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1.  Severe hypoxemia during veno-venous extracorporeal membrane oxygenation: exploring the limits of extracorporeal respiratory support 
Clinics  2014;69(3):173-178.
OBJECTIVE:
Veno-venous extracorporeal oxygenation for respiratory support has emerged as a rescue alternative for patients with hypoxemia. However, in some patients with more severe lung injury, extracorporeal support fails to restore arterial oxygenation. Based on four clinical vignettes, the aims of this article were to describe the pathophysiology of this concerning problem and to discuss possibilities for hypoxemia resolution.
METHODS:
Considering the main reasons and rationale for hypoxemia during veno-venous extracorporeal membrane oxygenation, some possible bedside solutions must be considered: 1) optimization of extracorporeal membrane oxygenation blood flow; 2) identification of recirculation and cannula repositioning if necessary; 3) optimization of residual lung function and consideration of blood transfusion; 4) diagnosis of oxygenator dysfunction and consideration of its replacement; and finally 5) optimization of the ratio of extracorporeal membrane oxygenation blood flow to cardiac output, based on the reduction of cardiac output.
CONCLUSION:
Therefore, based on the pathophysiology of hypoxemia during veno-venous extracorporeal oxygenation support, we propose a stepwise approach to help guide specific interventions.
doi:10.6061/clinics/2014(03)05
PMCID: PMC3935134  PMID: 24626942
Extracorporeal Membrane Oxygenation; Hypoxemia; Respiratory Failure; Respiratory Insufficiency
2.  What Can We Learn from Global Sensitivity Analysis of Biochemical Systems? 
PLoS ONE  2013;8(11):e79244.
Most biological models of intermediate size, and probably all large models, need to cope with the fact that many of their parameter values are unknown. In addition, it may not be possible to identify these values unambiguously on the basis of experimental data. This poses the question how reliable predictions made using such models are. Sensitivity analysis is commonly used to measure the impact of each model parameter on its variables. However, the results of such analyses can be dependent on an exact set of parameter values due to nonlinearity. To mitigate this problem, global sensitivity analysis techniques are used to calculate parameter sensitivities in a wider parameter space. We applied global sensitivity analysis to a selection of five signalling and metabolic models, several of which incorporate experimentally well-determined parameters. Assuming these models represent physiological reality, we explored how the results could change under increasing amounts of parameter uncertainty. Our results show that parameter sensitivities calculated with the physiological parameter values are not necessarily the most frequently observed under random sampling, even in a small interval around the physiological values. Often multimodal distributions were observed. Unsurprisingly, the range of possible sensitivity coefficient values increased with the level of parameter uncertainty, though the amount of parameter uncertainty at which the pattern of control was able to change differed among the models analysed. We suggest that this level of uncertainty can be used as a global measure of model robustness. Finally a comparison of different global sensitivity analysis techniques shows that, if high-throughput computing resources are available, then random sampling may actually be the most suitable technique.
doi:10.1371/journal.pone.0079244
PMCID: PMC3828278  PMID: 24244458
3.  Systematic Construction of Kinetic Models from Genome-Scale Metabolic Networks 
PLoS ONE  2013;8(11):e79195.
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.
doi:10.1371/journal.pone.0079195
PMCID: PMC3852239  PMID: 24324546
4.  A Computational Model of Liver Iron Metabolism 
PLoS Computational Biology  2013;9(11):e1003299.
Iron is essential for all known life due to its redox properties; however, these same properties can also lead to its toxicity in overload through the production of reactive oxygen species. Robust systemic and cellular control are required to maintain safe levels of iron, and the liver seems to be where this regulation is mainly located. Iron misregulation is implicated in many diseases, and as our understanding of iron metabolism improves, the list of iron-related disorders grows. Recent developments have resulted in greater knowledge of the fate of iron in the body and have led to a detailed map of its metabolism; however, a quantitative understanding at the systems level of how its components interact to produce tight regulation remains elusive. A mechanistic computational model of human liver iron metabolism, which includes the core regulatory components, is presented here. It was constructed based on known mechanisms of regulation and on their kinetic properties, obtained from several publications. The model was then quantitatively validated by comparing its results with previously published physiological data, and it is able to reproduce multiple experimental findings. A time course simulation following an oral dose of iron was compared to a clinical time course study and the simulation was found to recreate the dynamics and time scale of the systems response to iron challenge. A disease state simulation of haemochromatosis was created by altering a single reaction parameter that mimics a human haemochromatosis gene (HFE) mutation. The simulation provides a quantitative understanding of the liver iron overload that arises in this disease. This model supports and supplements understanding of the role of the liver as an iron sensor and provides a framework for further modelling, including simulations to identify valuable drug targets and design of experiments to improve further our knowledge of this system.
