be- tween appropriate stimulus and system response. The maximum specificity of 2 × 2 affinity matrices in a parametric setup is theoretically studied. Parameter optimisation methodology and specificity upper bounds are presented for maximum specificity estimates of a given affinity matrix. The quantification framework is then applied to experimental data from T-Cell signalling. Finally, generalisation of the scheme for stochastic systems is discussed.Open Acces
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