Statistical model comparison applied to common network motifs.

BACKGROUND: Network motifs are small modules that show interesting functional and dynamic properties, and are believed to be the building blocks of complex cellular processes. However, the mechanistic details of such modules are often unknown: there is uncertainty about the motif architecture as well as the functional form and parameter values when converted to ordinary differential equations (ODEs). This translates into a number of candidate models being compatible with the system under study. A variety of statistical methods exist for ranking models including maximum likelihood-based and Bayesian methods. Our objective is to show how such methods can be applied in a typical systems biology setting. RESULTS: We focus on four commonly occurring network motif structures and show that it is possible to differentiate between them using simulated data and any of the model comparison methods tested. We expand one of the motifs, the feed forward (FF) motif, for several possible parameterizations and apply model selection on simulated data. We then use experimental data on three biosynthetic pathways in Escherichia coli to formally assess how current knowledge matches the time series available. Our analysis confirms two of them as FF motifs. Only an expanded set of FF motif parameterizations using time delays is able to fit the third pathway, indicating that the true mechanism might be more complex in this case. CONCLUSIONS: Maximum likelihood as well as Bayesian model comparison methods are suitable for selecting a plausible motif model among a set of candidate models. Our work shows that it is practical to apply model comparison to test ideas about underlying mechanisms of biological pathways in a formal and quantitative way.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Information Routing Driven by Background Chatter in a Signaling Network

Living systems are capable of processing multiple sources of information simultaneously. This is true even at the cellular level, where not only coexisting signals stimulate the cell, but also the presence of fluctuating conditions is significant. When information is received by a cell signaling network via one specific input, the existence of other stimuli can provide a background activity –or chatter– that may affect signal transmission through the network and, therefore, the response of the cell. Here we study the modulation of information processing by chatter in the signaling network of a human cell, specifically, in a Boolean model of the signal transduction network of a fibroblast. We observe that the level of external chatter shapes the response of the system to information carrying signals in a nontrivial manner, modulates the activity levels of the network outputs, and effectively determines the paths of information flow. Our results show that the interactions and node dynamics, far from being random, confer versatility to the signaling network and allow transitions between different information-processing scenarios

Relaxation dynamics and frequency response of a noisy cell signaling network

We investigate the dynamics of cell signaling using an experimentally based Boolean model of the human fibroblast signal transduction network. We determine via systematic numerical simulations the relaxation dynamics of the network in response to a constant set of inputs, both in the absence and in the presence of environmental fluctuations. We then study the network's response to periodically modulated signals, uncovering different types of behaviors for different pairs of driven input and output nodes. The phenomena observed include low-pass, high-pass, and band-pass filtering of the input modulations, among other nontrivial responses, at frequencies around the relaxation frequency of the network. The results reveal that the dynamic response to the external modulation of biologically realistic signaling networks is versatile and robust to noise

Information routing driven by background chatter in a signaling network

Living systems are capable of processing multiple sources of information simultaneously. This is true even at the cellular level, where not only coexisting signals stimulate the cell, but also the presence of fluctuating conditions is significant. When information is received by a cell signaling network via one specific input, the existence of other stimuli can provide a background activity –or chatter– that may affect signal transmission through the network and, therefore, the response of the cell. Here we study the modulation of information processing by chatter in the signaling network of a human cell, specifically, in a Boolean model of the signal transduction network of a fibroblast. We observe that the level of external chatter shapes the response of the system to information carrying signals in a nontrivial manner, modulates the activity levels of the network outputs, and effectively determines the paths of information flow. Our results show that the interactions and node dynamics, far from being random, confer versatility to the signaling network and allow transitions between different information-processing scenarios.This work has been financially supported by the Spanish Network of Multiple Sclerosis (REEM, Instituto de Salud Carlos III), the Fundacion Mutua Madrileña (Spain), the Ministerio de Ciencia e Innovacion (project FIS2009-13360 and I3 program), and the Generalitat de Catalunya (project 2009SGR1168). P.R. is supported by a FI grant from the Generalitat de Catalunya. A.J.P. was supported by the Juan de la Cierva program of the Ministerio de Ciencia e Innovacion (Spain). J.G.O. also acknowledges financial support from the ICREA foundatio

Information routing driven by background chatter in a signaling network

Living systems are capable of processing multiple sources of information simultaneously. This is true even at the cellular level, where not only coexisting signals stimulate the cell, but also the presence of fluctuating conditions is significant. When information is received by a cell signaling network via one specific input, the existence of other stimuli can provide a background activity –or chatter– that may affect signal transmission through the network and, therefore, the response of the cell. Here we study the modulation of information processing by chatter in the signaling network of a human cell, specifically, in a Boolean model of the signal transduction network of a fibroblast. We observe that the level of external chatter shapes the response of the system to information carrying signals in a nontrivial manner, modulates the activity levels of the network outputs, and effectively determines the paths of information flow. Our results show that the interactions and node dynamics, far from being random, confer versatility to the signaling network and allow transitions between different information-processing scenarios.Peer Reviewe

