9,019 research outputs found
The interplay between discrete noise and nonlinear chemical kinetics in a signal amplification cascade
We used various analytical and numerical techniques to elucidate signal
propagation in a small enzymatic cascade which is subjected to external and
internal noise. The nonlinear character of catalytic reactions, which underlie
protein signal transduction cascades, renders stochastic signaling dynamics in
cytosol biochemical networks distinct from the usual description of stochastic
dynamics in gene regulatory networks. For a simple 2-step enzymatic cascade
which underlies many important protein signaling pathways, we demonstrated that
the commonly used techniques such as the linear noise approximation and the
Langevin equation become inadequate when the number of proteins becomes too
low. Consequently, we developed a new analytical approximation, based on mixing
the generating function and distribution function approaches, to the solution
of the master equation that describes nonlinear chemical signaling kinetics for
this important class of biochemical reactions. Our techniques work in a much
wider range of protein number fluctuations than the methods used previously. We
found that under certain conditions the burst-phase noise may be injected into
the downstream signaling network dynamics, resulting possibly in unusually
large macroscopic fluctuations. In addition to computing first and second
moments, which is the goal of commonly used analytical techniques, our new
approach provides the full time-dependent probability distributions of the
colored non-Gaussian processes in a nonlinear signal transduction cascade.Comment: 16 pages, 9 figure
Order Reduction of the Chemical Master Equation via Balanced Realisation
We consider a Markov process in continuous time with a finite number of
discrete states. The time-dependent probabilities of being in any state of the
Markov chain are governed by a set of ordinary differential equations, whose
dimension might be large even for trivial systems. Here, we derive a reduced
ODE set that accurately approximates the probabilities of subspaces of interest
with a known error bound. Our methodology is based on model reduction by
balanced truncation and can be considerably more computationally efficient than
the Finite State Projection Algorithm (FSP) when used for obtaining transient
responses. We show the applicability of our method by analysing stochastic
chemical reactions. First, we obtain a reduced order model for the
infinitesimal generator of a Markov chain that models a reversible,
monomolecular reaction. In such an example, we obtain an approximation of the
output of a model with 301 states by a reduced model with 10 states. Later, we
obtain a reduced order model for a catalytic conversion of substrate to a
product; and compare its dynamics with a stochastic Michaelis-Menten
representation. For this example, we highlight the savings on the computational
load obtained by means of the reduced-order model. Finally, we revisit the
substrate catalytic conversion by obtaining a lower-order model that
approximates the probability of having predefined ranges of product molecules.Comment: 12 pages, 6 figure
Stochastic Representations of Ion Channel Kinetics and Exact Stochastic Simulation of Neuronal Dynamics
In this paper we provide two representations for stochastic ion channel
kinetics, and compare the performance of exact simulation with a commonly used
numerical approximation strategy. The first representation we present is a
random time change representation, popularized by Thomas Kurtz, with the second
being analogous to a "Gillespie" representation. Exact stochastic algorithms
are provided for the different representations, which are preferable to either
(a) fixed time step or (b) piecewise constant propensity algorithms, which
still appear in the literature. As examples, we provide versions of the exact
algorithms for the Morris-Lecar conductance based model, and detail the error
induced, both in a weak and a strong sense, by the use of approximate
algorithms on this model. We include ready-to-use implementations of the random
time change algorithm in both XPP and Matlab. Finally, through the
consideration of parametric sensitivity analysis, we show how the
representations presented here are useful in the development of further
computational methods. The general representations and simulation strategies
provided here are known in other parts of the sciences, but less so in the
present setting.Comment: 39 pages, 6 figures, appendix with XPP and Matlab cod
Jump-Diffusion Approximation of Stochastic Reaction Dynamics: Error bounds and Algorithms
Biochemical reactions can happen on different time scales and also the
abundance of species in these reactions can be very different from each other.
Classical approaches, such as deterministic or stochastic approach, fail to
account for or to exploit this multi-scale nature, respectively. In this paper,
we propose a jump-diffusion approximation for multi-scale Markov jump processes
that couples the two modeling approaches. An error bound of the proposed
approximation is derived and used to partition the reactions into fast and slow
sets, where the fast set is simulated by a stochastic differential equation and
the slow set is modeled by a discrete chain. The error bound leads to a very
efficient dynamic partitioning algorithm which has been implemented for several
multi-scale reaction systems. The gain in computational efficiency is
illustrated by a realistically sized model of a signal transduction cascade
coupled to a gene expression dynamics.Comment: 32 pages, 7 figure
Synthesizing and tuning chemical reaction networks with specified behaviours
We consider how to generate chemical reaction networks (CRNs) from functional
specifications. We propose a two-stage approach that combines synthesis by
satisfiability modulo theories and Markov chain Monte Carlo based optimisation.
First, we identify candidate CRNs that have the possibility to produce correct
computations for a given finite set of inputs. We then optimise the reaction
rates of each CRN using a combination of stochastic search techniques applied
to the chemical master equation, simultaneously improving the of correct
behaviour and ruling out spurious solutions. In addition, we use techniques
from continuous time Markov chain theory to study the expected termination time
for each CRN. We illustrate our approach by identifying CRNs for majority
decision-making and division computation, which includes the identification of
both known and unknown networks.Comment: 17 pages, 6 figures, appeared the proceedings of the 21st conference
on DNA Computing and Molecular Programming, 201
Data-driven modelling of biological multi-scale processes
Biological processes involve a variety of spatial and temporal scales. A
holistic understanding of many biological processes therefore requires
multi-scale models which capture the relevant properties on all these scales.
In this manuscript we review mathematical modelling approaches used to describe
the individual spatial scales and how they are integrated into holistic models.
We discuss the relation between spatial and temporal scales and the implication
of that on multi-scale modelling. Based upon this overview over
state-of-the-art modelling approaches, we formulate key challenges in
mathematical and computational modelling of biological multi-scale and
multi-physics processes. In particular, we considered the availability of
analysis tools for multi-scale models and model-based multi-scale data
integration. We provide a compact review of methods for model-based data
integration and model-based hypothesis testing. Furthermore, novel approaches
and recent trends are discussed, including computation time reduction using
reduced order and surrogate models, which contribute to the solution of
inference problems. We conclude the manuscript by providing a few ideas for the
development of tailored multi-scale inference methods.Comment: This manuscript will appear in the Journal of Coupled Systems and
Multiscale Dynamics (American Scientific Publishers
- …