Naresuan University Journal
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P2X7R activation drives distinct IL-1 responses in dendritic cells compared to macrophages
No full textThe P2X7R is a functionally distinct member of the P2X family of non-selective cation channels associated with rapid activation of the inflammasome complex and signalling interleukin (IL)-1β release in macrophages. The main focus of this investigation was to compare P2X7R-driven IL-1 production by primary murine bone marrow derived dendritic cells (BMDC) and macrophages (BMM). P2X7R expression in murine BMDC and BMM at both transcriptional (P2X7A variant) and protein levels was demonstrated. Priming with lipopolysaccharide (LPS) and receptor activation with adenosine triphosphate (ATP) resulted in markedly enhanced IL-1 (α and β) secretion in BMDC compared with BMM. In both cell types IL-1 production was profoundly inhibited with a P2X7R-specific inhibitor (A-740003) demonstrating that this release is predominantly a P2X7R-dependent process. These data also suggest that P2X7R and caspase-1 activation drive IL-1α release from BMDC. Both cell types expressed constitutively the gain-of-function P2X7K as well as the full P2X7A variant at equivalent levels. LPS priming reduced significantly levels of P2X7A but not P2X7K transcripts in both BMDC and BMM. P2X7R-induced pore formation, assessed by YO-PRO-1 dye uptake, was greater in BMDC, and these cells were protected from cell death. These data demonstrate that DC and macrophages display distinct patterns of cytokine regulation, particularly with respect to IL-1, as a consequence of cell-type specific differences in the physicochemical properties of the P2X7R. Understanding the cell-specific regulation of these cytokines is essential for manipulating such responses in health and disease
Urban eco-modernisation and the policy context of new eco-city projects: Where Masdar City fails and why
No full textThe development of projects for new eco-cities is rapidly becoming a global phenomenon. Alleged eco-cities are being built across a variety of spaces via processes of urbanisation triggering substantial environmental, social and economic impacts. This article investigates how new eco-city projects interpret and practice urban sustainability by focusing on the policy context that underpins their development. The article argues that projects for new eco-cities are shaped in loci by policy agendas tailored around specific economic and political targets. In these terms, the ideas and strategies of urban sustainability adopted by eco-city developers are understood as reflections of broader policy priorities. The case study employed in this article, Masdar City, reveals how the Emirati eco-city initiative is the product of local agendas seeking economic growth via urbanisation to preserve the political institutions of Abu Dhabi. Following the economic imperatives set by the ruling class, the Masdar City project interprets sustainability as ecological modernisation and practices urban environmentalism almost exclusively in economic terms. The article shows how the developers of Masdar City capitalise on sustainability by building an urban platform to develop and commercialise clean-tech products, and concludes that the Emirati alleged eco-city is an example of urban eco-modernisation: a high-tech urban development informed by market analysis rather than ecological studies
Significant other behavioural responses and patient chronic fatigue syndrome symptom fluctuations in the context of daily life: An experience sampling study.
