Simulation-based model checking approach to cell fate specification during Caenorhabditis elegans vulval development by hybrid functional Petri net with extension

<p>Abstract</p> <p>Background</p> <p>Model checking approaches were applied to biological pathway validations around 2003. Recently, Fisher <it>et al</it>. have proved the importance of model checking approach by inferring new regulation of signaling crosstalk in <it>C. elegans </it>and confirming the regulation with biological experiments. They took a discrete and state-based approach to explore all possible states of the system underlying vulval precursor cell (VPC) fate specification for desired properties. However, since both discrete and continuous features appear to be an indispensable part of biological processes, it is more appropriate to use quantitative models to capture the dynamics of biological systems. Our key motivation of this paper is to establish a quantitative methodology to model and analyze <it>in silico </it>models incorporating the use of model checking approach.</p> <p>Results</p> <p>A novel method of modeling and simulating biological systems with the use of model checking approach is proposed based on hybrid functional Petri net with extension (HFPNe) as the framework dealing with both discrete and continuous events. Firstly, we construct a quantitative VPC fate model with 1761 components by using HFPNe. Secondly, we employ two major biological fate determination rules – Rule I and Rule II – to VPC fate model. We then conduct 10,000 simulations for each of 48 sets of different genotypes, investigate variations of cell fate patterns under each genotype, and validate the two rules by comparing three simulation targets consisting of fate patterns obtained from <it>in silico </it>and <it>in vivo </it>experiments. In particular, an evaluation was successfully done by using our VPC fate model to investigate one target derived from biological experiments involving hybrid lineage observations. However, the understandings of hybrid lineages are hard to make on a discrete model because the hybrid lineage occurs when the system comes close to certain thresholds as discussed by Sternberg and Horvitz in 1986. Our simulation results suggest that: Rule I that cannot be applied with qualitative based model checking, is more reasonable than Rule II owing to the high coverage of predicted fate patterns (except for the genotype of <it>lin-15ko; lin-12ko </it>double mutants). More insights are also suggested.</p> <p>Conclusion</p> <p>The quantitative simulation-based model checking approach is a useful means to provide us valuable biological insights and better understandings of biological systems and observation data that may be hard to capture with the qualitative one.</p

A review of modelling and verification approaches for computational biology

This paper reviews most frequently used computational modelling approaches and formal verification techniques in computational biology. The paper also compares a number of model checking tools and software suits used in analysing biological systems and biochemical networks and verifiying a wide range of biological properties

Towards Executable Biology

Heringa, J. [Promotor]Fokkink, W.J. [Promotor]Feenstra, K.A. [Copromotor

Simulation of a Petri net-based Model of the Terpenoid Biosynthesis Pathway

<p>Abstract</p> <p>Background</p> <p>The development and simulation of dynamic models of terpenoid biosynthesis has yielded a systems perspective that provides new insights into how the structure of this biochemical pathway affects compound synthesis. These insights may eventually help identify reactions that could be experimentally manipulated to amplify terpenoid production. In this study, a dynamic model of the terpenoid biosynthesis pathway was constructed based on the Hybrid Functional Petri Net (HFPN) technique. This technique is a fusion of three other extended Petri net techniques, namely Hybrid Petri Net (HPN), Dynamic Petri Net (HDN) and Functional Petri Net (FPN).</p> <p>Results</p> <p>The biological data needed to construct the terpenoid metabolic model were gathered from the literature and from biological databases. These data were used as building blocks to create an HFPNe model and to generate parameters that govern the global behaviour of the model. The dynamic model was simulated and validated against known experimental data obtained from extensive literature searches. The model successfully simulated metabolite concentration changes over time (pt) and the observations correlated with known data. Interactions between the intermediates that affect the production of terpenes could be observed through the introduction of inhibitors that established feedback loops within and crosstalk between the pathways.</p> <p>Conclusions</p> <p>Although this metabolic model is only preliminary, it will provide a platform for analysing various high-throughput data, and it should lead to a more holistic understanding of terpenoid biosynthesis.</p

Towards Big Biology: high-performance verification of large concurrent systems

Bal, H.E. [Promotor]Fokkink, W.J. [Promotor]Kielmann, T. [Copromotor

Time-dependent structural transformation analysis to high-level Petri net model with active state transition diagram