Author Summary
Iron is an essential nutrient required for healthy life but, in excess, is the cause of debilitating and even fatal conditions. The most common genetic disorder in humans caused by a mutation, haemochromatosis, results in an iron overload in the liver. Indeed, the liver plays a central role in the regulation of iron. Recently, an increasing amount of detail has been discovered about molecules related to iron metabolism, but an understanding of how they work together and regulate iron levels (in healthy people) or fail to do it (in disease) is still missing. We present a mathematical model of the regulation of liver iron metabolism that provides explanations of its dynamics and allows further hypotheses to be formulated and later tested in experiments. Importantly, the model reproduces accurately the healthy liver iron homeostasis and simulates haemochromatosis, showing how the causative mutation leads to iron overload. We investigate how best to control iron regulation and identified reactions that can be targets of new medicines to treat iron overload. The model provides a virtual laboratory for investigating iron metabolism and improves understanding of the method by which the liver senses and controls iron levels.
doi:10.1371/journal.pcbi.1003299
PMCID: PMC3820522  PMID: 24244122
5.  The Genome-Wide Early Temporal Response of Saccharomyces cerevisiae to Oxidative Stress Induced by Cumene Hydroperoxide 
PLoS ONE  2013;8(9):e74939.
Oxidative stress is a well-known biological process that occurs in all respiring cells and is involved in pathophysiological processes such as aging and apoptosis. Oxidative stress agents include peroxides such as hydrogen peroxide, cumene hydroperoxide, and linoleic acid hydroperoxide, the thiol oxidant diamide, and menadione, a generator of superoxide, amongst others. The present study analyzed the early temporal genome-wide transcriptional response of Saccharomyces cerevisiae to oxidative stress induced by the aromatic peroxide cumene hydroperoxide. The accurate dataset obtained, supported by the use of temporal controls, biological replicates and well controlled growth conditions, provided a detailed picture of the early dynamics of the process. We identified a set of genes previously not implicated in the oxidative stress response, including several transcriptional regulators showing a fast transient response, suggesting a coordinated process in the transcriptional reprogramming. We discuss the role of the glutathione, thioredoxin and reactive oxygen species-removing systems, the proteasome and the pentose phosphate pathway. A data-driven clustering of the expression patterns identified one specific cluster that mostly consisted of genes known to be regulated by the Yap1p and Skn7p transcription factors, emphasizing their mediator role in the transcriptional response to oxidants. Comparison of our results with data reported for hydrogen peroxide identified 664 genes that specifically respond to cumene hydroperoxide, suggesting distinct transcriptional responses to these two peroxides. Genes up-regulated only by cumene hydroperoxide are mainly related to the cell membrane and cell wall, and proteolysis process, while those down-regulated only by this aromatic peroxide are involved in mitochondrial function.
doi:10.1371/journal.pone.0074939
PMCID: PMC3779239  PMID: 24073228
6.  A model of yeast glycolysis based on a consistent kinetic characterisation of all its enzymes 
Febs Letters  2013;587(17):2832-2841.
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.
doi:10.1016/j.febslet.2013.06.043
PMCID: PMC3764422  PMID: 23831062
Glycolysis; Systems biology; Enzyme kinetic; Isoenzyme; Modelling
7.  An analysis of a ‘community-driven’ reconstruction of the human metabolic network 
Metabolomics  2013;9(4):757-764.
