Analysis of the degree of compliance with the EU Machinery Directive.

DUE TO COPYRIGHT RESTRICTIONS ONLY AVAILABLE FOR CONSULTATION AT ASTON UNIVERSITY LIBRARY AND INFORMATION SERVICES WITH PRIOR ARRANGEMENT

Submission for the degree of Doctor of Science at Aston University

DUE TO COPYRIGHT RESTRICTIONS ONLY AVAILABLE FOR CONSULTATION AT ASTON UNIVERSITY LIBRARY AND INFORMATION SERVICES WITH PRIOR ARRANGEMENT

Submission for the degree of Doctor of Science at Aston University

DUE TO COPYRIGHT RESTRICTIONS ONLY AVAILABLE FOR CONSULTATION AT ASTON UNIVERSITY LIBRARY AND INFORMATION SERVICES WITH PRIOR ARRANGEMENT

Bound volume of work submitted for the degree of Doctor of Science (also one book and five paper-back reports included)

DUE TO COPYRIGHT RESTRICTIONS ONLY AVAILABLE FOR CONSULTATION AT ASTON UNIVERSITY LIBRARY AND INFORMATION SERVICES WITH PRIOR ARRANGEMENT

Understanding the link between transglutaminase and the induction of fibrosis in cystic fibrosis (CF)

The emerging role of the multifunctional enzyme, Transglutaminase 2 (TG2) in Cystic Fibrosis (CF) has been linked to its increased expression and intracellular transamidating activity. However, a full understanding of the molecular mechanisms involved still remains unclear despite numerous studies that have attempted to delineate this process. These mechanisms include the NFκB and TGFβ1 pathway amongst others. This study reveals for the first time that the development of fibrosis in CF is due to a TG2-driven epithelial to mesenchymal transition (EMT) via a mechanism involving the activation of the pro-fibrotic cytokine TGFβ1. Using a human ΔF508/W1282X CFTR CF mutant bronchial cell (IB3-1), its CFTR corrected “add-back” cell (C38) as well as a primary human bronchial epithelial cell (HBEC), elevated TG2 levels in the CFTR mutant IB3 cell were shown to activate latent TGFβ1 leading to increased levels found in the culture medium. This activation process was blocked by the presence of cell-permeable and impermeable TG2 inhibitors while inhibition of TGFβ1 receptors blocked TG2 expression. This demonstrates the direct link between TG2 and TGFβ1 in CF. The presence of active cell surface TG2 correlated with an increase in the expression of EMT markers, associated with the CF mutant cells, which could be blocked by the presence of TG2 inhibitors. This was mimicked using the “addback” C38 cell and the primary human bronchial epithelial cell, HBEC, where an increase in TG2 expression and activity in the presence of TGFβ1 concurred with a change in cell morphology and an elevation in EMT marker expression. Conversely, a knockdown of TG2 in the CF mutant IB3 cells illustrated that an inhibition of TG2 blocks the increase in EMT marker expression as well as causing an increase in TEER measurement. This together with an increase in the migration profile of the CF mutant IB3 cell against the “add-back” C38 cell suggests that TG2 drives a mesenchymal phenotype in CF. The involvement of TG2 activated TGFβ1 in CF was further demonstrated with an elevation/inhibition of p- SMAD 2 and 3 activation in the presence of TGFβ1/TG2 cell-permeable/impermeable inhibitors respectively. The use of a comparative airway cell model where bronchial epithelial cells were cultured at the air liquid interface (ALI) confirmed the observations in submerged culture depicting the robustness of the model and reiterated the importance of TG2 in CF. Using a CFTR corrector combined with TG2 inhibitors, this study showed that the correction and stabilisation of the ΔF508 CFTR mutation in the mutant cell forged an increase in matured CFTR copies trafficking to the apical surface by circumventing proteosomal degradation. Thus the results presented here suggests that TG2 expression is elevated in the CFTR mutant bronchial cell via a TGFβ1 driven positive feedback cycle whereby activation of latent TGFβ1 by TG2 leads in turn to an elevation in its own expression by TGFβ1. This vicious cycle then drives EMT in CF ultimately leading to lung remodelling and fibrosis. Importantly, TG2 inhibition blocks TGFβ1 activation leading to an inhibition of EMT and further blocks the emerging fibrosis, thus stabilizing and supporting the maturation, trafficking and conductance of CFTR channels at the apical surface.

