| 1. |
- Carretero Chavez, Willow, et al.
(författare)
-
kboolnet : a toolkit for the verification, validation, and visualization of reaction-contingency (rxncon) models
- 2023
-
Ingår i: BMC Bioinformatics. - : BioMed Central (BMC). - 1471-2105. ; 24:1
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Computational models of cell signaling networks are extremely useful tools for the exploration of underlying system behavior and prediction of response to various perturbations. By representing signaling cascades as executable Boolean networks, the previously developed rxncon ("reaction-contingency") formalism and associated Python package enable accurate and scalable modeling of signal transduction even in large (thousands of components) biological systems. The models are split into reactions, which generate states, and contingencies, that impinge on reactions; this avoids the so-called "combinatorial explosion" of system size. Boolean description of the biological system compensates for the poor availability of kinetic parameters which are necessary for quantitative models. Unfortunately, few tools are available to support rxncon model development, especially for large, intricate systems.RESULTS: We present the kboolnet toolkit ( https://github.com/Kufalab-UCSD/kboolnet , complete documentation at https://github.com/Kufalab-UCSD/kboolnet/wiki ), an R package and a set of scripts that seamlessly integrate with the python-based rxncon software and collectively provide a complete workflow for the verification, validation, and visualization of rxncon models. The verification script VerifyModel.R checks for responsiveness to repeated stimulations as well as consistency of steady state behavior. The validation scripts TruthTable.R, SensitivityAnalysis.R, and ScoreNet.R provide various readouts for the comparison of model predictions to experimental data. In particular, ScoreNet.R compares model predictions to a cloud-stored MIDAS-format experimental database to provide a numerical score for tracking model accuracy. Finally, the visualization scripts allow for graphical representations of model topology and behavior. The entire kboolnet toolkit is cloud-enabled, allowing for easy collaborative development; most scripts also allow for the extraction and analysis of individual user-defined "modules".CONCLUSION: The kboolnet toolkit provides a modular, cloud-enabled workflow for the development of rxncon models, as well as their verification, validation, and visualization. This will enable the creation of larger, more comprehensive, and more rigorous models of cell signaling using the rxncon formalism in the future.
|
|
| 2. |
- Herrgård, Markus J, et al.
(författare)
-
A consensus yeast metabolic network reconstruction obtained from a community approach to systems biology
- 2008
-
Ingår i: Nature Biotechnology. ; 26:10, s. 1155-1160
-
Tidskriftsartikel (refereegranskat)abstract
- Genomic data allow the large-scale manual or semi-automated assembly of metabolic network reconstructions, which provide highly curated organism-specific knowledge bases. Although several genome-scale network reconstructions describe Saccharomyces cerevisiae metabolism, they differ in scope and content, and use different terminologies to describe the same chemical entities. This make comparisons between them difficult and underscores the desirability of a consolidated metabolic network that collects and formalizes the 'community knowledge' of yeast metabolism. We describe how we have produced a consensus metabolic network reconstruction for S. cerevisiae. In drafting it, we placed special emphasis on referencing molecules to persistent databases or using database-independent forms, such as SMILES or InChl strings, as this permits their chemical structure to be represented unambiguously and in a manner that permits automated reasoning. The reconstruction is readily available via a publicly accessible database and in the Systems Biology Markup Language (http://www.comp-sys-bio.org/yeastnet). It can be maintained as a resource that serves as a common denominator for studying the systems biology of yeast. Similar strategies should benefit communities studying genome-scale metabolic networks of other organisms.
|
|
| 3. |
- Klipp, Edda, et al.
(författare)
-
Integrative model of the response of yeast to osmotic shock
- 2005
-
Ingår i: Nature Biotechnology. - : Springer Science and Business Media LLC. - 1087-0156 .- 1546-1696. ; 23:8
-
Tidskriftsartikel (refereegranskat)abstract
- Integration of experimental studies with mathematical modeling allows insight into systems properties, prediction of perturbation effects and generation of hypotheses for further research. We present a comprehensive mathematical description of the cellular response of yeast to hyperosmotic shock. The model integrates a biochemical reaction network comprising receptor stimulation, mitogen-activated protein kinase cascade dynamics, activation of gene expression and adaptation of cellular metabolism with a thermodynamic description of volume regulation and osmotic pressure. Simulations agree well with experimental results obtained under different stress conditions or with specific mutants. The model is predictive since it suggests previously unrecognized features of the system with respect to osmolyte accumulation and feedback control, as confirmed with experiments. The mathematical description presented is a valuable tool for future studies on osmoregulation in yeast and—with appropriate modifications—other organisms. It also serves as a starting point for a comprehensive description of cellular signaling.
|
|
| 4. |
- Klipp, Edda, et al.
