Studies relating to molecular mechanism of CD44 augmented macrophage phagocytosis of apoptotic neutrophils

Apoptosis of neutrophil granulocytes is an essential process in the resolution of the inflammatory response, providing a safe mechanism for down-regulation of neutrophil function and clearance of potentially harmful inflammatory cells by macrophages. However, in chronic inflammatory conditions, the rate of cell death by apoptosis can exceed the macrophage clearance capacity leading to secondary necrosis, resulting in release of harmful cellular contents and damage to the surrounding tissues. There are many possible ways in which the rate and capacity of macrophage clearance of apoptotic cells may be influenced, including soluble mediators such as cytokines and glucocorticoid hormones or interactions with extracellular matrix components. CD44 is a surface receptor, which has been implicated in cellular adhesion to extracellular matrix proteins including hyaluronan. CD44 has also been shown to augment macrophage phagocytosis of apoptotic neutrophils after cross-linking surface receptors by a bivalent antibody. The aim of this thesis was to characterise the mechanism underlying this augmentation further and to investigate potential mechanisms responsible for the observed changes in macrophage phagocytic capacity. Ligation of CD44 by bivalent antibody was shown to exert a prolonged effect upon augmentation of macrophage phagocytosis of apoptotic neutrophils, suggesting that augmentation of macrophage phagocytosis by cross-linking of CD44 was unlikely to be mediated by intra-cellular signalling and might involve physical alterations to the CD44 receptor. However, analysis of the surface expression and distribution of CD44 by immunofluorescence microscopy did not support this hypothesis. To further characterise the mechanism of cross-linking of CD44 on macrophage phagocytosis, cation depletion studies were carried out. Data presented in this thesis demonstrates that augmentation of phagocytosis following CD44 cross-linking involved two components. My data indicate that CD44 cross-linking results in augmentation of macrophage phagocytosis via both a cation dependent and cation independent component. Depletion of divalent cations reduces the level of CD44 augmented phagocytosis but does not entirely block it. Treatment of macrophages with a variety of inhibitors and antibodies allowed identification of the molecule responsible for the cation dependent component - CD32 (FcyRII). CD44 antibodies were shown to be acting as a bridge between CD32 on the apoptotic neutrophil and CD44 on the macrophage. This highlighted the importance of using F(ab')2 fragments instead of whole antibodies for functional studies. To investigate potential signalling mechanisms involved in the divalent cation-dependent effect resulting in CD44 augmented phagocytosis anti-CD44 F(ab')2 fragments were generated and conjugated to 6pm microspheres, which were used to cross-link CD44 on the macrophage surface. Immunofluorescent microscopy was then used to image changes in cellular distribution of signalling molecules in response to CD44 cross-linking. The data presented in this thesis implicates redistribution of ezrin, actin, PKC and Rac2 in the augmentation of macrophage phagocytosis of apoptotic neutrophils following CD44 cross-linking. Western blot and inhibition studies indicated that ERK did not play a role in CD44 augmented phagocytosis. In summary, the studies presented in this thesis represent an analysis of the cellular and molecular events associated with augmentation of phagocytosis of apoptotic neutrophils. Whilst no gross alterations in CD44 distribution were seen, these studies suggest that the irreversible nature of the augmentation reflects redistribution of key cytoskeletal and signalling elements within the macrophage. Together, these studies provide a firm foundation for future studies and highlight the potential for modulation of phagocyte capacity for clearance of apoptotic cells in treatment of inflammatory disease

A STUDY OF THE RELATIONSHIP BETWEEN APPLICANTS SCORES ON THE THURSTONE TEST OF MENTAL ALERTNESS AND THE ALLPORT-VERNON-LINDZEY STUDY OF VALUES AND SUBSEQUENT SUCCESS AS PSYCHIATRIC AIDES

