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Formal modeling and analysis of the MAL-associated biological regulatory network: insight into cerebral malaria.

Ahmad J, Niazi U, Mansoor S, Siddique U, Bibby J - PLoS ONE (2012)

Bottom Line: This paves the way to accurately analyse a BRN and to make predictions about critical trajectories which lead to a normal or diseased response.In order to demonstrate the practical effectiveness of our current work, different trajectories and corresponding conditions that may lead to the development of cerebral malaria (CM) are identified.Our results suggest that the system converges towards hyperinflammation if Bruton's tyrosine kinase (BTK) remains constitutively active along with pre-existing high cytokine levels which may play an important role in CM pathogenesis.

View Article: PubMed Central - PubMed

Affiliation: Research Centre for Modeling and Simulation, National University of Sciences and Technology, Islamabad, Pakistan. dr.ahmad.jamil@gmail.com

ABSTRACT
The discrete modeling formalism of René Thomas is a well known approach for the modeling and analysis of Biological Regulatory Networks (BRNs). This formalism uses a set of parameters which reflect the dynamics of the BRN under study. These parameters are initially unknown but may be deduced from the appropriately chosen observed dynamics of a BRN. The discrete model can be further enriched by using the model checking tool HyTech along with delay parameters. This paves the way to accurately analyse a BRN and to make predictions about critical trajectories which lead to a normal or diseased response. In this paper, we apply the formal discrete and hybrid (discrete and continuous) modeling approaches to characterize behavior of the BRN associated with MyD88-adapter-like (MAL)--a key protein involved with innate immune response to infections. In order to demonstrate the practical effectiveness of our current work, different trajectories and corresponding conditions that may lead to the development of cerebral malaria (CM) are identified. Our results suggest that the system converges towards hyperinflammation if Bruton's tyrosine kinase (BTK) remains constitutively active along with pre-existing high cytokine levels which may play an important role in CM pathogenesis.

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State graph of the MAL associated BRN.The complete state graph is obtained by using the GENOTECH tool. Definitions 2 and 4 assist in setting the values of the K-parameters. The K-parameters are set such that they result in a model coherent with the observed steady states behaviors. In the case of MAL-associated BRN these states are (0,0,0,0,0) and (0,0,1,2,1). In the state (0,0,0,0,0) the system does nothing when there is no signal of pathogen or returns to this state after proper response. In the state (0,0,1,2,1), the system produces inflammation continuously. The set of logical parameters is: , , , , , , , , , , , , , , ,  and .
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pone-0033532-g003: State graph of the MAL associated BRN.The complete state graph is obtained by using the GENOTECH tool. Definitions 2 and 4 assist in setting the values of the K-parameters. The K-parameters are set such that they result in a model coherent with the observed steady states behaviors. In the case of MAL-associated BRN these states are (0,0,0,0,0) and (0,0,1,2,1). In the state (0,0,0,0,0) the system does nothing when there is no signal of pathogen or returns to this state after proper response. In the state (0,0,1,2,1), the system produces inflammation continuously. The set of logical parameters is: , , , , , , , , , , , , , , , and .

Mentions: GENOTECH is a tool for the qualitative (discrete) modeling of BRNs according to Thomas' formalism (see methods). It takes a BRN and corresponding logical parameters from a user in a simple graphical user interface (GUI) and then automatically generates the state graph in which stable states, cycles and paths between any two states can be identified. GENOTECH generates the state graph (qualitative model) of the MAL associated BRN (Figure 2) representing all possible transitions from one state to the other (Figure 3), where each state indicates the concentrations of every entity at a particular time. A state is represented by BTK, MAL, NF-B, INCY and SOCS-1, in the respective order. In a stable state, the whole system converges, halts and cannot proceed to any other state. The stable states are called sinks and the network from any initial state either moves towards these sinks, or ends up in a cyclic path if there is a cycle in the network. From any state other than the stable states, a path that leads to and culminates at a sink is called a trajectory; and all trajectories culminate at some sink or remain in a cycle. It is an inherent property of any system to attain stability; therefore whenever the system is perturbed from its stable state or sink, it tends to shift back or reach another stable state. For the functional and realistic model of MAL-associated BRN, the generation of a specific stable state where every component has a zero concentration is imperative as this state represents the system before any perturbation ( also called the virgin state).