(författare)
-
Shutting the MAP off - and on again?
- 2004
-
Ingår i: Current Genomics. - 1389-2029. ; 5:8, s. 637-647
-
Tidskriftsartikel (refereegranskat)abstract
- Signal transduction pathways are the cellular information routes with which cells monitor their surrounding as well as their own state and adjust to environmental changes or hormonal stimuli. MAP kinase pathways are one type of signalling systems in eukaryotes that control stress responses, cell growth and proliferation as well as differentiation. In this study we compare two very well studied yeast signalling systems, the pheromone response pathway and the osmosensing HOG pathway. We have recently generated mathematical models that allow in silico analysis of signalling properties for both pathways. Deactivation of signalling is as important as activation because inappropriate pathway activation causes cell cycle arrest (in the cases studied here) or uncontrolled proliferation. Both pathways are transiently activated by their stimulus, i.e. mating pheromone and osmostress, respectively, indicating rigorous feedback mechanisms. However, the HOG pathway can readily be reactivated by a subsequent stimulus and this is important for its biological role in mediating osmoadaptation. The pheromone response pathway, however, is desensitised and is unable to respond for a certain period of time. While some mechanisms of feedback control are similar in both systems (such as the downregulatory, role of protein phosphatases) the main difference seems to lie in the control of the sensors/receptors. The pheromone receptors are internalised and degraded following stimulation and hence are not available for further stimulation. The osmosensors on the other hand, seem to toggle between activated and deactivated state only controlled by osmotic changes. Together with subtle control by protein phosphatases this results in a system that is constantly receptive for stimulation.
|
|
| 5. |
- Krantz, Marcus, 1975, et al.
(författare)
-
Robustness and fragility in the high osmolarity glycerol (HOG) pathway in S. cerevisiae
- 2009
-
Ingår i: 10th International Conference on Systems Biology (ICSB2009) proceedings, 10th International Conference on Systems Biology (ICSB2009), Aug 30 - Sep 4, Stanford, California, USA.
-
Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Cellular signalling networks integrate environmental stimuli with information on cellular status. These networks must be robust against stochastic fluctuations in external stimuli as well as in the amounts of signalling components. Here [1], we challenge the yeast HOG signal transduction pathway with systematic perturbations in components’ expression levels implemented by a “genetic tug-of-war” methodology under various external conditions in search of nodes of fragilities. We observe a substantially higher frequency of fragile nodes in this signal transduction pathway than has been observed for other cellular processes. These fragilities disperse without any clear pattern over biochemical functions or location in pathway topology, with the most sensitive nodes being the proteins PBS2 and SSK1. They are also largely independent of pathway activation by external stimuli. However, the strongest toxicities are caused by pathway hyperactivation. We studied the influence of seven regulatory motifs around these HOG pathway components in silico through ODE models. Based on the SLN1 and the MAPK modules of a mathematical model of osmoregulation in budding yeast by Klipp et al. [2] we included new motifs and fitted the affected parameters to time courses of dually phosphorylated Hog1p generated by the original model under stress and stress-free conditions. The regulations taken into account by our analysis include Pbs2p scaffolding, Ssk1p and Pbs2p autoactivation, and the formation of a stable dimer between Ssk2p and Ssk1p. A subsequent sensitivity analysis identified Pbs2's role as a scaffold protein and Ssk1p-Ssk2p dimerization as the important contributors to the observed robustness pattern in silico. Thus, in vivo robustness data can be used to discriminate and improve mathematical models.
|
|
| 6. |
- Krantz, Marcus, 1975, et al.
(författare)
-
Robustness and fragility in the yeast high osmolarity glycerol (HOG) signal-transduction pathway.
- 2009
-
Ingår i: Molecular systems biology. - : EMBO. - 1744-4292. ; 5
-
Tidskriftsartikel (refereegranskat)abstract
- Cellular signalling networks integrate environmental stimuli with the information on cellular status. These networks must be robust against stochastic fluctuations in stimuli as well as in the amounts of signalling components. Here, we challenge the yeast HOG signal-transduction pathway with systematic perturbations in components' expression levels under various external conditions in search for nodes of fragility. We observe a substantially higher frequency of fragile nodes in this signal-transduction pathway than that has been observed for other cellular processes. These fragilities disperse without any clear pattern over biochemical functions or location in pathway topology and they are largely independent of pathway activation by external stimuli. However, the strongest toxicities are caused by pathway hyperactivation. In silico analysis highlights the impact of model structure on in silico robustness, and suggests complex formation and scaffolding as important contributors to the observed fragility patterns. Thus, in vivo robustness data can be used to discriminate and improve mathematical models.
|
|
| 7. |
- Kuehn, Clemens, et al.
