The role of the formyl-peptide receptor in multi-organ fibrosis mechanisms

PhD ThesisMitochondrial Damage-associated molecular patterns (mtDAMPs) are an emerging source of endogenous alarmins. N-formylated peptides bind members of the formyl-peptide receptor (FPR) family. From its original role in chemotaxis of immune cells towards sites of infection the part that this G-protein coupled receptor (GPCR) plays in the human body is expanding with expression evident in cells of non-phagocyte origin as well as neutrophils and macrophage. To investigate how FPR1 affects the development of pulmonary fibrosis the bleomycin acute injury in vivo model was employed as its pathogenesis shares features with Idiopathic pulmonary fibrosis (IPF). Transgenic mice lacking functional fpr1 displayed a reduced inflammatory profile and fibrotic phenotype at acute and end-stage endpoints respectively post-bleomycin instillation. In vivo models of fibrosis in different organs such as the liver and kidney there was not the same protective effect with deletion of fpr1 as with acute bleomycin lung injury mechanism. This in turn brought the pathogenesis of the in vivo models into question particularly due to the abundance of fpr1 expression on neutrophils, the first line of defense of the immune system. By depleting neutrophils prior to the bleomycin injury the nature of these myeloid cells in this lung fibrosis model and through evaluation of the inflammatory and fibrotic phases post-instillation it is evident that these cells play a major role in how the disease develops. Translation to the human disease (IPF) was a vital step to elucidate the true role of FPR1 in chronic fibrosis mechanisms. Expression was demonstrated by immunofluorescence in CD45+ leukocytes as well as in isolated fibroblasts. This was corroborated by mRNA levels in primary cultured cells when FPR1 expression was ‘primed’ by inflammatory stimuli such as lipopolysaccharide (LPS). With effects observed in a murine setting and also in primary tissue/cells the FPR1 effect may be microenvironment/neutrophil dependent

Studies of membrane fusion by influenza haemagglutinins, and their application to liposome delivery systems in gene therapy

The aim of the work presented in this thesis was to investigate the membrane fusion activity of influenza haemagglutinin (HA), particularly with regard to the contribution of receptor binding to the efficiency of the membrane fusion process. Since the membrane fusion potential of HA could provide an efficient mechanism to deliver molecules to the cell cytoplasm the ability of HA—containing liposomes to fuse with membranes was also established. The role of receptor binding by HA with regard to the efficiency of membrane fusion has been extensively investigated. Liposome coupled anti-HA monoclonal Fab' fragments with various specificities towards the HA molecule were used as surrogate receptors for HA. Electron microscopy (EM) studies of HA-receptor complexes using liposome coupled Fab' fragments as surrogate receptors are reported. On the basis of results from EM, membrane fusion experiments were done between HA containing lipid vesicles (virosomes) and anti HA Fab' coupled liposomes. The virosomes used contained two antigenically distinct strains of HA, which underwent their acid induced conformational change at a significantly different pH from each other. Anti HA Fab' fragments which recognised one of the two HA strains were used as surrogate receptors. These experiments concluded that HA bound to receptor can be more efficient at causing membrane fusion than a HA molecule held close to but not directly bound by the target membrane. These results have implications for the design of a HA based delivery vector which are discussed. Various procedures were investigated for the reconstitution of HA containing lipid vesicles (virosomes), using purified HA and purified lipids. Using the detergent octaethylene glycol monododecyl ether virosomes with a lipid composition of phosphatidylcholine and cholesterol (2:1 molar ratio) were made. These virosomes could participate in HA mediated membrane fusion. Virosomes made using the detergent octylglucoside were not fusion - active. The fusion efficiency of reconstituted vesicles containing HA was shown to be lower than that of influenza virus. Initial experiments using virosomes as vehicles for DNA delivery are also presented

Review: emerging concepts in the pathogenesis of tendinopathy

Tendinopathy is a common clinical problem and has a significant disease burden attached, not only in terms of health care costs, but also for patients directly in terms of time off work and impact upon quality of life. Controversy surrounds the pathogenesis of tendinopathy, however the recent systematic analysis of the evidence has demonstrated that many of the claims of an absence of inflammation in tendinopathy were more based around belief than robust scientific data. This review is a summary of the emerging research in this topical area, with a particular focus on the role of neuronal regulation and inflammation in tendinopathy

Constrained coordinated distributed control of smart grid with asynchronous information exchange

