8,365 research outputs found
Scalable reaction network modeling with automatic validation of consistency in Event-B
Constructing a large biological model is a difficult, error-prone process. Small errors in writing a part of the model cascade to the system level and their sources are difficult to trace back. In this paper we extend a recent approach based on Event-B, a state-based formal method with refinement as its central ingredient, allowing us to validate for model consistency step-by-step in an automated way. We demonstrate this approach on a model of the heat shock response in eukaryotes and its scalability on a model of the ErbB signaling pathway. All consistency properties of the model were proved automatically with computer support.</p
Methods for construction and analysis of computational models in systems biology: applications to the modelling of the heat shock response and the self-assembly of intermediate filaments
Systems biology is a new, emerging and rapidly developing, multidisciplinary
research field that aims to study biochemical and biological systems from
a holistic perspective, with the goal of providing a comprehensive, system-
level understanding of cellular behaviour. In this way, it addresses one of
the greatest challenges faced by contemporary biology, which is to compre-
hend the function of complex biological systems. Systems biology combines
various methods that originate from scientific disciplines such as molecu-
lar biology, chemistry, engineering sciences, mathematics, computer science
and systems theory. Systems biology, unlike “traditional” biology, focuses
on high-level concepts such as: network, component, robustness, efficiency,
control, regulation, hierarchical design, synchronization, concurrency, and
many others. The very terminology of systems biology is “foreign” to “tra-
ditional” biology, marks its drastic shift in the research paradigm and it
indicates close linkage of systems biology to computer science.
One of the basic tools utilized in systems biology is the mathematical
modelling of life processes tightly linked to experimental practice. The stud-
ies contained in this thesis revolve around a number of challenges commonly
encountered in the computational modelling in systems biology. The re-
search comprises of the development and application of a broad range of
methods originating in the fields of computer science and mathematics for
construction and analysis of computational models in systems biology. In
particular, the performed research is setup in the context of two biolog-
ical phenomena chosen as modelling case studies: 1) the eukaryotic heat
shock response and 2) the in vitro self-assembly of intermediate filaments,
one of the main constituents of the cytoskeleton. The range of presented
approaches spans from heuristic, through numerical and statistical to ana-
lytical methods applied in the effort to formally describe and analyse the
two biological processes. We notice however, that although applied to cer-
tain case studies, the presented methods are not limited to them and can
be utilized in the analysis of other biological mechanisms as well as com-
plex systems in general. The full range of developed and applied modelling
techniques as well as model analysis methodologies constitutes a rich mod-
elling framework. Moreover, the presentation of the developed methods,
their application to the two case studies and the discussions concerning
their potentials and limitations point to the difficulties and challenges one
encounters in computational modelling of biological systems. The problems
of model identifiability, model comparison, model refinement, model inte-
gration and extension, choice of the proper modelling framework and level
of abstraction, or the choice of the proper scope of the model run through
this thesis
Effects of Fibril Morphology and Interfacial Interactions on the Behavior of Polymer-Grafted Cellulose Nanofibril Reinforced Thermoplastic Composites
Mechanically refined cellulose nanofibrils (CNFs) promise to be a high-volume, sustainable, nanoscale reinforcement for thermoplastic composites. They are currently held back by poor interfacial interactions with composite matrices, energy intensive drying, and drying induced fibril aggregation. In this dissertation, we explored how a grafting-through polymerization scheme modified the surface of CNFs with a wide variety of commodity polymers and overcame many of these technical challenges.
The first phase of the research was concerned with characterizing the unique morphology of these CNFs as a function of refinement energy. This characterization was employed to understand how the materials’ morphologies affected their interfacial interactions with porous substrates. In this work, optical, scanning electron, and atomic force microscopy were used to characterize the materials and mechanical testing was used to assess their interfacial interactions with porous model substrates. The second phase of the research explored how the grafting-through polymerization of commodity monomers occurred in the presence of methacrylated CNFs. Infrared spectroscopy measurements were used to explore the degree of grafting and microscopic analyses were employed to understand how these modifications affected the materials’ suspension morphology.