Following a strategy similar to that used in baker’s yeast (Herrgård et al. Nat Biotechnol 26:1155–1160, 2008). A consensus yeast metabolic network obtained from a community approach to systems biology (Herrgård et al. 2008; Dobson et al. BMC Syst Biol 4:145, 2010). Further developments towards a genome-scale metabolic model of yeast (Dobson et al. 2010; Heavner et al. BMC Syst Biol 6:55, 2012). Yeast 5—an expanded reconstruction of the Saccharomyces cerevisiae metabolic network (Heavner et al. 2012) and in Salmonella typhimurium (Thiele et al. BMC Syst Biol 5:8, 2011). A community effort towards a knowledge-base and mathematical model of the human pathogen Salmonellatyphimurium LT2 (Thiele et al. 2011), a recent paper (Thiele et al. Nat Biotechnol 31:419–425, 2013). A community-driven global reconstruction of human metabolism (Thiele et al. 2013) described a much improved ‘community consensus’ reconstruction of the human metabolic network, called Recon 2, and the authors (that include the present ones) have made it freely available via a database at http://humanmetabolism.org/ and in SBML format at Biomodels (http://identifiers.org/biomodels.db/MODEL1109130000). This short analysis summarises the main findings, and suggests some approaches that will be able to exploit the availability of this model to advantage.
doi:10.1007/s11306-013-0564-3
PMCID: PMC3715687  PMID: 23888127
Metabolism; Modelling; Systems biology; Networks; Metabolic networks
8.  The Variability of the Serve Toss in Tennis Under the Influence of Artificial Crosswind 
This study was made to analyze the variability and stability of the serve toss in tennis, on the x (side-to-side), y (back-to-front) and z (vertical) axes, with 12 experienced players under the influence of crosswind (induced aerodynamic flow) produced by an industrial ventilator. The players were analyzed individually after serving at maximum speed and accuracy to the intersection point of the centre line and service line (“T ”point). The results allow us to conclude that the experienced players tend to stabilize the vertical dimension of the service (z axis). Additionally, this study confirms the invariability of the player height ratio: height of impact (1:1.5) in experienced players even when constrained by the “artificial crosswind. ”Given the above, the vertical dimension of the tennis serve is assumed as a constant feature, which is guaranteed in the remaining varying dimensions (y and x axes) of the ball toss. Thus, the variability should be seen as part of the solution and not as something to be avoided by players and coaches.
Key PointsAnalysis of the tennis serve variability under the effect of artificial crosswindTwelve experienced tennis players performed a set of 20 free serves (without wind constraints), and four other sets of 20 serves under different practice conditions (with different crosswind intensities)The players tend to stabilize in the z axis and vary in the y- (back-to-front) and x-axes (side-to-side) during the ball toss tennis serve in all the practice conditions (with and without crosswind)The maintenance of a player height ratio: impact height of approximately 1:1.5 in experienced players, even when constrained by “artificial crosswind”.
PMCID: PMC3761841  PMID: 24149810
Variability; tennis serve; performance; crosswind; motor control
9.  A Method for Comparing Multivariate Time Series with Different Dimensions 
PLoS ONE  2013;8(2):e54201.
In many situations it is desirable to compare dynamical systems based on their behavior. Similarity of behavior often implies similarity of internal mechanisms or dependency on common extrinsic factors. While there are widely used methods for comparing univariate time series, most dynamical systems are characterized by multivariate time series. Yet, comparison of multivariate time series has been limited to cases where they share a common dimensionality. A semi-metric is a distance function that has the properties of non-negativity, symmetry and reflexivity, but not sub-additivity. Here we develop a semi-metric – SMETS – that can be used for comparing groups of time series that may have different dimensions. To demonstrate its utility, the method is applied to dynamic models of biochemical networks and to portfolios of shares. The former is an example of a case where the dependencies between system variables are known, while in the latter the system is treated (and behaves) as a black box.
doi:10.1371/journal.pone.0054201
PMCID: PMC3564859  PMID: 23393554
10.  An in vivo control map for the eukaryotic mRNA translation machinery 
A new quantitative strategy has generated a comprehensive rate control map for protein synthesis in exponentially growing yeast cells. This analysis reveals the modularity of the system as well as highly non-stoichiometric relationships between components.
A ‘genetic titration' method has generated a map of the in vivo rate control properties of components of the protein synthesis machinery in Saccharomyces cerevisiae and has been used to parameterize a new comprehensive model of the translation pathway.The translation machinery is found to be a highly modular system in functional terms yet the intracellular concentrations of its components range from a few thousand to one million molecules per cell.This approach identifies non-intuitive features of the system such as the strongest rate control being exercised by high abundance elongation factors.The rate control analysis allows us to identify a surprising fine-control function for duplicated translation factor genes.
