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1.  ProbMetab: an R package for Bayesian probabilistic annotation of LC–MS-based metabolomics 
Bioinformatics  2014;30(9):1336-1337.
Summary: We present ProbMetab, an R package that promotes substantial improvement in automatic probabilistic liquid chromatography–mass spectrometry-based metabolome annotation. The inference engine core is based on a Bayesian model implemented to (i) allow diverse source of experimental data and metadata to be systematically incorporated into the model with alternative ways to calculate the likelihood function and (ii) allow sensitive selection of biologically meaningful biochemical reaction databases as Dirichlet-categorical prior distribution. Additionally, to ensure result interpretation by system biologists, we display the annotation in a network where observed mass peaks are connected if their candidate metabolites are substrate/product of known biochemical reactions. This graph can be overlaid with other graph-based analysis, such as partial correlation networks, in a visualization scheme exported to Cytoscape, with web and stand-alone versions.
Availability and implementation: ProbMetab was implemented in a modular manner to fit together with established upstream (xcms, CAMERA, AStream, mzMatch.R, etc) and downstream R package tools (GeneNet, RCytoscape, DiffCorr, etc). ProbMetab, along with extensive documentation and case studies, is freely available under GNU license at: http://labpib.fmrp.usp.br/methods/probmetab/.
Contact: rvencio@usp.br
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btu019
PMCID: PMC3998140  PMID: 24443383
2.  Telling metabolic stories to explore metabolomics data: a case study on the yeast response to cadmium exposure 
Bioinformatics  2013;30(1):61-70.
Motivation: The increasing availability of metabolomics data enables to better understand the metabolic processes involved in the immediate response of an organism to environmental changes and stress. The data usually come in the form of a list of metabolites whose concentrations significantly changed under some conditions, and are thus not easy to interpret without being able to precisely visualize how such metabolites are interconnected.
Results: We present a method that enables to organize the data from any metabolomics experiment into metabolic stories. Each story corresponds to a possible scenario explaining the flow of matter between the metabolites of interest. These scenarios may then be ranked in different ways depending on which interpretation one wishes to emphasize for the causal link between two affected metabolites: enzyme activation, enzyme inhibition or domino effect on the concentration changes of substrates and products. Equally probable stories under any selected ranking scheme can be further grouped into a single anthology that summarizes, in a unique subnetwork, all equivalently plausible alternative stories. An anthology is simply a union of such stories. We detail an application of the method to the response of yeast to cadmium exposure. We use this system as a proof of concept for our method, and we show that we are able to find a story that reproduces very well the current knowledge about the yeast response to cadmium. We further show that this response is mostly based on enzyme activation. We also provide a framework for exploring the alternative pathways or side effects this local response is expected to have in the rest of the network. We discuss several interpretations for the changes we see, and we suggest hypotheses that could in principle be experimentally tested. Noticeably, our method requires simple input data and could be used in a wide variety of applications.
Availability and implementation: The code for the method presented in this article is available at http://gobbolino.gforge.inria.fr.
Contact: pvmilreu@gmail.com; vincent.lacroix@univ-lyon1.fr; marie-france.sagot@inria.fr
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btt597
PMCID: PMC3866556  PMID: 24167155
3.  Flux Analysis of the Trypanosoma brucei Glycolysis Based on a Multiobjective-Criteria Bioinformatic Approach 
Advances in Bioinformatics  2012;2012:159423.
Trypanosoma brucei is a protozoan parasite of major of interest in discovering new genes for drug targets. This parasite alternates its life cycle between the mammal host(s) (bloodstream form) and the insect vector (procyclic form), with two divergent glucose metabolism amenable to in vitro culture. While the metabolic network of the bloodstream forms has been well characterized, the flux distribution between the different branches of the glucose metabolic network in the procyclic form has not been addressed so far. We present a computational analysis (called Metaboflux) that exploits the metabolic topology of the procyclic form, and allows the incorporation of multipurpose experimental data to increase the biological relevance of the model. The alternatives resulting from the structural complexity of networks are formulated as an optimization problem solved by a metaheuristic where experimental data are modeled in a multiobjective function. Our results show that the current metabolic model is in agreement with experimental data and confirms the observed high metabolic flexibility of glucose metabolism. In addition, Metaboflux offers a rational explanation for the high flexibility in the ratio between final products from glucose metabolism, thsat is, flux redistribution through the malic enzyme steps.
doi:10.1155/2012/159423
PMCID: PMC3477527  PMID: 23097667
4.  Intuitive Visualization and Analysis of Multi-Omics Data and Application to Escherichia coli Carbon Metabolism 
PLoS ONE  2011;6(6):e21318.