The final phase of the research looked at the modifications’ effects on drying behavior, surface energetics, and reinforcement ability in poly(lactic acid) (PLA). Scanning electron microscopy and inverse gas chromatography provided insights into how the grafted-polymer modifications improved the fibrillar morphology of spray-dried CNFs and increased their interfacial adhesion to PLA. Tensile testing and rheological characterization of composites made from these spray dried materials revealed their improved dispersion and network formation in the PLA matrix. Scale up of bench scale reactions to the pilot scale are demonstrated and 3D printing trials were conducted. Dramatic improvements in mechanical properties were seen for 3D printed samples modified with poly(N-isopropyl acrylamide). These improvements in mechanical properties were explored by dynamic mechanical analysis and tensile testing, revealing the effects of fibril alignment during printing
Optimising Geopolymer Formation
Geopolymers are versatile materials, often made with ash from coal Power Stations. Applications include low green-house-gas emission cement, fireproof barriers and many more. This thesis furthered the understanding of geopolymer formulation by: • Demonstrating novel methods for mixture design and determining the degree of reaction during and after curing. • Analysing the role of formulation on cost and green-house-gas emission. • Developing a new material that can be used for structural neutron shielding
Consciosusness in Cognitive Architectures. A Principled Analysis of RCS, Soar and ACT-R
This report analyses the aplicability of the principles of consciousness developed in the ASys project to three of the most relevant cognitive architectures. This is done in relation to their aplicability to build integrated control systems and studying their support for general mechanisms of real-time consciousness.\ud
To analyse these architectures the ASys Framework is employed. This is a conceptual framework based on an extension for cognitive autonomous systems of the General Systems Theory (GST).\ud
A general qualitative evaluation criteria for cognitive architectures is established based upon: a) requirements for a cognitive architecture, b) the theoretical framework based on the GST and c) core design principles for integrated cognitive conscious control systems
\u3ci\u3eIn silico\u3c/i\u3e Driven Metabolic Engineering Towards Enhancing Biofuel and Biochemical Production
The development of a secure and sustainable energy economy is likely to require the production of fuels and commodity chemicals in a renewable manner. There has been renewed interest in biological commodity chemical production recently, in particular focusing on non-edible feedstocks. The fields of metabolic engineering and synthetic biology have arisen in the past 20 years to address the challenge of chemical production from biological feedstocks. Metabolic modeling is a powerful tool for studying the metabolism of an organism and predicting the effects of metabolic engineering strategies. Various techniques have been developed for modeling cellular metabolism, with the underlying principle of mass balance driving the analysis. In this dissertation, two industrially relevant organisms were examined for their potential to produce biofuels.
First, Saccharomyces cerevisiae was used to create biodiesel in the form of fatty acid ethyl esters (FAEEs) through expression of a heterologous acyl-transferase enzyme. Several genetic manipulations of lipid metabolic and / or degradation pathways were rationally chosen to enhance FAEE production, and then culture conditions were modified to enhance FAEE production further. The results were used to identify the rate-limiting step in FAEE production, and provide insight to further optimization of FAEE production.
Next, Clostridium thermocellum, a cellulolytic thermophile with great potential for consolidated bioprocessing but a weakly understood metabolism, was investigated for enhanced ethanol production. To accomplish the analysis, two models were created for C. thermocellum metabolism. The core metabolic model was used with extensive fermentation data to elucidate kinetic bottlenecks hindering ethanol production. The genome scale metabolic model was constructed and tuned using extensive fermentation data as well, and the refined model was used to investigate complex cellular phenotypes with Flux Balance Analysis.
The work presented within provide a platform for continued study of S. cerevisiae and C. thermocellum for the production of valuable biofuels and biochemicals
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From Micro- to Nano-porous Cellular Materials with Layered 2D Microstructure
A large body of work has been committed to studying the unique properties of 2D materials such as graphene, with advancements in both the material quality and scale of mechanical exfoliation and chemical vapour deposition (CVD) methods. These emergent 2D materials have recently been engineered as the cell walls in three-dimensional structures, but their superb material properties are yet to be fully realized in this new form. This thesis investigates the CVD processing of a range of catalytic templates to open new routes towards the controlled fabrication of graphitic foams and lattices. As part of a full feedback loop, mechanical characterization of these unique cellular materials was undertaken in order to examine their deformation and failure mechanisms, including capturing their behaviour in a new hierarchical model framework. These novel structures have the potential to combine the properties of structured porous materials, i.e. low density, high geometric surface area, permeability and mechanical stability, with the intrinsic properties of 2D materials such as enhanced electrical and thermal conductivity, high mechanical strength and stiffness as well as resistance to damage from extreme temperatures and chemical attack. Such high quality 2D-material based cellular structures have manifold potential applications in electrochemistry, catalysis and filtration.
