13,197 research outputs found
Discrete time piecewise affine models of genetic regulatory networks
We introduce simple models of genetic regulatory networks and we proceed to
the mathematical analysis of their dynamics. The models are discrete time
dynamical systems generated by piecewise affine contracting mappings whose
variables represent gene expression levels. When compared to other models of
regulatory networks, these models have an additional parameter which is
identified as quantifying interaction delays. In spite of their simplicity,
their dynamics presents a rich variety of behaviours. This phenomenology is not
limited to piecewise affine model but extends to smooth nonlinear discrete time
models of regulatory networks. In a first step, our analysis concerns general
properties of networks on arbitrary graphs (characterisation of the attractor,
symbolic dynamics, Lyapunov stability, structural stability, symmetries, etc).
In a second step, focus is made on simple circuits for which the attractor and
its changes with parameters are described. In the negative circuit of 2 genes,
a thorough study is presented which concern stable (quasi-)periodic
oscillations governed by rotations on the unit circle -- with a rotation number
depending continuously and monotonically on threshold parameters. These regular
oscillations exist in negative circuits with arbitrary number of genes where
they are most likely to be observed in genetic systems with non-negligible
delay effects.Comment: 34 page
On the effects of firing memory in the dynamics of conjunctive networks
Boolean networks are one of the most studied discrete models in the context
of the study of gene expression. In order to define the dynamics associated to
a Boolean network, there are several \emph{update schemes} that range from
parallel or \emph{synchronous} to \emph{asynchronous.} However, studying each
possible dynamics defined by different update schemes might not be efficient.
In this context, considering some type of temporal delay in the dynamics of
Boolean networks emerges as an alternative approach. In this paper, we focus in
studying the effect of a particular type of delay called \emph{firing memory}
in the dynamics of Boolean networks. Particularly, we focus in symmetric
(non-directed) conjunctive networks and we show that there exist examples that
exhibit attractors of non-polynomial period. In addition, we study the
prediction problem consisting in determinate if some vertex will eventually
change its state, given an initial condition. We prove that this problem is
{\bf PSPACE}-complete
Transcriptional delay stabilizes bistable gene networks
Transcriptional delay can significantly impact the dynamics of gene networks.
Here we examine how such delay affects bistable systems. We investigate several
stochastic models of bistable gene networks and find that increasing delay
dramatically increases the mean residence times near stable states. To explain
this, we introduce a non-Markovian, analytically tractable reduced model. The
model shows that stabilization is the consequence of an increased number of
failed transitions between stable states. Each of the bistable systems that we
simulate behaves in this manner
Attribute Exploration of Discrete Temporal Transitions
Discrete temporal transitions occur in a variety of domains, but this work is
mainly motivated by applications in molecular biology: explaining and analyzing
observed transcriptome and proteome time series by literature and database
knowledge. The starting point of a formal concept analysis model is presented.
The objects of a formal context are states of the interesting entities, and the
attributes are the variable properties defining the current state (e.g.
observed presence or absence of proteins). Temporal transitions assign a
relation to the objects, defined by deterministic or non-deterministic
transition rules between sets of pre- and postconditions. This relation can be
generalized to its transitive closure, i.e. states are related if one results
from the other by a transition sequence of arbitrary length. The focus of the
work is the adaptation of the attribute exploration algorithm to such a
relational context, so that questions concerning temporal dependencies can be
asked during the exploration process and be answered from the computed stem
base. Results are given for the abstract example of a game and a small gene
regulatory network relevant to a biomedical question.Comment: Only the email address and reference have been replace
A Method to Identify and Analyze Biological Programs through Automated Reasoning.
