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

Regularized Optimal Transport and the Rot Mover's Distance

This paper presents a unified framework for smooth convex regularization of discrete optimal transport problems. In this context, the regularized optimal transport turns out to be equivalent to a matrix nearness problem with respect to Bregman divergences. Our framework thus naturally generalizes a previously proposed regularization based on the Boltzmann-Shannon entropy related to the Kullback-Leibler divergence, and solved with the Sinkhorn-Knopp algorithm. We call the regularized optimal transport distance the rot mover's distance in reference to the classical earth mover's distance. We develop two generic schemes that we respectively call the alternate scaling algorithm and the non-negative alternate scaling algorithm, to compute efficiently the regularized optimal plans depending on whether the domain of the regularizer lies within the non-negative orthant or not. These schemes are based on Dykstra's algorithm with alternate Bregman projections, and further exploit the Newton-Raphson method when applied to separable divergences. We enhance the separable case with a sparse extension to deal with high data dimensions. We also instantiate our proposed framework and discuss the inherent specificities for well-known regularizers and statistical divergences in the machine learning and information geometry communities. Finally, we demonstrate the merits of our methods with experiments using synthetic data to illustrate the effect of different regularizers and penalties on the solutions, as well as real-world data for a pattern recognition application to audio scene classification

Soft beams: when capillarity induces axial compression

We study the interaction of an elastic beam with a liquid drop in the case where bending and extensional effects are both present. We use a variational approach to derive equilibrium equations and constitutive relation for the beam. This relation is shown to include a term due to surface energy in addition of the classical Young's modulus term, leading to a modification of Hooke's law. At the triple point where solid, liquid, and vapor phases meet we find that the external force applied on the beam is parallel to the liquid-vapor interface. Moreover, in the case where solid-vapor and solid-liquid interface energies do not depend on the extension state of the beam, we show that the extension in the beam is continuous at the triple point and that the wetting angle satisfy the classical Young-Dupr\'e relation

Finite element reduced order models for nonlinear vibrations of piezoelectric layered beams with applications to NEMS

This article presents a finite element reduced order model for the nonlinear vibrations of piezoelectric layered beams with application to NEMS. In this model, the geometrical nonlinearities are taken into account through a von Kármán nonlinear strain–displacement relationship. The originality of the finite element electromechanical formulation is that the system electrical state is fully described by only a couple of variables per piezoelectric patches, namely the electric charge contained in the electrodes and the voltage between the electrodes. Due to the geometrical nonlinearity, the piezoelectric actuation introduces an original parametric excitation term in the equilibrium equation. The reduced-order formulation of the discretized problem is obtained by expanding the mechanical displacement unknown vector onto the short-circuit eigenmode basis. A particular attention is paid to the computation of the unknown nonlinear stiffness coefficients of the reduced-order model. Due to the particular form of the von Kármán nonlinearities, these coefficients are computed exactly, once for a given geometry, by prescribing relevant nodal displacements in nonlinear static solutions settings. Finally, the low-order model is computed with an original purely harmonic-based continuation method. Our numerical tool is then validated by computing the nonlinear vibrations of a mechanically excited homogeneous beam supported at both ends referenced in the literature. The more difficult case of the nonlinear oscillations of a layered nanobridge piezoelectrically actuated is also studied. Interesting vibratory phenomena such as parametric amplification or patch length dependence of the frequency output response are highlighted in order to help in the design of these nanodevices.This research is part of the NEMSPIEZO project, under funds from the French National Research Agency (Project ANR-08-NAN O-015-04), for which the authors are grateful

General combination rules for qualitative and quantitative beliefs

Martin and Osswald \cite{Martin07} have recently proposed many generalizations of combination rules on quantitative beliefs in order to manage the conflict and to consider the specificity of the responses of the experts. Since the experts express themselves usually in natural language with linguistic labels, Smarandache and Dezert \cite{Li07} have introduced a mathematical framework for dealing directly also with qualitative beliefs. In this paper we recall some element of our previous works and propose the new combination rules, developed for the fusion of both qualitative or quantitative beliefs

Priority-based intersection management with kinodynamic constraints

We consider the problem of coordinating a collection of robots at an intersection area taking into account dynamical constraints due to actuator limitations. We adopt the coordination space approach, which is standard in multiple robot motion planning. Assuming the priorities between robots are assigned in advance and the existence of a collision-free trajectory respecting those priorities, we propose a provably safe trajectory planner satisfying kinodynamic constraints. The algorithm is shown to run in real time and to return safe (collision-free) trajectories. Simulation results on synthetic data illustrate the benefits of the approach.Comment: to be presented at ECC2014; 6 page

Accurate numerical potential and field in razor-thin axisymmetric discs

We demonstrate the high accuracy of the density splitting method to compute the gravitational potential and field in the plane of razor-thin, axially symmetric discs, as preliminarily outlined in Pierens & Hure (2004). Because residual kernels in Poisson integrals are not C^infinity-class functions, we use a dynamical space mapping in order to increase the efficiency of advanced quadrature schemes. In terms of accuracy, results are better by orders of magnitude than for the classical FFT-methods.Comment: 11 pages, 5 color figures, 2 table