‘Just want to surf, make boards and party’: how do we identify lifestyle entrepreneurs within the lifestyle sports industry?

This paper aims to further our understanding of the identity of the lifestyle entrepreneur operating within the lifestyle sports industry. The lifestyle entrepreneur has to date been the subject of numerous definitions. However, understanding the context in which entrepreneurs operate has been identified by researchers as impacting upon the actions they take, and so therefore linking context to the entrepreneur is critical to the understanding of these individuals. A mixed methods study comprising of 80 questionnaire responses, and 21 semi-structured interviews focussed on identifying lifestyle sports entrepreneurs. Two groups of entrepreneurs were targeted; those entrepreneurs operating within a sport (Engagers) and those who run a business to participate (Enablers). Issues surrounding the identification of lifestyle entrepreneurs are presented. Through the analysis of the data, entrepreneurs identified through their own narratives how their identities are created. The results demonstrate that while the current external interpretation of the lifestyle entrepreneur is of a fixed nature, the entrepreneurs themselves evidence a much more complex approach to their identities

Regulation of neutrophilic inflammation by hypoxic signalling pathways

Neutrophils are essential for effective innate immunity. Conversely, inappropriate or excessive neutrophil activation can result in damaging inflammation. This damage is implicated in the pathogenesis of a number of respiratory diseases including acute respiratory distress syndrome (ARDS) and chronic obstructive pulmonary disease (COPD) which are also both frequently complicated by hypoxia. Cells sense and respond to hypoxia through the activity of the transcription factor HIF (hypoxia inducible factor) and its regulatory hydroxylases, the prolyl hydroxylase domain enzymes (PHDs) 1- 3. In the presence of oxygen, PHDs hydroxylate HIF, preventing the HIF mediated transcriptional response. Close links exist between the pathways which regulate hypoxic and inflammatory responses. Our group has previously found that in mouse models of infection, acute hypoxia leads to increased sickness and that this is driven by neutrophilic inflammation. I have used a murine model of Lipopolysaccharide (LPS) -induced acute lung injury, characterised by neutrophil influx, to investigate how exposure to hypoxia alters lung inflammation. Using high-resolution mass spectrometry, I have defined the proteome of the inflammatory lung neutrophil. I have shown that hypoxia results in a distinct proteomic signature in inflammatory neutrophils. Hypoxia drives lung neutrophilic inflammation through increased neutrophil degranulation and upregulation of inflammatory receptors. I have also identified key metabolic alterations in hypoxic neutrophils. The hypoxic lung represents a low glucose, high protein environment and neutrophils adapt to exploit this. I have shown that neutrophils can scavenge proteins from their extracellular environment, catabolise these proteins in the lysosome and utilise the breakdown products for metabolism. These processes are upregulated in hypoxic lung neutrophils which show increased lysosomal protein expression, increased protein uptake and increased glutaminolysis. Utilising heavy labelled protein extracts, I have traced breakdown products from scavenged proteins into central carbon metabolism, demonstrating that extracellular protein can fuel neutrophilic inflammation. Finally, I have investigated the role of the prolyl hydroxylase PHD1 in regulating neutrophilic inflammation. Using a neutrophil specific PHD1 knockout mouse line, I have identified a specific role for PHD1 in regulating neutrophil metabolism and survival. I have found that the micro-environment, particularly oxygen availability, determines the impact of PHD1 loss with consequences for inflammation resolution in vivo. In summary, hypoxia is a key regulator of neutrophil function and is associated with increased neutrophilic inflammation. Utilising a proteomic approach, I have identified the mechanisms which drive the hyperinflammatory phenotype including the ability of neutrophils to scavenge proteins from the environment to fuel inflammation. I have also shown that PHD1, a key component of the hypoxic signalling pathway, may regulate these functions. A more complete understanding of these mechanisms will help to identify therapeutic targets for treatment of neutrophilic inflammation in the lung

The growth of ‘Dry January’: promoting participation and the benefits of participation

This article explores contributors to the rapid growth of the annual UK alcohol abstinence challenge ‘Dry January’ and the benefits of registration. Evidence from four sources is presented: (i) registrations via the Dry January website, (ii) surveys of population-representative samples of drinkers, (iii) surveys of Dry January registrants and (iv) surveys of a control group of drinkers who wanted to change to their drinking behaviour but had not registered for Dry January. The data revealed that Dry January registrations increased 15-fold in 4 years. Participants reported that encouragement received from Dry January helped them to avoid drinking. Comparisons of Dry January registrants to the control group suggest that registering for Dry January reduced problematic drinking and enhanced the capacity to refuse alcohol. The four sources of data suggest that ‘social contagion’ and ‘diffusion’ have aided the growth of the awareness, appeal and practice of Dry January

A submillimetre survey of the kinematics of the Perseus molecular cloud - III. Clump kinematics

