BioModels: ten-year anniversary

Chelliah, Vijayalakshmi; Juty, Nick; Ajmera, Ishan; Raza, Ali; Dumousseau, Marine; Glonț, Mihai; Hucka, Michael; Jalowicki, Gaël; Keating, Sarah M.; Knight-Schrijver, Vincent; Lloret-Villas, Audald; Natarajan, Kedar Nath; Pettit, Jean-Baptiste; Rodríguez, Nicolás; Schubert, Michaël; Wimalaratne, Sarala M.; Zhao, Yangyang; Hermjakob, Henning; Novère, Nicolas Le; Laibe, Camille

doi:10.1093/nar/gku1181

Cited by 293 publications

(290 citation statements)

References 26 publications

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“…A complete list of all species, reactions, and kinetic parameters in the model is provided in Datasets S1 and S2, and SI Appendix, Table S1. Furthermore, an SBML version of this model was deposited in BioModels (60) and assigned the identifier MODEL1601140000. To facilitate experimental parameterization and validation of the model, the system was partitioned into intracellular and extracellular (growth media) compartments, assuming rapid diffusion of O 2 and NO · across the cell membrane (61, 62) (SI Appendix, Supporting Methods).…”

Section: δCytmentioning

confidence: 99%

Discovery and dissection of metabolic oscillations in the microaerobic nitric oxide response network ofEscherichia coli

Robinson

Brynildsen

2016

Proc. Natl. Acad. Sci. U.S.A.

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The virulence of many pathogens depends upon their ability to cope with immune-generated nitric oxide (NO · ). In Escherichia coli, the major NO · detoxification systems are Hmp, an NO · dioxygenase (NOD), and NorV, an NO · reductase (NOR). It is well established that Hmp is the dominant system under aerobic conditions, whereas NorV dominates anaerobic conditions; however, the quantitative contributions of these systems under the physiologically relevant microaerobic regime remain ill defined. Here, we investigated NO · detoxification in environments ranging from 0 to 50 μM O 2 , and discovered a regime in which E. coli NO · defenses were severely compromised, as well as conditions that exhibited oscillations in the concentration of NO · . Using an integrated computational and experimental approach, E. coli NO · detoxification was found to be extremely impaired at low O 2 due to a combination of its inhibitory effects on NorV, Hmp, and translational activities, whereas oscillations were found to result from a kinetic competition for O 2 between Hmp and respiratory cytochromes. Because at least 777 different bacterial species contain the genetic requirements of this stress response oscillator, we hypothesize that such oscillatory behavior could be a widespread phenomenon. In support of this hypothesis, Pseudomonas aeruginosa, whose respiratory and NO · response networks differ considerably from those of E. coli, was found to exhibit analogous oscillations in low O 2 environments. This work provides insight into how bacterial NO · defenses function under the low O 2 conditions that are likely to be encountered within host environments.nitrosative stress | E. coli | microaerobic | Pseudomonas aeruginosa | kinetic modeling N itric oxide (NO · ) plays a critical role in mammalian innate immunity as a potent antimicrobial (1-3), where its broad reactivity contributes to a diverse repertoire of cytotoxic effects including respiratory inhibition, thiol nitrosation, iron-sulfur cluster ([Fe-S]) destruction, DNA deamination, and tyrosine nitration/ nitrosylation (4, 5). To cope with this stress, many pathogens harbor defenses to detoxify NO · and its reaction products, and repair NO · -mediated damage to biomolecules (6, 7). Disruption of these defenses has been shown to attenuate virulence in many pathogenic species, such as Neisseria meningitides, Pseudomonas aeruginosa, Yersinia pestis, Mycobacterium tuberculosis, Vibrio cholerae, uropathogenic and enterohemorrhagic Escherichia coli (UPEC and EHEC, respectively), Staphylococcus aureus, and Salmonella enterica serovar Typhimurium (4, 6), which underscores the importance of NO · to immune function and highlights microbial NO · defense networks as a promising source of targets for the development of next-generation antiinfectives (8). This potential has inspired many investigations of bacterial NO · stress, from which major defense systems, such as NO · dioxygenase (NOD) (9, 10) and NO · reductase (NOR) (11, 12), have been identified. NODs are widely distributed among dif...

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Section: δCytmentioning

confidence: 99%

Discovery and dissection of metabolic oscillations in the microaerobic nitric oxide response network ofEscherichia coli

Robinson

Brynildsen

2016

Proc. Natl. Acad. Sci. U.S.A.