(författare)
-
Exploring the impact of osmoadaptation on glycolysis using time-varying response-coefficients
- 2008
-
Ingår i: Genome informatics. International Conference on Genome Informatics. - 0919-9454. ; 20, s. 77-90
-
Konferensbidrag (refereegranskat)abstract
- We present a model of osmoadaptation in S.cerevisiae based on existing experimental and theoretical work. In order to investigate the impact of osmoadaptation on glycolysis, this model focuses on the interactions between glycolysis and osmoadaptation, namely the production of glycerol and its influence on flux towards pyruvate. Evaluation of this model shows that, depending on initial relations between glycerol and pyruvate production, the increased glycerol production can have a substantial negative effect on the pyruvate production rate. Existing experimental data and a detailed analysis of the model lead to the suggestion of an interaction between activated Hog1 and activators of glycolysis such as Pfk26.
|
|
| 8. |
- Kühn, Clemens, 1981, et al.
(författare)
-
Formal Representation of the High Osmolarity Glycerol Pathway in Yeast
- 2009
-
Ingår i: Genome informatics. International Conference on Genome Informatics. - 0919-9454. ; 22, s. 69-83
-
Tidskriftsartikel (refereegranskat)abstract
- The high osmolarity glycerol (HOG) signalling system in yeast belongs to the class of Mitogen Activated Protein Kinase (MAPK) pathways that are found in all eukaryotic organisms. It includes at least three scaffold proteins that form complexes, and involves reactions that are strictly dependent on the set of species bound to a certain complex. The scaffold proteins lead to a combinatorial increase in the number of possible states. To date, representations of the HOG pathway have used simplifying assumptions to avoid this combinatorial problem. Such assumptions are hard to make and may obscure or remove essential properties of the system.This paper presents a detailed generic formal representation of the HOG system without such assumptions, showing the molecular interactions known from the literature. The model takes complexes into account, and summarises existing knowledge in an unambiguous and detailed representation. It can thus be used to anchor discussions about the HOG system. In the commonly used Systems Biology Markup Language (SBML), such a model would need to explicitly enumerate all state variables. The \emph{Kappa} modelling language which we use supports representation of complexes without such enumeration.To conclude, we compare \emph{Kappa} with a few other modelling languages and software tools that could also be used to represent and model the HOG system.
|
|
| 9. |
|
|
| 10. |
- Nordlander, Bodil, 1976, et al.
(författare)
-
Modelling signalling pathways-A yeast approach
- 2005
-
Ingår i: In Alberghina L, Westerhoff H (eds) “Systems Biology”. In the series “Topics in Current Genetics” (vol 13, Hohmann S, Ed). - Berlin, Heidelberg : Springer Berlin Heidelberg. ; , s. 277-304
-
Bokkapitel (övrigt vetenskapligt/konstnärligt)
|
|
| 11. |
- Ottosson, Lars-Göran, et al.
(författare)
-
Robustness and fragility in the yeast High Osmolarity Glycerol (HOG) signal transduction pathway
- 2009
-
Ingår i: Abstracts of the 24th International Conference on Yeast Genetics and Molecular Biology (Supplement to Yeast Volume 26 Issue S1), 25th International Conference on Yeast Genetics & Molecular Biology, July 19-24, Manchester, UK. ; 26:Issue S1
-
Konferensbidrag (refereegranskat)abstract
- Cellular signalling networks integrate environmental stimuli with information on cellular status. These networks must be robust against stochastic fluctuations in stimuli as well as in the amounts of signalling components. Here, we challenge the yeast HOG signal transduction pathway with systematic perturbations in components’ expression levels implemented by a “genetic tug-of-war” methodology under various external conditions in search of nodes of fragilities. We observe a substantially higher frequency of fragile nodes in this signal transduction pathway than has been observed for other cellular processes. These fragilities disperse without any clear pattern over biochemical functions or location in pathway topology, with the most sensitive node being the scaffold protein PBS2. They are also largely independent of pathway activation by external stimuli. However, the strongest toxicities are caused by pathway hyperactivation. In silico analysis highlights the impact of model structure on in silico robustness, and suggests complex formation and scaffolding as important contributors to the observed fragility patterns. Thus, in vivo robustness data can be used to discriminate and improve mathematical models.
|
|
| 12. |
- Petelenz-Kurdziel, Elzbieta, et al.