Rate control analysis defines the in vivo control map governing yeast protein synthesis and generates an extensively parameterized digital model of the translation pathway. Among other non-intuitive outcomes, translation demonstrates a high degree of functional modularity and comprises a non-stoichiometric combination of proteins manifesting functional convergence on a shared maximal translation rate. In exponentially growing cells, polypeptide elongation (eEF1A, eEF2, and eEF3) exerts the strongest control. The two other strong control points are recruitment of mRNA and tRNAi to the 40S ribosomal subunit (eIF4F and eIF2) and termination (eRF1; Dbp5). In contrast, factors that are found to promote mRNA scanning efficiency on a longer than-average 5′untranslated region (eIF1, eIF1A, Ded1, eIF2B, eIF3, and eIF5) exceed the levels required for maximal control. This is expected to allow the cell to minimize scanning transition times, particularly for longer 5′UTRs. The analysis reveals these and other collective adaptations of control shared across the factors, as well as features that reflect functional modularity and system robustness. Remarkably, gene duplication is implicated in the fine control of cellular protein synthesis.
doi:10.1038/msb.2012.73
PMCID: PMC3564266  PMID: 23340841
eukaryotic translation machinery; gene duplication; in vivo rate control; post-transcriptional gene expression; system modularity
11.  Effects of Ocean Acidification on the Ballast of Surface Aggregates Sinking through the Twilight Zone 
PLoS ONE  2012;7(12):e50865.
The dissolution of CaCO3 is one of the ways ocean acidification can, potentially, greatly affect the ballast of aggregates. A diminution of the ballast could reduce the settling speed of aggregates, resulting in a change in the carbon flux to the deep sea. This would mean lower amounts of more refractory organic matter reaching the ocean floor. This work aimed to determine the effect of ocean acidification on the ballast of sinking surface aggregates. Our hypothesis was that the decrease of pH will increase the dissolution of particulate inorganic carbon ballasting the aggregates, consequently reducing their settling velocity and increasing their residence time in the upper twilight zone. Using a new methodology for simulation of aggregate settling, our results suggest that future pCO2 conditions can significantly change the ballast composition of sinking aggregates. The change in aggregate composition had an effect on the size distribution of the aggregates, with a shift to smaller aggregates. A change also occurred in the settling velocity of the particles, which would lead to a higher residence time in the water column, where they could be continuously degraded. In the environment, such an effect would result in a reduction of the carbon flux to the deep-sea. This reduction would impact those benthic communities, which rely on the vertical flow of carbon as primary source of energy.
doi:10.1371/journal.pone.0050865
PMCID: PMC3525580  PMID: 23272075
13.  First-year experience of a Brazilian tertiary medical center in supporting severely ill patients using extracorporeal membrane oxygenation 
Clinics  2012;67(10):1157-1163.
OBJECTIVES:
The aim of this manuscript is to describe the first year of our experience using extracorporeal membrane oxygenation support.
METHODS:
Ten patients with severe refractory hypoxemia, two with associated severe cardiovascular failure, were supported using venous-venous extracorporeal membrane oxygenation (eight patients) or veno-arterial extracorporeal membrane oxygenation (two patients).
RESULTS:
The median age of the patients was 31 yr (range 14–71 yr). Their median simplified acute physiological score three (SAPS3) was 94 (range 84–118), and they had a median expected mortality of 95% (range 87–99%). Community-acquired pneumonia was the most common diagnosis (50%), followed by P. jiroveci pneumonia in two patients with AIDS (20%). Six patients were transferred from other ICUs during extracorporeal membrane oxygenation support, three of whom were transferred between ICUs within the hospital (30%), two by ambulance (20%) and one by helicopter (10%). Only one patient (10%) was anticoagulated with heparin throughout extracorporeal membrane oxygenation support. Eighty percent of patients required continuous venous-venous hemofiltration. Three patients (30%) developed persistent hypoxemia, which was corrected using higher positive end-expiratory pressure, higher inspired oxygen fractions, recruitment maneuvers, and nitric oxide. The median time on extracorporeal membrane oxygenation support was five (range 3–32) days. The median length of the hospital stay was 31 (range 3-97) days. Four patients (40%) survived to 60 days, and they were free from renal replacement therapy and oxygen support.
CONCLUSIONS:
The use of extracorporeal membrane oxygenation support in severely ill patients is possible in the presence of a structured team. Efforts must be made to recognize the necessity of extracorporeal respiratory support at an early stage and to prompt activation of the extracorporeal membrane oxygenation team.
doi:10.6061/clinics/2012(10)07
PMCID: PMC3460018  PMID: 23070342
Extracorporeal Membrane Oxygenation; Respiratory Failure; Mechanical Ventilation; Patient Care Team; Intensive Care Unit
14.  Condor-COPASI: high-throughput computing for biochemical networks 
BMC Systems Biology  2012;6:91.
