213 research outputs found
Phosphoinositidase C, Inositol Polyphosphates and Force Generation of Airways Smooth Muscle
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The rise and fall of the Labour league of youth
No full textThis thesis charts the rise and fall of the Labour Party’s first and most enduring youth organisation, the Labour League of Youth. The history of the League, from its birth in the early nineteen twenties to its demise in the late nineteen fifties, is placed in the context of the Labour Party’s subsequent fruitless attempts to establish and maintain a vibrant and functional youth organisation. A narrative is incorporated that illuminates the culture, organisation and political activism of the League and establishes it as a predominantly working class radical organisation. The reluctance on the part of the Labour Party to grant autonomy to its youth sections resulted in the history of the League of Youth being one of control, suppression and tension. This state of affairs ensured that subsequent youth groups, the Young Socialists and Young Labour, would be established in an atmosphere of reservation and scepticism.
The thesis places the prime responsibility for the failure of the party’s youth organisations with the party leadership but also considers the contributory factors of changing social and political circumstances. A number of themes are explored which include the impact of structure and agency factors, the power of the Parliamentary Labour Party, the political socialisation of leading figures within the party, the social context in which each of the groups emerged and the extent to which the youth groups were prey to intra-party factionalism.
The thesis redresses the balance of research where most accounts have focussed on the Young Socialists and traces the common characteristics that are prevalent in the way the party leadership has approached its relationship with its youth organisations. Use has been made of previously unpublished primary source material, the major source being the League of Youth members themselves whose recollections have helped to demonstrate the arguments put forward in this thesis
Author response: Cardiovascular adaptation to hypoxia and the role of peripheral resistance
No full textHypoxia. Hypoxia, hypoxia inducible factor and myeloid cell function
No full textWith little in the way of effective therapeutic strategies to target the innate immune response, a better understanding of the critical pathways regulating neutrophil and macrophage responses in inflammation is key to the development of novel therapies. Hypoxia inducible factor (HIF) was originally identified as a central transcriptional regulator of cellular responses to oxygen deprivation. However, the HIF signalling pathway now appears, in myeloid cells at least, to be a master regulator of both immune cell function and survival. As such, understanding the biology of HIF and its regulators may provide new approaches to myeloid-specific therapies that are urgently needed
The Neutrophil Life Cycle.
No full textNeutrophils are recognized as an essential part of the innate immune response, but an active debate still exists regarding the life cycle of these cells. Neutrophils first differentiate in the bone marrow through progenitor intermediaries before entering the blood, in a process that gauges the extramedullary pool size. Once believed to be directly eliminated in the marrow, liver, and spleen, neutrophils, after circulating for less than 1 day, are now known to redistribute into multiple tissues with poorly understood kinetics. In this review, we provide an update on the dynamic distribution of neutrophils across tissues in health and disease, and emphasize differences between humans and model organisms. We further highlight issues to be addressed to exploit the unique features of neutrophils in the clinic
Priming and de-priming of neutrophil responses in vitro and in vivo
No full textThe activation status of neutrophils can cycle from basal through primed to fully activated (“green-amber-red”), and at least in vitro, primed cells can spontaneously revert to a near basal phenotype. This broad range of neutrophil responsiveness confers extensive functional flexibility, allowing neutrophils to respond rapidly and appropriately to varied and evolving threats throughout the body. Primed and activated cells display dramatically enhanced bactericidal capacity (including augmented respiratory burst activity, degranulation and longevity), but this enhancement also confers the capacity for significant unintended tissue injury. Neutrophil priming and its consequences have been associated with adverse outcomes in a range of disease states, hence understanding the signalling processes that regulate the transition between basal and primed states (and back again) may offer new opportunities for therapeutic intervention in pathological settings. A wide array of host- and pathogen-derived molecules is able to modulate the functional status of these versatile cells. Reflecting this extensive repertoire of potential mediators, priming can be established by a range of signalling pathways (including mitogen-activated protein kinases, phosphoinositide 3-kinases, phospholipase D and calcium transients) and intracellular processes (including endocytosis, vesicle trafficking and the engagement of adhesion molecules). The signalling pathways engaged, and the exact cellular phenotype that results, vary according to the priming agent(s) to which the neutrophil is exposed and the precise environmental context. Herein we describe the signals that establish priming (in particular for enhanced respiratory burst, degranulation and prolonged lifespan) and describe the recently recognised process of de-priming, correlating in vitro observations with in vivo significance
Mathematical modeling supports the presence of neutrophil depriming in vivo.
No full textAbstract Following migration into the intestinal mucosa in inflammatory bowel disease (IBD), neutrophils enter the intestinal lumen and are excreted. This provides a basis for quantification of disease activity by measuring excreted label following injection of In-111-labeled neutrophils. In severe pan-colitis, 50% of the injected In-111 is typically recovered in the feces, indicating that 50% of neutrophil turnover is via fecal excretion. Neutrophils have an intravascular lifespan of ~10 h and a distribution volume of ~10 L, so total body neutrophil turnover is 10.N/10 cells/h, where N is the peripheral blood neutrophil count (cells/L). Neutrophil loss via the colon in a patient with 50% fecal In-111 loss is therefore N/120 cells/min. Pan-colonic mucosal-blood flow in pan-colitis is 200 mL/min, which would deliver N/5 neutrophils to the colon per min. Therefore, 5/120, or 4%, of incoming neutrophils undergo migration into inflamed bowel. If the 96% of nonmigrating cells exit in a primed state, then at steady state >90% of circulating neutrophils would be primed if no depriming took place. As the highest level of priming seen in IBD is ~40%, this indicates that depriming within the circulation must take place. Using the above values in the steady state equation relating priming rate to depriming rate plus primed-cell destruction rate gives a mean depriming time of 35 min. We conclude that a very small proportion of neutrophils entering a site of inflammation migrate and that in vivo depriming must take place to limit the numbers of primed neutrophils in the circulation
Human Cytomegalovirus Use Activated Neutrophils To Further Their Own Pathological Advantage
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