Reducing Spatial Stochastic Models of Membrane Receptors to Approximately Equivalent Chemical Reaction Networks through Coarse Graining

Computational models are necessary for understanding how biological functionality emerges from a complex network of molecular interactions such as in cell signaling. Due to the complexity of biological systems, the normal scientific method of hypothesizing then testing predictions is becoming increasingly difficult. The large number of processes limits the level of modeling detail; signaling models typically adopt a non-spatial representation where each molecular process is characterized by a few parameters.;However, modern microscopic imaging of receptors on cell membranes reveals an intricate structure of microdomains. Receptors, such as epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor (VEGFR), and others, tend to be grouped in the microdomains as clusters that range from a few to hundreds of biomolecules. While the origin of these clusters is not well understood, a likely explanation is the existence of microdomains with an affinity for the receptors. Using this hypothesis, we can ignore the underlying cause of the microdomains. The size and geometry of these domains can be inferred directly from microscopy; however, the relevant physical properties can only be verified through simulations. In this thesis, I propose a flexible approach to performing such simulations in a coarse grained model that is validated through solving the differential equations when possible and through equilibrium calculations when not.;Due to the non-trival nature of these cell membrane features, fully spatial models can be used to address these issues. However, fully spatial models are computationally intense and little insight can be gained from them, because of this I propose a method to construct the Well-Mixed model from the spatial one. The primary issue is the difficulty of extracting the correct kinetic coefficients and that limits the predictive power of spatial models due to the inherent challenges of estimating dynamical parameters. Because of complexity and nonlinearity, parameter uncertainty may result in the same model predicting several qualitatively different behaviors. Because of this difficulty, I will use the Metropolis-Hastings Algorithm to extract these parameters from the fully spatial simulations (I use the spatial model as an intermediary step because the spatial simulations can be matched to experimental techniques that provide molecular level resolution, such as single particle tracking (SPT) data). I will then discuss issues that emerge from a baseline comparison between spatial and non-spatial simulations of a simple reversible dimerization process; the spatial simulation employed an algorithm similar to Smoldyn. Specifically, there are three aspects that need to be addressed when considering a non-spatial correspondent for a spatial model: (1) dimer and monomer lifetimes in the presence of geminate recombination (2) the time course of dimerization / dissociation (3) equilibrium fluctuations

Religiosity In Rural England : The Examination Of Towler's Conventional Religious Types

In 1984 Towler published The Need for Certainty, which sets out five ideal-types of conventional religiosity; exemplarism, conversionism, theism, gnosticism and traditionalism. This thesis aims to examine the nature of 'religious belief, as defined by Towler, in a sample of rural parishioners interviewed during the Rural Church Project (1988-91). Towler's work originated from letters written to John Robinson, then Bishop of Woolwich, when he published Honest to God. Consequently, his work is empirical but qualitative rather than quantitative. A weakness he recognises by indicating that he has only revealed the spectrum of religious belief rather than examining it. The Social Science Citation Index shows Towler's work to have been widely reviewed but sparingly cited between 1984-95. This thesis seeks to be strong where Towler's work is weak by using a quantitative and representative sample. The data is divided into religious belief sub-samples using 12 statements from which respondents selected one as being closest to their own religious outlook. The five subsamples which correspond with Towler's religious types represent 44% of the whole sample. Each sub-sample is assessed against religious characteristics which Towler attributes to that type; in conversionism and traditionalism the compatibility is good, there are similarities with theism and gnosticism but little common ground for exemplarism. The sociography of each sub-sample is developed and a similar picture of compatibility appears. The remainder of the sample chose two statements. This thesis suggests these two sub-samples, shown to be religiously and sociographically distinct, constitute conventional religious types which did not appear in Towler's data. The first involves those who are still 'searching for the Truth', they are perhaps similar to Hedonism as defined by Wilson (1985) . The second group are religiously uncertain and detached but not irreligious, perhaps representing agnostics

Fungi at the scene of the crime: innocent bystanders or accomplices in oral infections?

Purpose of Review: Over the last decade, microbiome studies have enhanced our knowledge and understanding of the polymicrobial nature of oral infections. Recently, profiling of the fungal microbiome has expanded our conventional understanding of oral ecology, revealing the critical importance of yeasts within this complex microbiome. This review aims to explore our current appreciation of interkingdom interactions in oral disease. Recent Findings: There is a growing evidence base of interactions and pathogenic synergy and antagonism with bacterial species within oral disease. Recent studies have helped to develop our knowledge of how Candida albicans, alongside bacteria such as Porphyromonas gingivalis, Streptococcus mutans, Staphylococcus aureus, Enterococcus faecalis, and Lactobacillus species, influence overall pathogenicity. Summary: Clinical and experimental evidence makes a compelling case for a role for C. albicans in a number of oral infections, though whether its role is an active accomplice or passive bystander remains to be determined