<p>Abstract</p> <p>Background</p> <p>With an accumulation of <it>in silico </it>data obtained by simulating large-scale biological networks, a new interest of research is emerging for elucidating how living organism functions over time in cells.</p> <p>Investigating the dynamic features of current computational models promises a deeper understanding of complex cellular processes. This leads us to develop a method that utilizes structural properties of the model over all simulation time steps. Further, user-friendly overviews of dynamic behaviors can be considered to provide a great help in understanding the variations of system mechanisms.</p> <p>Results</p> <p>We propose a novel method for constructing and analyzing a so-called <it>active state transition diagram </it>(ASTD) by using time-course simulation data of a high-level Petri net. Our method includes two new algorithms. The first algorithm extracts a series of subnets (called <it>temporal subnets</it>) reflecting biological components contributing to the dynamics, while retaining positive mathematical qualities. The second one creates an ASTD composed of unique temporal subnets. ASTD provides users with concise information allowing them to grasp and trace how a key regulatory subnet and/or a network changes with time. The applicability of our method is demonstrated by the analysis of the underlying model for circadian rhythms in <it>Drosophila</it>.</p> <p>Conclusions</p> <p>Building ASTD is a useful means to convert a hybrid model dealing with discrete, continuous and more complicated events to finite time-dependent states. Based on ASTD, various analytical approaches can be applied to obtain new insights into not only systematic mechanisms but also dynamics.</p

An overview of existing modeling tools making use of model checking in the analysis of biochemical networks

Model checking is a well-established technique for automaticallyverifying complex systems. Recently, model checkers have appearedin computer tools for the analysis of biochemical (and generegulatory) networks. We survey several such tools to assess thepotential of model checking in computational biology. Next, our overviewfocuses on direct applications of existing model checkers, as well ason algorithms for biochemical network analysis influenced by modelchecking, such as those using binary decision diagrams or Booleansatisfiability solvers. We conclude with advantages and drawbacks ofmodel checking for the analysis of biochemical networks

A diversity-aware computational framework for systems biology

L'abstract è presente nell'allegato / the abstract is in the attachmen

"Antelope": a hybrid-logic model checker for branching-time Boolean GRN analysis

<p>Abstract</p> <p>Background</p> <p>In Thomas' formalism for modeling gene regulatory networks (GRNs), <it>branching time</it>, where a state can have <it>more than one possible future</it>, plays a prominent role. By representing a certain degree of unpredictability, branching time can model several important phenomena, such as (a) asynchrony, (b) incompletely specified behavior, and (c) interaction with the environment. Introducing more than one possible future for a state, however, creates a difficulty for ordinary simulators, because <it>infinitely many </it>paths may appear, limiting ordinary simulators to statistical conclusions. <it>Model checkers </it>for branching time, by contrast, are able to prove properties in the presence of infinitely many paths.</p> <p>Results</p> <p>We have developed <it>Antelope </it>("Analysis of Networks through TEmporal-LOgic sPEcifications", <url>http://turing.iimas.unam.mx:8080/AntelopeWEB/</url>), a model checker for analyzing and constructing Boolean GRNs. Currently, software systems for Boolean GRNs use branching time almost exclusively for asynchrony. <it>Antelope</it>, by contrast, also uses branching time for incompletely specified behavior and environment interaction. We show the usefulness of modeling these two phenomena in the development of a Boolean GRN of the <it>Arabidopsis thaliana </it>root stem cell niche.</p> <p>There are two obstacles to a direct approach when applying model checking to Boolean GRN analysis. First, ordinary model checkers normally only verify whether or not a <it>given </it>set of model states has a given property. In comparison, a model checker for Boolean GRNs is preferable if it <it>reports </it>the set of states having a desired property. Second, for efficiency, the expressiveness of many model checkers is limited, resulting in the inability to express some interesting properties of Boolean GRNs.</p> <p><it>Antelope </it>tries to overcome these two drawbacks: Apart from reporting the set of all states having a given property, our model checker can express, at the expense of efficiency, some properties that ordinary model checkers (e.g., NuSMV) cannot. This additional expressiveness is achieved by employing a logic extending the standard Computation-Tree Logic (CTL) with hybrid-logic operators.</p> <p>Conclusions</p> <p>We illustrate the advantages of <it>Antelope </it>when (a) modeling incomplete networks and environment interaction, (b) exhibiting the set of all states having a given property, and (c) representing Boolean GRN properties with hybrid CTL.</p