1,678 research outputs found
Global parameter identification of stochastic reaction networks from single trajectories
We consider the problem of inferring the unknown parameters of a stochastic
biochemical network model from a single measured time-course of the
concentration of some of the involved species. Such measurements are available,
e.g., from live-cell fluorescence microscopy in image-based systems biology. In
addition, fluctuation time-courses from, e.g., fluorescence correlation
spectroscopy provide additional information about the system dynamics that can
be used to more robustly infer parameters than when considering only mean
concentrations. Estimating model parameters from a single experimental
trajectory enables single-cell measurements and quantification of cell--cell
variability. We propose a novel combination of an adaptive Monte Carlo sampler,
called Gaussian Adaptation, and efficient exact stochastic simulation
algorithms that allows parameter identification from single stochastic
trajectories. We benchmark the proposed method on a linear and a non-linear
reaction network at steady state and during transient phases. In addition, we
demonstrate that the present method also provides an ellipsoidal volume
estimate of the viable part of parameter space and is able to estimate the
physical volume of the compartment in which the observed reactions take place.Comment: Article in print as a book chapter in Springer's "Advances in Systems
Biology
Partial differential equations for self-organization in cellular and developmental biology
Understanding the mechanisms governing and regulating the emergence of structure and heterogeneity within cellular systems, such as the developing embryo, represents a multiscale challenge typifying current integrative biology research, namely, explaining the macroscale behaviour of a system from microscale dynamics. This review will focus upon modelling how cell-based dynamics orchestrate the emergence of higher level structure. After surveying representative biological examples and the models used to describe them, we will assess how developments at the scale of molecular biology have impacted on current theoretical frameworks, and the new modelling opportunities that are emerging as a result. We shall restrict our survey of mathematical approaches to partial differential equations and the tools required for their analysis. We will discuss the gap between the modelling abstraction and biological reality, the challenges this presents and highlight some open problems in the field
Stochastic analysis of nonlinear dynamics and feedback control for gene regulatory networks with applications to synthetic biology
The focus of the thesis is the investigation of the generalized repressilator model
(repressing genes ordered in a ring structure). Using nonlinear bifurcation analysis
stable and quasi-stable periodic orbits in this genetic network are characterized
and a design for a switchable and controllable genetic oscillator is proposed. The
oscillator operates around a quasi-stable periodic orbit using the classical engineering
idea of read-out based control. Previous genetic oscillators have been
designed around stable periodic orbits, however we explore the possibility of
quasi-stable periodic orbit expecting better controllability.
The ring topology of the generalized repressilator model has spatio-temporal
symmetries that can be understood as propagating perturbations in discrete lattices.
Network topology is a universal cross-discipline transferable concept and
based on it analytical conditions for the emergence of stable and quasi-stable
periodic orbits are derived. Also the length and distribution of quasi-stable oscillations
are obtained. The findings suggest that long-lived transient dynamics
due to feedback loops can dominate gene network dynamics.
Taking the stochastic nature of gene expression into account a master equation
for the generalized repressilator is derived. The stochasticity is shown to influence
the onset of bifurcations and quality of oscillations. Internal noise is shown to
have an overall stabilizing effect on the oscillating transients emerging from the
quasi-stable periodic orbits.
The insights from the read-out based control scheme for the genetic oscillator
lead us to the idea to implement an algorithmic controller, which would direct
any genetic circuit to a desired state. The algorithm operates model-free, i.e. in
principle it is applicable to any genetic network and the input information is a
data matrix of measured time series from the network dynamics. The application
areas for readout-based control in genetic networks range from classical tissue
engineering to stem cells specification, whenever a quantitatively and temporarily
targeted intervention is required
MOLNs: A cloud platform for interactive, reproducible and scalable spatial stochastic computational experiments in systems biology using PyURDME
Computational experiments using spatial stochastic simulations have led to
important new biological insights, but they require specialized tools, a
complex software stack, as well as large and scalable compute and data analysis
resources due to the large computational cost associated with Monte Carlo
computational workflows. The complexity of setting up and managing a
large-scale distributed computation environment to support productive and
reproducible modeling can be prohibitive for practitioners in systems biology.
This results in a barrier to the adoption of spatial stochastic simulation
tools, effectively limiting the type of biological questions addressed by
quantitative modeling. In this paper, we present PyURDME, a new, user-friendly
spatial modeling and simulation package, and MOLNs, a cloud computing appliance
for distributed simulation of stochastic reaction-diffusion models. MOLNs is
based on IPython and provides an interactive programming platform for
development of sharable and reproducible distributed parallel computational
experiments
Multi-Level Kinetic Model of mRNA Delivery via Transfection of Lipoplexes
Recent work on the use of mRNA lipoplexes for gene delivery demonstrates the need for a mathematical model that simulates and predicts kinetics and transfection efficiency. The small copy numbers involved make it necessary to use stochastic models and include statistical analysis of the variation observed in the experimental data. The modeling requirements are further complicated by the multi-level nature of the problem, where mRNA molecules are contained in lipoplexes, which are in turn contained in endosomes, where each of these entities displays a behavior of its own. We have created a mathematical model that reproduces both the time courses and the statistical variance observed in recent experiments using single-cell tracking of GFP expression after transfection. By applying a few key simplifications and assumptions, we have limited the number of free parameters to five, which we optimize to match five experimental determinants by means of a simulated annealing algorithm. The models demonstrate the need for modeling of nested species in order to reproduce the shape of the dose-response and expression-level curves
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