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“…This allows all intracellular species concentrations to reach a steady state by 200 seconds. All simulations were performed using the ode15s integrator in MATLAB 2013a (MathWorks, Natick, MA, see supplement S7 for the MATLAB code and supplement S8 for the SBML model; the SBML model is available online on the Biomodels database [18] (https://www.ebi.ac.uk/biomodels-main/). …”

Section: Resultsmentioning

confidence: 99%

“…Our model is based on the IP 3 -Ca 2+ cross coupling model proposed in [17, 18] with the following modifications: we retain the kinetic equations for intracellular fluxes and IP 3 receptor dynamics, but our treatment of IP 3 synthesis relies on hormone receptor dynamics instead of the constant receptor activation value used in [17, 18]; we account for intercellular interactions by including gap junctions connecting the adjacent hepatocytes (Figure 1). Hepatocyte gap junctions are primarily composed of Connexins 32 and 26 [19] .…”

Section: Model Developmentmentioning

confidence: 99%

Computational Modeling of Spatiotemporal Ca²⁺Signal Propagation Along Hepatocyte Cords

Verma

Makadia

Hoek

et al. 2016

IEEE Trans. Biomed. Eng.

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Objective The purpose of the present study is to model the dynamics of lobular Ca2+ wave propagation induced by an extracellular stimulus and to analyze the effect of spatially systematic variations in cell-intrinsic signaling parameters on sinusoidal Ca2+ response. Methods We developed a computational model of lobular scale Ca2+ signaling that accounts for receptor-mediated initiation of cell-intrinsic Ca2+ signal in hepatocytes and its propagation to neighboring hepatocytes through gap junction-mediated molecular exchange. Results Analysis of the simulations showed that a pericentral-to-periportal spatial gradient in hormone sensitivity and/or rates of IP3 synthesis underlies the Ca2+ wave propagation. We simulated specific cases corresponding to localized disruptions in the graded pattern of these parameters along a hepatic sinusoid. Simulations incorporating locally altered parameters exhibited Ca2+ waves that do not propagate throughout the hepatic plate. Increased gap junction coupling restored normal Ca2+ wave propagation when hepatocytes with low Ca2+ signaling ability were localized in the mid-lobular or the pericentral region. Conclusion Multiple spatial patterns in intracellular signaling parameters can lead to Ca2+ wave propagation that is consistent with the experimentally observed spatial patterns of Ca2+ dynamics. Based on simulations and analysis, we predict that increased gap junction-mediated intercellular coupling can induce robust Ca2+ signals in otherwise poorly responsive hepatocytes, at least partly restoring the sinusoidally oriented Ca2+ waves. Significance Our bottom-up model of agonist-evoked spatial Ca2+ patterns can be integrated with detailed descriptions of liver histology to study Ca2+ regulation at the tissue level.

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“…With these parameters the V max values were calculated by converting the mass (mg of protein) of the specific activity of a given enzyme to volume in litres to represent V max values 41 as explained in Table S4. The model is encoded in the systems biology markup language (SBML) 42 and was submitted to the BioModels Database, a repository for computational models of biological processes 43 . This means that the model is accessible and can be updated as the biological knowledge of the system advances.…”

Section: Methodsmentioning

confidence: 99%

A mathematical model of microbial folate biosynthesis and utilisation: implications for antifolate development

Salcedo-Sora

Auley

2016

Mol. BioSyst.

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The metabolic biochemistry of folate biosynthesis and utilisation has evolved into a complex network of reactions. Although this complexity represents challenges to the field of folate research it has also provided a renewed source for antimetabolite targets. A range of improved folate chemotherapy continues to be developed and applied particularly to cancer and chronic inflammatory diseases. However, new or better antifolates against infectious diseases remain much more elusive. In this paper we describe the assembly of a generic deterministic mathematical model of microbial folate metabolism. Our aim is to explore how a mathematical model could be used to explore the dynamics of this inherently complex set of biochemical reactions. Using the model it was found that: 1) a particular small set of folate intermediates are overrepresented, 2) inhibitory profiles can be quantified by the level of key folate products, 3) using the model to scan for the most effective combinatorial inhibitions of folate enzymes we identified specific targets which could complement current antifolates, and 4) the model substantiates the case for a substrate cycle in the folinic acid biosynthesis reaction. Our model is coded in the systems biology markup language and has been deposited in the BioModels Database (MODEL1511020000), this makes it accessible to the community as a whole.

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BioModels: ten-year anniversary

Cited by 293 publications

References 26 publications

Discovery and dissection of metabolic oscillations in the microaerobic nitric oxide response network ofEscherichia coli

Discovery and dissection of metabolic oscillations in the microaerobic nitric oxide response network ofEscherichia coli

Computational Modeling of Spatiotemporal Ca²⁺Signal Propagation Along Hepatocyte Cords

A mathematical model of microbial folate biosynthesis and utilisation: implications for antifolate development

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BioModels: ten-year anniversary

Cited by 293 publications

References 26 publications

Discovery and dissection of metabolic oscillations in the microaerobic nitric oxide response network ofEscherichia coli

Discovery and dissection of metabolic oscillations in the microaerobic nitric oxide response network ofEscherichia coli

Computational Modeling of Spatiotemporal Ca2+Signal Propagation Along Hepatocyte Cords

A mathematical model of microbial folate biosynthesis and utilisation: implications for antifolate development

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Product

Resources

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Computational Modeling of Spatiotemporal Ca²⁺Signal Propagation Along Hepatocyte Cords