Search

Introduction The human genome-scale metabolic reconstruction details all known metabolic reactions occurring in humans, and thereby holds substantial promise for studying complex diseases and phenotypes. Capturing the whole human metabolic reconstruction is an on-going task and since the last community effort generated a consensus reconstruction, several updates have been developed. Objectives We report a new consensus version, Recon 2.2, which integrates various alternative versions with significant additional updates. In addition to re-establishing a consensus reconstruction, further key objectives included providing more comprehensive annotation of metabolites and genes, ensuring full mass and charge balance in all reactions, and developing a model that correctly predicts ATP production on a range of carbon sources. Methods Recon 2.2 has been developed through a combination of manual curation and automated error checking. Specific and significant manual updates include a respecification of fatty acid metabolism, oxidative phosphorylation and a coupling of the electron transport chain to ATP synthase activity. All metabolites have definitive chemical formulae and charges specified, and these are used to ensure full mass and charge reaction balancing through an automated linear programming approach. Additionally, improved integration with transcriptomics and proteomics data has been facilitated with the updated curation of relationships between genes, proteins and reactions. Results Recon 2.2 now represents the most predictive model of human metabolism to date as demonstrated here. Extensive manual curation has increased the reconstruction size to 5324 metabolites, 7785 reactions and 1675 associated genes, which now are mapped to a single standard. The focus upon mass and charge balancing of all reactions, along with better representation of energy generation, has produced a flux model that correctly predicts ATP yield on different carbon sources. Conclusion Throug

The human genome-scale metabolic reconstruction details all known metabolic reactions occurring in humans, and thereby holds substantial promise for studying complex diseases and phenotypes. Capturing the whole human metabolic reconstruction is an on-going task and since the last community effort generated a consensus reconstruction, several updates have been developed.

Learning curves have been proposed as an adequate description of learning processes, no matter whether the processes manifest within minutes or across years. Different mechanisms underlying skill acquisition can lead to differences in the shape of learning curves. In the current study, we analyze the tournament performance data of 1383 chess players who begin competing at young age and play tournaments for at least 10 years. We analyze the performance development with the goal to test the adequacy of learning curves, and the skill acquisition theories they are based on, for describing and predicting expertise acquisition. On the one hand, we show that the skill acquisition theories implying a negative exponential learning curve do a better job in both describing early performance gains and predicting later trajectories of chess performance than those theories implying a power function learning curve. On the other hand, the learning curves of a large proportion of players show systematic qualitative deviations from the predictions of either type of skill acquisition theory. While skill acquisition theories predict larger performance gains in early years and smaller gains in later years, a substantial number of players begin to show substantial improvements with a delay of several years (and no improvement in the first years), deviations not fully accounted for by quantity of practice. The current work adds to the debate on how learning processes on a small time scale combine to large-scale changes., Peer Reviewed

We present an experimental and computational pipeline for the generation of kinetic models of metabolism, and demonstrate its application to glycolysis in Saccharomyces cerevisiae. Starting from an approximate mathematical model, we employ a ‘‘cycle of knowledge’’ strategy, identifying the steps with most control over flux. Kinetic parameters of the individual isoenzymes within these steps are measured experimentally under a standardised set of conditions. Experimental strategies are applied to establish a set of in vivo concentrations for isoenzymes and metabolites. The data are integrated into a mathematical model that is used to predict a new set of metabolite concentrations and reevaluate the control properties of the system. This bottom-up modelling study reveals that control over the metabolic network most directly involved in yeast glycolysis is more widely distributed than previously thought.

The quantitative effects of environmental and genetic perturbations on metabolism can be studied in silico using kinetic models. We present a strategy for large-scale model construction based on a logical layering of data such as reaction fluxes, metabolite concentrations, and kinetic constants. The resulting models contain realistic standard rate laws and plausible parameters, adhere to the laws of thermodynamics, and reproduce a predefined steady state. These features have not been simultaneously achieved by previous workflows. We demonstrate the advantages and limitations of the workflow by translating the yeast consensus metabolic network into a kinetic model. Despite crudely selected data, the model shows realistic control behaviour, a stable dynamic, and realistic response to perturbations in extracellular glucose concentrations. The paper concludes by outlining how new data can continuously be fed into the workflow and how iterative model building can assist in directing experiments.

One of the goals of Systems Biology is to develop and utilise high-throughput methods for the measurement of parameters and concentrations on a genome-wide scale, while at the same time generating predictive models for system behaviour. In studying genome-scale metabolic networks, the task of exhaustively assaying and measuring all reaction components can be daunting, because hundreds or even thousands of enzymes (activities and concentrations) need to be considered for the construction of a full-scale, detailed model. There is a clear need for strategies that allow us to systematically select the subsets of pathways and reactions which should be prioritized when studying metabolism. We present a methodology for selecting those reactions that carry the overwhelming majority of the carbon flux through the metabolic network. The recent community-driven reconstruction of the metabolic network of baker’s yeast [1] provides the basis for our analysis. Flux Balance Analysis provides a theoretical flux distribution. Results are constrained with GC-MS exometabolomic measurements of the carbon flux. Flux calculations can also be improved by using 13C measurements to determine intracellular metabolic fluxes. The solution of the constrained FBA problem gives us a ranked list of reactions, based on the amount of carbon flux through each reaction. We improve the specificity of the method further by performing an Elementary Flux Mode analysis, which provides us with target pathways consisting of the reactions that carry the most carbon flux. Our methodology allows us to cover more than 95% of the carbon flux by studying but a small subset of the reactions of the genome-scale metabolic network of baker’s yeast.