Background
Mathematical modelling has become a standard technique to improve our understanding of complex biological systems. As models become larger and more complex, simulations and analyses require increasing amounts of computational power. Clusters of computers in a high-throughput computing environment can help to provide the resources required for computationally expensive model analysis. However, exploiting such a system can be difficult for users without the necessary expertise.
Results
We present Condor-COPASI, a server-based software tool that integrates COPASI, a biological pathway simulation tool, with Condor, a high-throughput computing environment. Condor-COPASI provides a web-based interface, which makes it extremely easy for a user to run a number of model simulation and analysis tasks in parallel. Tasks are transparently split into smaller parts, and submitted for execution on a Condor pool. Result output is presented to the user in a number of formats, including tables and interactive graphical displays.
Conclusions
Condor-COPASI can effectively use a Condor high-throughput computing environment to provide significant gains in performance for a number of model simulation and analysis tasks. Condor-COPASI is free, open source software, released under the Artistic License 2.0, and is suitable for use by any institution with access to a Condor pool. Source code is freely available for download at http://code.google.com/p/condor-copasi/, along with full instructions on deployment and usage.
doi:10.1186/1752-0509-6-91
PMCID: PMC3527284  PMID: 22834945
Systems biology; Computational modelling; High-throughput computing; Distributed computing; Simulation
15.  Biochemical fluctuations, optimisation and the linear noise approximation 
BMC Systems Biology  2012;6:86.
Background
Stochastic fluctuations in molecular numbers have been in many cases shown to be crucial for the understanding of biochemical systems. However, the systematic study of these fluctuations is severely hindered by the high computational demand of stochastic simulation algorithms. This is particularly problematic when, as is often the case, some or many model parameters are not well known. Here, we propose a solution to this problem, namely a combination of the linear noise approximation with optimisation methods. The linear noise approximation is used to efficiently estimate the covariances of particle numbers in the system. Combining it with optimisation methods in a closed-loop to find extrema of covariances within a possibly high-dimensional parameter space allows us to answer various questions. Examples are, what is the lowest amplitude of stochastic fluctuations possible within given parameter ranges? Or, which specific changes of parameter values lead to the increase of the correlation between certain chemical species? Unlike stochastic simulation methods, this has no requirement for small numbers of molecules and thus can be applied to cases where stochastic simulation is prohibitive.
Results
We implemented our strategy in the software COPASI and show its applicability on two different models of mitogen-activated kinases (MAPK) signalling -- one generic model of extracellular signal-regulated kinases (ERK) and one model of signalling via p38 MAPK. Using our method we were able to quickly find local maxima of covariances between particle numbers in the ERK model depending on the activities of phospho-MKKK and its corresponding phosphatase. With the p38 MAPK model our method was able to efficiently find conditions under which the coefficient of variation of the output of the signalling system, namely the particle number of Hsp27, could be minimised. We also investigated correlations between the two parallel signalling branches (MKK3 and MKK6) in this model.
Conclusions
Our strategy is a practical method for the efficient investigation of fluctuations in biochemical models even when some or many of the model parameters have not yet been fully characterised.
doi:10.1186/1752-0509-6-86
PMCID: PMC3814289  PMID: 22805626
Linear noise approximation; Optimisation; Mitogen-activated kinases signalling; COPASI; Intrinsic noise; Stochastic biochemical models; Systems biology
16.  Improving metabolic flux predictions using absolute gene expression data 
BMC Systems Biology  2012;6:73.
Background
Constraint-based analysis of genome-scale metabolic models typically relies upon maximisation of a cellular objective function such as the rate or efficiency of biomass production. Whilst this assumption may be valid in the case of microorganisms growing under certain conditions, it is likely invalid in general, and especially for multicellular organisms, where cellular objectives differ greatly both between and within cell types. Moreover, for the purposes of biotechnological applications, it is normally the flux to a specific metabolite or product that is of interest rather than the rate of production of biomass per se.
