3,873 research outputs found
Model Checking to Assess T-Helper Cell Plasticity
Computational modeling constitutes a crucial step toward the functional understanding of complex cellular networks. In particular, logical modeling has proven suitable for the dynamical analysis of large signaling and transcriptional regulatory networks. In this context, signaling input components are generally meant to convey external stimuli, or environmental cues. In response to such external signals, cells acquire specific gene expression patterns modeled in terms of attractors (e.g., stable states). The capacity for cells to alter or reprogram their differentiated states upon changes in environmental conditions is referred to as cell plasticity. In this article, we present a multivalued logical framework along with computational methods recently developed to efficiently analyze large models. We mainly focus on a symbolic model checking approach to investigate switches between attractors subsequent to changes of input conditions. As a case study, we consider the cellular network regulating the differentiation of T-helper (Th) cells, which orchestrate many physiological and pathological immune responses. To account for novel cellular subtypes, we present an extended version of a published model of Th cell differentiation. We then use symbolic model checking to analyze reachability properties between Th subtypes upon changes of environmental cues. This allows for the construction of a synthetic view of Th cell plasticity in terms of a graph connecting subtypes with arcs labeled by input conditions. Finally, we explore novel strategies enabling specific Th cell polarizing or reprograming events.LabEx MemoLife, Ecole Normale Supérieure, FCT grants: (PEst-OE/EEI/LA0021/2013, IF/01333/2013), Ph.D.program of the Agence National de Recherche sur Le Sida (ANRS), European Research Council consolidator grant
Boolean Networks as Predictive Models of Emergent Biological Behaviors
Interacting biological systems at all organizational levels display emergent
behavior. Modeling these systems is made challenging by the number and variety
of biological components and interactions (from molecules in gene regulatory
networks to species in ecological networks) and the often-incomplete state of
system knowledge (e.g., the unknown values of kinetic parameters for
biochemical reactions). Boolean networks have emerged as a powerful tool for
modeling these systems. We provide a methodological overview of Boolean network
models of biological systems. After a brief introduction, we describe the
process of building, analyzing, and validating a Boolean model. We then present
the use of the model to make predictions about the system's response to
perturbations and about how to control (or at least influence) its behavior. We
emphasize the interplay between structural and dynamical properties of Boolean
networks and illustrate them in three case studies from disparate levels of
biological organization.Comment: Review, to appear in the Cambridge Elements serie
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
Boolean Network Topologies and the Determinative Power of Nodes
Boolean networks have been used extensively for modeling networks whose node activity could be simplified to a binary outcome, such as on-off. Each node is influenced by the states of the other nodes via a logical Boolean function. The network is described by its topological properties which refer to the links between nodes, and its dynamical properties which refer to the way each node uses the information obtained from other nodes to update its state. This work explores the correlation between the information stored in the Boolean functions for each node in a property known as the determinative power and some topological properties of each node, in particular the clustering coefficient and the betweenness centrality. The determinative power of nodes is defined using concepts from information theory, in particular the mutual information. The primary motivation is to construct models of real world networks to examine if the determinative power is sensitive to any of the considered topological properties. The findings indicate that, for a homogeneous network in which all nodes obey the same threshold function under three different topologies, the determinative power can have a negative correlation with the clustering coefficient and a positive correlation with the betweenness centrality, depending on the topological properties of the network. A statistical analysis on a collection of 36 Boolean models of signal transduction networks reveals that the correlations observed in the theoretical cases are suppressed in the biological networks, thus supporting previous research results
Network Physiology reveals relations between network topology and physiological function
The human organism is an integrated network where complex physiologic
systems, each with its own regulatory mechanisms, continuously interact, and
where failure of one system can trigger a breakdown of the entire network.
Identifying and quantifying dynamical networks of diverse systems with
different types of interactions is a challenge. Here, we develop a framework to
probe interactions among diverse systems, and we identify a physiologic
network. We find that each physiologic state is characterized by a specific
network structure, demonstrating a robust interplay between network topology
and function. Across physiologic states the network undergoes topological
transitions associated with fast reorganization of physiologic interactions on
time scales of a few minutes, indicating high network flexibility in response
to perturbations. The proposed system-wide integrative approach may facilitate
the development of a new field, Network Physiology.Comment: 12 pages, 9 figure
Patterns of subnet usage reveal distinct scales of regulation in the transcriptional regulatory network of Escherichia coli
The set of regulatory interactions between genes, mediated by transcription
factors, forms a species' transcriptional regulatory network (TRN). By
comparing this network with measured gene expression data one can identify
functional properties of the TRN and gain general insight into transcriptional
control. We define the subnet of a node as the subgraph consisting of all nodes
topologically downstream of the node, including itself. Using a large set of
microarray expression data of the bacterium Escherichia coli, we find that the
gene expression in different subnets exhibits a structured pattern in response
to environmental changes and genotypic mutation. Subnets with less changes in
their expression pattern have a higher fraction of feed-forward loop motifs and
a lower fraction of small RNA targets within them. Our study implies that the
TRN consists of several scales of regulatory organization: 1) subnets with more
varying gene expression controlled by both transcription factors and
post-transcriptional RNA regulation, and 2) subnets with less varying gene
expression having more feed-forward loops and less post-transcriptional RNA
regulation.Comment: 14 pages, 8 figures, to be published in PLoS Computational Biolog
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