The impact of high density receptor clusters on VEGF signaling

Vascular endothelial growth factor (VEGF) signaling is involved in the process of blood vessel development and maintenance. Signaling is initiated by binding of the bivalent VEGF ligand to the membrane-bound receptors (VEGFR), which in turn stimulates receptor dimerization. Herein, we discuss experimental evidence that VEGF receptors localize in caveloae and other regions of the plasma membrane, and for other receptors, it has been shown that receptor clustering has an impact on dimerization and thus also on signaling. Overall, receptor clustering is part of a complex ecosystem of interactions and how receptor clustering impacts dimerization is not well understood. To address these questions, we have formulated the simplest possible model. We have postulated the existence of a single high affinity region in the cell membrane, which acts as a transient trap for receptors. We have defined an ODE model by introducing high- and low-density receptor variables and introduce the corresponding reactions from a realistic model of VEGF signal initiation. Finally, we use the model to investigate the relation between the degree of VEGFR concentration, ligand availability, and signaling. In conclusion, our simulation results provide a deeper understanding of the role of receptor clustering in cell signaling.Comment: In Proceedings HSB 2013, arXiv:1308.572

Forests as Commons – Changing Traditions and Governance in Europe

Commons are complex institutions and exist across the world in a wide range of situations regarding locally developed governance and management systems of many different natural resources. For many people commons remain associated with Hardin’s theory concerning the “Tragedy of the Commons” (1968), in which he assumed that local users of a natural resource are unable to formulate governance and management structures concerning their own choices that took into account the long-term sustainability of the resource itself. As a result, Hardin articulated that the tragedy was that the resource would inevitably become degraded in such situations and that the solution was private or public ownership. However, across Europe many forests have for a very long period of time successfully been managed as commons, just as they have in many other parts of the world. This chapter has three main aims: It will provide an introduction to the various types of commons before going on to link the issue of commons to the traditional forest landscapes of Europe, and it will look at how the role of forests and forest landscapes has changed and how it may change further in the future

Isbourne Catchment Community Report: Potential for Natural Flood Management in the Catchment

The School of Natural and Social Sciences (SNSS) and the Countryside and Communities Research Institute (CCRI) at the University of Gloucestershire were commissioned by the Isbourne Catchment Group (ICG) and the Environment Agency (EA) to undertake an initial assessment of the River Isbourne to determine the feasibility and potential benefits of applying natural flood management (NFM) techniques across the Isbourne catchment. Other engineering options had been considered in an analysis of the catchment in 2010 (Haycock 2010) and some minor changes have been made by the EA in the last few years. However, most significant engineering options were not considered to be cost effective whilst soft engineering options such as land use change and natural flood management were recommended for further investigation, which is the focus of this report – no assessment of hard engineering possibilities are made in this report as it is beyond the remit of the investigation. The report describes the catchment characteristics, gives an overview of potential NFM options and provides recommendations of which of these could be implemented in the catchments and ways forward

Reconciling pastoral agriculture and nature conservation: developing a co-management approach in the English uplands

The article assesses the influence of the Common Agricultural Policy (CAP) on the pastoral farming systems in a National Park within the south west of England and more recent attempts to use innovative and participatory techniques to reconcile pastoral farming systems with wildlife management. The paper confirms evidence that the economic sustainability of farm businesses in the UK involved in pastoral farming is reducing, and that wildlife-orientated schemes are changing traditional farming systems in a way that might not be in the long-term interest of wildlife. The data gathered raise questions about the cost-effectiveness of the current environmental approaches, which are government-run with centrally determined prescriptions relating to the natural resource and wildlife. Drawing on the concept of co-management, an alternative approach is identified and explored with both farmers and nature conservation regulators. This approach places more emphasis upon adjusting the traditional farming system of this marginal type of farming to align with the sustainable management of a fragile ecosystem

Nonpositively curved 2-complexes with isolated flats

We introduce the class of nonpositively curved 2-complexes with the Isolated Flats Property. These 2-complexes are, in a sense, hyperbolic relative to their flats. More precisely, we show that several important properties of Gromov-hyperbolic spaces hold `relative to flats' in nonpositively curved 2-complexes with the Isolated Flats Property. We introduce the Relatively Thin Triangle Property, which states roughly that the fat part of a geodesic triangle lies near a single flat. We also introduce the Relative Fellow Traveller Property, which states that pairs of quasigeodesics with common endpoints fellow travel relative to flats, in a suitable sense. The main result of this paper states that in the setting of CAT(0) 2-complexes, the Isolated Flats Property is equivalent to the Relatively Thin Triangle Property and is also equivalent to the Relative Fellow Traveller Property.Comment: Published by Geometry and Topology at http://www.maths.warwick.ac.uk/gt/GTVol8/paper5.abs.htm

Study of Determined Town and Village Green Applications: Final Report to Common Land Team, Defra

The purpose of the research, as set out in the Project Brief, was to ‘examine a sample of the sites which have been registered as town or village greens (TVGs) since January 2004 as well as a sample of those that have not been registered’. The common term for both successful and unsuccessful applications is that either outcome has been ‘determined’ by Commons Registration Authority (CRA), therefore the study was an investigation into determined town and village green (dTVG) applications. The project also set out to examine whether the sites were earmarked for development in local development plans or subject to planning applications. The full diversity of sites, both approved and rejected, was analysed