References of "Fleming, Ronan MT 50001792"
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See detailDistributedFBA.jl: High-level, high-performance flux balance analysis in Julia.
Heirendt, Laurent UL; Thiele, Ines UL; Fleming, Ronan MT UL

in Bioinformatics (2017)

MOTIVATION: Flux balance analysis, and its variants, are widely used methods for predicting steady-state reaction rates in biochemical reaction networks. The exploration of high dimensional networks with ... [more ▼]

MOTIVATION: Flux balance analysis, and its variants, are widely used methods for predicting steady-state reaction rates in biochemical reaction networks. The exploration of high dimensional networks with such methods is currently hampered by software performance limitations. RESULTS: DistributedFBA.jl is a high-level, high-performance, open-source implementation of flux balance analysis in Julia. It is tailored to solve multiple flux balance analyses on a subset or all the reactions of large and huge-scale networks, on any number of threads or nodes. AVAILABILITY: The code is freely available on github.com/opencobra/COBRA.jl. The documentation can be found at opencobra.github.io/COBRA.jl. [less ▲]

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See detailReliable and efficient solution of genome-scale models of Metabolism and macromolecular Expression
Ma, Ding; Yang, Laurence; Fleming, Ronan MT UL et al

in Scientific Reports (2017)

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See detailConditions for duality between fluxes and concentrations in biochemical networks
Fleming, Ronan MT UL; Vlassis, Nikos; Thiele, Ines UL et al

in Journal of Theoretical Biology (2016), 409(21), 1-10

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See detailGeneration of genome-scale metabolic reconstructions for 773 members of the human gut microbiota
Magnusdottir, Stefania UL; Heinken, Almut Katrin UL; Kutt, Laura et al

in Nature Biotechnology (2016)

Genome-scale metabolic models derived from human gut metagenomic data can be used as a framework to elucidate how microbial communities modulate human metabolism and health. We present AGORA (assembly of ... [more ▼]

Genome-scale metabolic models derived from human gut metagenomic data can be used as a framework to elucidate how microbial communities modulate human metabolism and health. We present AGORA (assembly of gut organisms through reconstruction and analysis), a resource of genome-scale metabolic reconstructions semi-automatically generated for 773 human gut bacteria. Using this resource, we identified a defined growth medium for Bacteroides caccae ATCC 34185. We also showed that interactions among modeled species depend on both the metabolic potential of each species and the nutrients available. AGORA reconstructions can integrate either metagenomic or 16S rRNA sequencing data sets to infer the metabolic diversity of microbial communities. AGORA reconstructions could provide a starting point for the generation of high-quality, manually curated metabolic reconstructions. AGORA is fully compatible with Recon 2, a comprehensive metabolic reconstruction of human metabolism, which will facilitate studies of host–microbiome interactions. [less ▲]

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See detailReconMap: An interactive visualisation of human metabolism
Noronha, Alberto UL; Danielsdóttir, Anna Dröfn; Jóhannsson, Freyr et al

in Bioinformatics (2016)

A genome-scale reconstruction of human metabolism, Recon 2, is available but no interface exists to interactively visualise its content integrated with omics data and simulation results. We manually drew ... [more ▼]

A genome-scale reconstruction of human metabolism, Recon 2, is available but no interface exists to interactively visualise its content integrated with omics data and simulation results. We manually drew a comprehensive map, ReconMap 2.0, that is consistent with the content of Recon 2. We present it within a web interface that allows content query, visualization of custom datasets and submission of feedback to manual curators. ReconMap can be accessed via http://vmh.uni.lu, with network export in a Systems Biology Graphical Notation compliant format. A Constraint-Based Reconstruction and Analysis (COBRA) Toolbox extension to interact with ReconMap is available via https://github.com/opencobra/cobratoolbox. [less ▲]

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See detailAdvantages and challenges of microfluidic cell culture in polydimethylsiloxane devices
Halldórsson, Skarphédinn; Lucumi Moreno, Edinson UL; Gómez-Sjöberg, Rafael et al

in Biosensors and Bioelectronics (2015), 63

Culture of cells using various microfluidic devices is becoming more common within experimental cell biology. At the same time, a technological radiation of microfluidic cell culture device designs is ... [more ▼]

