Identification of control targets in Boolean molecular network models via computational algebra

Motivation: Many problems in biomedicine and other areas of the life sciences can be characterized as control problems, with the goal of finding strategies to change a disease or otherwise undesirable state of a biological system into another, more desirable, state through an intervention, such as a drug or other therapeutic treatment. The identification of such strategies is typically based on a mathematical model of the process to be altered through targeted control inputs. This paper focuses on processes at the molecular level that determine the state of an individual cell, involving signaling or gene regulation. The mathematical model type considered is that of Boolean networks. The potential control targets can be represented by a set of nodes and edges that can be manipulated to produce a desired effect on the system. Experimentally, node manipulation requires technology to completely repress or fully activate a particular gene product while edge manipulations only require a drug that inactivates the interaction between two gene products. Results: This paper presents a method for the identification of potential intervention targets in Boolean molecular network models using algebraic techniques. The approach exploits an algebraic representation of Boolean networks to encode the control candidates in the network wiring diagram as the solutions of a system of polynomials equations, and then uses computational algebra techniques to find such controllers. The control methods in this paper are validated through the identification of combinatorial interventions in the signaling pathways of previously reported control targets in two well studied systems, a p53-mdm2 network and a blood T cell lymphocyte granular leukemia survival signaling network.Comment: 12 pages, 4 figures, 2 table

Formal Verification of Probabilistic SystemC Models with Statistical Model Checking

Transaction-level modeling with SystemC has been very successful in describing the behavior of embedded systems by providing high-level executable models, in which many of them have inherent probabilistic behaviors, e.g., random data and unreliable components. It thus is crucial to have both quantitative and qualitative analysis of the probabilities of system properties. Such analysis can be conducted by constructing a formal model of the system under verification and using Probabilistic Model Checking (PMC). However, this method is infeasible for large systems, due to the state space explosion. In this article, we demonstrate the successful use of Statistical Model Checking (SMC) to carry out such analysis directly from large SystemC models and allow designers to express a wide range of useful properties. The first contribution of this work is a framework to verify properties expressed in Bounded Linear Temporal Logic (BLTL) for SystemC models with both timed and probabilistic characteristics. Second, the framework allows users to expose a rich set of user-code primitives as atomic propositions in BLTL. Moreover, users can define their own fine-grained time resolution rather than the boundary of clock cycles in the SystemC simulation. The third contribution is an implementation of a statistical model checker. It contains an automatic monitor generation for producing execution traces of the model-under-verification (MUV), the mechanism for automatically instrumenting the MUV, and the interaction with statistical model checking algorithms.Comment: Journal of Software: Evolution and Process. Wiley, 2017. arXiv admin note: substantial text overlap with arXiv:1507.0818

Problem Understanding through Landscape Theory

In order to understand the structure of a problem we need to measure some features of the problem. Some examples of measures suggested in the past are autocorrelation and fitness-distance correlation. Landscape theory, developed in the last years in the field of combinatorial optimization, provides mathematical expressions to efficiently compute statistics on optimization problems. In this paper we discuss how can we use optimización combinatoria in the context of problem understanding and present two software tools that can be used to efficiently compute the mentioned measures.Ministerio de Economía y Competitividad (TIN2011-28194

A directed isoperimetric inequality with application to Bregman near neighbor lower bounds

Bregman divergences $D_\phi$ are a class of divergences parametrized by a convex function $\phi$ and include well known distance functions like $\ell_2^2$ and the Kullback-Leibler divergence. There has been extensive research on algorithms for problems like clustering and near neighbor search with respect to Bregman divergences, in all cases, the algorithms depend not just on the data size $n$ and dimensionality $d$, but also on a structure constant $\mu \ge 1$ that depends solely on $\phi$ and can grow without bound independently. In this paper, we provide the first evidence that this dependence on $\mu$ might be intrinsic. We focus on the problem of approximate near neighbor search for Bregman divergences. We show that under the cell probe model, any non-adaptive data structure (like locality-sensitive hashing) for $c$-approximate near-neighbor search that admits $r$ probes must use space $\Omega(n^{1 + \frac{\mu}{c r}})$. In contrast, for LSH under $\ell_1$ the best bound is $\Omega(n^{1+\frac{1}{cr}})$. Our new tool is a directed variant of the standard boolean noise operator. We show that a generalization of the Bonami-Beckner hypercontractivity inequality exists "in expectation" or upon restriction to certain subsets of the Hamming cube, and that this is sufficient to prove the desired isoperimetric inequality that we use in our data structure lower bound. We also present a structural result reducing the Hamming cube to a Bregman cube. This structure allows us to obtain lower bounds for problems under Bregman divergences from their $\ell_1$ analog. In particular, we get a (weaker) lower bound for approximate near neighbor search of the form $\Omega(n^{1 + \frac{1}{cr}})$ for an $r$-query non-adaptive data structure, and new cell probe lower bounds for a number of other near neighbor questions in Bregman space.Comment: 27 page

The Computational Complexity of Generating Random Fractals

In this paper we examine a number of models that generate random fractals. The models are studied using the tools of computational complexity theory from the perspective of parallel computation. Diffusion limited aggregation and several widely used algorithms for equilibrating the Ising model are shown to be highly sequential; it is unlikely they can be simulated efficiently in parallel. This is in contrast to Mandelbrot percolation that can be simulated in constant parallel time. Our research helps shed light on the intrinsic complexity of these models relative to each other and to different growth processes that have been recently studied using complexity theory. In addition, the results may serve as a guide to simulation physics.Comment: 28 pages, LATEX, 8 Postscript figures available from [email protected]