(författare)
-
Quantitative Analysis of Glycerol Accumulation, Glycolysis and Growth under Hyper Osmotic Stress
- 2013
-
Ingår i: PLoS Computational Biology. - : Public Library of Science (PLoS). - 1553-734X .- 1553-7358. ; 9:6
-
Tidskriftsartikel (refereegranskat)abstract
- We provide an integrated dynamic view on a eukaryotic osmolyte system, linking signaling with regulation of gene expression, metabolic control and growth. Adaptation to osmotic changes enables cells to adjust cellular activity and turgor pressure to an altered environment. The yeast Saccharomyces cerevisiae adapts to hyperosmotic stress by activating the HOG signaling cascade, which controls glycerol accumulation. The Hog1 kinase stimulates transcription of genes encoding enzymes required for glycerol production (Gpd1, Gpp2) and glycerol import (Stl1) and activates a regulatory enzyme in glycolysis (Pfk26/27). In addition, glycerol outflow is prevented by closure of the Fps1 glycerol facilitator. In order to better understand the contributions to glycerol accumulation of these different mechanisms and how redox and energy metabolism as well as biomass production are maintained under such conditions we collected an extensive dataset. Over a period of 180 min after hyperosmotic shock we monitored in wild type and different mutant cells the concentrations of key metabolites and proteins relevant for osmoadaptation. The dataset was used to parameterize an ODE model that reproduces the generated data very well. A detailed computational analysis using time-dependent response coefficients showed that Pfk26/27 contributes to rerouting glycolytic flux towards lower glycolysis. The transient growth arrest following hyperosmotic shock further adds to redirecting almost all glycolytic flux from biomass towards glycerol production. Osmoadaptation is robust to loss of individual adaptation pathways because of the existence and upregulation of alternative routes of glycerol accumulation. For instance, the Stl1 glycerol importer contributes to glycerol accumulation in a mutant with diminished glycerol production capacity. In addition, our observations suggest a role for trehalose accumulation in osmoadaptation and that Hog1 probably directly contributes to the regulation of the Fps1 glycerol facilitator. Taken together, we elucidated how different metabolic adaptation mechanisms cooperate and provide hypotheses for further experimental studies.
|
|
| 13. |
|
|
| 14. |
- Schaber, Jörg, et al.
(författare)
-
Biophysical properties of Saccharomyces cerevisiae and their relationship with HOG pathway activation.
- 2010
-
Ingår i: European biophysics journal : EBJ. - : Springer Science and Business Media LLC. - 1432-1017 .- 0175-7571. ; 39:11, s. 1547-56
-
Tidskriftsartikel (refereegranskat)abstract
- Parameterized models of biophysical and mechanical cell properties are important for predictive mathematical modeling of cellular processes. The concepts of turgor, cell wall elasticity, osmotically active volume, and intracellular osmolarity have been investigated for decades, but a consistent rigorous parameterization of these concepts is lacking. Here, we subjected several data sets of minimum volume measurements in yeast obtained after hyper-osmotic shock to a thermodynamic modeling framework. We estimated parameters for several relevant biophysical cell properties and tested alternative hypotheses about these concepts using a model discrimination approach. In accordance with previous reports, we estimated an average initial turgor of 0.6 ± 0.2 MPa and found that turgor becomes negligible at a relative volume of 93.3 ± 6.3% corresponding to an osmotic shock of 0.4 ± 0.2 Osm/l. At high stress levels (4 Osm/l), plasmolysis may occur. We found that the volumetric elastic modulus, a measure of cell wall elasticity, is 14.3 ± 10.4 MPa. Our model discrimination analysis suggests that other thermodynamic quantities affecting the intracellular water potential, for example the matrix potential, can be neglected under physiological conditions. The parameterized turgor models showed that activation of the osmosensing high osmolarity glycerol (HOG) signaling pathway correlates with turgor loss in a 1:1 relationship. This finding suggests that mechanical properties of the membrane trigger HOG pathway activation, which can be represented and quantitatively modeled by turgor.
|
|
| 15. |
- Schulz, M., et al.