This is a study of the relationship between scores made by applicants on the Thurstone Test of Mental Alertness and the Allport-Vernon-Lindzey Study of Values and subsequent job success as Psychiatric Aides in the Parsons State Hospital and Training Center. During the period covered by the study, there was a total of 93 applicants tested. Of that number, 16 were hired as Psychiatric Aide Trainees. One of the Trainees failed to complete the 14 week training program. Of the 15 trainees who were promoted to the Aide position, one entered the armed forces. When the TMA and the Study of Values were introduced into the selection program, there were no norms specifically applicable for the selection of Psychiatric Aides on either of the tests, In order to make immediate use of the test results, cutting scores were developed by the Psychology Department on the basis of educated guesses. In assessing the predictive validity of these cutting scores, two criteria of job success were used. Both criteria were derived from ratings made by Nursing Supervisors. Rank order correlations were computed between test scores and one criterion. An expectancy table developed using the predictive ratings of a Psychologist and the overall ratings of the Nursing Supervisors. Product Moment correlations were computed between the Psychologist\u27s ratings and the two criteria of job success. The general conclusions from these procedures were that the test scores, as they are being used, are not valid predictors of job success. Information obtained from the study also presented some doubt as to the reliability of the rating system being used by the Nurses. Certain recommendations are made for revisions in the use of the test scores and the rating scale in an effort to improve the predictive validity of the tests and the reliability of ratings given by Nurses

BSHI guideline: HLA matching and donor selection for haematopoietic progenitor cell transplantation

A review of the British Society for Histocompatibility and Immunogenetics (BSHI) Guideline ‘HLA matching and donor selection for haematopoietic progenitor cell transplantation’ published in 2016 was undertaken by a BSHI appointed writing committee. Literature searches were performed and the data extracted were presented as recommendations according to the GRADE nomenclature

Vendre son âme à Dieu – réflexions autour d’un topos supposé dans Les Misérables

This study examines some of the literary topoi in Victor Hugo’s work Les Misérables, to see how these topoi resemble the topoi present in the typical stories of the devil. The study also poses the question of whether the theme “selling your soul to God” qualifies as a topos. The study uses the definition of a “topos” according to the article “Comment repérer et définir le topos” (2016) (“How to spot and define the topos” [2016]). The result of this study indicates that Hugo on the one hand uses many of the same topoi which can be found in the stories of the devil, but on the other hand one could argue that Hugo uses them in a reverse way. The question of whether the theme “selling your soul to God” qualifies as a topos is not possible to answer without further studies

The Role of British Agents and Engineers in the Early Westernization of Japan with a Focus on the Robinson and Waters Brothers

Much has been written about the many Western experts, particularly engineers, who travelled to Japan and contributed to the country's modernization in the years following the Meiji Restoration (1868). In this paper it is argued that more emphasis could be placed on the contribution made, not only by experts in situ, but also by agents who remained in the West and sent out instructions and materials, enabling extraordinary changes under the new centralized Japanese government. The author traces the achievements of the Waters and Robinson families who, as agents, engineers, entrepreneurs and opportunists, combined to contribute to a decade of advancement now known to Japanese historians as the Waters era

Thomas James Waters (1842-1898) and the Mint at Osaka

One of the first and most important initiatives of the incoming Meiji Government in 1868 was the building of a Mint at Osaka. This was necessary for the production of a new uniform coinage of high quality. The important role played by Irishman Thomas James Waters in the planning and construction of the Osaka Mint is discussed here, with speculation, too, about Waters' connection with the Hong Kong Mint, built several years earlier. Attention is also drawn to other links between the Mint at Hong Kong and the Mint at Osaka. Early in 1869 Waters was put in sole charge of the Osaka project. Making use of a selection of materials purchased from the by then obsolete Mint in Hong Kong, he took on the complex task of designing and supervising the construction of the new coin-making facility, along with adjacent western-style buildings. Faced with multiple setbacks, he had overseen the completion of most of the work by late 1870, an extraordinary accomplishment for someone so young, and with limited experience in such a vast and difficult project. His successful completion of the Mint facility would establish Waters as a man of integrity, imagination and ability, and he and his two brothers would go on to make a significant contribution to the further Westernisation of Japan, particularly in and around Tokyo, during a period now known as the Waters era