Results
An alternative objective function is presented, that is based upon maximising the correlation between experimentally measured absolute gene expression data and predicted internal reaction fluxes. Using quantitative transcriptomics data acquired from Saccharomyces cerevisiae cultures under two growth conditions, the method outperforms traditional approaches for predicting experimentally measured exometabolic flux that are reliant upon maximisation of the rate of biomass production.
Conclusion
Due to its improved prediction of experimentally measured metabolic fluxes, and of its lack of a requirement for knowledge of the biomass composition of the organism under the conditions of interest, the approach is likely to be of rather general utility. The method has been shown to predict fluxes reliably in single cellular systems. Subsequent work will investigate the method’s ability to generate condition- and tissue-specific flux predictions in multicellular organisms.
doi:10.1186/1752-0509-6-73
PMCID: PMC3477026  PMID: 22713172
Flux balance analysis; Metabolic flux; Metabolic networks; Transcriptomics; RNA-Seq; Exometabolomics
17.  Yeast 5 – an expanded reconstruction of the Saccharomyces cerevisiae metabolic network 
BMC Systems Biology  2012;6:55.
Background
Efforts to improve the computational reconstruction of the Saccharomyces cerevisiae biochemical reaction network and to refine the stoichiometrically constrained metabolic models that can be derived from such a reconstruction have continued since the first stoichiometrically constrained yeast genome scale metabolic model was published in 2003. Continuing this ongoing process, we have constructed an update to the Yeast Consensus Reconstruction, Yeast 5. The Yeast Consensus Reconstruction is a product of efforts to forge a community-based reconstruction emphasizing standards compliance and biochemical accuracy via evidence-based selection of reactions. It draws upon models published by a variety of independent research groups as well as information obtained from biochemical databases and primary literature.
Results
Yeast 5 refines the biochemical reactions included in the reconstruction, particularly reactions involved in sphingolipid metabolism; updates gene-reaction annotations; and emphasizes the distinction between reconstruction and stoichiometrically constrained model. Although it was not a primary goal, this update also improves the accuracy of model prediction of viability and auxotrophy phenotypes and increases the number of epistatic interactions. This update maintains an emphasis on standards compliance, unambiguous metabolite naming, and computer-readable annotations available through a structured document format. Additionally, we have developed MATLAB scripts to evaluate the model’s predictive accuracy and to demonstrate basic model applications such as simulating aerobic and anaerobic growth. These scripts, which provide an independent tool for evaluating the performance of various stoichiometrically constrained yeast metabolic models using flux balance analysis, are included as Additional files 1, 2 and 3.
Conclusions
Yeast 5 expands and refines the computational reconstruction of yeast metabolism and improves the predictive accuracy of a stoichiometrically constrained yeast metabolic model. It differs from previous reconstructions and models by emphasizing the distinction between the yeast metabolic reconstruction and the stoichiometrically constrained model, and makes both available as Additional file 4 and Additional file 5 and at http://yeast.sf.net/ as separate systems biology markup language (SBML) files. Through this separation, we intend to make the modeling process more accessible, explicit, transparent, and reproducible.
doi:10.1186/1752-0509-6-55
PMCID: PMC3413506  PMID: 22663945
Metabolic; Reconstruction; Yeast; Flux balance analysis; GEM; GENRE; Model
18.  Efficient discovery of anti-inflammatory small molecule combinations using evolutionary computing 
Nature chemical biology  2011;7(12):902-908.
The control of biochemical fluxes is distributed and to perturb complex intracellular networks effectively it is often necessary to modulate several steps simultaneously. However, the number of possible permutations leads to a combinatorial explosion in the number of experiments that would have to be performed in a complete analysis. We used a multi-objective evolutionary algorithm (EA) to optimize reagent combinations from a dynamic chemical library of 33 compounds with established or predicted targets in the regulatory network controlling IL-1β expression. The EA converged on excellent solutions within 11 generations during which we studied just 550 combinations out of the potential search space of ~ 9 billion. The top five reagents with the greatest contribution to combinatorial effects throughout the EA were then optimized pairwise. A p38 MAPK inhibitor with either an inhibitor of IκB kinase or a chelator of poorly liganded iron yielded synergistic inhibition of macrophage IL-1β expression. Evolutionary searches provide a powerful and general approach to the discovery of novel combinations of pharmacological agents with potentially greater therapeutic indices than those of single drugs.
doi:10.1038/nchembio.689
PMCID: PMC3223407  PMID: 22020553
19.  Controlled vocabularies and semantics in systems biology 
The use of computational modeling to describe and analyze biological systems is at the heart of systems biology. This Perspective discusses the development and use of ontologies that are designed to add semantic information to computational models and simulations.
