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- Bimolecular Reaction (1)
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Background: The linear noise approximation (LNA) is commonly used to predict how noise is regulated and exploited at the cellular level. These predictions are exact for reaction networks composed exclusively of first order reactions or for networks involving bimolecular reactions and large numbers of molecules. It is however well known that gene regulation involves bimolecular interactions with molecule numbers as small as a single copy of a particular gene. It is therefore questionable how reliable are the LNA predictions for these systems.
Results: We implement in the software package intrinsic Noise Analyzer (iNA), a system size expansion based method which calculates the mean concentrations and the variances of the fluctuations to an order of accuracy higher than the LNA. We then use iNA to explore the parametric dependence of the Fano factors and of the coefficients of variation of the mRNA and protein fluctuations in models of genetic networks involving nonlinear protein degradation, post-transcriptional, post-translational and negative feedback regulation. We find that the LNA can significantly underestimate the amplitude and period of noise-induced oscillations in genetic oscillators. We also identify cases where the LNA predicts that noise levels can be optimized by tuning a bimolecular rate constant whereas our method shows that no such regulation is possible. All our results are confirmed by stochastic simulations.
Conclusion: The software iNA allows the investigation of parameter regimes where the LNA fares well and where it does not. We have shown that the parametric dependence of the coefficients of variation and Fano factors for common gene regulatory networks is better described by including terms of higher order than LNA in the system size expansion. This analysis is considerably faster than stochastic simulations due to the extensive ensemble averaging needed to obtain statistically meaningful results. Hence iNA is well suited for performing computationally efficient and quantitative studies of intrinsic noise in gene regulatory networks.
Linked linear mixed models
(2016)
The complexity of eye-movement control during reading allows measurement of many dependent variables, the most prominent ones being fixation durations and their locations in words. In current practice, either variable may serve as dependent variable or covariate for the other in linear mixed models (LMMs) featuring also psycholinguistic covariates of word recognition and sentence comprehension. Rather than analyzing fixation location and duration with separate LMMs, we propose linking the two according to their sequential dependency. Specifically, we include predicted fixation location (estimated in the first LMM from psycholinguistic covariates) and its associated residual fixation location as covariates in the second, fixation-duration LMM. This linked LMM affords a distinction between direct and indirect effects (mediated through fixation location) of psycholinguistic covariates on fixation durations. Results confirm the robustness of distributed processing in the perceptual span. They also offer a resolution of the paradox of the inverted optimal viewing position (IOVP) effect (i.e., longer fixation durations in the center than at the beginning and end of words) although the opposite (i.e., an OVP effect) is predicted from default assumptions of psycholinguistic processing efficiency: The IOVP effect in fixation durations is due to the residual fixation-location covariate, presumably driven primarily by saccadic error, and the OVP effect (at least the left part of it) is uncovered with the predicted fixation-location covariate, capturing the indirect effects of psycholinguistic covariates. We expect that linked LMMs will be useful for the analysis of other dynamically related multiple outcomes, a conundrum of most psychonomic research.
The Smoothing Spline ANOVA (SS-ANOVA) requires a specialized construction of basis and penalty terms in order to incorporate prior knowledge about the data to be fitted. Typically, one resorts to the most general approach using tensor product splines. This implies severe constraints on the correlation structure, i.e. the assumption of isotropy of smoothness can not be incorporated in general. This may increase the variance of the spline fit, especially if only a relatively small set of observations are given. In this article, we propose an alternative method that allows to incorporate prior knowledge without the need to construct specialized bases and penalties, allowing the researcher to choose the spline basis and penalty according to the prior knowledge of the observations rather than choosing them according to the analysis to be done. The two approaches are compared with an artificial example and with analyses of fixation durations during reading.