Vendre son âme à Dieu – réflexions autour d’un topos supposé dans Les Misérables

This study examines some of the literary topoi in Victor Hugo’s work Les Misérables, to see how these topoi resemble the topoi present in the typical stories of the devil. The study also poses the question of whether the theme “selling your soul to God” qualifies as a topos. The study uses the definition of a “topos” according to the article “Comment repérer et définir le topos” (2016) (“How to spot and define the topos” [2016]). The result of this study indicates that Hugo on the one hand uses many of the same topoi which can be found in the stories of the devil, but on the other hand one could argue that Hugo uses them in a reverse way. The question of whether the theme “selling your soul to God” qualifies as a topos is not possible to answer without further studies

Dealing With Difference: Evidence of European Women in Early Contact History

As historians attempt to reconstruct details of early contactbetween Europeans and Aborigines, evidence contained in thewriting of European women appears to have been largely overlooked. In Australian colonial times women's writing was usually relegated to the private sphere and not seen as an important part of thecolonial enterprise. There was, and perhaps still is, suspicion about the subjective, and possibly trivial, nature of women's writing. In any case, in spite of over thirty years of research and, more recently, some improvement in the use of women's evidence, there is a surprising lack of reference to primary female sources in texts that deal with contact history.In this article I look briefly at the writings of a selection of womenwho lived in what is now northern New South Wales and Queensland.This includes the edited letters of Jane Bardsley, which give anexcellent account of a woman's life on a remote station in the Gulfregion of far northern Queensland in the early decades of the twentieth century. I examine earlier information from the Hughenden region compiled between 1868-1870, found in Lucy Gray's originalhandwritten manuscript, now in the John Oxley Library, as well as thework of the prominent Aboriginal rights campaigner Mary Bennett,who spent part of her childhood in northern Queensland

An Irish Engineer: The Extraordinary Achievements of Thomas J Waters and Family in Early Meiji Japan and Beyond

When a young Irish engineer set out from England in 1864 to convert the world to his evangelical way of thinking, he found himself instead at the forefront of a remarkable revolution. At a time when industry and transport driven by steam power had already transformed the western world, and engineers were looking elsewhere for employment, Thomas James Waters was to make a name for himself in what was known as the Far East, in a country which had been, until the 1850s, essentially closed to the Western world and Western progress. That country was Japan, and the revolution was the Meiji Restoration. Although this is the story of an individual - or more accurately several individuals, as other members of Tom Waters' family play an important part - it reflects the story of many. It mirrors a movement of young men from the West who made their way to Japan to introduce mechanisation and Western-style buildings, and ultimately to instruct the Japanese in, not only engineering and architectural skills, but also in medicine, agriculture, economics, law, art and education. By 1874, over 500 foreign experts were employed by the Japanese Government on one- or two-year contracts, with many more employed privately. This was part of a drive, first of all by various principalities, and then by a centralised government, which aimed at achieving equal status with the West, thus safeguarding Japan's sovereignty and independence

Mick and the Manager: Two Goondiwindi Cattlemen

This is the story of two very different men - an Aboriginal stockman, Mick Lynch, and a station manager, Tom Atkinson - whose lives touched for a period during the first half of the 20th century on a cattle station in southern Queensland. It is also my story, or at least part of my story, as Tom Atkinson was my father. The book can be read too as an historical account of life in the Queensland bush during a period that followed the early conflict between the indigenous people and the new settlers - well before the advent of television, computers and mobile phones. On a personal level I have found it necessary in some chapters to call on my memory and imagination to recreate certain details about the lives of Mick and Tom and their interaction with each other. Such chapters appear in the present tense. By adopting this approach I feel I have been able to delve into essential truths concerning the two men which might otherwise have been overlooked in a more rigid academic study. Having said this, I must emphasise that all stories are structured around events that actually happened. 'Ah,' I hear you say. 'It is a kind of dual biography interspersed with autobiography and some history, both Aboriginal and European.' You would of course be right in thinking this. However, there is a fourth protagonist that stands behind this book and determines the lives of all those who pass across its pages. That protagonist is the Queensland bush