The Matrix Method of Determining the Fault Tolerance Degree of a Computer Network Topology

This work presents a theoretical-graph method of determining the fault tolerance degree of the computer network interconnections and nodes. Experimental results received from simulations of this method over a distributed computing network environment are also presented.

Degree of vertical integration and its buffering effects on political uncertainty

The focus of this study is on the governance decisions in a concurrent channels context, in the case of uncertainty. The study examines how a firm chooses to deploy its sales force in times of uncertainty, and the subsequent performance outcome of those deployment choices. The theoretical framework is based on multiple theories of governance, including transaction cost analysis (TCA), agency theory, and institutional economics. Three uncertainty variables are investigated in this study. The first two are demand and competitive uncertainty which are considered to be industry-level market uncertainty forms. The third uncertainty, political uncertainty, is chosen as it is an important dimension of institutional environments, capturing non-economic circumstances such as regulations and political systemic issues. The study employs longitudinal secondary data from a Thai hotel chain, comprising monthly observations from January 2007 – December 2012. This hotel chain has its operations in 4 countries, Thailand, the Philippines, United Arab Emirates – Dubai, and Egypt, all of which experienced substantial demand, competitive, and political uncertainty during the study period. This makes them ideal contexts for this study. Two econometric models, both deploying Newey-West estimations, are employed to test 13 hypotheses. The first model considers the relationship between uncertainty and governance. The second model is a version of Newey-West, using an Instrumental Variables (IV) estimator and a Two-Stage Least Squares model (2SLS), to test the direct effect of uncertainty on performance and the moderating effect of governance on the relationship between uncertainty and performance. The observed relationship between uncertainty and governance observed follows a core prediction of TCA; that vertical integration is the preferred choice of governance when uncertainty rises. As for the subsequent performance outcomes, the results corroborate that uncertainty has a negative effect on performance. Importantly, the findings show that becoming more vertically integrated cannot help moderate the effect of demand and competitive uncertainty, but can significantly moderate the effect of political uncertainty. These findings have significant theoretical and practical implications, and extend our knowledge of the impact on uncertainty significantly, as well as bringing an institutional perspective to TCA. Further, they offer managers novel insight into the nature of different types of uncertainty, their impact on performance, and how channel decisions can mitigate these impacts.

A fittség (m)értéke. A fizikai inaktivitás nemzetgazdasági terhei Magyarországon (The value (degree) of fitness. The national economic costs of physical inactivity in Hungary)

Az elmúlt években Magyarországon is fokozatosan nőtt az érdeklődés az életminőség vizsgálata iránt. A 2004-2006 közötti időszakra készült első Nemzeti Fejlesztési Terv fő célkitűzése a lakosság életminőségének javítása volt, de célját nem érte el, mivel a WHO 2010 májusában közzétett statisztikája szerint a magyarországi életminőség-mutatók az európai rangsor végén találhatók. Elszomorító az Eurobarométer 2010. évi reprezentatív kutatásának eredménye: a népesség 77 százalékának életmódja mozgásszegény, fizikailag inaktív. Kutatásunk során azt a ténylegesen hiánypótló célt kívántuk elérni, hogy meghatározzuk és számszerűsítsük a mozgásszegény életmódból adódó nemzetgazdasági terheket, valamint megbecsüljük a fizikai inaktivitás csökkentésével elérhető megtakarítások számszerűsíthető mértékét. Az Országos Egészségbiztosítási Pénztár (OEP) és egy saját országos kérdőíves kutatás (n = 1158) adataira támaszkodtunk. A fizikai inaktivitás betegségeire vonatkozó megtakarítási lehetőségeket tételesen határoztuk meg, majd megállapítottuk az inaktivitásból származó gazdasági terheket, aminek alapján a döntéshozók elkészíthetik a fizikai inaktivitás csökkentésre alkalmas akcióterveiket. Ezzel nemcsak a lakosság "közérzete" javulhat számottevően, de komolyabb költségeket is meg lehet takarítani közép- és hosszú távon. / === / Interest in examining the quality of life has increased steadily in Hungary in recent years. Improving it was the main objective of the first National Development Plan, for the 2004-6 period, but it failed to do so, for Hungary's indices for quality of life were at the bottom of the European list according to figures published by the WHO in May 2010. The results of the representative research Furobarometer 2010 are saddening: 77 per cent of the population pursue a low-exercise, physically inactive lifestyle. The authors' researches sought to fill a gap by measuring and quantifying the national economic costs of a low-exercise lifestyle and to estimate quantitatively the savings to be made by reducing such physical inactivity. The paper relics on the data of the National Health Insurance Fund and on an authors' questionnaire (n = 1158). The potential savings on illness relating to physical activity are listed one by one. to arrive at the economic costs of such inactivity, based on which it is possible for decision-makers to prepare adequate action plans for reducing physical inactivity. This will improve the "morale" of the public and bring appreciable savings in the medium and long term.