Herein, freestanding graphitic foams are fabricated across a range of relative densities, and their uniaxial compressive responses are measured to investigate the operative deformation and failure mechanisms that govern the mechanical response of such foams. For this purpose, a hierarchical micromechanical model is developed, which traces the deformation of the hollow cell struts to the axial stretching of the cell walls. The waviness of the multilayered graphitic wall increases the axial compliance of each cell wall, and it is established that axial straining within the cell wall occurs by interlayer shearing. Crucially, this mechanism demonstrates that the continuum properties of such foams are dictated by the weak out-of-plane shear properties of the layered cell wall material, leading to a large knockdown in the macroscopic mechanical properties of the foam.
Ordered graphene gyroid lattices possessing nanoscale unit cell sizes are then fabricated and characterized through a combination of nanoindentation and a multi-scale finite element analysis (FEA) study. These structured nanolattices were found to be highly conductive and possessed a high degree of elastic recovery and strength owing to the structural efficiency afforded by the stretching-dominated cellular architecture. However, the nanoscale interlayer shearing deformation mechanism was again found to be active in the cell walls of these structures, attenuating the continuum response of the lattice. The hierarchical micromechanical model developed herein rationalizes why CVD-grown multilayer graphitic foams and lattices possess diminished continuum elastic moduli and yield strengths in comparison to the exemplary in-plane mechanical properties of 2D materials, presenting a first step towards the understanding of porous materials whose cell walls are comprised of emergent 2D materials.
In addition, the direct shrinkage of commercial polymer foams and 3D printed templates is used herein to offer a very simple and low-cost method for reaching identically-shaped structures with sub-200 μm unit cell sizes. The conformal addition of different thicknesses of alumina is shown to control the level of isotropic shrinkage, reducing the shrinkage ratio from 125x to 4x after addition of 25 nm of alumina, while inducing a surface stress mismatch that drastically increases the surface roughness of the material. Furthermore, efficient graphitization was demonstrated through the use of an electrolessly deposited Nickel film, resulting in the formation of a conductive multilayer graphenic coating at temperatures below 1100°C. These processes present the flexible production of multifunctional cellular materials with sub-mm unit cells, tuneable size, roughness and conductivity.
A final study investigates the preparation of a nascent 2D material, WS, through the use of a deconstructed metal organic chemical vapour deposition (MOCVD) process which allowed insight into the role of each process step. The catalytic effect of an Au substrate is unambiguously demonstrated, which allowed for a reduction in the precursor partial pressures required to nucleate and grow WS by over an order of magnitude in comparison to competing methods. This enabled the efficient low-pressure growth of WS films with low levels of carbon contamination. Furthermore, the reaction process developed herein exhibited a self-limiting monolayer growth behaviour with exposure cycles lasting just 10 minutes, a significant improvement over prior MOCVD processes requiring growth times in excess of 1 hour. These insights foster our understanding of the key underlying mechanisms of WS growth for future integrated manufacturing of transition metal dichalcogenides (TMDCs) and other 2D materials.Funded by the EPSRC (EP/G037221/1) - Cambridge NanoScience through Engineering to Application Doctoral Training Centre: Assembly of Functional NanoMaterials and NanoDevices, EPSRC (EP/K016636/1) - CVD enabled Graphene Technology and Devices (GRAPHTED), ERC (279342) - In-situ metrology for the controlled growth and interfacing of nanomaterials and ERC (206409) - Multi-phase lattice materials
Second Generation General System Theory: Perspectives in Philosophy and Approaches in Complex Systems
Following the classical work of Norbert Wiener, Ross Ashby, Ludwig von Bertalanffy and many others, the concept of System has been elaborated in different disciplinary fields, allowing interdisciplinary approaches in areas such as Physics, Biology, Chemistry, Cognitive Science, Economics, Engineering, Social Sciences, Mathematics, Medicine, Artificial Intelligence, and Philosophy. The new challenge of Complexity and Emergence has made the concept of System even more relevant to the study of problems with high contextuality. This Special Issue focuses on the nature of new problems arising from the study and modelling of complexity, their eventual common aspects, properties and approaches—already partially considered by different disciplines—as well as focusing on new, possibly unitary, theoretical frameworks. This Special Issue aims to introduce fresh impetus into systems research when the possible detection and correction of mistakes require the development of new knowledge. This book contains contributions presenting new approaches and results, problems and proposals. The context is an interdisciplinary framework dealing, in order, with electronic engineering problems; the problem of the observer; transdisciplinarity; problems of organised complexity; theoretical incompleteness; design of digital systems in a user-centred way; reaction networks as a framework for systems modelling; emergence of a stable system in reaction networks; emergence at the fundamental systems level; behavioural realization of memoryless functions
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