| 1. |
- Kowalewski, Jacob M., et al.
(författare)
-
Generation of Slow Calcium oscillations in Spatial Cell Models Driven by Store Operated Calcium Entry
- 2004
-
Konferensbidrag (refereegranskat)abstract
- Calcium signaling is involved in many cellular processes ranging from fertilization to apoptosis. We have created two general mathematical models to simulate calcium transport between the endoplasmic reticulum (ER), the cytosol and the extracellular environment. Active in this process is inositol-1,4,5-trisphosphate (InsP3). The behavior of the changes in calcium concentration was studied. The first model is compartmental and uses ordinary differential equations. The second one is a spatial model, which uses partial differential equations. The tools used in constructing these models were MATLAB and Virtual Cell. Store operated calcium entry can be observed in experiments with living cells when the sarco(endo)plasmic reticulum calcium-ATPase (SERCA) pumps are blocked by cyclopiazonic acid (CPA) or thapsigargin. We have developed a phenomenological model of store operated calcium channels (SOC). This model involves a diffusible messenger that leaves the ER and binds to a channel in the plasma membrane. Many parameters in the models are not fully known. A basic assumption is that the parameters can be estimated from the fact that a cell at rest has an almost constant level of calcium. Results from both the compartmental and the spatial simulations show that InsP3 can cause the cytosolic calcium level to oscillate at frequencies between 1 and 5 mHz. Experimental studies have shown than calcium oscillations in this frequency range are present in renal cells. The SERCA blocking simulations show good similarity with experimental results. The results also show that the high surface-to-volume ratio of the ER is important for causing oscillations.
|
|
| 2. |
- 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.
|
|
| 3. |
- 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.
|
|
| 4. |
- Krantz, Marcus, 1975, et al.
(författare)
-
Robustness and fragility in the yeast High Osmolarity signal transduction pathway
- 2008
-
Ingår i: 2008 Yeast Genetics and Molecular Biology Meeting Program and Abstract Book, 2008 Yeast Genetics and Molecular Biology Meeting, July 22-27, 2008.
-
Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- The cellular signalling networks that integrate various environmental stimuli with information on cellular status must be robust to stimuli fluctuations as well as to stochastic differences in the amounts of signalling components. Here, we challenge the Hog signal transduction pathway with systematic disturbances in components’ expression levels implemented by a “genetic tug-of-war”, or gToW, methodology. The disturbances were performed under various external perturbations, including pathway activation by osmotic shock. Ideally, the obtained sensitivity profiles will allow us to impose parameter constraints. However, a more important aspect is the qualitative improvement of model structures, when local fragilities cannot be explained by the model structure. The resulting phenotypes in this particular study reflect a wide range of sensitivities, and disperse without any clear pattern over biochemical functions and pathway modules alike, with the most sensitive nodes being PBS2 and SSK1. Surprisingly, the “neighbouring” nodes HOG1 and SSK2 were affected to a much lesser extent, questioning our current understanding.
|
|
| 5. |
- Krantz, Marcus, 1975, et al.
(författare)
-
Robustness and fragility in the yeast High Osmolarity signal transduction pathway
- 2008
-
Ingår i: 9th International Conference on Systems Biology (ICSB2008) proceedings, 9th International Conference on Systems Biology (ICSB2008), August 22-28, Gothenburg.
-
Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Objective: The cellular signalling networks that integrate various environmental stimuli with information on cellular status must be robust to stimuli fluctuations as well as to stochastic differences in the amounts of signalling components. Here, we challenge the high osmolarity glycerol response (HOG) signal transduction pathway in the yeast Saccharomyces cerevisiae with systematic disturbances in components’ expression levels implemented by a “genetic tug-of-war”, or gTOW, methodology. Results: The disturbances were performed under various external perturbations, including pathway activation by osmotic shock. The resulting phenotypes in this particular study reflect a wide range of sensitivities, and disperse without any clear pattern over biochemical functions and pathway modules alike, with the most sensitive nodes being PBS2 and SSK1. Conclusions: Ideally, the obtained sensitivity profiles will allow us to impose parameter constraints. However, a more important aspect is the qualitative improvement of model structures, when local fragilities cannot be explained by the model structure. Surprisingly, the “neighboring” nodes HOG1 and SSK2 were affected to a much lesser extent, questioning our current understanding.
|
|
| 6. |
- Nordling, Torbjörn E. M., et al.
