Target Control of Boolean Networks with Permanent Edgetic Perturbations

Boolean network is a popular and well-established modelling framework for gene regulatory networks. The steady-state behaviour of Boolean networks can be described as attractors, which are hypothesised to characterise cellular phenotypes. In this work, we study the target control problem of Boolean networks, which has important applications for cellular reprogramming. More specifically, we want to reduce the total number of attractors of a Boolean network to a single target attractor. Different from existing approaches to solving control problems of Boolean networks with node perturbations, we aim to develop an approach utilising edgetic perturbations. Namely, our objective is to modify the update functions of a Boolean network such that there remains only one attractor. The design of our approach is inspired by Thomas’ first rule, and we primarily focus on the removal of cycles in the interaction graph of a Boolean network. We further use results in the literature to only remove positive cycles which are responsible for the appearance of multiple attractors. We apply our solution to a number of real-life biological networks modelled as Boolean networks, and the experimental results demonstrate its efficacy and efficiency

Computational Methods for Analysing Long-run Dynamics of Large Biological Networks

Systems biology combines developments in the fields of computer science, mathematics, engineering, statistics, and biology to study biological networks from a holistic point of view in order to provide a comprehensive, system level understanding of the underlying system. Recent developments in biological laboratory techniques have led to a slew of increasingly complex and large biological networks. This poses a challenge for formal representation and analysis of those large networks efficiently. To understand biology at the system level, the focus should be on understanding the structure and dynamics of cellular and organismal function, rather than on the characteristics of isolated parts of a cell or organism. One of the most important focuses is the long-run dynamics of a network, as they often correspond to the functional states, such as proliferation, apoptosis, and differentiation. In this thesis, we concentrate on how to analyse long-run dynamics of biological networks. In particular, we examine situations where the networks in question are very large. In the literature, quite a few mathematical models, such as ordinary differential equations, Petri nets, and Boolean networks (BNs), have been proposed for representing biological networks. These models provide different levels of details and have different advantages. Since we are interested in large networks and their long-run dynamics, we need to use ``coarse-grained" level models that focus on the system behaviour of the network while neglecting molecular details. In particular, we use probabilistic Boolean networks (PBNs) to describe biological networks. By focusing on the wiring of a network, a PBN not only simplifies the representation of the network, but it also captures the important characteristics of the dynamics of the network. Within the framework of PBNs, the analysis of long-run dynamics of a biological network can be performed with regard to two aspects. The first aspect lies in the identification of the so-called attractors of the constituent BNs of a PBN. An attractor of a BN is a set of states, inside which the network will stay forever once it goes in; thus capturing the network's long-term behaviour. A few methods have been discussed for computing attractors in the literature. For example, the binary decision diagram based approach and the satisfiability based approach. These methods, however, are either restricted by the network size, or can only be applied to synchronous networks where all the elements in the network are updated synchronously at each time step. To overcome these issues, we propose a decomposition-based method. The method works in three steps: we decompose a large network into small sub-networks, detect attractors in sub-networks, and recover the attractors of the original network using the attractors of the sub-networks. Our methods can be applied to both asynchronous networks, where only one element in the network is updated at each time step, and synchronous networks. Experimental results show that our proposed method is significantly faster than the state-of-the-art methods. The second aspect lies in the computation of steady-state probabilities of a PBN with perturbations. The perturbations of a PBN allow for a random, with a small probability, alteration of the current state of the PBN. In a PBN with perturbations, the long-run dynamics is characterised by the steady-state probability of being in a certain set of states. Various methods for computing steady-state probabilities can be applied to small networks. However, for large networks, the simulation-based statistical methods remain the only viable choice. A crucial issue for such methods is the efficiency. The long-run analysis of large networks requires the computation of steady-state probabilities to be finished as soon as possible. To reach this goal, we apply various techniques. First, we revive an efficient Monte Carlo simulation method called the two-state Markov chain approach for making the computations. We identify an initialisation problem, which may lead to biased results of this method, and propose several heuristics to avoid this problem. Secondly, we develop several techniques to speed up the simulation of PBNs. These techniques include the multiple central processing unit based parallelisation, the multiple graphic processing unit based parallelisation, and the structure-based parallelisation. Experimental results show that these techniques can lead to speedups from ten times to several hundreds of times. Lastly, we have implemented the above mentioned techniques for identification of attractors and the computation of steady-state probabilities in a tool called ASSA-PBN. A case-study for analysing an apoptosis network with this tool is provided

