Toward Accessible Multilevel Modeling in Systems Biology: A Rule-based Language Concept

Promoted by advanced experimental techniques for obtaining high-quality data and the steadily accumulating knowledge about the complexity of life, modeling biological systems at multiple interrelated levels of organization attracts more and more attention recently. Current approaches for modeling multilevel systems typically lack an accessible formal modeling language or have major limitations with respect to expressiveness. The aim of this thesis is to provide a comprehensive discussion on associated problems and needs and to propose a concrete solution addressing them

A diversity-aware computational framework for systems biology

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

Recent advances in petri nets and concurrency

CEUR Workshop Proceeding

Qualitatively modelling genetic regulatory networks : Petri net techniques and tools

The development of post-genomic technologies has led to a paradigm shift in the way we study genetic regulatory networks (GRNs) - the underlying systems which mediate cell function. To complement this, the focus is on devising scalable, unambiguous and automated formal techniques for holistically modelling and analysing these complex systems. Quantitative approaches offer one possible solution, but do not appear to be commensurate with currently available data. This motivates qualitative approaches such as Boolean networks (BNs) , which abstractly model the system without requiring such a high level of data completeness. Qualitative approaches enable fundamental dynamical properties to be studied, and are well-suited to initial investigations. However, strengthened formal techniques and tool support are required if they are to meet the demands of the biological community. This thesis aims to investigate, develop and evaluate the application of Petri nets (PNs) for qualitatively modelling and analysing GRNs. PNs are well-established in the field of computer science, and enjoy a number of attractive benefits, such a wide range of techniques and tools, which make them ideal for studying biological systems. We take an existing qualitative PN approach for modelling GRNs based on BNs, and extend it to more general models based on multi-valued networks (MVNs). Importantly, we develop tool support to automate model construction. We illustrate our approach with two detailed case studies on Boolean models for carbon stress in Escherichia coli and sporulation in Bacillus subtilis, and then consider a multi-valued model of the former. These case studies explore the analysis power of PN s by exploiting a range of techniques and tools. A number of behavioural differences are identified between the two E. coli models which lead us to question their formal relationship. We investigate this by proposing a framework for reasoning about the behaviour of MVNs at different levels of abstraction. We develop tool support for practical models, and show a number of important results which motivate the need for multi-valued modelling. Asynchronous BN s can be seen to be more biologically realistic than their synchronous counterparts. However, they have the drawback of capturing behaviour which is unrealisable in practice. We propose a novel approach for refining such behaviour using signal transition graphs, a PN formalism from asynchronous circuit design. We automate our approach, and demonstrate it using a BN of the lysis-lysogeny switch in phage A. Our results show that a more realistic asynchronous model can be derived which preserves the stochastic switch.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Current approaches to gene regulatory network modelling

Many different approaches have been developed to model and simulate gene regulatory networks. We proposed the following categories for gene regulatory network models: network parts lists, network topology models, network control logic models, and dynamic models. Here we will describe some examples for each of these categories. We will study the topology of gene regulatory networks in yeast in more detail, comparing a direct network derived from transcription factor binding data and an indirect network derived from genome-wide expression data in mutants. Regarding the network dynamics we briefly describe discrete and continuous approaches to network modelling, then describe a hybrid model called Finite State Linear Model and demonstrate that some simple network dynamics can be simulated in this model