Design and development of a one-degree-of-freedom force-reflecting manual controller prototype for teleoperation

The present research is carried out from the viewpoint of primarily space applications where human lives may be in danger if they are to work under these conditions. This work proposes to develop a one-degree-of-freedom (1-DOF) force-reflecting manual controller (FRMC) prototype for teleoperation, and address the effects of time delays commonly found in space applications where the control is accomplished via the earth-based control stations. To test the FRMC, a mobile robot (PPRK) and a slider-bar were developed and integrated to the 1-DOF FRMC. The software developed in Visual Basic is able to telecontrol any platform that uses an SV203 controller through the internet and it allows the remote system to send feedback information which may be in the form of visual or force signals. Time delay experiments were conducted on the platform and the effects of time delay on the FRMC system operation have been studied and delineated.

Degree of conversion of different composite resins photo-activated with light-emitting diode and argon ion laser

This study evaluated the degree of conversion (DC%) of one experimental and different brands of composite resins light-cured by two light sources (one LED and one argon laser). The percentage of unreacted C = C was determined from the ratio of absorbance intensities of aliphatic C = C (peak at 1637 cm−1) against internal standards before and after curing: aromatic C–C (peak at 1610 cm−1) except for P90, where %C = C bonds was given for C–O–C (883 cm−1) and C–C (1257 cm−1). ANOVA and Tukey’s test revealed no statistically significant difference among Z350 (67.17), Z250 (69.52) and experimental (66.61 ± 2.03) with LED, just among them and Evolu-X (75.51) and P90 (32.05) that showed higher and lower DC%, respectively. For the argon laser, there were no differences among Z250 (70.67), Z350 (69.60), experimental (65.66) and Evolu-X (73, 37), however a significant difference was observed for P90 (36.80), which showed lowest DC%. The light sources showed similar DC%, however the main difference was observed regarding the composite resins. The lowest DC% was observed for the argon laser. P90 showed the lowest DC% for both light-curing sources.

Evaluation of degree of conversion and hardness of dental composites photo-activated with different light guide tips

Objective: The aim of this study was to evaluate the degree of conversion and hardness of different composite resins, photo-activated for 40 s with two different light guide tips, fiber optic and polymer. Methods: Five specimens were made for each group evaluated. The percentage of unreacted carbon double bonds (% C═C) was determined from the ratio of absorbance intensities of aliphatic C═C (peak at 1637 cm−1) against internal standard before and after curing of the specimen: aromatic C-C (peak at 1610 cm−1). The Vickers hardness measurements were performed in a universal testing machine. A 50 gf load was used and the indenter with a dwell time of 30 seconds. The degree of conversion and hardness mean values were analyzed separately by ANOVA and Tukey’s test, with a significance level set at 5%. Results: The mean values of degree of conversion for the polymer and fiber optic light guide tip were statistically different (P<.001). The hardness mean values were statistically different among the light guide tips (P<.001), but also there was difference between top and bottom surfaces (P<.001). Conclusions: The results showed that the resins photo-activated with the fiber optic light guide tip promoted higher values for degree of conversion and hardness.