(författare)
-
Introduction to Systems Biology
- 2010
-
Ingår i: Systems Biology in Psychiatric Research. - Weinheim, Germany : Wiley-VCH Verlagsgesellschaft. ; , s. 81-95
-
Bokkapitel (refereegranskat)
|
|
| 16. |
- Talemi, Soheil Rastgou, et al.
(författare)
-
Systems Level Analysis of the Yeast Osmo-Stat
- 2016
-
Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6
-
Tidskriftsartikel (refereegranskat)abstract
- Adaptation is an important property of living organisms enabling them to cope with environmental stress and maintaining homeostasis. Adaptation is mediated by signaling pathways responding to different stimuli. Those signaling pathways might communicate in order to orchestrate the cellular response to multiple simultaneous stimuli, a phenomenon called crosstalk. Here, we investigate possible mechanisms of crosstalk between the High Osmolarity Glycerol (HOG) and the Cell Wall Integrity (CWI) pathways in yeast, which mediate adaptation to hyper- and hypo-osmotic challenges, respectively. We combine ensemble modeling with experimental investigations to test in quantitative terms different hypotheses about the crosstalk of the HOG and the CWI pathways. Our analyses indicate that for the conditions studied i) the CWI pathway activation employs an adaptive mechanism with a variable volume-dependent threshold, in contrast to the HOG pathway, whose activation relies on a fixed volume-dependent threshold, ii) there is no or little direct crosstalk between the HOG and CWI pathways, and iii) its mainly the HOG alone mediating adaptation of cellular osmotic pressure for both hyper- as well as hypo-osmotic stress. Thus, by iteratively combining mathematical modeling with experimentation we achieved a better understanding of regulatory mechanisms of yeast osmo-homeostasis and formulated new hypotheses about osmo-sensing.
|
|
| 17. |
- Tiger, Carl Fredrik, et al.
(författare)
-
A framework for mapping, visualisation and automatic model creation of signal-transduction networks.
- 2012
-
Ingår i: Molecular systems biology. - : EMBO. - 1744-4292. ; 8
-
Tidskriftsartikel (refereegranskat)abstract
- Intracellular signalling systems are highly complex. This complexity makes handling, analysis and visualisation of available knowledge a major challenge in current signalling research. Here, we present a novel framework for mapping signal-transduction networks that avoids the combinatorial explosion by breaking down the network in reaction and contingency information. It provides two new visualisation methods and automatic export to mathematical models. We use this framework to compile the presently most comprehensive map of the yeast MAP kinase network. Our method improves previous strategies by combining (I) more concise mapping adapted to empirical data, (II) individual referencing for each piece of information, (III) visualisation without simplifications or added uncertainty, (IV) automatic visualisation in multiple formats, (V) automatic export to mathematical models and (VI) compatibility with established formats. The framework is supported by an open source software tool that facilitates integration of the three levels of network analysis: definition, visualisation and mathematical modelling. The framework is species independent and we expect that it will have wider impact in signalling research on any system.
|
|
| 18. |
- Zi, Zhike, et al.
(författare)
-
Quantitative analysis of transient and sustained transforming growth factor-beta signaling dynamics
- 2011
-
Ingår i: Molecular Systems Biology. - : EMBO and Macmillan Publishers Limited. - 1744-4292 .- 1744-4292. ; 7:492
-
Tidskriftsartikel (refereegranskat)abstract
- Mammalian cells can decode the concentration of extracellular transforming growth factor-beta (TGF-beta) and transduce this cue into appropriate cell fate decisions. How variable TGF-beta ligand doses quantitatively control intracellular signaling dynamics and how continuous ligand doses are translated into discontinuous cellular fate decisions remain poorly understood. Using a combined experimental and mathematical modeling approach, we discovered that cells respond differently to continuous and pulsating TGF-beta stimulation. The TGF-beta pathway elicits a transient signaling response to a single pulse of TGF-beta stimulation, whereas it is capable of integrating repeated pulses of ligand stimulation at short time interval, resulting in sustained phospho-Smad2 and transcriptional responses. Additionally, the TGF-beta pathway displays different sensitivities to ligand doses at different time scales. While ligand-induced short-term Smad2 phosphorylation is graded, long-term Smad2 phosphorylation is switch-like to a small change in TGF-beta levels. Correspondingly, the short-term Smad7 gene expression is graded, while long-term PAI-1 gene expression is switch-like, as is the long-term growth inhibitory response. Our results suggest that long-term switch-like signaling responses in the TGF-beta pathway might be critical for cell fate determination.
|
|