Combinations of ‘omics’ investigations (i.e, transcriptomic, proteomic, metabolomic and/or fluxomic) are increasingly applied to get comprehensive understanding of biological systems. Because the latter are organized as complex networks of molecular and functional interactions, the intuitive interpretation of multi-omics datasets is difficult. Here we describe a simple strategy to visualize and analyze multi-omics data. Graphical representations of complex biological networks can be generated using Cytoscape where all molecular and functional components could be explicitly represented using a set of dedicated symbols. This representation can be used i) to compile all biologically-relevant information regarding the network through web link association, and ii) to map the network components with multi-omics data. A Cytoscape plugin was developed to increase the possibilities of both multi-omic data representation and interpretation. This plugin allowed different adjustable colour scales to be applied to the various omics data and performed the automatic extraction and visualization of the most significant changes in the datasets. For illustration purpose, the approach was applied to the central carbon metabolism of Escherichia coli. The obtained network contained 774 components and 1232 interactions, highlighting the complexity of bacterial multi-level regulations. The structured representation of this network represents a valuable resource for systemic studies of E. coli, as illustrated from the application to multi-omics data. Some current issues in network representation are discussed on the basis of this work.
doi:10.1371/journal.pone.0021318
PMCID: PMC3120879  PMID: 21731702
5.  MetExplore: a web server to link metabolomic experiments and genome-scale metabolic networks 
Nucleic Acids Research  2010;38(Web Server issue):W132-W137.
High-throughput metabolomic experiments aim at identifying and ultimately quantifying all metabolites present in biological systems. The metabolites are interconnected through metabolic reactions, generally grouped into metabolic pathways. Classical metabolic maps provide a relational context to help interpret metabolomics experiments and a wide range of tools have been developed to help place metabolites within metabolic pathways. However, the representation of metabolites within separate disconnected pathways overlooks most of the connectivity of the metabolome. By definition, reference pathways cannot integrate novel pathways nor show relationships between metabolites that may be linked by common neighbours without being considered as joint members of a classical biochemical pathway. MetExplore is a web server that offers the possibility to link metabolites identified in untargeted metabolomics experiments within the context of genome-scale reconstructed metabolic networks. The analysis pipeline comprises mapping metabolomics data onto the specific metabolic network of an organism, then applying graph-based methods and advanced visualization tools to enhance data analysis. The MetExplore web server is freely accessible at http://metexplore.toulouse.inra.fr.
doi:10.1093/nar/gkq312
PMCID: PMC2896158  PMID: 20444866
6.  Use of reconstituted metabolic networks to assist in metabolomic data visualization and mining 
Metabolomics  2010;6(2):312-321.
Metabolomics experiments seldom achieve their aim of comprehensively covering the entire metabolome. However, important information can be gleaned even from sparse datasets, which can be facilitated by placing the results within the context of known metabolic networks. Here we present a method that allows the automatic assignment of identified metabolites to positions within known metabolic networks, and, furthermore, allows automated extraction of sub-networks of biological significance. This latter feature is possible by use of a gap-filling algorithm. The utility of the algorithm in reconstructing and mining of metabolomics data is shown on two independent datasets generated with LC–MS LTQ-Orbitrap mass spectrometry. Biologically relevant metabolic sub-networks were extracted from both datasets. Moreover, a number of metabolites, whose presence eluded automatic selection within mass spectra, could be identified retrospectively by virtue of their inferred presence through gap filling.
Electronic supplementary material
The online version of this article (doi:10.1007/s11306-009-0196-9) contains supplementary material, which is available to authorized users.
doi:10.1007/s11306-009-0196-9
PMCID: PMC2874485  PMID: 20526351
Metabolic network; Graph algorithm; Gap-filling; Metabolomics
7.  Metabolic network visualization eliminating node redundance and preserving metabolic pathways 
BMC Systems Biology  2007;1:29.
Background
The tools that are available to draw and to manipulate the representations of metabolism are usually restricted to metabolic pathways. This limitation becomes problematic when studying processes that span several pathways. The various attempts that have been made to draw genome-scale metabolic networks are confronted with two shortcomings: 1- they do not use contextual information which leads to dense, hard to interpret drawings, 2- they impose to fit to very constrained standards, which implies, in particular, duplicating nodes making topological analysis considerably more difficult.
Results
We propose a method, called MetaViz, which enables to draw a genome-scale metabolic network and that also takes into account its structuration into pathways. This method consists in two steps: a clustering step which addresses the pathway overlapping problem and a drawing step which consists in drawing the clustered graph and each cluster.
Conclusion
The method we propose is original and addresses new drawing issues arising from the no-duplication constraint. We do not propose a single drawing but rather several alternative ways of presenting metabolism depending on the pathway on which one wishes to focus. We believe that this provides a valuable tool to explore the pathway structure of metabolism.
doi:10.1186/1752-0509-1-29
PMCID: PMC1934383  PMID: 17608928

Results 1-7 (7)