We explore the kinematics of continuum clumps in the Perseus molecular cloud, derived from C18O J=3-2 data. Two populations are examined, identified using the automated algorithms CLFIND and GAUSSCLUMPS on existing SCUBA data. The clumps have supersonic linewidths with distributions which suggest the C18O line probes a lower-density 'envelope' rather than a dense inner core. Similar linewidth distributions for protostellar and starless clumps implies protostars do not have a significant impact on their immediate environment. The proximity to an active young stellar cluster seems to affect the linewidths: those in NGC1333 are greater than elsewhere. In IC348 the proximity to the old IR cluster has little influence, with the linewidths being the smallest of all. A virial analysis suggests that the clumps are bound and close to equipartition. In particular, the starless clumps occupy the same parameter space as the protostars, suggesting they are true stellar precursors and will go on to form stars. We also search for ordered C18O velocity gradients across the face of each core, usually interpreted as rotation. We note a correlation between the directions of the identified gradients and outflows across protostars, indicating we may not have a purely rotational signature. The fitted gradients are larger than found in previous work, probably as a result of the higher resolution of our data and/or outflow contamination. These gradients, if interpreted solely in terms of rotation, suggest that rotation is not dynamically significant. Furthermore, derived specific angular momenta are smaller than observed in previous studies, centred around j~0.001 km/s pc, which indicates we have identified lower levels of rotation, or that the C18O J=3-2 line probes conditions significantly denser and/or colder than n~10^5 per cc and T~10 K.Comment: 20 pages, 20 figures, accepted for publication by MNRAS. Supplementary, on-line only material available from http://www.mrao.cam.ac.uk/~eic22/Papers/CR10b_suppmaterial.pd

IL4Rα signaling abrogates hypoxic neutrophil survival and limits acute lung injury responses <i>in vivo</i>

Rationale: Acute respiratory distress syndrome is defined by the presence of systemic hypoxia and consequent on disordered neutrophilic inflammation. Local mechanisms limiting the duration and magnitude of this neutrophilic response remain poorly understood.  Objectives: To test the hypothesis that during acute lung inflammation tissue production of proresolution type 2 cytokines (IL-4 and IL-13) dampens the proinflammatory effects of hypoxia through suppression of HIF-1a (hypoxia-inducible factor-1a)mediated neutrophil adaptation, resulting in resolution of lung injury.  Methods: Neutrophil activation of IL4Ra (IL-4 receptor a) signaling pathways was explored ex vivo in human acute respiratory distress syndrome patient samples, in vitro after the culture of human peripheral blood neutrophils with recombinant IL-4 under conditions of hypoxia, and in vivo through the study of IL4Ra-deficient neutrophils in competitive chimera models and wild-type mice treated with IL-4.  Measurements and Main Results: IL-4 was elevated in human BAL from patients with acute respiratory distress syndrome, and its receptor was identified on patient blood neutrophils. Treatment of human neutrophils with IL-4 suppressed HIF-1a-dependent hypoxic survival and limited proinflammatory transcriptional responses. Increased neutrophil apoptosis in hypoxia, also observed with IL-13, required active STAT signaling, and was dependent on expression of the oxygen-sensing prolyl hydroxylase PHD2. In vivo, IL-4Ra-deficient neutrophils had a survival advantage within a hypoxic inflamed niche; in contrast, inflamed lung treatment with IL-4 accelerated resolution through increased neutrophil apoptosis.  Conclusions: We describe an important interaction whereby IL4Ra-dependent type 2 cytokine signaling can directly inhibit hypoxic neutrophil survival in tissues and promote resolution of neutrophil-mediated acute lung injury

Hypoxia drives murine neutrophil protein scavenging to maintain central carbon metabolism

Limiting dysfunctional neutrophilic inflammation while preserving effective immunity requires a better understanding of the processes that dictate neutrophil function in the tissues. Quantitative mass-spectrometry identified how inflammatory murine neutrophils regulated expression of cell surface receptors, signal transduction networks, and metabolic machinery to shape neutrophil phenotypes in response to hypoxia. Through the tracing of labeled amino acids into metabolic enzymes, proinflammatory mediators, and granule proteins, we demonstrated that ongoing protein synthesis shapes the neutrophil proteome. To maintain energy supplies in the tissues, neutrophils consumed extracellular proteins to fuel central carbon metabolism. The physiological stresses of hypoxia and hypoglycemia, characteristic of inflamed tissues, promoted this extracellular protein scavenging with activation of the lysosomal compartment, further driving exploitation of the protein-rich inflammatory milieu. This study provides a comprehensive map of neutrophil proteomes, analysis of which has led to the identification of active catabolic and anabolic pathways that enable neutrophils to sustain synthetic and effector functions in the tissues

Hypoxia shapes the immune landscape in lung injury and promotes the persistence of inflammation

Hypoxemia is a defining feature of acute respiratory distress syndrome (ARDS), an often-fatal complication of pulmonary or systemic inflammation, yet the resulting tissue hypoxia, and its impact on immune responses, is often neglected. In the present study, we have shown that ARDS patients were hypoxemic and monocytopenic within the first 48 h of ventilation. Monocytopenia was also observed in mouse models of hypoxic acute lung injury, in which hypoxemia drove the suppression of type I interferon signaling in the bone marrow. This impaired monopoiesis resulted in reduced accumulation of monocyte-derived macrophages and enhanced neutrophil-mediated inflammation in the lung. Administration of colony-stimulating factor 1 in mice with hypoxic lung injury rescued the monocytopenia, altered the phenotype of circulating monocytes, increased monocyte-derived macrophages in the lung and limited injury. Thus, tissue hypoxia altered the dynamics of the immune response to the detriment of the host and interventions to address the aberrant response offer new therapeutic strategies for ARDS