Cardiac Adaptation To Chronic Blockade Of Voltage-Gated, L-Type Calcium Channels In The Sarcolemma

L-type Ca2+ channels (dihydropyridine receptors, DHPRs) in the sarcolemma are essential to cardiac excitation-contraction (E-C) coupling. Thus, Ca2+ influx through DHPRs upon cardiomyocyte excitation triggers Ca2+ release from the sarcoplasmic reticulum (SR) through ryanodine receptors (RyRs) to initiate myofilament activation and muscle contraction. Muscle relaxation occurs upon sequestration of Ca2+ back into the SR lumen by sarco/endoplasmic reticulum calcium-ATPase (SERCA) in the SR. As a treatment option for hypertension, long-term use of DHPR blockers is associated with increased risk of heart failure; underlying mechanisms are unknown. This research used male Wistar rats treated with verapamil (subcutaneously, 625 µg/h/kg for 4 weeks) to determine the impact of chronic DHPR blockade in vivo, on E-C coupling events and heart function at all levels ranging from molecules to whole organism. The results presented in chapter 2 demonstrate that chronic DHPR blockade caused functional remodeling of RyRs and spatio-temporal dyssynchrony of E-C coupling events, resulting in systolic dysfunction and enhanced susceptibility to arrhythmia. Findings in chapter 3 reveal that chronic DHPR blockade was accompanied by depressed SERCA function, abnormal cardiomyocyte Ca2+ handling, and diastolic dysfunction. Results in chapter 4 reveal adaptational changes in protein phosphorylation-dependent regulation of SR/cardiomyocyte Ca2+ cycling due to chronic DHPR blockade. These include over-expression of Ca2+/calmodulin-dependent protein kinases II (CaMKII), hyper-phosphorylation of SR Ca2+ cycling proteins by CaMKII and cAMP-dependent protein kinase (PKA), paradoxically diminished SR Ca2+ content and contractile reserve, and blunted inotropic response to beta-adrenergic stimulation. The above adaptations to chronic DHPR blockade occurred in the absence of cardiac hypertrophy or fibrosis. Thus, molecular remodeling may invoke cardiac pathology and heart failure without microscopic structural changes in cardiomyocytes. The findings from this thesis reveal, for the first time, integrated mechanisms underlying the increased risk of heart failure associated with chronic DHPR blockade. In addition to urging caution in the conventional clinical use of DHPR blockers, the novel mechanistic events and molecular remodeling revealed here imply that manipulation of the stoichiometry of molecular players in E-C coupling demand critical attention and careful scrutiny in the design and deployment of therapeutic approaches for heart diseases

Light-emitting diodes from polyfluorenes: characterisation and stability of performance

This thesis deals with polymer light-emitting diodes (LEDs) containing materials from the polyfluorene family, and investigates their behaviour when employed in device structures. A study of poly(9,9’-dioctylfluorene-co-bis-N,N’-(4-butylphenyl)-bis-N,N’-phenyl-1,4-phenylenediamine) (PFB) by photothermal deflection spectroscopy (PDS) shows that the polymer undergoes a doping reaction with poly(styrene sulphonic acid). This is important because the two materials are found in intimate contact in LED structures. The conditions for reaction are investigated, and it is proposed that the reacted states are directly responsible for the drive-induced degradation of LEDs containing these two materials. LEDs are studied which contain various combinations of poly(9,9’-dioctylfluorene-co-N-(4-butylphenyl)diphenylamine) (TFB) and poly(9,9’-dioctylfluorene-co-benzothiadiazole) (F8BT), using pulsed electroluminescence. A strongly morphology-dependent spike-transient is observed in the electroluminescence at turn-on, and this is investigated by numerical modelling. Although not all features of the system can be well represented in the model, the spike transient is explicitly predicted without the need to impose any special conditions. The origin of this feature is elucidated by repeatedly running the model to a range of end-points and studying the time-evolution of space-charge distributions which result. Finally, F8BT devices are considered on their own, in order to study the evolution of device performance under low-intensity electrical excitation. A phenomenon is investigated in which the quantum efficiency is dramatically increased during the early stages of driving. Ionic motions are ruled out, and the observations are attributed to the trapping of charge in the vicinity of the anode, leading to enhanced hole injection. The reverse-bias behaviour of the effect, in which a further enhancement is seen, is also examined. The analogy is made with polymer LEDs in general which increase in performance following a period of reverse bias, and it is suggested that the causes may be related

CREATING A COHERENT SCORE: THE MUSIC OF SINGLE-PLAYER FANTASY COMPUTER ROLE-PLAYING GAMES

This thesis provides a comprehensive exploration into the music of the ludic genre (Hourigan, 2005) known as a Computer Role-Playing Game (CRPG) and its two main sub-divisions: Japanese and Western Role-Playing Games (JRPGs & WRPGs). It focuses on the narrative category known as genre fiction, concentrating on fantasy fiction (Turco, 1999) and seeks to address one overall question: How do fantasy CRPG composers incorporate the variety of musical material needed to create a coherent score across the JRPG and WRPG divide? Seven main chapters form the thesis text. Chapter One provides an introduction to the thesis, detailing the research contributions in addition to outlining a variety of key terms that must be understood to continue with the rest of the text. A database accompanying this thesis showcases the vast range of CRPGs available; a literature review tackles relevant existing materials. Chapters Two and Three seek to provide the first canonical history of soundtracks used in CRPGs by dissecting typical narrative structures for games so as to provide context to their musical scores. Through analysis of existing game composer interviews, cultural influences are revealed. Chapters Four and Five mirror one another with detailed discussion respectively regarding JRPG and WRPG music including the influence that anime and Hollywood cinema have had upon them. In Chapter Six, the use of CRPG music outside of video games is explored, particularly the popularity of JRPG soundtracks in the concert hall. Chapter Seven concludes the thesis, summarising research contributions achieved and areas for future work. Throughout these chapters, the core task is to explain how the two primary sub-genres of CRPGs parted ways and why the music used to accompany these games differs so drastically