The use of computational modeling to describe and analyze biological systems is at the heart of systems biology. Model structures, simulation descriptions and numerical results can be encoded in structured formats, but there is an increasing need to provide an additional semantic layer. Semantic information adds meaning to components of structured descriptions to help identify and interpret them unambiguously. Ontologies are one of the tools frequently used for this purpose. We describe here three ontologies created specifically to address the needs of the systems biology community. The Systems Biology Ontology (SBO) provides semantic information about the model components. The Kinetic Simulation Algorithm Ontology (KiSAO) supplies information about existing algorithms available for the simulation of systems biology models, their characterization and interrelationships. The Terminology for the Description of Dynamics (TEDDY) categorizes dynamical features of the simulation results and general systems behavior. The provision of semantic information extends a model's longevity and facilitates its reuse. It provides useful insight into the biology of modeled processes, and may be used to make informed decisions on subsequent simulation experiments.
doi:10.1038/msb.2011.77
PMCID: PMC3261705  PMID: 22027554
dynamics; kinetics; model; ontology; simulation
20.  Bioinformatics tools for cancer metabolomics 
Metabolomics  2011;7(3):329-343.
It is well known that significant metabolic change take place as cells are transformed from normal to malignant. This review focuses on the use of different bioinformatics tools in cancer metabolomics studies. The article begins by describing different metabolomics technologies and data generation techniques. Overview of the data pre-processing techniques is provided and multivariate data analysis techniques are discussed and illustrated with case studies, including principal component analysis, clustering techniques, self-organizing maps, partial least squares, and discriminant function analysis. Also included is a discussion of available software packages.
doi:10.1007/s11306-010-0270-3
PMCID: PMC3155682  PMID: 21949492
Metabolomics; Cancer; Metabolite profiling; NMR; Mass spectrometry; Bioinformatics
21.  A Systems Biology View of Cancer 
Biochimica et biophysica acta  2009;1796(2):129-139.
SUMMARY
In order to understand how a cancer cell is functionally different from a normal cell it is necessary to assess the complex network of pathways involving gene regulation, signaling, and cell metabolism, and the alterations in its dynamics caused by the several different types of mutations leading to malignancy. Since the network is typically complex, with multiple connections between pathways and important feedback loops, it is crucial to represent it in the form of a computational model that can be used for a rigorous analysis. This is the approach of systems biology, made possible by new –omics data generation technologies. The goal of this review is to illustrate this approach and its utility for our understanding of cancer. After a discussion of recent progress using a network-centric approach, three case studies related to diagnostics, therapy, and drug development are presented in detail. They focus on breast cancer, B cell lymphomas, and colorectal cancer. The discussion is centered on key mathematical and computational tools common to a systems biology approach.
doi:10.1016/j.bbcan.2009.06.001
PMCID: PMC2782452  PMID: 19505535
systems biology; cancer; mathematical modeling
22.  Systematic integration of experimental data and models in systems biology 
BMC Bioinformatics  2010;11:582.
Background
The behaviour of biological systems can be deduced from their mathematical models. However, multiple sources of data in diverse forms are required in the construction of a model in order to define its components and their biochemical reactions, and corresponding parameters. Automating the assembly and use of systems biology models is dependent upon data integration processes involving the interoperation of data and analytical resources.
Results
Taverna workflows have been developed for the automated assembly of quantitative parameterised metabolic networks in the Systems Biology Markup Language (SBML). A SBML model is built in a systematic fashion by the workflows which starts with the construction of a qualitative network using data from a MIRIAM-compliant genome-scale model of yeast metabolism. This is followed by parameterisation of the SBML model with experimental data from two repositories, the SABIO-RK enzyme kinetics database and a database of quantitative experimental results. The models are then calibrated and simulated in workflows that call out to COPASIWS, the web service interface to the COPASI software application for analysing biochemical networks. These systems biology workflows were evaluated for their ability to construct a parameterised model of yeast glycolysis.
Conclusions
Distributed information about metabolic reactions that have been described to MIRIAM standards enables the automated assembly of quantitative systems biology models of metabolic networks based on user-defined criteria. Such data integration processes can be implemented as Taverna workflows to provide a rapid overview of the components and their relationships within a biochemical system.
doi:10.1186/1471-2105-11-582
PMCID: PMC3008707  PMID: 21114840
23.  Mining metabolites: extracting the yeast metabolome from the literature 
Metabolomics  2010;7(1):94-101.