Transient oscillatory dynamics of interferon beta signaling in macrophages

Background: Interferon-beta (IFN-beta) activates the immune response through the type I IFN signaling pathway. IFN-beta is important in the response to pathogen infections and is used as a therapy for Multiple Sclerosis. The mechanisms of self-regulation and control of this pathway allow precise and environment-dependent response of the cells in different conditions. Here we analyzed type I IFN signaling in response to IFN-beta in the macrophage cell line RAW 264.7 by RT-PCR, ELISA and xMAP assays. The experimental results were interpreted by means of a theoretical model of the pathway. Results: Phosphorylation of the STAT1 protein (pSTAT1) and mRNA levels of the pSTAT1 inhibitor SOCS1 displayed an attenuated oscillatory behavior after IFN-beta activation. In turn, mRNA levels of the interferon regulatory factor IRF1 grew rapidly in the first 50–90 minutes after stimulation until a maximum value, and started to decrease slowly around 200–250 min. The analysis of our kinetic model identified a significant role of the negative feedback from SOCS1 in driving the observed damped oscillatory dynamics, and of the positive feedback from IRF1 in increasing STAT1 basal levels. Our study shows that the system works as a biological damped relaxation oscillator based on a phosphorylation-dephosphorylation network centered on STAT1. Moreover, a bifurcation analysis identified translocation of pSTAT1 dimers to the nucleus as a critical step for regulating the dynamics of type I IFN pathway in the first steps, which may be important in defining the response to IFN-beta therapy. Conclusions: The immunomodulatory effect of IFN-beta signaling in macrophages takes the form of transient oscillatory dynamics of the JAK-STAT pathway, whose specific relaxation properties determine the lifetime of the cellular response to the cytokine.This work was supported by the EU 6FP ComplexDis project (NEST-043241), the EU 7FP – Marie Curie initial training network UEPHA*MS (ITN-212877) and Fundacion Cellex to PV; by the Spanish network of excellence in MS of the Instituto de Salud Carlos III, Spain to PV and JGO (RD07/0060) and by the Fundación Mutua Madrileña to PV and JGO; by a grant of the Ministerio de Economia y Competitividad and Fondo Europeo de Desarrollo Regional (Spain, project FIS2012-37655) and by the ICREA Academia program to JG

Transient oscillatory dynamics of interferon beta signaling in macrophages

Background: Interferon-beta (IFN-beta) activates the immune response through the type I IFN signaling pathway. IFN-beta is important in the response to pathogen infections and is used as a therapy for Multiple Sclerosis. The mechanisms of self-regulation and control of this pathway allow precise and environment-dependent response of the cells in different conditions. Here we analyzed type I IFN signaling in response to IFN-beta in the macrophage cell line RAW 264.7 by RT-PCR, ELISA and xMAP assays. The experimental results were interpreted by means of a theoretical model of the pathway. Results: Phosphorylation of the STAT1 protein (pSTAT1) and mRNA levels of the pSTAT1 inhibitor SOCS1 displayed an attenuated oscillatory behavior after IFN-beta activation. In turn, mRNA levels of the interferon regulatory factor IRF1 grew rapidly in the first 50–90 minutes after stimulation until a maximum value, and started to decrease slowly around 200–250 min. The analysis of our kinetic model identified a significant role of the negative feedback from SOCS1 in driving the observed damped oscillatory dynamics, and of the positive feedback from IRF1 in increasing STAT1 basal levels. Our study shows that the system works as a biological damped relaxation oscillator based on a phosphorylation-dephosphorylation network centered on STAT1. Moreover, a bifurcation analysis identified translocation of pSTAT1 dimers to the nucleus as a critical step for regulating the dynamics of type I IFN pathway in the first steps, which may be important in defining the response to IFN-beta therapy. Conclusions: The immunomodulatory effect of IFN-beta signaling in macrophages takes the form of transient oscillatory dynamics of the JAK-STAT pathway, whose specific relaxation properties determine the lifetime of the cellular response to the cytokine.This work was supported by the EU 6FP ComplexDis project (NEST-043241), the EU 7FP – Marie Curie initial training network UEPHA*MS (ITN-212877) and Fundacion Cellex to PV; by the Spanish network of excellence in MS of the Instituto de Salud Carlos III, Spain to PV and JGO (RD07/0060) and by the Fundación Mutua Madrileña to PV and JGO; by a grant of the Ministerio de Economia y Competitividad and Fondo Europeo de Desarrollo Regional (Spain, project FIS2012-37655) and by the ICREA Academia program to JG

Relaxation dynamics and frequency response of a noisy cell signaling network

We investigate the dynamics of cell signaling using an experimentally based Boolean model of the human fibroblast signal transduction network. We determine via systematic numerical simulations the relaxation dynamics of the network in response to a constant set of inputs, both in the absence and in the presence of environmental fluctuations. We then study the network’s response to periodically modulated signals, uncovering different types of behaviors for different pairs of driven input and output nodes. The phenomena observed include low-pass, high-pass, and band-pass filtering of the input modulations, among other nontrivial responses, at frequencies around the relaxation frequency of the network. The results reveal that the dynamic response to the external modulation of biologically realistic signaling networks is versatile and robust to noise.Peer Reviewe