Culture of cells using various microfluidic devices is becoming more common within experimental cell biology. At the same time, a technological radiation of microfluidic cell culture device designs is currently in progress. Ultimately, the utility of microfluidic cell culture will be determined by its capacity to permit new insights into cellular function. Especially insights that would otherwise be difficult or impossible to obtain with macroscopic cell culture in traditional polystyrene dishes, flasks or well-plates. Many decades of heuristic optimization have gone into perfecting conventional cell culture devices and protocols. In comparison, even for the most commonly used microfluidic cell culture devices, such as those fabricated from polydimethylsiloxane (PDMS), collective understanding of the differences in cellular behavior between microfluidic and macroscopic culture is still developing. Moving in vitro culture from macroscopic culture to PDMS based devices can come with unforeseen challenges. Changes in device material, surface coating, cell number per unit surface area or per unit media volume may all affect the outcome of otherwise standard protocols. In this review, we outline some of the advantages and challenges that may accompany a transition from macroscopic to microfluidic cell culture. We focus on decisive factors that distinguish macroscopic from microfluidic cell culture to encourage a reconsideration of how macroscopic cell culture principles might apply to microfluidic cell culture. [less ▲]

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See detailDo Genome-scale Models Need Exact Solvers or Clearer Standards?
Ebrahim, Ali; Almaas, Eivind; Bauer, Eugen UL et al

in Molecular Systems Biology (2015), 11(10), 1

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See detailAccelerating the DC algorithm for smooth functions
Aragón Artacho, Francisco Javier UL; Fleming, Ronan MT UL; Phan, Vuong UL

E-print/Working paper (2015)

We introduce two new algorithms to minimise smooth difference of convex (DC) functions that accelerate the convergence of the classical DC algorithm (DCA). We prove that the point computed by DCA can be ... [more ▼]

We introduce two new algorithms to minimise smooth difference of convex (DC) functions that accelerate the convergence of the classical DC algorithm (DCA). We prove that the point computed by DCA can be used to define a descent direction for the objective function evaluated at this point. Our algorithms are based on a combination of DCA together with a line search step that uses this descent direction. Convergence of the algorithms is proved and the rate of convergence is analysed under the Łojasiewicz property of the objective function. We apply our algorithms to a class of smooth DC programs arising in the study of biochemical reaction networks, where the objective function is real analytic and thus satisfies the Łojasiewicz property. Numerical tests on various biochemical models clearly show that our algorithms outperforms DCA, being on average more than four times faster in both computational time and the number of iterations. The algorithms are globally convergent to a non-equilibrium steady state of a biochemical network, with only chemically consistent restrictions on the network topology. [less ▲]

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See detailPrediction of intracellular metabolic states from extracellular metabolomic data
Aurich, Maike Kathrin UL; Paglia, Guiseppe; Rolfsson, Ottar et al

in Metabolomics : Official journal of the Metabolomic Society (2015), 11(3), 603-619

Metabolic models can provide a mechanistic framework to analyze information-rich omics data sets, and are increasingly being used to investigate metabolic alternations in human diseases. An expression of ... [more ▼]

Metabolic models can provide a mechanistic framework to analyze information-rich omics data sets, and are increasingly being used to investigate metabolic alternations in human diseases. An expression of the altered metabolic pathway utilization is the selection of metabolites consumed and released by cells. However, methods for the inference of intracellular metabolic states from extracellular measurements in the context of metabolic models remain underdeveloped compared to methods for other omics data. Herein, we describe a workflow for such an integrative analysis emphasizing on extracellular metabolomics data. We demonstrate, using the lymphoblastic leukemia cell lines Molt-4 and CCRF-CEM, how our methods can reveal differences in cell metabolism. Our models explain metabolite uptake and secretion by predicting a more glycolytic phenotype for the CCRFCEM model and a more oxidative phenotype for the Molt-4 model, which was supported by our experimental data. Gene expression analysis revealed altered expression of gene products at key regulatory steps in those central metabolic pathways, and literature query emphasized the role of these genes in cancer metabolism. Moreover, in silico gene knock-outs identified unique control points for each cell line model, e.g., phosphoglycerate dehydrogenase for the Molt-4 model. Thus, our workflow is well-suited to the characterization of cellular metabolic traits based on extracellular metabolomic data, and it allows the integration of multiple omics data sets into a cohesive picture based on a defined model context. [less ▲]

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See detailGlobally convergent algorithms for finding zeros of duplomonotone mappings
Aragón Artacho, Francisco Javier UL; Fleming, Ronan MT UL

in Optimization Letters (2015), 3(3), 569584

We introduce a new class of mappings, called duplomonotone, which is strictly broader than the class of monotone mappings. We study some of the main properties of duplomonotone functions and provide ... [more ▼]