Modelling methodologies for railway asset management

Management of railway assets incurs significant expenditure. Railway asset management modelling can predict the cost and efficacy of an asset management plan, and thus support the asset management planning process. Modelling frameworks can be used to facilitate the development of large, multi-asset, whole life cycle models which can be used to represent large sections of rail track and associated assets. This is achieved with libraries of models and tools with a high level of inter-compatibility. This research set out to support the development of modelling frameworks for railway asset management. It sought to determine the state of the art of railway asset management modelling in order to find which assets require further modelling development before they can be suitably represented in a framework’s model library. It also sought to determine the most accurate and suitable modelling methodology to base the framework upon. These aims were met by first carrying out a literature review to determine the state of the art of asset management modelling for major railway asset types. This review found Petri net models solved via Monte Carlo methods to be the most suitable modelling methodology for asset management. The level crossing asset class was chosen for the development of several models to explore the different types of Petri net model, concentrating on the computational resources required. This asset class was chosen as no asset management model was found in literature, and the diversity of the asset interactions. Literature review found several asset classes in need of further development, and some where asset management modelling may not be possible without other advances. The level crossing Petri net models developed demonstrated that computational requirements differ between the various types of Petri net. Stochastic Petri nets were found to simulate quickly, but had a high memory requirement. Coloured Petri nets were found to have the opposite requirements. A novel Petri net type, the Simple Coloured Petri net was developed to create a balance in computational cost. It was further found that complex processes such as scheduling and resource allocation can only be carried out using Coloured Petri nets due to their enhanced feature set. This work has found that further research on modelling specific asset classes is required to enable the development of a complete asset modelling library for use in a framework. If large models are to be developed, it is recommended that the Simple Coloured Petri net be used to balance computational requirements. Any models requiring complex functions should be developed using the Coloured Petri net methodology

Biomolecular System Design: Architecture, Synthesis, and Simulation

The advancements in systems and synthetic biology have been broadening the range of realizable systems with increasing complexity both in vitro and in vivo. Systems for digital logic operations, signal processing, analog computation, program flow control, as well as those composed of different functions – for example an on-site diagnostic system based on multiple biomarker measurements and signal processing – have been realized successfully. However, the efforts to date tend to tackle each design problem separately, relying on ad hoc strategies rather than providing more general solutions based on a unified and extensible architecture, resulting in long development cycle and rigid systems that require redesign even for small specification changes.Inspired by well-tested techniques adopted in electronics design automation (EDA), this work aims to remedy current design methodology by establishing a standardized, complete flow for realizing biomolecular systems. Given a behavior specification, the flow streamlines all the steps from modeling, synthesis, simulation, to final technology mapping onto implementing chassis. The resulted biomolecular systems of our design flow are all built on top of an FPGA-like reconfigurable architecture with recurring modules. Each module is designed the function of eachmodule depends on the concentrations of assigned auxiliary species acting as the “tuning knobs.” Reconfigurability not only simplifies redesign for altered specification or post-simulation correction, but also makes post-manufacture fine-tuning – even after system deployment – possible. This flexibility is especially important in synthetic biology due to the unavoidable variations in both the deployed biological environment and the biomolecular reactions forming the designed system.In fact, by combining the system’s reconfigurability and neural network’s self-adaptiveness through learning, we further demonstrate the high compatibility of neuromorphic computation to our proposed architecture. Simulation results verified that with each module implementing a neuron of selected model (ex. spike-based, threshold-gate-like, etc.), accompanied by an appropriate choice of reconfigurable properties (ex. threshold value, synaptic weight, etc.), the system built from our proposed flow can indeed perform desired neuromorphic functions

Algorithms and Software for Biological MP Modeling by Statistical and Optimization Techniques