STARGATE-X: a Python package for statistical analysis on the REACTOME network

Many important aspects of biological knowledge at the molecular level can be represented by pathways. Through their analysis, we gain mechanistic insights and interpret lists of interesting genes from experiments (usually omics and functional genomic experiments). As a result, pathways play a central role in the development of bioinformatics methods and tools for computing predictions from known molecular-level mechanisms. Qualitative as well as quantitative knowledge about pathways can be effectively represented through biochemical networks linking the biochemical reactions and the compounds (e.g., proteins) occurring in the considered pathways. So, repositories providing biochemical networks for known pathways play a central role in bioinformatics and in systems biology. Here we focus on Reactome, a free, comprehensive, and widely used repository for biochemical networks and pathways. In this paper, we: (1) introduce a tool StARGate-X (STatistical Analysis of the Reactome multi-GrAph Through nEtworkX) to carry out an automated analysis of the connectivity properties of Reactome biochemical reaction network and of its biological hierarchy (i.e., cell compartments, namely, the closed parts within the cytosol, usually surrounded by a membrane); the code is freely available at https://github.com/marinoandrea/stargate-x; (2) show the effectiveness of our tool by providing an analysis of the Reactome network, in terms of centrality measures, with respect to in- and out-degree. As an example of usage of StARGate-X, we provide a detailed automated analysis of the Reactome network, in terms of centrality measures. We focus both on the subgraphs induced by single compartments and on the graph whose nodes are the strongly connected components. To the best of our knowledge, this is the first freely available tool that enables automatic analysis of the large biochemical network within Reactome through easy-to-use APIs (Application Programming Interfaces)

Toward a further understanding of object feature binding: a cognitive neuroscience perspective.

The aim of this thesis is to lead to a further understanding of the neural mechanisms underlying object feature binding in the human brain. The focus is on information processing and integration in the visual system and visual shortterm memory. From a review of the literature it is clear that there are three major competing binding theories, however, none of these individually solves the binding problem satisfactorily. Thus the aim of this research is to conduct behavioural experimentation into object feature binding, paying particular attention to visual short-term memory. The behavioural experiment was designed and conducted using a within-subjects delayed responset ask comprising a battery of sixty-four composite objects each with three features and four dimensions in each of three conditions (spatial, temporal and spatio-temporal).Findings from the experiment,which focus on spatial and temporal aspects of object feature binding and feature proximity on binding errors, support the spatial theories on object feature binding, in addition we propose that temporal theories and convergence, through hierarchical feature analysis, are also involved. Because spatial properties have a dedicated processing neural stream, and temporal properties rely on limited capacity memory systems, memories for sequential information would likely be more difficult to accuratelyr ecall. Our study supports other studies which suggest that both spatial and temporal coherence to differing degrees,may be involved in object feature binding. Traditionally, these theories have purported to provide individual solutions, but this thesis proposes a novel unified theory of object feature binding in which hierarchical feature analysis, spatial attention and temporal synchrony each plays a role. It is further proposed that binding takes place in visual short-term memory through concerted and integrated information processing in distributed cortical areas. A cognitive model detailing this integrated proposal is given. Next, the cognitive model is used to inform the design and suggested implementation of a computational model which would be able to test the theory put forward in this thesis. In order to verify the model, future work is needed to implement the computational model.Thus it is argued that this doctoral thesis provides valuable experimental evidence concerning spatio-temporal aspects of the binding problem and as such is an additional building block in the quest for a solution to the object feature binding problem