Sediment age, abundance of planktonic foraminifera shells, degree of their dissolution, percentage of benthic foraminifera in total foram fauna, Core GC-11, Sea of Okhotsk

Taxonomic composition and distribution of planktonic foraminifera are studied in section of Core GC-11 penetrated through Upper Quaternary sediments of the Bowers Ridge western slope, south Bering Sea. It is shown that structure of foraminiferal assemblage and productivity varied substantially during the last 32000 calendar years in response to changes in surface water temperatures and water mass circulation in the North Pacific including the Bering Sea. Productivity was maximal during the deglaciation epoch, being notably lower in Holocene and minimal at glaciation time.

Is Pairing with a Relative Heritable? : Estimating Female and Male Genetic Contributions to the Degree of Biparental Inbreeding in Song Sparrows (Melospiza melodia)

We thank the Tsawout and Tseycum First Nation bands for access to Mandarte, everyone who contributed to the long-term data collection, and the European Research Council and Royal Society for funding. We thank J.D. Hadfield, P. Bijma, E. Postma, and L.F. Keller for illuminatingdiscussions. Also, L.E.B. Kruuk, R. Bonduriansky, and an anonymous reviewer provided insightful comments that improved the manuscript.

Conceptual designs of multi-degree of freedom compliant parallel manipulators composed of wire-beam based compliant mechanisms

This paper proposes conceptual designs of multi-degree(s) of freedom (DOF) compliant parallel manipulators (CPMs) including 3-DOF translational CPMs and 6-DOF CPMs using a building block based pseudo-rigid-body-model (PRBM) approach. The proposed multi-DOF CPMs are composed of wire-beam based compliant mechanisms (WBBCMs) as distributed-compliance compliant building blocks (CBBs). Firstly, a comprehensive literature review for the design approaches of compliant mechanisms is conducted, and a building block based PRBM is then presented, which replaces the traditional kinematic sub-chain with an appropriate multi-DOF CBB. In order to obtain the decoupled 3-DOF translational CPMs (XYZ CPMs), two classes of kinematically decoupled 3-PPPR (P: prismatic joint, R: revolute joint) translational parallel mechanisms (TPMs) and 3-PPPRR TPMs are identified based on the type synthesis of rigid-body parallel mechanisms, and WBBCMs as the associated CBBs are further designed. Via replacing the traditional actuated P joint and the traditional passive PPR/PPRR sub-chain in each leg of the 3-DOF TPM with the counterpart CBBs (i.e. WBBCMs), a number of decoupled XYZ CPMs are obtained by appropriate arrangements. In order to obtain the decoupled 6-DOF CPMs, an orthogonally-arranged decoupled 6-PSS (S: spherical joint) parallel mechanism is first identified, and then two example 6-DOF CPMs are proposed by the building block based PRBM method. It is shown that, among these designs, two types of monolithic XYZ CPM designs with extended life have been presented.

Does the degree of coarctation of the aorta influence wall shear stress focal heterogeneity?

The development of atherosclerosis in the aorta is associated with low and oscillatory wall shear stress for normal patients. Moreover, localized differences in wall shear stress heterogeneity have been correlated with the presence of complex plaques in the descending aorta. While it is known that coarctation of the aorta can influence indices of wall shear stress, it is unclear how the degree of narrowing influences resulting patterns. We hypothesized that the degree of coarctation would have a strong influence on focal heterogeneity of wall shear stress. To test this hypothesis, we modeled the fluid dynamics in a patient-specific aorta with varied degrees of coarctation. We first validated a massively parallel computational model against experimental results for the patient geometry and then evaluated local shear stress patterns for a range of degrees of coarctation. Wall shear stress patterns at two cross sectional slices prone to develop atherosclerotic plaques were evaluated. Levels at different focal regions were compared to the conventional measure of average circumferential shear stress to enable localized quantification of coarctation-induced shear stress alteration. We find that the coarctation degree causes highly heterogeneous changes in wall shear stress.