No full textOBJECTIVE: Significant other responses to patients' symptoms are important for patient illness outcomes in chronic fatigue syndrome (CFS/ME); negative responses have been associated with increased patient depression, whilst increased disability and fatigue have been associated with solicitous significant other responses. The current study aimed to examine the relationship between significant other responses and patient outcomes within the context of daily life. DESIGN: Experience Sampling Methodology (ESM). METHOD: Twenty-three patients with CFS/ME and their significant others were recruited from specialist CFS/ME services. Sixty momentary assessments, delivered using individual San Francisco Android Smartphones, were conducted over a period of 6 days. All participants reported on affect, dyadic contact, and significant other responses to the patient. Patients reported on symptom severity, disability, and activity management strategies. RESULTS: Negative significant other responses were associated with increased patient symptom severity and distress reported at the same momentary assessment; there was evidence of a potentially mediating role of concurrent distress on symptom severity. Patient-perceived solicitous responses were associated with reduced patient activity and disability reported at the same momentary assessment. Lagged analyses indicate that momentary associations between significant other responses and patient outcomes are largely transitory; significant other responses were not associated with any of the patient outcomes at the subsequent assessment. CONCLUSION: The results indicate that significant other responses are important influences on the day-to-day experience of CFS/ME. Further research examining patient outcomes in association with specific significant other behavioural responses is warranted and future interventions that target such significant other behaviours may be beneficial. Statement of contribution What is already known on this subject? The existing literature has identified that significant other responses are important with respect to patient outcomes in CFS/ME. In particular, when examined cross-sectionally and longitudinally, negative and solicitous significant other responses are associated with poorer illness outcomes. This study is the first to examine the momentary associations between negative and solicitous responses, as reported by the patient and significant other, and patient-reported outcomes. An ESM paradigm was used to assess these temporal relationships within the context of participants' daily life. What does this study add? Negative responses were associated with increased momentary patient distress and symptoms. Perceived solicitousness was associated with activity limitation but less perceived disability. The impact of significant other responses on patient outcomes was found to be transitory
Global mRNA selection mechanisms for translation initiation.
No full textBACKGROUND: The selection and regulation of individual mRNAs for translation initiation from a competing pool of mRNA are poorly understood processes. The closed loop complex, comprising eIF4E, eIF4G and PABP, and its regulation by 4E-BPs are perceived to be key players. Using RIP-seq, we aimed to evaluate the role in gene regulation of the closed loop complex and 4E-BP regulation across the entire yeast transcriptome. RESULTS: We find that there are distinct populations of mRNAs with coherent properties: one mRNA pool contains many ribosomal protein mRNAs and is enriched specifically with all of the closed loop translation initiation components. This class likely represents mRNAs that rely heavily on the closed loop complex for protein synthesis. Other heavily translated mRNAs are apparently under-represented with most closed loop components except Pab1p. Combined with data showing a close correlation between Pab1p interaction and levels of translation, these data suggest that Pab1p is important for the translation of these mRNAs in a closed loop independent manner. We also identify a translational regulatory mechanism for the 4E-BPs; these appear to self-regulate by inhibiting translation initiation of their own mRNAs. CONCLUSIONS: Overall, we show that mRNA selection for translation initiation is not as uniformly regimented as previously anticipated. Components of the closed loop complex are highly relevant for many mRNAs, but some heavily translated mRNAs interact poorly with this machinery. Therefore, alternative, possibly Pab1p-dependent mechanisms likely exist to load ribosomes effectively onto mRNAs. Finally, these studies identify and characterize a complex self-regulatory circuit for the yeast 4E-BPs
Stationary rotary force waves on the liquid–air core interface of a swirl atomizer
No full textA one-dimensional wave equation, applicable to the waves on the surface of the air-core of a swirl atomizer is derived analytically, by analogy to the similar one-dimensional wave equation derivation for shallowwater gravity waves. In addition an analogy to the flow of water over a weir is used to produce an analytical derivation of the flow over the lip of the outlet of a swirl atomizer using the principle of maximum flow. The principle of maximum flow is substantiated by reference to continuity of the discharge in the direction of streaming. For shallowwater gravity waves, the phase velocity is the same expression as for the critical velocity over the weir. Similarly, in the present work, the wave phase velocity on the surface of the air-core is shown to be the same expression as for the critical velocity for the flow at the outlet. In addition, this wave phase velocity is shown to be the square root of the product of the radial acceleration and the liquid thickness, as analogous with the wave phase velocity for shallow water gravity waves, which is the square root of the product of the acceleration due to gravity and the water depth. The work revisits the weirs and flumes work of Binnie et al. but using a different methodology. The results corroborate with the work of Binnie. High speed video, Laser Doppler Anemometry and deflected laser beam experimental work has been carried out on an oversize Perspex (Plexiglas) swirl atomizer. Three distinctive types of waves were detected: helical striations, low amplitude random ripples and low frequency stationary waves. It is the latter wave type that is considered further in this article. The experimentally observed waves appear to be stationary upon the axially moving flow. The mathematical analysis allows for the possibility of a negative value for the phase velocity expression. Therefore the critical velocity and the wave phase velocity do indeed lead to stationary waves in the atomizer. A quantitative comparison between the analytically derived wave phase velocity and that measured experimentally, for this stationary pulsating wave, show very good agreement within a few percent
Data Resource Profile: Clinical Practice Research Datalink (CPRD).
