19,095 research outputs found
Using in silico models to simulate dual perturbation experiments: procedure development and interpretation of outcomes.
BackgroundA growing number of realistic in silico models of metabolic functions are being formulated and can serve as 'dry lab' platforms to prototype and simulate experiments before they are performed. For example, dual perturbation experiments that vary both genetic and environmental parameters can readily be simulated in silico. Genetic and environmental perturbations were applied to a cell-scale model of the human erythrocyte and subsequently investigated.ResultsThe resulting steady state fluxes and concentrations, as well as dynamic responses to the perturbations were analyzed, yielding two important conclusions: 1) that transporters are informative about the internal states (fluxes and concentrations) of a cell and, 2) that genetic variations can disrupt the natural sequence of dynamic interactions between network components. The former arises from adjustments in energy and redox states, while the latter is a result of shifting time scales in aggregate pool formation of metabolites. These two concepts are illustrated for glucose-6 phosphate dehydrogenase (G6PD) and pyruvate kinase (PK) in the human red blood cell.ConclusionDual perturbation experiments in silico are much more informative for the characterization of functional states than single perturbations. Predictions from an experimentally validated cellular model of metabolism indicate that the measurement of cofactor precursor transport rates can inform the internal state of the cell when the external demands are altered or a causal genetic variation is introduced. Finally, genetic mutations that alter the clinical phenotype may also disrupt the 'natural' time scale hierarchy of interactions in the network
Complex networks theory for analyzing metabolic networks
One of the main tasks of post-genomic informatics is to systematically
investigate all molecules and their interactions within a living cell so as to
understand how these molecules and the interactions between them relate to the
function of the organism, while networks are appropriate abstract description
of all kinds of interactions. In the past few years, great achievement has been
made in developing theory of complex networks for revealing the organizing
principles that govern the formation and evolution of various complex
biological, technological and social networks. This paper reviews the
accomplishments in constructing genome-based metabolic networks and describes
how the theory of complex networks is applied to analyze metabolic networks.Comment: 13 pages, 2 figure
A geometric method for model reduction of biochemical networks with polynomial rate functions
Model reduction of biochemical networks relies on the knowledge of slow and
fast variables. We provide a geometric method, based on the Newton polytope, to
identify slow variables of a biochemical network with polynomial rate
functions. The gist of the method is the notion of tropical equilibration that
provides approximate descriptions of slow invariant manifolds. Compared to
extant numerical algorithms such as the intrinsic low dimensional manifold
method, our approach is symbolic and utilizes orders of magnitude instead of
precise values of the model parameters. Application of this method to a large
collection of biochemical network models supports the idea that the number of
dynamical variables in minimal models of cell physiology can be small, in spite
of the large number of molecular regulatory actors
Stochastic kinetic models: Dynamic independence, modularity and graphs
The dynamic properties and independence structure of stochastic kinetic
models (SKMs) are analyzed. An SKM is a highly multivariate jump process used
to model chemical reaction networks, particularly those in biochemical and
cellular systems. We identify SKM subprocesses with the corresponding counting
processes and propose a directed, cyclic graph (the kinetic independence graph
or KIG) that encodes the local independence structure of their conditional
intensities. Given a partition of the vertices, the graphical
separation in the undirected KIG has an intuitive chemical
interpretation and implies that is locally independent of given . It is proved that this separation also results in global independence of
the internal histories of and conditional on a history of the jumps in
which, under conditions we derive, corresponds to the internal history of
. The results enable mathematical definition of a modularization of an SKM
using its implied dynamics. Graphical decomposition methods are developed for
the identification and efficient computation of nested modularizations.
Application to an SKM of the red blood cell advances understanding of this
biochemical system.Comment: Published in at http://dx.doi.org/10.1214/09-AOS779 the Annals of
Statistics (http://www.imstat.org/aos/) by the Institute of Mathematical
Statistics (http://www.imstat.org
Reduction of dynamical biochemical reaction networks in computational biology
Biochemical networks are used in computational biology, to model the static
and dynamical details of systems involved in cell signaling, metabolism, and
regulation of gene expression. Parametric and structural uncertainty, as well
as combinatorial explosion are strong obstacles against analyzing the dynamics
of large models of this type. Multi-scaleness is another property of these
networks, that can be used to get past some of these obstacles. Networks with
many well separated time scales, can be reduced to simpler networks, in a way
that depends only on the orders of magnitude and not on the exact values of the
kinetic parameters. The main idea used for such robust simplifications of
networks is the concept of dominance among model elements, allowing
hierarchical organization of these elements according to their effects on the
network dynamics. This concept finds a natural formulation in tropical
geometry. We revisit, in the light of these new ideas, the main approaches to
model reduction of reaction networks, such as quasi-steady state and
quasi-equilibrium approximations, and provide practical recipes for model
reduction of linear and nonlinear networks. We also discuss the application of
model reduction to backward pruning machine learning techniques
Revealing networks from dynamics: an introduction
What can we learn from the collective dynamics of a complex network about its
interaction topology? Taking the perspective from nonlinear dynamics, we
briefly review recent progress on how to infer structural connectivity (direct
interactions) from accessing the dynamics of the units. Potential applications
range from interaction networks in physics, to chemical and metabolic
reactions, protein and gene regulatory networks as well as neural circuits in
biology and electric power grids or wireless sensor networks in engineering.
Moreover, we briefly mention some standard ways of inferring effective or
functional connectivity.Comment: Topical review, 48 pages, 7 figure
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