I sistemi biologici sono gruppi di entit\ue0 biologiche (es. molecole ed organismi), che interagiscono producendo specifiche dinamiche. Questi sistemi sono solitamente caratterizzati da una elevata complessit\ue0 perch\ue8 coinvolgono un elevato numero di componenti con molte interconnessioni. La comprensione dei meccanismi che governano i sistemi biologici e la previsione dei loro comportamenti in condizioni normali e patologiche \ue8 una sfida cruciale della biologia dei sistemi (in inglese detta systems biology), un'area di ricerca al confine tra biologia, medicina, matematica ed informatica. In questa tesi i P sistemi metabolici, detti brevemente sistemi MP, sono stati utilizzati come modello discreto per l'analisi di dinamiche biologiche. Essi sono una classe deterministica dei P sistemi classici, che utilizzano regole di riscrittura per rappresentare le reazioni chimiche e "funzioni di regolazioni di flusso" per regolare la reattivit\ue0 di ciascuna reazione rispetto alla quantita' di sostanze presenti istantaneamente nel sistema. Dopo un excursus sulla letteratura relativa ad alcuni modelli convenzionali (come le equazioni differenziali ed i modelli stocastici proposti da Gillespie) e non-convenzionali (come i P sistemi ed i P sistemi metabolici), saranno presentati i risultati della mia ricerca. Essi riguardano tre argomenti principali: i) l'equivalenza tra sistemi MP e reti di Petri ibride funzionali, ii) le prospettive statistiche e di ottimizzazione nella generazione di sistemi MP a partire da dati sperimentali, iii) lo sviluppo di un laboratorio virtuale chiamato MetaPlab, un software Java basato sui sistemi MP. L'equivalenza tra i sistemi MP e le reti di Petri ibride funzionali \ue8 stata dimostrata per mezzo di due teoremi ed alcuni esperimenti al computer per il caso di studio del meccanismo regolativo del gene operone lac nella pathway glicolitica. Il secondo argomento di ricerca concerne nuovi approcci per la sintesi delle funzioni di regolazione di flusso. La regressione stepwise e le reti neurali sono state impiegate come approssimatori di funzioni, mentre algoritmi di ottimizzazione classici ed evolutivi (es. backpropagation, algoritmi genetici, particle swarm optimization ed algoritmi memetici) sono stati impiegati per l'addestramento dei modelli. Una completo workflow per l'analisi dei dati sperimentali \ue8 stato presentato. Esso gestisce ed indirizza l'intero processo di sintesi delle funzioni di regolazione, dalla preparazione dei dati alla selezione delle variabili, fino alla generazione dei modelli ed alla loro validazione. Le metodologie proposte sono state testate con successo tramite esperimenti al computer sui casi di studio dell'oscillatore mitotico negli embrioni anfibi e del non photochemical quenching (NPQ). L'ultimo tema di ricerca \ue8 infine piu' applicativo e riguarda la progettazione e lo sviluppo di una architettura Java basata su plugin e di una serie di plugin che consentono di automatizzare varie fasi del processo di modellazione con sistemi MP, come la simulazione di dinamiche, la determinazione dei flussi e la generazione delle funzioni di regolazione.Biological systems are groups of biological entities, (e.g., molecules and organisms), that interact together producing specific dynamics. These systems are usually characterized by a high complexity, since they involve a large number of components having many interconnections. Understanding biological system mechanisms, and predicting their behaviors in normal and pathological conditions is a crucial challenge in systems biology, which is a central research area on the border among biology, medicine, mathematics and computer science. In this thesis metabolic P systems, also called MP systems, have been employed as discrete modeling framework for the analysis of biological system dynamics. They are a deterministic class of P systems employing rewriting rules to represent chemical reactions and "flux regulation functions" to tune reactions reactivity according to the amount of substances present in the system. After an excursus on the literature about some conventional (i.e., differential equations, Gillespie's models) and unconventional (i.e., P systems and metabolic P systems) modeling frameworks, the results of my research are presented. They concern three research topics: i) equivalences between MP systems and hybrid functional Petri nets, ii) statistical and optimization perspectives in the generation of MP models from experimental data, iii) development of the virtual laboratory MetaPlab, a Java software based on MP systems. The equivalence between MP systems and hybrid functional Petri nets is proved by two theorems and some in silico experiments for the case study of the lac operon gene regulatory mechanism and glycolytic pathway. The second topic concerns new approaches to the synthesis of flux regulation functions. Stepwise linear regression and neural networks are employed as function approximators, and classical/evolutionary optimization algorithms (e.g., backpropagation, genetic algorithms, particle swarm optimization, memetic algorithms) as learning techniques. A complete pipeline for data analysis is also presented, which addresses the entire process of flux regulation function synthesis, from data preparation to feature selection, model generation and statistical validation. The proposed methodologies have been successfully tested by means of in silico experiments on the mitotic oscillator in early amphibian embryos and the non photochemical quenching (NPQ). The last research topic is more applicative, and pertains the design and development of a Java plugin architecture and several plugins which enable to automatize many tasks related to MP modeling, such as, dynamics computation, flux discovery, and regulation function synthesis

