The relationship between P2X4 and P2X7: a physiologically important interaction?

Purinergic signaling within the kidney is becoming an important focus in the study of renal health and disease. The effectors of ATP signaling, the P2Y and P2X receptors, are expressed to varying extents in and along the nephron. There are many studies demonstrating the importance of the P2Y2 receptor on kidney function, and other P2 receptors are now emerging as participants in renal regulation. The P2X4 receptor has been linked to epithelial sodium transport in the nephron and expression levels of the P2X7 receptor are up-regulated in certain pathophysiological states. P2X7 antagonism has been shown to ameliorate rodent models of DOCA salt-induced hypertension and P2X4 null mice are hypertensive. Interestingly, polymorphisms in the genetic loci of P2X4 and P2X7 have been linked to blood pressure variation in human studies. In addition to the increasing evidence linking these two P2X receptors to renal function and health, a number of studies link the two receptors in terms of physical associations between their subunits, demonstrated both in vitro and in vivo. This review will analyze the current literature regarding interactions between P2X4 and P2X7 and assess the potential impact of these with respect to renal function

A reappraisal of explosive–effusive silicic eruption dynamics: syn-eruptive assembly of lava from the products of cryptic fragmentation

Silicic volcanic eruptions range in style from gently effusive to highly explosive, and may switch style unpredictably during a single eruption. Direct observations of subaerial rhyolitic eruptions (Chaiten 2008, Cordón Caulle 2011–2012, Chile) challenged long-standing paradigms of explosive and effusive eruptive styles and led to the formulation of new models of hybrid activity. However, the processes that govern such hybrid explosive–effusive activity remain poorly understood. Here, we bring together observations of the well-studied 2011–2012 Cordón Caulle eruption with new textural and petrologic data on erupted products, and video and still imagery of the eruption. We infer that all of the activity – explosive, effusive, and hybrid – was fed by explosive fragmentation at depth, and that effusive behaviour arose from sticking and sintering, in the shallow vent region, of the clastic products of deeper, cryptic fragmentation. We use a scaling approach to determine that there is sufficient time available, during emplacement, for diffusive pyroclast degassing and sintering to produce a degassed plug that occludes the shallow conduit, feeding clastogenic, apparently effusive, lava-like deposits. Based on evidence from Cordón Caulle, and from other similar eruptions, we further argue that hybrid explosive–effusive activity is driven by episodic gas-fracking of the occluding lava plug, fed by the underlying pressurized ash- and pyroclast-laden region. The presence of a pressurized pocket of ash-laden gas within the conduit provides a mechanism for generation of harmonic tremor, and for syn-eruptive laccolith intrusion, both of which were features of the Cordón Caulle eruption. We conclude that the cryptic fragmentation models is more consistent with available evidence than the prevailing model for effusion of silicic lava that assume coherent non-fragmental rise of magma from depth to the surface without wholesale explosive fragmentation

Self-reported ill health in male UK Gulf War veterans: a retrospective cohort study

BACKGROUND: Forces deployed to the first Gulf War report more ill health than veterans who did not serve there. Many studies of post-Gulf morbidity are based on relatively small sample sizes and selection bias is often a concern. In a setting where selection bias relating to the ill health of veterans may be reduced, we: i) examined self-reported adult ill health in a large sample of male UK Gulf War veterans and a demographically similar non-deployed comparison group; and ii) explored self-reported ill health among veterans who believed that they had Gulf War syndrome. METHODS: This study uses data from a retrospective cohort study of reproduction and child health in which a validated postal questionnaire was sent to all UK Gulf War veterans (GWV) and a comparison cohort of Armed Service personnel who were not deployed to the Gulf (NGWV). The cohort for analysis comprises 42,818 males who responded to the questionnaire. RESULTS: We confirmed that GWV report higher rates of general ill health. GWV were significantly more likely to have reported at least one new medical symptom or disease since 1990 than NGWV (61% versus 37%, OR 2.7, 95% CI 2.5–2.8). They were also more likely to report higher numbers of symptoms. The strongest associations were for mood swings (OR 20.9, 95%CI 16.2–27.0), memory loss/lack of concentration (OR 19.6, 95% CI 15.5–24.8), night sweats (OR 9.9, 95% CI 6.5–15.2), general fatigue (OR 9.6, 95% CI 8.3–11.1) and sexual dysfunction (OR 4.6, 95%CI 3.2–6.6). 6% of GWV believed they had Gulf War syndrome (GWS), and this was associated with the highest symptom reporting. CONCLUSIONS: Increased levels of reported ill health among GWV were confirmed. This study was the first to use a questionnaire which did not focus specifically on the veterans' symptoms themselves. Nevertheless, the results are consistent with those of other studies of post-Gulf war illness and thus strengthen overall findings in this area of research. Further examination of the mechanisms underlying the reporting of ill health is required

