196 research outputs found
A family tree of Markov models in systems biology
Motivated by applications in systems biology, we seek a probabilistic
framework based on Markov processes to represent intracellular processes. We
review the formal relationships between different stochastic models referred to
in the systems biology literature. As part of this review, we present a novel
derivation of the differential Chapman-Kolmogorov equation for a general
multidimensional Markov process made up of both continuous and jump processes.
We start with the definition of a time-derivative for a probability density but
place no restrictions on the probability distribution, in particular, we do not
assume it to be confined to a region that has a surface (on which the
probability is zero). In our derivation, the master equation gives the jump
part of the Markov process while the Fokker-Planck equation gives the
continuous part. We thereby sketch a {}``family tree'' for stochastic models in
systems biology, providing explicit derivations of their formal relationship
and clarifying assumptions involved.Comment: 18 pages, 2 figure
A Plea for More Theory in Molecular Biology
The integrationist principles of systems theory have proven hugely
successful in the physical sciences and engineering. It is an underlying assumption
made in the systems approach to biology that they can also be used to
understand biological phenomena at the level of an entire organism or organ.
Within this holistic vision, the vastmajority of systems biology research projects
investigate phenomena at the level of the cell, with the belief that unifying principles
established at the most basic level can establish a framework within which
we may understand phenomena at higher levels of organization. In this spirit,
and to use a celestial analogy, if a disease effecting an organ or entire body is
our universe of discourse, then the cell is the star we gaze at. In building an
understanding of disease and the effect of drugs, systems biology makes an
implicit assumption about direct causal entailment between cell function and
physiology. A skeptic might argue that this is about the same as trying to predict
the world economy from observations made at a local supermarket. However,
assuming for the moment that the money and hope we are investing inmolecular
biology, genomics, and systems biology is justified, how should this amazing
118 O. Wolkenhauer, M. Mesarovi´c, P. Wellstead
intellectual achievement be possible? In this chapter we argue that an essential
tool to progress is a systems theory that allows biological objects and their operational
characteristics to be captured in a succinct yet general form. Armed
with this conceptual framework, we construct mathematical representations of
standard cellular and intercellular functions which can be integrated to describe
more general processes of cell complexes, and potentially entire organ
A model checking approach to the parameter estimation of biochemical pathways
Model checking has historically been an important tool to
verify models of a wide variety of systems. Typically a model has to exhibit
certain properties to be classed ‘acceptable’. In this work we use
model checking in a new setting; parameter estimation. We characterise
the desired behaviour of a model in a temporal logic property and alter
the model to make it conform to the property (determined through
model checking). We have implemented a computational system called
MC2(GA) which pairs a model checker with a genetic algorithm. To
drive parameter estimation, the fitness of set of parameters in a model is
the inverse of the distance between its actual behaviour and the desired
behaviour. The model checker used is the simulation-based Monte Carlo
Model Checker for Probabilistic Linear-time Temporal Logic with numerical
constraints, MC2(PLTLc). Numerical constraints as well as the
overall probability of the behaviour expressed in temporal logic are used
to minimise the behavioural distance. We define the theory underlying
our parameter estimation approach in both the stochastic and continuous
worlds. We apply our approach to biochemical systems and present
an illustrative example where we estimate the kinetic rate constants in
a continuous model of a signalling pathway
Stronger computational modelling of signalling pathways using both continuous and discrete-state methods
Starting from a biochemical signalling pathway model expresses in a process algebra enriched with quantitative information, we automatically derive both continuous-space and discrete-space representations suitable for numerical evaluation. We compare results obtained using approximate stochastic simulation thereby exposing a flaw in the use of the differentiation procedure producing misleading results
On-the-fly Uniformization of Time-Inhomogeneous Infinite Markov Population Models
This paper presents an on-the-fly uniformization technique for the analysis
of time-inhomogeneous Markov population models. This technique is applicable to
models with infinite state spaces and unbounded rates, which are, for instance,
encountered in the realm of biochemical reaction networks. To deal with the
