On control of singleton attractors in multiple Boolean networks: integer programming-based method

published_or_final_versionThe Twelfth Asia Pacific Bioinformatics Conference (APBC 2014), Shanghai, China. 17-19 January 2014. In BMC Systems Biology, 2014, v. 8, Suppl. 1, article no. S

Therapeutic target discovery using Boolean network attractors: avoiding pathological phenotypes

Target identification, one of the steps of drug discovery, aims at identifying biomolecules whose function should be therapeutically altered in order to cure the considered pathology. This work proposes an algorithm for in silico target identification using Boolean network attractors. It assumes that attractors of dynamical systems, such as Boolean networks, correspond to phenotypes produced by the modeled biological system. Under this assumption, and given a Boolean network modeling a pathophysiology, the algorithm identifies target combinations able to remove attractors associated with pathological phenotypes. It is tested on a Boolean model of the mammalian cell cycle bearing a constitutive inactivation of the retinoblastoma protein, as seen in cancers, and its applications are illustrated on a Boolean model of Fanconi anemia. The results show that the algorithm returns target combinations able to remove attractors associated with pathological phenotypes and then succeeds in performing the proposed in silico target identification. However, as with any in silico evidence, there is a bridge to cross between theory and practice, thus requiring it to be used in combination with wet lab experiments. Nevertheless, it is expected that the algorithm is of interest for target identification, notably by exploiting the inexpensiveness and predictive power of computational approaches to optimize the efficiency of costly wet lab experiments.Comment: Since the publication of this article and among the possible improvements mentioned in the Conclusion, two improvements have been done: extending the algorithm for multivalued logic and considering the basins of attraction of the pathological attractors for selecting the therapeutic bullet

Finding optimal control policy by using dynamic programming in conjunction with state reduction

In this paper we study the problem of finding optimal control policy for probabilistic Boolean networks (PBNs). Previous works have been done by using dynamic programming-based (DP) method. However, due to the high computational complexity of PBNs, DP method is computationally inefficient for large networks. Inspired by the state reduction strategies studied in [10], we consider using dynamic programming in conjunction with state reduction approach to reduce the computational cost of DP method. Numerical examples are given to demonstrate the efficiency of our proposed method. © 2011 IEEE.published_or_final_versionThe 2011 IEEE International Conference on Systems Biology (ISB), Zhuhai, China, 2-4 September 2011. In Proceedings of ISB, 2011, p. 274-27

Modeling multi-valued biological interaction networks using Fuzzy Answer Set Programming

Fuzzy Answer Set Programming (FASP) is an extension of the popular Answer Set Programming (ASP) paradigm that allows for modeling and solving combinatorial search problems in continuous domains. The recent development of practical solvers for FASP has enabled its applicability to real-world problems. In this paper, we investigate the application of FASP in modeling the dynamics of Gene Regulatory Networks (GRNs). A commonly used simplifying assumption to model the dynamics of GRNs is to assume only Boolean levels of activation of each node. Our work extends this Boolean network formalism by allowing multi-valued activation levels. We show how FASP can be used to model the dynamics of such networks. We experimentally assess the efficiency of our method using real biological networks found in the literature, as well as on randomly-generated synthetic networks. The experiments demonstrate the applicability and usefulness of our proposed method to find network attractors

Real-time support for high performance aircraft operation

The feasibility of real-time processing schemes using artificial neural networks (ANNs) is investigated. A rationale for digital neural nets is presented and a general processor architecture for control applications is illustrated. Research results on ANN structures for real-time applications are given. Research results on ANN algorithms for real-time control are also shown

Approximating attractors of Boolean networks by iterative CTL model checking

This paper introduces the notion of approximating asynchronous attractors of Boolean networks by minimal trap spaces. We define three criteria for determining the quality of an approximation: “faithfulness” which requires that the oscillating variables of all attractors in a trap space correspond to their dimensions, “univocality” which requires that there is a unique attractor in each trap space, and “completeness” which requires that there are no attractors outside of a given set of trap spaces. Each is a reachability property for which we give equivalent model checking queries. Whereas faithfulness and univocality can be decided by model checking the corresponding subnetworks, the naive query for completeness must be evaluated on the full state space. Our main result is an alternative approach which is based on the iterative refinement of an initially poor approximation. The algorithm detects so-called autonomous sets in the interaction graph, variables that contain all their regulators, and considers their intersection and extension in order to perform model checking on the smallest possible state spaces. A benchmark, in which we apply the algorithm to 18 published Boolean networks, is given. In each case, the minimal trap spaces are faithful, univocal, and complete, which suggests that they are in general good approximations for the asymptotics of Boolean networks

Cell fate reprogramming by control of intracellular network dynamics

Identifying control strategies for biological networks is paramount for practical applications that involve reprogramming a cell's fate, such as disease therapeutics and stem cell reprogramming. Here we develop a novel network control framework that integrates the structural and functional information available for intracellular networks to predict control targets. Formulated in a logical dynamic scheme, our approach drives any initial state to the target state with 100% effectiveness and needs to be applied only transiently for the network to reach and stay in the desired state. We illustrate our method's potential to find intervention targets for cancer treatment and cell differentiation by applying it to a leukemia signaling network and to the network controlling the differentiation of helper T cells. We find that the predicted control targets are effective in a broad dynamic framework. Moreover, several of the predicted interventions are supported by experiments.Comment: 61 pages (main text, 15 pages; supporting information, 46 pages) and 12 figures (main text, 6 figures; supporting information, 6 figures). In revie

Finding optimal control policy in probabilistic Boolean networks with hard constraints by using integer programming and dynamic programming

Session 2 regularIn this paper, we study control problems of Boolean Networks (BNs) and Probabilistic Boolean Networks (PBNs). For BN CONTROL, by applying external control, we propose to derive the network to the desired state within a few time steps. For PBN CONTROL, we propose to find a control sequence such that the network will terminate in the desired state with a maximum probability. Also, we propose to minimize the maximum cost of the terminal state to which the network will enter. Integer linear programming and dynamic programming in conjunction with hard constraints are then employed to solve the above problems. Numerical experiments are given to demonstrate the effectiveness of our algorithms.We also present a hardness result suggesting that PBN CONTROL is harder than BN CONTROL. ©2010 IEEE.published_or_final_versio