We introduce a new class of mappings, called duplomonotone, which is strictly broader than the class of monotone mappings. We study some of the main properties of duplomonotone functions and provide various examples, including nonlinear duplomonotone functions arising from the study of systems of biochemical reactions. Finally, we present three variations of a derivative-free line search algorithm for finding zeros of systems of duplomonotone equations, and we prove their linear convergence to a zero of the function. [less ▲]

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See detailA constraint-based modelling approach to metabolic dysfunction in Parkinson's disease
Mao, Longfei UL; Nicolae, Averina UL; Oliveira, Miguel UL et al

in Computational and Structural Biotechnology Journal (2015), 13

Abstract One of the hallmarks of sporadic Parkinson's disease is degeneration of dopaminergic neurons in the pars compacta of the substantia nigra. The aetiopathogenesis of this degeneration is still not ... [more ▼]

Abstract One of the hallmarks of sporadic Parkinson's disease is degeneration of dopaminergic neurons in the pars compacta of the substantia nigra. The aetiopathogenesis of this degeneration is still not fully understood, with dysfunction of many biochemical pathways in different subsystems suggested to be involved. Recent advances in constraint-based modelling approaches hold great potential to systematically examine the relative contribution of dysfunction in disparate pathways to dopaminergic neuronal degeneration, but few studies have employed these methods in Parkinson's disease research. Therefore, this review outlines a framework for future constraint-based modelling of dopaminergic neuronal metabolism to decipher the multi-factorial mechanisms underlying the neuronal pathology of Parkinson's disease. [less ▲]

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See detailDifferentiation of neuroepithelial stem cells into functional dopaminergic neurons in 3D microfluidic cell culture
Lucumi Moreno, Edinson UL; Hachi, Siham UL; Hemmer, Kathrin UL et al

in Lab on a Chip - Miniaturisation for Chemistry & Biology (2015), 15

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See detailFASTGAPFILL: Efficient gap filling in metabolic networks
Thiele, Ines UL; Vlassis, Nikos UL; Fleming, Ronan MT UL

in Bioinformatics (2014), 30(17), 2529-2531

Motivation: Genome-scale metabolic reconstructions summarize current knowledge about a target organism in a structured manner and as such highlight missing information. Such gaps can be filled ... [more ▼]

Motivation: Genome-scale metabolic reconstructions summarize current knowledge about a target organism in a structured manner and as such highlight missing information. Such gaps can be filled algorithmically. Scalability limitations of available algorithms for gap filling hinder their application to compartmentalized reconstructions. Results:We present FASTGAPFILL, a computationally efficient,tractable extension to the COBRA toolbox that permits theidentification of candidate missing knowledge from a universal biochemical reaction database (e.g., KEGG) for a given (compart-mentalized) metabolic reconstruction. The stoichiometric consistency of the universal reaction database and of the metabolic reconstruction can be tested for permitting the computation of biologically more relevant solutions. We demonstrate the efficiency and scalability of fastGapFill on a range of metabolic reconstructions. [less ▲]

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See detailModeling the effects of commonly used drugs on human metabolism
Sahoo, Swagatika UL; Haraldsdottir, Hulda UL; Fleming, Ronan MT UL et al

in FEBS Journal (2014)

Metabolism contributes significantly to the pharmacokinetics and pharmacodynamics of a drug. In addition, diet and genetics have a profound effect on cellular metabolism under health and disease. Herein ... [more ▼]

Metabolism contributes significantly to the pharmacokinetics and pharmacodynamics of a drug. In addition, diet and genetics have a profound effect on cellular metabolism under health and disease. Herein, we assembled a comprehensive, literature-based drug metabolic reconstruction of the 18 most highly prescribed drug groups including statins, antihypertensives, immunosuppressants, and analgesics. This reconstruction captures in detail our current understanding of their absorption, intra-cellular distribution, metabolism, and elimination. We combined this drug module with the most comprehensive reconstruction of human metabolism, Recon 2, yielding Recon2_DM1796, which accounts for 2803 metabolites and 8161 reactions. By defining 50 specific drug objectives that captured the overall drug metabolism of these compounds, we investigated effects of dietary composition and inherited metabolic disorders on drug metabolism and drug-drug interactions. Our main findings include (i) shift in dietary patterns significantly affect statins and acetaminophen metabolism, (ii) disturbed statin metabolism contributes to the clinical phenotype of mitochondrial energy disorders, and (iii) the interaction between statins and cyclosporine can be explained by several common metabolic and transport pathways other than the previously established CYP3A4 connection. This work holds the potential for studying adverse drug reactions and designing patient-specific therapies. [less ▲]

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