ADAM: Analysis of Discrete Models of Biological Systems Using Computer Algebra

Background: Many biological systems are modeled qualitatively with discrete models, such as probabilistic Boolean networks, logical models, Petri nets, and agent-based models, with the goal to gain a better understanding of the system. The computational complexity to analyze the complete dynamics of these models grows exponentially in the number of variables, which impedes working with complex models. Although there exist sophisticated algorithms to determine the dynamics of discrete models, their implementations usually require labor-intensive formatting of the model formulation, and they are oftentimes not accessible to users without programming skills. Efficient analysis methods are needed that are accessible to modelers and easy to use. Method: By converting discrete models into algebraic models, tools from computational algebra can be used to analyze their dynamics. Specifically, we propose a method to identify attractors of a discrete model that is equivalent to solving a system of polynomial equations, a long-studied problem in computer algebra. Results: A method for efficiently identifying attractors, and the web-based tool Analysis of Dynamic Algebraic Models (ADAM), which provides this and other analysis methods for discrete models. ADAM converts several discrete model types automatically into polynomial dynamical systems and analyzes their dynamics using tools from computer algebra. Based on extensive experimentation with both discrete models arising in systems biology and randomly generated networks, we found that the algebraic algorithms presented in this manuscript are fast for systems with the structure maintained by most biological systems, namely sparseness, i.e., while the number of nodes in a biological network may be quite large, each node is affected only by a small number of other nodes, and robustness, i.e., small number of attractors

The Computational Cost of Asynchronous Neural Communication

Biological neural computation is inherently asynchronous due to large variations in neuronal spike timing and transmission delays. So-far, most theoretical work on neural networks assumes the synchronous setting where neurons fire simultaneously in discrete rounds. In this work we aim at understanding the barriers of asynchronous neural computation from an algorithmic perspective. We consider an extension of the widely studied model of synchronized spiking neurons [Maass, Neural Networks 97] to the asynchronous setting by taking into account edge and node delays. - Edge Delays: We define an asynchronous model for spiking neurons in which the latency values (i.e., transmission delays) of non self-loop edges vary adversarially over time. This extends the recent work of [Hitron and Parter, ESA\u2719] in which the latency values are restricted to be fixed over time. Our first contribution is an impossibility result that implies that the assumption that self-loop edges have no delays (as assumed in Hitron and Parter) is indeed necessary. Interestingly, in real biological networks self-loop edges (a.k.a. autapse) are indeed free of delays, and the latter has been noted by neuroscientists to be crucial for network synchronization. To capture the computational challenges in this setting, we first consider the implementation of a single NOT gate. This simple function already captures the fundamental difficulties in the asynchronous setting. Our key technical results are space and time upper and lower bounds for the NOT function, our time bounds are tight. In the spirit of the distributed synchronizers [Awerbuch and Peleg, FOCS\u2790] and following [Hitron and Parter, ESA\u2719], we then provide a general synchronizer machinery. Our construction is very modular and it is based on efficient circuit implementation of threshold gates. The complexity of our scheme is measured by the overhead in the number of neurons and the computation time, both are shown to be polynomial in the largest latency value, and the largest incoming degree ? of the original network. - Node Delays: We introduce the study of asynchronous communication due to variations in the response rates of the neurons in the network. In real brain networks, the round duration varies between different neurons in the network. Our key result is a simulation methodology that allows one to transform the above mentioned synchronized solution under edge delays into a synchronized under node delays while incurring a small overhead w.r.t space and time

Should We Learn Probabilistic Models for Model Checking? A New Approach and An Empirical Study

Many automated system analysis techniques (e.g., model checking, model-based testing) rely on first obtaining a model of the system under analysis. System modeling is often done manually, which is often considered as a hindrance to adopt model-based system analysis and development techniques. To overcome this problem, researchers have proposed to automatically "learn" models based on sample system executions and shown that the learned models can be useful sometimes. There are however many questions to be answered. For instance, how much shall we generalize from the observed samples and how fast would learning converge? Or, would the analysis result based on the learned model be more accurate than the estimation we could have obtained by sampling many system executions within the same amount of time? In this work, we investigate existing algorithms for learning probabilistic models for model checking, propose an evolution-based approach for better controlling the degree of generalization and conduct an empirical study in order to answer the questions. One of our findings is that the effectiveness of learning may sometimes be limited.Comment: 15 pages, plus 2 reference pages, accepted by FASE 2017 in ETAP

Mathematical modelling plant signalling networks

During the last two decades, molecular genetic studies and the completion of the sequencing of the Arabidopsis thaliana genome have increased knowledge of hormonal regulation in plants. These signal transduction pathways act in concert through gene regulatory and signalling networks whose main components have begun to be elucidated. Our understanding of the resulting cellular processes is hindered by the complex, and sometimes counter-intuitive, dynamics of the networks, which may be interconnected through feedback controls and cross-regulation. Mathematical modelling provides a valuable tool to investigate such dynamics and to perform in silico experiments that may not be easily carried out in a laboratory. In this article, we firstly review general methods for modelling gene and signalling networks and their application in plants. We then describe specific models of hormonal perception and cross-talk in plants. This sub-cellular analysis paves the way for more comprehensive mathematical studies of hormonal transport and signalling in a multi-scale setting

Hardware emulation of stochastic p-bits for invertible logic

The common feature of nearly all logic and memory devices is that they make use of stable units to represent 0's and 1's. A completely different paradigm is based on three-terminal stochastic units which could be called "p-bits", where the output is a random telegraphic signal continuously fluctuating between 0 and 1 with a tunable mean. p-bits can be interconnected to receive weighted contributions from others in a network, and these weighted contributions can be chosen to not only solve problems of optimization and inference but also to implement precise Boolean functions in an inverted mode. This inverted operation of Boolean gates is particularly striking: They provide inputs consistent to a given output along with unique outputs to a given set of inputs. The existing demonstrations of accurate invertible logic are intriguing, but will these striking properties observed in computer simulations carry over to hardware implementations? This paper uses individual micro controllers to emulate p-bits, and we present results for a 4-bit ripple carry adder with 48 p-bits and a 4-bit multiplier with 46 p-bits working in inverted mode as a factorizer. Our results constitute a first step towards implementing p-bits with nano devices, like stochastic Magnetic Tunnel Junctions