Flux imbalance analysis and the sensitivity of cellular growth to changes in metabolite pools

Stoichiometric models of metabolism, such as flux balance analysis (FBA), are classically applied to predicting steady state rates - or fluxes - of metabolic reactions in genome-scale metabolic networks. Here we revisit the central assumption of FBA, i.e. that intracellular metabolites are at steady state, and show that deviations from flux balance (i.e. flux imbalances) are informative of some features of in vivo metabolite concentrations. Mathematically, the sensitivity of FBA to these flux imbalances is captured by a native feature of linear optimization, the dual problem, and its corresponding variables, known as shadow prices. First, using recently published data on chemostat growth of Saccharomyces cerevisae under different nutrient limitations, we show that shadow prices anticorrelate with experimentally measured degrees of growth limitation of intracellular metabolites. We next hypothesize that metabolites which are limiting for growth (and thus have very negative shadow price) cannot vary dramatically in an uncontrolled way, and must respond rapidly to perturbations. Using a collection of published datasets monitoring the time-dependent metabolomic response of Escherichia coli to carbon and nitrogen perturbations, we test this hypothesis and find that metabolites with negative shadow price indeed show lower temporal variation following a perturbation than metabolites with zero shadow price. Finally, we illustrate the broader applicability of flux imbalance analysis to other constraint-based methods. In particular, we explore the biological significance of shadow prices in a constraint-based method for integrating gene expression data with a stoichiometric model. In this case, shadow prices point to metabolites that should rise or drop in concentration in order to increase consistency between flux predictions and gene expression data. In general, these results suggest that the sensitivity of metabolic optima to violations of the steady state constraints carries biologically significant information on the processes that control intracellular metabolites in the cell.Published versio

Efficient Gaussian Sampling for Solving Large-Scale Inverse Problems using MCMC Methods

The resolution of many large-scale inverse problems using MCMC methods requires a step of drawing samples from a high dimensional Gaussian distribution. While direct Gaussian sampling techniques, such as those based on Cholesky factorization, induce an excessive numerical complexity and memory requirement, sequential coordinate sampling methods present a low rate of convergence. Based on the reversible jump Markov chain framework, this paper proposes an efficient Gaussian sampling algorithm having a reduced computation cost and memory usage. The main feature of the algorithm is to perform an approximate resolution of a linear system with a truncation level adjusted using a self-tuning adaptive scheme allowing to achieve the minimal computation cost. The connection between this algorithm and some existing strategies is discussed and its efficiency is illustrated on a linear inverse problem of image resolution enhancement.Comment: 20 pages, 10 figures, under review for journal publicatio

Robust localization methods for passivity enforcement of linear macromodels

In this paper we solve a non-smooth convex formulation for passivity enforcement of linear macromodels using robust localization based algorithms such as the ellipsoid and the cutting plane methods. Differently from existing perturbation based techniques, we solve the formulation based on the direct ℌ∞ norm minimization through perturbation of state-space model parameters. We provide a systematic way of defining an initial set which is guaranteed to contain the global optimum. We also provide a lower bound on the global minimum, that grows tighter at each iteration and hence guarantees δ - optimality of the computed solution. We demonstrate the robustness of our implementation by generating accurate passive models for challenging examples for which existing algorithms either failed or exhibited extremely slow convergenc

Differential-Algebraic Equations and Beyond: From Smooth to Nonsmooth Constrained Dynamical Systems

The present article presents a summarizing view at differential-algebraic equations (DAEs) and analyzes how new application fields and corresponding mathematical models lead to innovations both in theory and in numerical analysis for this problem class. Recent numerical methods for nonsmooth dynamical systems subject to unilateral contact and friction illustrate the topicality of this development.Comment: Preprint of Book Chapte

Inferring Multiple Graphical Structures

Gaussian Graphical Models provide a convenient framework for representing dependencies between variables. Recently, this tool has received a high interest for the discovery of biological networks. The literature focuses on the case where a single network is inferred from a set of measurements, but, as wetlab data is typically scarce, several assays, where the experimental conditions affect interactions, are usually merged to infer a single network. In this paper, we propose two approaches for estimating multiple related graphs, by rendering the closeness assumption into an empirical prior or group penalties. We provide quantitative results demonstrating the benefits of the proposed approaches. The methods presented in this paper are embeded in the R package 'simone' from version 1.0-0 and later