infinite state space, we dynamically maintain a finite subset of the states
where most of the probability mass is located. This approach yields an
underapproximation of the original, infinite system. We present experimental
results to show the applicability of our technique
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
Systems biologists seek fuller integration of systems biology approaches in new cancer research programs
Systems biology takes an interdisciplinary approach to the systematic study of complex interactions in biological systems. This approach seeks to decipher the emergent behaviors of complex systems rather than focusing only on their constituent properties. As an increasing number of examples illustrate the value of systems biology approaches to understand the initiation, progression, and treatment of cancer, systems biologists from across Europe and the United States hope for changes in the way their field is currently perceived among cancer researchers. In a recent EU-US workshop, supported by the European Commission, the German Federal Ministry for Education and Research, and the National Cancer Institute of the NIH, the participants discussed the strengths, weaknesses, hurdles, and opportunities in cancer systems biology
The edges of understanding
A culture's icons are a window onto its soul. Few would disagree that, in the culture of molecular biology that dominated much of the life sciences for the last third of the 20th century, the dominant icon was the double helix. In the present, post-modern, 'systems biology' era, however, it is, arguably, the hairball
The RNA workbench: best practices for RNA and high-throughput sequencing bioinformatics in Galaxy
RNA-based regulation has become a major research topic in molecular biology. The analysis of epigenetic and expression data is therefore incomplete if RNA-based regulation is not taken into account. Thus, it is increasingly important but not yet standard to combine RNA-centric data and analysis tools with other types of experimental data such as RNA-seq or ChIP-seq. Here, we present the RNA workbench, a comprehensive set of analysis tools and consolidated workflows that enable the researcher to combine these two worlds. Based on the Galaxy framework the workbench guarantees simple access, easy extension, flexible adaption to personal and security needs, and sophisticated analyses that are independent of command-line knowledge. Currently, it includes more than 50 bioinformatics tools that are dedicated to different research areas of RNA biology including RNA structure analysis, RNA alignment, RNA annotation, RNA-protein interaction, ribosome profiling, RNA-seq analysis and RNA target prediction. The workbench is developed and maintained by experts in RNA bioinformatics and the Galaxy framework. Together with the growing community evolving around this workbench, we are committed to keep the workbench up-to-date for future standards and needs, providing researchers with a reliable and robust framework for RNA data analysis. Availability: The RNA workbench is available at https://github.com/bgruening/galaxy-rna-workbench
Differential Dynamic Properties of Scleroderma Fibroblasts in Response to Perturbation of Environmental Stimuli
Diseases are believed to arise from dysregulation of biological systems (pathways) perturbed by environmental triggers. Biological systems as a whole are not just the sum of their components, rather ever-changing, complex and dynamic systems over time in response to internal and external perturbation. In the past, biologists have mainly focused on studying either functions of isolated genes or steady-states of small biological pathways. However, it is systems dynamics that play an essential role in giving rise to cellular function/dysfunction which cause diseases, such as growth, differentiation, division and apoptosis. Biological phenomena of the entire organism are not only determined by steady-state characteristics of the biological systems, but also by intrinsic dynamic properties of biological systems, including stability, transient-response, and controllability, which determine how the systems maintain their functions and performance under a broad range of random internal and external perturbations. As a proof of principle, we examine signal transduction pathways and genetic regulatory pathways as biological systems. We employ widely used state-space equations in systems science to model biological systems, and use expectation-maximization (EM) algorithms and Kalman filter to estimate the parameters in the models. We apply the developed state-space models to human fibroblasts obtained from the autoimmune fibrosing disease, scleroderma, and then perform dynamic analysis of partial TGF-β pathway in both normal and scleroderma fibroblasts stimulated by silica. We find that TGF-β pathway under perturbation of silica shows significant differences in dynamic properties between normal and scleroderma fibroblasts. Our findings may open a new avenue in exploring the functions of cells and mechanism operative in disease development
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