Modelling methodologies for railway asset management

Management of railway assets incurs significant expenditure. Railway asset management modelling can predict the cost and efficacy of an asset management plan, and thus support the asset management planning process. Modelling frameworks can be used to facilitate the development of large, multi-asset, whole life cycle models which can be used to represent large sections of rail track and associated assets. This is achieved with libraries of models and tools with a high level of inter-compatibility. This research set out to support the development of modelling frameworks for railway asset management. It sought to determine the state of the art of railway asset management modelling in order to find which assets require further modelling development before they can be suitably represented in a framework’s model library. It also sought to determine the most accurate and suitable modelling methodology to base the framework upon. These aims were met by first carrying out a literature review to determine the state of the art of asset management modelling for major railway asset types. This review found Petri net models solved via Monte Carlo methods to be the most suitable modelling methodology for asset management. The level crossing asset class was chosen for the development of several models to explore the different types of Petri net model, concentrating on the computational resources required. This asset class was chosen as no asset management model was found in literature, and the diversity of the asset interactions. Literature review found several asset classes in need of further development, and some where asset management modelling may not be possible without other advances. The level crossing Petri net models developed demonstrated that computational requirements differ between the various types of Petri net. Stochastic Petri nets were found to simulate quickly, but had a high memory requirement. Coloured Petri nets were found to have the opposite requirements. A novel Petri net type, the Simple Coloured Petri net was developed to create a balance in computational cost. It was further found that complex processes such as scheduling and resource allocation can only be carried out using Coloured Petri nets due to their enhanced feature set. This work has found that further research on modelling specific asset classes is required to enable the development of a complete asset modelling library for use in a framework. If large models are to be developed, it is recommended that the Simple Coloured Petri net be used to balance computational requirements. Any models requiring complex functions should be developed using the Coloured Petri net methodology

Computing multi-scale organizations built through assembly

The ability to generate and control assembling structures built over many orders of magnitude is an unsolved challenge of engineering and science. Many of the presumed transformational benefits of nanotechnology and robotics are based directly on this capability. There are still significant theoretical difficulties associated with building such systems, though technology is rapidly ensuring that the tools needed are becoming available in chemical, electronic, and robotic domains. In this thesis a simulated, general-purpose computational prototype is developed which is capable of unlimited assembly and controlled by external input, as well as an additional prototype which, in structures, can emulate any other computing device. These devices are entirely finite-state and distributed in operation. Because of these properties and the unique ability to form unlimited size structures of unlimited computational power, the prototypes represent a novel and useful blueprint on which to base scalable assembly in other domains. A new assembling model of Computational Organization and Regulation over Assembly Levels (CORAL) is also introduced, providing the necessary framework for this investigation. The strict constraints of the CORAL model allow only an assembling unit of a single type, distributed control, and ensure that units cannot be reprogrammed - all reprogramming is done via assembly. Multiple units are instead structured into aggregate computational devices using a procedural or developmental approach. Well-defined comparison of computational power between levels of organization is ensured by the structure of the model. By eliminating ambiguity, the CORAL model provides a pragmatic answer to open questions regarding a framework for hierarchical organization. Finally, a comparison between the designed prototypes and units evolved using evolutionary algorithms is presented as a platform for further research into novel scalable assembly. Evolved units are capable of recursive pairing ability under the control of a signal, a primitive form of unlimited assembly, and do so via symmetry-breaking operations at each step. Heuristic evidence for a required minimal threshold of complexity is provided by the results, and challenges and limitations of the approach are identified for future evolutionary studies