Adipocyte NR1D1 dictates adipose tissue expansion during obesity

From eLife via Jisc Publications RouterHistory: received 2020-09-22, collection 2021, accepted 2021-07-30, pub-electronic 2021-08-05Publication status: PublishedFunder: Biotechnology and Biological Sciences Research Council; FundRef: http://dx.doi.org/10.13039/501100000268; Grant(s): BB/I018654/1Funder: Medical Research Council; FundRef: http://dx.doi.org/10.13039/501100000265; Grant(s): MR/N021479/1Funder: Medical Research Council; FundRef: http://dx.doi.org/10.13039/501100000265; Grant(s): MR/P00279X/1Funder: Medical Research Council; FundRef: http://dx.doi.org/10.13039/501100000265; Grant(s): MR/P011853/1Funder: Medical Research Council; FundRef: http://dx.doi.org/10.13039/501100000265; Grant(s): MR/P023576/1Funder: Wellcome Trust; FundRef: http://dx.doi.org/10.13039/100004440; Grant(s): 107849/Z/15/ZFunder: Wellcome Trust; FundRef: http://dx.doi.org/10.13039/100004440; Grant(s): 107851/Z/15/ZThe circadian clock component NR1D1 (REVERBα) is considered a dominant regulator of lipid metabolism, with global Nr1d1 deletion driving dysregulation of white adipose tissue (WAT) lipogenesis and obesity. However, a similar phenotype is not observed under adipocyte-selective deletion (Nr1d1Flox2-6:AdipoqCre), and transcriptional profiling demonstrates that, under basal conditions, direct targets of NR1D1 regulation are limited, and include the circadian clock and collagen dynamics. Under high-fat diet (HFD) feeding, Nr1d1Flox2-6:AdipoqCre mice do manifest profound obesity, yet without the accompanying WAT inflammation and fibrosis exhibited by controls. Integration of the WAT NR1D1 cistrome with differential gene expression reveals broad control of metabolic processes by NR1D1 which is unmasked in the obese state. Adipocyte NR1D1 does not drive an anticipatory daily rhythm in WAT lipogenesis, but rather modulates WAT activity in response to alterations in metabolic state. Importantly, NR1D1 action in adipocytes is critical to the development of obesity-related WAT pathology and insulin resistance

The relationship between P2X4 and P2X7: a physiologically important interaction?

Purinergic signaling within the kidney is becoming an important focus in the study of renal health and disease. The effectors of ATP signaling, the P2Y and P2X receptors, are expressed to varying extents in and along the nephron. There are many studies demonstrating the importance of the P2Y2 receptor on kidney function, and other P2 receptors are now emerging as participants in renal regulation. The P2X4 receptor has been linked to epithelial sodium transport in the nephron and expression levels of the P2X7 receptor are up-regulated in certain pathophysiological states. P2X7 antagonism has been shown to ameliorate rodent models of DOCA salt-induced hypertension and P2X4 null mice are hypertensive. Interestingly, polymorphisms in the genetic loci of P2X4 and P2X7 have been linked to blood pressure variation in human studies. In addition to the increasing evidence linking these two P2X receptors to renal function and health, a number of studies link the two receptors in terms of physical associations between their subunits, demonstrated both in vitro and in vivo. This review will analyze the current literature regarding interactions between P2X4 and P2X7 and assess the potential impact of these with respect to renal function

Differences in cortisol concentrations in South Asian and European men living in the United Kingdom