Formal modeling and analysis of the MAL-associated biological regulatory network: insight into cerebral malaria.

Ahmad J, Niazi U, Mansoor S, Siddique U, Bibby J - PLoS ONE (2012)

State graph of the MAL associated BRN.The complete state graph is obtained by using the GENOTECH tool. Definitions 2 and 4 assist in setting the values of the K-parameters. The K-parameters are set such that they result in a model coherent with the observed steady states behaviors. In the case of MAL-associated BRN these states are (0,0,0,0,0) and (0,0,1,2,1). In the state (0,0,0,0,0) the system does nothing when there is no signal of pathogen or returns to this state after proper response. In the state (0,0,1,2,1), the system produces inflammation continuously. The set of logical parameters is: , , , , , , , , , , , , , , ,  and .
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3316585&req=5

pone-0033532-g003: State graph of the MAL associated BRN.The complete state graph is obtained by using the GENOTECH tool. Definitions 2 and 4 assist in setting the values of the K-parameters. The K-parameters are set such that they result in a model coherent with the observed steady states behaviors. In the case of MAL-associated BRN these states are (0,0,0,0,0) and (0,0,1,2,1). In the state (0,0,0,0,0) the system does nothing when there is no signal of pathogen or returns to this state after proper response. In the state (0,0,1,2,1), the system produces inflammation continuously. The set of logical parameters is: , , , , , , , , , , , , , , , and .
Mentions: GENOTECH is a tool for the qualitative (discrete) modeling of BRNs according to Thomas' formalism (see methods). It takes a BRN and corresponding logical parameters from a user in a simple graphical user interface (GUI) and then automatically generates the state graph in which stable states, cycles and paths between any two states can be identified. GENOTECH generates the state graph (qualitative model) of the MAL associated BRN (Figure 2) representing all possible transitions from one state to the other (Figure 3), where each state indicates the concentrations of every entity at a particular time. A state is represented by BTK, MAL, NF-B, INCY and SOCS-1, in the respective order. In a stable state, the whole system converges, halts and cannot proceed to any other state. The stable states are called sinks and the network from any initial state either moves towards these sinks, or ends up in a cyclic path if there is a cycle in the network. From any state other than the stable states, a path that leads to and culminates at a sink is called a trajectory; and all trajectories culminate at some sink or remain in a cycle. It is an inherent property of any system to attain stability; therefore whenever the system is perturbed from its stable state or sink, it tends to shift back or reach another stable state. For the functional and realistic model of MAL-associated BRN, the generation of a specific stable state where every component has a zero concentration is imperative as this state represents the system before any perturbation ( also called the virgin state).

Bottom Line: This paves the way to accurately analyse a BRN and to make predictions about critical trajectories which lead to a normal or diseased response.In order to demonstrate the practical effectiveness of our current work, different trajectories and corresponding conditions that may lead to the development of cerebral malaria (CM) are identified.Our results suggest that the system converges towards hyperinflammation if Bruton's tyrosine kinase (BTK) remains constitutively active along with pre-existing high cytokine levels which may play an important role in CM pathogenesis.

View Article: PubMed Central - PubMed

Affiliation: Research Centre for Modeling and Simulation, National University of Sciences and Technology, Islamabad, Pakistan. dr.ahmad.jamil@gmail.com

ABSTRACT
The discrete modeling formalism of René Thomas is a well known approach for the modeling and analysis of Biological Regulatory Networks (BRNs). This formalism uses a set of parameters which reflect the dynamics of the BRN under study. These parameters are initially unknown but may be deduced from the appropriately chosen observed dynamics of a BRN. The discrete model can be further enriched by using the model checking tool HyTech along with delay parameters. This paves the way to accurately analyse a BRN and to make predictions about critical trajectories which lead to a normal or diseased response. In this paper, we apply the formal discrete and hybrid (discrete and continuous) modeling approaches to characterize behavior of the BRN associated with MyD88-adapter-like (MAL)--a key protein involved with innate immune response to infections. In order to demonstrate the practical effectiveness of our current work, different trajectories and corresponding conditions that may lead to the development of cerebral malaria (CM) are identified. Our results suggest that the system converges towards hyperinflammation if Bruton's tyrosine kinase (BTK) remains constitutively active along with pre-existing high cytokine levels which may play an important role in CM pathogenesis.

Show MeSH
Related in: MedlinePlus