(författare)
-
Deduction of intracellular sub-systems from a topological description of the network
- 2007
-
Ingår i: Molecular BioSystems. - : Royal Society of Chemistry (RSC). - 1742-206X .- 1742-2051. ; 3:8, s. 523-529
-
Tidskriftsartikel (refereegranskat)abstract
- Non-linear behaviour of biochemical networks, such as intracellular gene, protein or metabolic networks, is commonly represented using graphs of the underlying topology. Nodes represent abundance of molecules and edges interactions between pairs of molecules. These graphs are linear and thus based on an implicit linearization of the kinetic reactions in one or several dynamic modes of the total system. It is common to use data from different sources - experiments conducted under different conditions or even on different species - meaning that the graph will be a superposition of linearizations made in many different modes. The mixing of different modes makes it hard to identify functional modules, that is subsystems that carry out a specific biological function, since the graph will contain many interactions that do not naturally occur at the same time. The ability to establish a boundary between the sub- system and its environment is critical in the definition of a module, contrary to a motif in which only internal interactions count. Identification of functional modules should therefore be done on graphs depicting the mode in which their function is carried out, i.e. graphs that only contain edges representing interactions active in the specific mode. In general, when an interaction between two molecules is established, one should always state the mode of the system in which it is active.
|
|
| 7. |
- Ostaszewski, Marek, et al.
(författare)
-
COVID19 Disease Map, a computational knowledge repository of virus-host interaction mechanisms
- 2021
-
Ingår i: Molecular Systems Biology. - : John Wiley & Sons. - 1744-4292 .- 1744-4292. ; 17:10
-
Tidskriftsartikel (refereegranskat)abstract
- We need to effectively combine the knowledge from surging literature with complex datasets to propose mechanistic models of SARS-CoV-2 infection, improving data interpretation and predicting key targets of intervention. Here, we describe a large-scale community effort to build an open access, interoperable and computable repository of COVID-19 molecular mechanisms. The COVID-19 Disease Map (C19DMap) is a graphical, interactive representation of disease-relevant molecular mechanisms linking many knowledge sources. Notably, it is a computational resource for graph-based analyses and disease modelling. To this end, we established a framework of tools, platforms and guidelines necessary for a multifaceted community of biocurators, domain experts, bioinformaticians and computational biologists. The diagrams of the C19DMap, curated from the literature, are integrated with relevant interaction and text mining databases. We demonstrate the application of network analysis and modelling approaches by concrete examples to highlight new testable hypotheses. This framework helps to find signatures of SARS-CoV-2 predisposition, treatment response or prioritisation of drug candidates. Such an approach may help deal with new waves of COVID-19 or similar pandemics in the long-term perspective.
|
|
| 8. |
- Ottosson, Lars-Göran, et al.
(författare)
-
Robustness analysis of HOG pathway related genes in budding yeast
- 2007
-
Ingår i: ICSB 2007 Conference Proceedings, 8th International Conference on Systems Biology (ICSB2007), October 1-6, 2007.
-
Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- We applied a novel genetic screening method, named “genetic tug-of-war” (gTOW) to estimate the upper limit of gene copy numbers in Saccharomyces cerevisiae. The study involved 29 HOG pathway related genes which included kinases, phosphatases and transcription factors to cover different set of players in the signal transduction system. In addition a phenotypic profiling was conducted in four different growth conditions with three outputs: lag phase, growth phase and efficiency of growth. A number of interesting hits were identified, including PBS2 which had low numbers of gene copies. It will be of interest to expand the study to encompass the entire known signal transduction system in yeast to search for sensitive nodes.
|
|
| 9. |
- 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.
|
|
| 10. |
- 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.
|
|