Smart grid constrained optimal control is a complex issue due to the constant growth of grid complexity and the large volume of data available as input to smart device control. In this context, traditional centralized control paradigms may suffer in terms of the timeliness of optimization results due to the volume of data to be processed and the delayed asynchronous nature of the data transmission. To address these limits of centralized control, this paper presents a coordinated, distributed algorithm based on distributed, local controllers and a central coordinator for exchanging summarized global state information. The proposed model for exchanging global state information is resistant to fluctuations caused by the inherent interdependence between local controllers, and is robust to delays in information exchange. In addition, the algorithm features iterative refinement of local state estimations that is able to improve local controller ability to operate within network constraints. Application of the proposed coordinated, distributed algorithm through simulation shows its effectiveness in optimizing a global goal within a complex distribution system operating under constraints, while ensuring network operation stability under varying levels of information exchange delay, and with a range of network sizes

A Framework for Speechreading Acquisition Tools

At least 360 million people worldwide have disabling hearing loss that frequently causes difficulties in day-to-day conversations. Hearing aids often fail to offer enough benefits and have low adoption rates. However, people with hearing loss find that speechreading can improve their understanding during conversation. Speechreading (often called lipreading) refers to using visual information about the movements of a speaker's lips, teeth, and tongue to help understand what they are saying. Speechreading is commonly used by people with all severities of hearing loss to understand speech, and people with typical hearing also speechread (albeit subconsciously) to help them understand others. However, speechreading is a skill that takes considerable practice to acquire. Publicly-funded speechreading classes are sometimes provided, and have been shown to improve speechreading acquisition. However, classes are only provided in a handful of countries around the world and students can only practice effectively when attending class. Existing tools have been designed to help improve speechreading acquisition, but are often not effective because they have not been designed within the context of contemporary speechreading lessons or practice. To address this, in this thesis I present a novel speechreading acquisition framework that can be used to design Speechreading Acquisition Tools (SATs) - a new type of technology to improve speechreading acquisition.Comment: PhD Thesis, supervised by Dr David R. Flatl

Radio-Continuum study of the Nearby Sculptor Group Galaxies. Part 1: NGC 300 at lambda = 20 cm

A series of new radio-continuum (lambda=20 cm) mosaic images focused on the NGC 300 galactic system were produced using archived observational data from the VLA and/or ATCA. These new images are both very sensitive (rms=60 microJy) and feature high angular resolution (<10"). The most prominent new feature is the galaxy's extended radio-continuum emission, which does not match its optical appearance. Using these newly created images a number of previously unidentified discrete sources have been discovered. Furthermore, we demonstrate that a joint deconvolution approach to imaging this complete data-set is inferior when compared to an immerge approach.Comment: 13 pages, 12 figures, accepted to APSS, new version to correct the missing reference

Preliminary Report on the 2018 Field Season of the American Excavations at Morgantina: Contrada Agnese Project (CAP)

In its sixth season, the American Excavations at Morgantina: Contrada Agnese Project (CAP) continued archaeological investigations inside the House of the Two Mills, a modestly-appointed house of Hellenistic date located near the western edge of the ancient city of Morgantina. This report gives a phase-by-phase summary of the significant discoveries from the 2018 excavation season, highlighting the architectural development of the building as well as evidence for the various activities that took place there over the course of its occupation

The initiation and evolution of the River Nile

This work was funded by a NERC Open CASE PhD studentship award NE/I018433/1, the NERC Isotope Geoscience Facilities Steering Committee (IP-1248-0511, IP-1299-0512), and BP Egypt who we also thank for provision of samples and assistance in Egypt. We thank C. Stewart, V. Pashley and N. Roberts at NIGL for valuable laboratory assistance. This paper benefited from careful reviews by D. Chew and an anonymous reviewer.Peer reviewedPublisher PD

A survey of carbon nanotube interconnects for energy efficient integrated circuits

This article is a review of the state-of-art carbon nanotube interconnects for Silicon application with respect to the recent literature. Amongst all the research on carbon nanotube interconnects, those discussed here cover 1) challenges with current copper interconnects, 2) process &amp; growth of carbon nanotube interconnects compatible with back-end-of-line integration, and 3) modeling and simulation for circuit-level benchmarking and performance prediction. The focus is on the evolution of carbon nanotube interconnects from the process, theoretical modeling, and experimental characterization to on-chip interconnect applications. We provide an overview of the current advancements on carbon nanotube interconnects and also regarding the prospects for designing energy efficient integrated circuits. Each selected category is presented in an accessible manner aiming to serve as a survey and informative cornerstone on carbon nanotube interconnects relevant to students and scientists belonging to a range of fields from physics, processing to circuit design