OBJECTIVE: The metabolic syndrome is more prevalent in South Asians in Britain than in the general population. Furthering our understanding of the underlying mechanisms is important because of the increased risk of cardiovascular disease associated with the metabolic syndrome. As it has been proposed that increased activity of the hypothalamic pituitary adrenal axis might underlie the metabolic syndrome, we hypothesized that plasma cortisol levels would be higher in South Asians and that increased cortisol levels would be associated with cardiovascular risk factors comprising the metabolic syndrome. The aim of the study was to examine ethnic differences in cortisol levels and to compare the relationships between cortisol levels and cardiovascular risk factors in men from different ethnic groups. DESIGN: Cross-sectional population-based study, Newcastle upon Tyne, UK. (Newcastle Heart project). Participants One hundred men, 40-67 years old, of European and South Asian (Indian, Pakistani, Bangladeshi) ancestry, with and without cardiovascular risk factors of the metabolic syndrome. MEASUREMENTS: Measurement of plasma cortisol and corticosteroid binding globulin in stored sera. RESULTS: After adjustment for age and the presence of cardiovascular risk factors, mean cortisol was 27% (95% CI, 10%, 40%) lower in South Asians compared to Europeans. Cortisol levels were higher in all men with cardiovascular risk factors than those without. CONCLUSIONS: Cortisol levels are lower in South Asian than in European men resident in the UK. Despite lower cortisol levels in South Asians, the relations between cortisol and cardiovascular risk factors remain strong

Scanning electrochemical microscopy (SECM) studies of catalytic EC′ processes : theory and experiment for feedback, generation/collection and imaging measurements

This paper describes the use of scanning electrochemical microscopy (SECM) in the tip generation/substrate collection (TG/SC), or feedback, mode and substrate generation/tip collection (SG/TC) mode to measure homogeneous kinetics in the catalytic EC' process. Theoretical analyses of both configurations have been developed numerically to allow the optimal conditions for sensitive kinetic measurements to be determined. This is shown to involve collection efficiency measurements as a function of tip-substrate electrode distance in the case of TG/SC measurements and tip (collector current) images in a plane normal to the substrate electrode for the SG/TC mode. An important consideration for the SECM configuration (particularly for TG/SC and feedback measurements) is that the electroinactive co-reactant may be depleted more significantly than with other electrode geometries, because of cycling of the redox couple in the tip/substrate electrode gap, while the co-reactant can only enter this gap by hindered diffusion. The approaches described are examined through studies of the oxidation of amidopyrine by electrogenerated Fe(CN)(6)(3-) in 0.5 mol dm(-3) aqueous KOH solution. A second-order rate constant of 390 +/- 80 dm(3) mol(-1) s(-1) is obtained from TG/SC measurements, consistent with SG/TC quantitative imaging measurements. The consistency of the kinetic measurements confirms the validity of the approaches described. The kinetic constant is lower than expected based on previous ultramicroelectrode (UME) studies, and this is attributed to the fact that background currents for the direct heterogeneous oxidation of amidopyrine are more significant with conventional UME measurements, which will tend to enhance the current measured and may therefore lead to an overestimation of kinetic constants. The TG/SC approach, on the other hand, provides a means of making dual-electrode collection efficiency measurements with diffusional feedback of the redox couple, leading to superior voltammetric responses and enabling more accurate kinetic determination

Adipocyte NR1D1 dictates adipose tissue expansion during obesity

The circadian clock component NR1D1 (REVERBα) is considered a dominant regulator of lipid metabolism, with global Nr1d1 deletion driving dysregulation of white adipose tissue (WAT) lipogenesis and obesity. However, a similar phenotype is not observed under adipocyte-selective deletion (Nr1d1Flox2-6:AdipoqCre), and transcriptional profiling demonstrates that, under basal conditions, direct targets of NR1D1 regulation are limited, and include the circadian clock and collagen dynamics. Under high-fat diet (HFD) feeding, Nr1d1Flox2-6:AdipoqCre mice do manifest profound obesity, yet without the accompanying WAT inflammation and fibrosis exhibited by controls. Integration of the WAT NR1D1 cistrome with differential gene expression reveals broad control of metabolic processes by NR1D1 which is unmasked in the obese state. Adipocyte NR1D1 does not drive an anticipatory daily rhythm in WAT lipogenesis, but rather modulates WAT activity in response to alterations in metabolic state. Importantly, NR1D1 action in adipocytes is critical to the development of obesity-related WAT pathology and insulin resistance