No full textThe Clinical Practice Research Datalink (CPRD) is an ongoing primary care database of anonymised medical records from general practitioners, with coverage of over 11.3 million patients from 674 practices in the UK. With 4.4 million active (alive, currently registered) patients meeting quality criteria, approximately 6.9% of the UK population are included and patients are broadly representative of the UK general population in terms of age, sex and ethnicity. General practitioners are the gatekeepers of primary care and specialist referrals in the UK. The CPRD primary care database is therefore a rich source of health data for research, including data on demographics, symptoms, tests, diagnoses, therapies, health-related behaviours and referrals to secondary care. For over half of patients, linkage with datasets from secondary care, disease-specific cohorts and mortality records enhance the range of data available for research. The CPRD is very widely used internationally for epidemiological research and has been used to produce over 1000 research studies, published in peer-reviewed journals across a broad range of health outcomes. However, researchers must be aware of the complexity of routinely collected electronic health records, including ways to manage variable completeness, misclassification and development of disease definitions for research
Exome sequencing in HFE C282Y homozygous men with extreme phenotypes identifies a GNPAT variant associated with severe iron overload.
No full textTo identify polymorphisms associated with variability of iron overload severity in HFE-associated hemochromatosis, we performed exome sequencing of DNA from 35 male HFE C282Y homozygotes with either markedly increased iron stores (n = 22; cases) or with normal or mildly increased iron stores (n = 13; controls). The 35 participants, residents of the United States, Canada, and Australia, reported no or light alcohol consumption. Sequencing data included 82,068 single-nucleotide variants, and 10,337 genes were tested for a difference between cases and controls. A variant in the GNPAT gene showed the most significant association with severe iron overload (P = 3 × 10(-6) ; P = 0.033 by the likelihood ratio test after correction for multiple comparisons). Sixteen of twenty-two participants with severe iron overload had glyceronephosphate O-acyltransferase (GNPAT) polymorphism p.D519G (rs11558492; 15 heterozygotes, one homozygote). No control participant had this polymorphism. To examine functional consequences of GNPAT deficiency, we performed small interfering RNA-based knockdown of GNPAT in the human liver-derived cell line, HepG2/C3A. This knockdown resulted in a >17-fold decrease in expression of the messenger RNA encoding the iron-regulatory hormone, hepcidin.CONCLUSION: GNPAT p.D519G is associated with a high-iron phenotype in HFE C282Y homozygotes and may participate in hepcidin regulation. (Hepatology 2015)
“It’s All About Time”::Time as Contested Terrain in the Management and Experience of Domiciliary Care Work in England
No full textDrawing on a multilevel study of commissioning, employers, and care staff, this article explores the role of time in the management of domiciliary care work for older adults in England and the consequences for the employment conditions of care staff. An index of fragmented time practices among 52 independent-sector domiciliary care providers reveals widespread tendencies to use zero-hours contracts and limit paid hours to face-to-face contact time, leaving travel time and other work-related activities unpaid. Care staff interviews reveal how fragmented time creates insecurities and demands high work engagement. Time management practices are shown to derive directly from strict time-based local authority commissioning. Subcontractors, both independent small fi rms and those belonging to national chains, can at best adopt human resource (HR) policies that are partial routes to failure, as evident in widespread recruitment and retention problems. Informal HR practices to accommodate working-time preferences help to retain individual staff, but adjustments are often marginal, adversely affect other staff and fail to expand the recruitment pool for social care. Labor shortages are likely to persist as long as workers are required to adapt to a regime of fragmented time and to work more hours than are paid, even at pay rates close to the national minimum wage