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1
Content available Sensitivity analysis of deterministic signaling pathways models
100%
Puszyński K. , Lachor P. , Kardyńska M. , Śmieja J.
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2012
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tom Vol. 60, nr 3
471-479
EN
The paper is focused on application of sensitivity methods to analysis of signaling pathway models. Two basic methods are compared: local, based on standard sensitivity functions, and global, based on Sobol indices. Firstly, a general outline of modeling of signaling pathways by means of ordinary differential equations is briefly described. Afterwards, the methods of sensitivity analysis, known from literature, are introduced and illustrated with a simple example of a dynamical system of the second order. Subsequently, the analysis of the p53/Mdm2 regulatory module, which is a key element of any pathway involving p53 protein, is presented. The results of this analysis suggest that no single method should be chosen for investigation of any signaling pathway model but several of them should be applied to answer important questions about sources of heterogeneity in cells behavior, robustness of signaling pathways and possible molecular drug targets.
2
Content available remote Model based analysis of signaling pathways
80%
Smieja J.
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tom 18
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nr 2
139-145
EN
The paper is concerned with application of mathematical modeling to the analysis of signaling pathways. Two issues, deterministic modeling of gene transcription and model-driven discovery of regulatory elements, are dealt with. First, the biological background is given and the importance of the stochastic nature of biological processes is addressed. The assumptions underlying deterministic modeling are presented. Special emphasis is put on describing gene transcription. A framework for including unknown processes activating gene transcription by means of first-order lag elements is introduced and discussed. Then, a particular interferon-β induced pathway is introduced, limited to early events that precede activation of gene transcription. It is shown how to simplify the system description based on the goals of modeling. Further, a computational analysis is presented, facilitating better understanding of the mechanisms underlying regulation of key components in the pathway. The analysis is illustrated by a comparison of simulation and experimental data.
3
Content available remote Coupled analytical and numerical approach to uncovering new regulatory mechanisms of intracellular processes
80%
Śmieja J.
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tom 20
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nr 4
781-788
EN
The paper deals with the analysis of signaling pathways aimed at uncovering new regulatory processes regulating cell responses. First, general issues of comparing simulation and experimental data are discussed, and various aspects of data normalization are covered. Then, a model of a particular signaling pathway, induced by Interferon-β, is briefly introduced. It serves as an example illustrating how mathematical modeling can be used for inferring the structure of a regulatory system governing the dynamics of intracellular processes. In this pathway, experimental results suggest that a hitherto unknown process is responsible for a decrease in the levels of one of the important molecules used in the pathway. Then, equilibrium points of the model are analyzed, allowing the rejection of all but one explanation of the phenomena observed experimentally. Numerical simulations confirm that the model can mimic the dynamics of the processes in the pathway under consideration. Finally, some remarks about the applicability of the method based on an analysis of equilibrium points are made.
4
Contemporary views on human aging and longevity
60%
Chmielewski P. , Borysławski K. , Strzelec B.
Anthropological Review
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2016
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tom 79
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nr 2
115-142
EN
Aging is currently stimulating intense interest of both researchers and the general public. In developed countries, the average life expectancy has increased by roughly 30 years within the last century, and human senescence has been delayed by around a decade. Although aging is arguably the most familiar aspect of human biology, its proximate and ultimate causes have not been elucidated fully and understood yet. Nowadays there are two main approaches to the ultimate causes of aging. These are deterministic and stochastic models. The proximate theories constitute a distinct group of explanations. They focus on mechanistic causes of aging. In this view, there is no reason to believe that there is only one biological mechanism responsible for aging. The aging process is highly complex and results from an accumulation of random molecular damage. Currently, the disposable soma theory (DST), proposed by Thomas Kirkwood, is the most influential and coherent line of reasoning in biogerontology. This model does not postulate any particular mechanism underpinning somatic defense. Therefore, it is compatible with various models, including mechanistic and evolutionary explanations. Recently, however, an interesting theory of hyper-function of mTOR as a more direct cause of aging has been formulated by Mikhail Blagosklonny, offering an entirely different approach to numerous problems and paradoxes in current biogerontology. In this view, aging is quasi-programmed, which means that it is an aimless continuation of developmental growth. This mTOR-centric model allows the prediction of completely new relationships. The aim of this article is to present and compare the views of both parties in the dispute, based on the results of some recent experimental studies, and the contemporary knowledge of selected major aspects of human aging and longevity
5
Content available remote Sensitivity Analysis Aimed at Finding Potential Molecular Drug Targets
60%
Śmieja J. , Kardyńska M. , Pudlo M.
Mathematica Applicanda
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2019
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tom Vol. 47, no. 2
197--205
EN
Sensitivity analysis has become one of the standard tools in analysis of models of intracellular processes. Various methods have been proposed, developer for either local or global sensitivity of systems under investigation. In this work, we propose a method that may be used to find potential molecular drug targets, taking into account heterogeneity of population of cells with respect to their responses to a particular drug agent.
PL
Analiza wrażliwości stała się jednym ze standardowych narzędzi w analizie modeli procesów wewnątrzkomórkowych. Do tej pory zaproponowano różne metody, opracowane dla lokalnej lub globalnej wrażliwości badanych systemów. W niniejszej pracy proponujemy metodę, która może być wykorzystana do znalezienia potencjalnych molekularnych celów leków, biorąc pod uwagę heterogeniczność populacji komórek w odniesieniu do ich odpowiedzi na konkretny lek.
6
Content available remote Coupled analytical and numerical approach to uncovering new regulatory mechanisms of intracellular processes
60%
Śmieja J.
International Journal of Applied Mathematics and Computer Science
|
2010
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tom Vol. 20, no 4
781-788
EN
The paper deals with the analysis of signaling pathways aimed at uncovering new regulatory processes regulating cell responses. First, general issues of comparing simulation and experimental data are discussed, and various aspects of data normalization are covered. Then, a model of a particular signaling pathway, induced by Interferon-\beta, is briefly introduced. It serves as an example illustrating how mathematical modeling can be used for inferring the structure of a regulatory system governing the dynamics of intracellular processes. In this pathway, experimental results suggest that a hitherto unknown process is responsible for a decrease in the levels of one of the important molecules used in the pathway. Then, equilibrium points of the model are analyzed, allowing the rejection of all but one explanation of the phenomena observed experimentally. Numerical simulations confirm that the model can mimic the dynamics of the processes in the pathway under consideration. Finally, some remarks about the applicability of the method based on an analysis of equilibrium points are made.
7
Content available remote Model based analysis of signaling pathways
51%
Śmieja J.
International Journal of Applied Mathematics and Computer Science
|
2008
|
tom Vol. 18, no 2
139-145
EN
The paper is concerned with application of mathematical modeling to the analysis of signaling pathways. Two issues, deterministic modeling of gene transcription and model-driven discovery of regulatory elements, are dealt with. First, the biological background is given and the importance of the stochastic nature of biological processes is addressed. The assumptions underlying deterministic modeling are presented. Special emphasis is put on describing gene transcription. A framework for including unknown processes activating gene transcription by means of first-order lag elements is introduced and discussed. Then, a particular interferon-ß induced pathway is introduced, limited to early events that precede activation of gene transcription. It is shown how to simplify the system description based on the goals of modeling. Further, a computational analysis is presented, facilitating better understanding of the mechanisms underlying regulation of key components in the pathway. The analysis is illustrated by a comparison of simulation and experimental data.
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