Predictive biology is elusive because rigorous, data-constrained, mechanistic models of complex biological systems are difficult to derive and validate. Current approaches tend to construct and examine static interaction network models, which are descriptively rich but often lack explanatory and predictive power, or dynamic models that can be simulated to reproduce known behavior. However, in such approaches implicit assumptions are introduced as typically only one mechanism is considered, and exhaustively investigating all scenarios is impractical using simulation. To address these limitations, we present a methodology based on automated formal reasoning, which permits the synthesis and analysis of the complete set of logical models consistent with experimental observations. We test hypotheses against all candidate models, and remove the need for simulation by characterizing and simultaneously analyzing all mechanistic explanations of observed behavior. Our methodology transforms knowledge of complex biological processes from sets of possible interactions and experimental observations to precise, predictive biological programs governing cell function
Extreme learning machines for reverse engineering of gene regulatory networks from expression time series
The reconstruction of gene regulatory networks (GRNs) from genes profiles has a growing interest in bioinformatics for understanding the complex regulatory mechanisms in cellular systems. GRNs explicitly represent the cause-effect of regulation among a group of genes and its reconstruction is today a challenging computational problem. Several methods were proposed, but most of them require different input sources to provide an acceptable prediction. Thus, it is a great challenge to reconstruct a GRN only from temporal gene-expression data. Results: Extreme Learning Machine (ELM) is a new supervised neural model that has gained interest in the last years because of its higher learning rate and better performance than existing supervised models in terms of predictive power. This work proposes a novel approach for GRNs reconstruction in which ELMs are used for modeling the relationships between gene expression time series. Artificial datasets generated with the well-known benchmark tool used in DREAM competitions were used. Real datasets were used for validation of this novel proposal with well-known GRNs underlying the time series. The impact of increasing the size of GRNs was analyzed in detail for the compared methods. The results obtained confirm the superiority of the ELM approach against very recent state-of-the-art methods in the same experimental conditions.Fil: Rubiolo, Mariano. Consejo Nacional de Investigaciones CientÃficas y Técnicas. Centro CientÃfico Tecnológico Conicet - Santa Fe. Instituto de Investigación en Señales, Sistemas e Inteligencia Computacional. Universidad Nacional del Litoral. Facultad de IngenierÃa y Ciencias HÃdricas. Instituto de Investigación en Señales, Sistemas e Inteligencia Computacional; ArgentinaFil: Milone, Diego Humberto. Consejo Nacional de Investigaciones CientÃficas y Técnicas. Centro CientÃfico Tecnológico Conicet - Santa Fe. Instituto de Investigación en Señales, Sistemas e Inteligencia Computacional. Universidad Nacional del Litoral. Facultad de IngenierÃa y Ciencias HÃdricas. Instituto de Investigación en Señales, Sistemas e Inteligencia Computacional; ArgentinaFil: Stegmayer, Georgina. Consejo Nacional de Investigaciones CientÃficas y Técnicas. Centro CientÃfico Tecnológico Conicet - Santa Fe. Instituto de Investigación en Señales, Sistemas e Inteligencia Computacional. Universidad Nacional del Litoral. Facultad de IngenierÃa y Ciencias HÃdricas. Instituto de Investigación en Señales, Sistemas e Inteligencia Computacional; Argentin
A temporal logic approach to modular design of synthetic biological circuits
We present a new approach for the design of a synthetic biological circuit
whose behaviour is specified in terms of signal temporal logic (STL) formulae.
We first show how to characterise with STL formulae the input/output behaviour
of biological modules miming the classical logical gates (AND, NOT, OR). Hence,
we provide the regions of the parameter space for which these specifications
are satisfied. Given a STL specification of the target circuit to be designed
and the networks of its constituent components, we propose a methodology to
constrain the behaviour of each module, then identifying the subset of the
parameter space in which those constraints are satisfied, providing also a
measure of the robustness for the target circuit design. This approach, which
leverages recent results on the quantitative semantics of Signal Temporal
Logic, is illustrated by synthesising a biological implementation of an
half-adder
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Modeling Cell-to-Cell Communication Networks Using Response-Time Distributions.
Cell-to-cell communication networks have critical roles in coordinating diverse organismal processes, such as tissue development or immune cell response. However, compared with intracellular signal transduction networks, the function and engineering principles of cell-to-cell communication networks are far less understood. Major complications include: cells are themselves regulated by complex intracellular signaling networks; individual cells are heterogeneous; and output of any one cell can recursively become an additional input signal to other cells. Here, we make use of a framework that treats intracellular signal transduction networks as "black boxes" with characterized input-to-output response relationships. We study simple cell-to-cell communication circuit motifs and find conditions that generate bimodal responses in time, as well as mechanisms for independently controlling synchronization and delay of cell-population responses. We apply our modeling approach to explain otherwise puzzling data on cytokine secretion onset times in T cells. Our approach can be used to predict communication network structure using experimentally accessible input-to-output measurements and without detailed knowledge of intermediate steps
Hopf bifurcation in a gene regulatory network model: Molecular movement causes oscillations
Gene regulatory networks, i.e. DNA segments in a cell which interact with each other indirectly through their RNA and protein products, lie at the heart of many important intracellular signal transduction processes. In this paper we analyse a mathematical model of a canonical gene regulatory network consisting of a single negative feedback loop between a protein and its mRNA (e.g. the Hes1 transcription factor system). The model consists of two partial differential equations describing the spatio-temporal interactions between the protein and its mRNA in a 1-dimensional domain. Such intracellular negative feedback systems are known to exhibit oscillatory behaviour and this is the case for our model, shown initially via computational simulations. In order to investigate this behaviour more deeply, we next solve our system using Greens functions and then undertake a linearized stability analysis of the steady states of the model. Our results show that the diffusion coefficient of the protein/mRNA acts as a bifurcation parameter and gives rise to a Hopf bifurcation. This shows that the spatial movement of the mRNA and protein molecules alone is sufficient to cause the oscillations. This has implications for transcription factors such as p53, NF-B and heat shock proteins which are involved in regulating important cellular processes such as inflammation, meiosis, apoptosis and the heat shock response, and are linked to diseases such as arthritis and cancer
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