Imperial College London
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DrJosephChallenger

Faculty of Medicine, School of Public Health

Research Fellow
 
 
 
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Contact

 

j.challenger Website

 
 
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Location

 

409School of Public HealthWhite City Campus

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Summary

 

Publications

Citation

BibTex format

@article{Pahle:2012:10.1186/1752-0509-6-86,
author = {Pahle, J and Challenger, JD and Mendes, P and McKane, AJ},
doi = {10.1186/1752-0509-6-86},
journal = {BMC Systems Biology},
pages = {1--13},
title = {Biochemical fluctuations, optimisation and the linear noise approximation},
url = {http://dx.doi.org/10.1186/1752-0509-6-86},
volume = {6},
year = {2012}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - BackgroundStochastic fluctuations in molecular numbers have been in many cases shown to be crucial for the understanding of biochemical systems. However, the systematic study of these fluctuations is severely hindered by the high computational demand of stochastic simulation algorithms. This is particularly problematic when, as is often the case, some or many model parameters are not well known. Here, we propose a solution to this problem, namely a combination of the linear noise approximation with optimisation methods. The linear noise approximation is used to efficiently estimate the covariances of particle numbers in the system. Combining it with optimisation methods in a closed-loop to find extrema of covariances within a possibly high-dimensional parameter space allows us to answer various questions. Examples are, what is the lowest amplitude of stochastic fluctuations possible within given parameter ranges? Or, which specific changes of parameter values lead to the increase of the correlation between certain chemical species? Unlike stochastic simulation methods, this has no requirement for small numbers of molecules and thus can be applied to cases where stochastic simulation is prohibitive.ResultsWe implemented our strategy in the software COPASI and show its applicability on two different models of mitogen-activated kinases (MAPK) signalling -- one generic model of extracellular signal-regulated kinases (ERK) and one model of signalling via p38 MAPK. Using our method we were able to quickly find local maxima of covariances between particle numbers in the ERK model depending on the activities of phospho-MKKK and its corresponding phosphatase. With the p38 MAPK model our method was able to efficiently find conditions under which the coefficient of variation of the output of the signalling system, namely the particle number of Hsp27, could be minimised. We also investigated correlations between the two parallel signalling branches (MKK3 and MKK6) in this model
AU  - Pahle,J
AU  - Challenger,JD
AU  - Mendes,P
AU  - McKane,AJ
DO  - 10.1186/1752-0509-6-86
EP  - 13
PY  - 2012///
SN  - 1752-0509
SP  - 1
TI  - Biochemical fluctuations, optimisation and the linear noise approximation
T2  - BMC Systems Biology
UR  - http://dx.doi.org/10.1186/1752-0509-6-86
UR  - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000307248500001&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
UR  - https://bmcsystbiol.biomedcentral.com/articles/10.1186/1752-0509-6-86
UR  - http://hdl.handle.net/10044/1/84509
VL  - 6
ER  -
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