Text mining methods have added considerably to our capacity to extract biological knowledge from the literature. Recently the field of systems biology has begun to model and simulate metabolic networks, requiring knowledge of the set of molecules involved. While genomics and proteomics technologies are able to supply the macromolecular parts list, the metabolites are less easily assembled. Most metabolites are known and reported through the scientific literature, rather than through large-scale experimental surveys. Thus it is important to recover them from the literature. Here we present a novel tool to automatically identify metabolite names in the literature, and associate structures where possible, to define the reported yeast metabolome. With ten-fold cross validation on a manually annotated corpus, our recognition tool generates an f-score of 78.49 (precision of 83.02) and demonstrates greater suitability in identifying metabolite names than other existing recognition tools for general chemical molecules. The metabolite recognition tool has been applied to the literature covering an important model organism, the yeast Saccharomyces cerevisiae, to define its reported metabolome. By coupling to ChemSpider, a major chemical database, we have identified structures for much of the reported metabolome and, where structure identification fails, been able to suggest extensions to ChemSpider. Our manually annotated gold-standard data on 296 abstracts are available as supplementary materials. Metabolite names and, where appropriate, structures are also available as supplementary materials.
Electronic supplementary material
The online version of this article (doi:10.1007/s11306-010-0251-6) contains supplementary material, which is available to authorized users.
doi:10.1007/s11306-010-0251-6
PMCID: PMC3111869  PMID: 21687783
Text mining; Named entity recognition; Yeast metabolome
24.  Further developments towards a genome-scale metabolic model of yeast 
BMC Systems Biology  2010;4:145.
Background
To date, several genome-scale network reconstructions have been used to describe the metabolism of the yeast Saccharomyces cerevisiae, each differing in scope and content. The recent community-driven reconstruction, while rigorously evidenced and well annotated, under-represented metabolite transport, lipid metabolism and other pathways, and was not amenable to constraint-based analyses because of lack of pathway connectivity.
Results
We have expanded the yeast network reconstruction to incorporate many new reactions from the literature and represented these in a well-annotated and standards-compliant manner. The new reconstruction comprises 1102 unique metabolic reactions involving 924 unique metabolites - significantly larger in scope than any previous reconstruction. The representation of lipid metabolism in particular has improved, with 234 out of 268 enzymes linked to lipid metabolism now present in at least one reaction. Connectivity is emphatically improved, with more than 90% of metabolites now reachable from the growth medium constituents. The present updates allow constraint-based analyses to be performed; viability predictions of single knockouts are comparable to results from in vivo experiments and to those of previous reconstructions.
Conclusions
We report the development of the most complete reconstruction of yeast metabolism to date that is based upon reliable literature evidence and richly annotated according to MIRIAM standards. The reconstruction is available in the Systems Biology Markup Language (SBML) and via a publicly accessible database http://www.comp-sys-bio.org/yeastnet/.
doi:10.1186/1752-0509-4-145
PMCID: PMC2988745  PMID: 21029416
25.  A General Map of Iron Metabolism and Tissue-specific Subnetworks 
Molecular bioSystems  2009;5(5):422-443.
Iron is required for survival of mammalian cells. Recently, understanding of iron metabolism and trafficking has increased dramatically, revealing a complex, interacting network largely unknown just a few years ago. This provides an excellent model for systems biology development and analysis. The first step in such an analysis is the construction of a structural network of iron metabolism, which we present here. This network was created using CellDesigner version 3.5.2 and includes reactions occurring in mammalian cells of numerous tissue types. The iron metabolic network contains 151 chemical species and 107 reactions and transport steps. Starting from this general model, we construct iron networks for specific tissues and cells that are fundamental to maintaining body iron homeostasis. We include subnetworks for cells of the intestine and liver, tissues important in iron uptake and storage, respectively; as well as the reticulocyte and macrophage, key cells in iron utilization and recycling. The addition of kinetic information to our structural network will permit the simulation of iron metabolism in different tissues as well as in health and disease.
doi:10.1039/b816714c
PMCID: PMC2680238  PMID: 19381358
iron; liver; macrophage; reactive oxygen species; red blood cells

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