Synaptic Currents Generated by Neuronal Acetylcholine Receptors Sensitive to α-Bungarotoxin

AbstractNicotinic acetylcholine receptors are widely distributed throughout the nervous system, but their functions remain largely unknown. One of the most abundant is a class of receptors that contains the α7 gene product, has a high relative permeability to calcium, and binds α-bungarotoxin. Here, we report that receptors sensitive to α-bungarotoxin, though concentrated in perisynaptic clusters on neurons, can generate a large amount of the synaptic current. Residual currents through other nicotinic receptors are sufficient to elicit action potentials, but with slower rise times. This demonstrates a postsynaptic response for α-bungarotoxin-sensitive receptors on neurons and suggests that the functional domain of the postsynaptic membrane is broader than previously recognized

Underground mining of aggregates. Main report

This report examines the economic feasibility of underground mining for crushed rock aggregates in the UK, but particularly in the London, South East and East of England regions (the South East area of England). These regions import substantial volumes of crushed rock, primarily from the East Midlands and South West regions, requiring relatively long transport distances to market for this bulk commodity. A key part of the research was to determine whether or not aggregate could be produced and delivered to a local market from an underground aggregates operation at a cost comparable with that for production and transport of the commodity from traditional surface quarries located further afield. In essence the investigation asked – could the reduced transport costs compensate for the higher production costs underground so that underground crushed rock aggregates producers can compete with the established Leicestershire and Somerset surface quarries exporting to the South East? Work Programme The research effort involved establishing and verifying cost models for aggregates production, stone processing (sizing and sorting), haulage of product to market, environmental impact mitigation, health and safety, decommissioning and restoration. Another major element of the work was the re-examination of the BGS exploratory borehole and geophysical databases to identify potential areas of crushed rock aggregates resource at depth in the South East area of England. Land use pressure is typically higher in this area of England than elsewhere so another major part of the research was the identification of potential concurrent uses of land around the surface facilities of underground aggregates mines. The value, development costs for specific developments and determination of yields expected, from these uses were estimated. These were also used to investigate potential economic benefits associated with after uses of remediated surface land above potential underground aggregates mines and also for the new underground space that would be created. Key technical issues such as subsidence within relatively heavily populated areas of the South East area of England were also addressed. Economic Results The discounted cost of aggregate delivered at a discount rate of 10% was the metric used to appraise the options. This is the price of aggregate that leads to a zero net present value of project cash flows realised over the aggregates project life. The results show that the discounted costs of aggregate delivered to a local South East area of England market from an underground mine producing 3.5 million tonnes per annum (MTPA) of crushed rock aggregates, are in the range of £13.03 per tonne to £13.93 per tonne for the top six prospect locations. These are greater than the corresponding cost for a “reference” quarry in Leicestershire producing 3.5 MTPA (£10.95 per tonne), but lower than a “reference” quarry in Leicestershire producing 1.25 MTPA (£16.48 per tonne). These figures indicate that underground crushed rock aggregate mines located within the South East area of England may be able to compete for a share in the overall market by replacing / displacing aggregate imported from the quarries in Leicestershire and Somerset producing around or less than 1.25 MTPA. The surprise in these figures is not really that the more remote surface quarry has a lower discounted cost of aggregate delivered, but that the values for the quarry and underground mine are so close. The capital intensity for the development of underground aggregates mines was found to be higher than that required for surface quarries of comparable scale, by a factor ranging from 1.33 to 1.65 and thus may represent a disincentive for aggregates operators. Carbon Emissions The total carbon emissions of the ‘reference’ 3.5 MTPA quarry in Leicestershire were estimated at 9.28 kg CO2/tonne aggregate delivered and this is to be compared with carbon emissions for the 150 metre deep underground mines serving the local market which were estimated at 9.31 kg CO2/tonne delivered for a Bletchley prospect using an adit to access the sub-surface and 14.25 kg CO2/tonne delivered for a prospect based on the Chitty bore hole using a shaft. Depth of the mine is a key factor in determination of the relative carbon emissions from each of the underground mining operations considered as electricity consumption for ventilation, pumping and winding is proportional to depth. Recommendations The current research generated seven principal recommendations which are discussed in detail in the concluding section of the report. These are: Appraise policy incentives for underground aggregates mining. Conduct an industry-wide consultation on findings from the current research. Obtain public and stakeholder opinion on new uses for underground space. Conduct research to reducing the energy intensity of mine services. Develop a deep level aggregates-specific drilling campaign. Investigate underground aggregates mines developed from existing surface quarries. Investigate underground aggregates as co-products of industrial minerals mining

Proposed evolutionary changes in the role of myelin

© 2013 Stiefel, Torben-Nielsen and Coggan. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these termsMyelin is the multi-layered lipid sheet periodically wrapped around neuronal axons. It is most frequently found in vertebrates. Myelin allows for saltatory action potential (AP) conduction along axons. During this form of conduction, the AP travels passively along the myelin-covered part of the axon, and is recharged at the intermittent nodes of Ranvier. Thus, myelin can reduce the energy load needed and/or increase the speed of AP conduction. Myelin first evolved during the Ordovician period. We hypothesize that myelin's first role was mainly energy conservation. During the later "Mesozoic marine revolution," marine ecosystems changed toward an increase in marine predation pressure. We hypothesize that the main purpose of myelin changed from energy conservation to conduction speed increase during this Mesozoic marine revolution. To test this hypothesis, we optimized models of myelinated axons for a combination of AP conduction velocity and energy efficiency. We demonstrate that there is a trade-off between these objectives. We then compared the simulation results to empirical data and conclude that while the data are consistent with the theory, additional measurements are necessary for a complete evaluation of the proposed hypothesis.Peer reviewedFinal Published versio

Multifaceted intervention to reduce haemodialysis catheter related bloodstream infections: REDUCCTION stepped wedge, cluster randomised trial.

OBJECTIVE: To identify whether multifaceted interventions, or care bundles, reduce catheter related bloodstream infections (CRBSIs) from central venous catheters used for haemodialysis. DESIGN: Stepped wedge, cluster randomised design. SETTING: 37 renal services across Australia. PARTICIPANTS: All adults (age ≥18 years) under the care of a renal service who required insertion of a new haemodialysis catheter. INTERVENTIONS: After a baseline observational phase, a service-wide, multifaceted intervention bundle that included elements of catheter care (insertion, maintenance, and removal) was implemented at one of three randomly assigned time points (12 at the first time point, 12 at the second, and 13 at the third) between 20 December 2016 and 31 March 2020. MAIN OUTCOMES MEASURE: The primary endpoint was the rate of CRBSI in the baseline phase compared with intervention phase at the renal service level using the intention-to-treat principle. RESULTS: 1.14 million haemodialysis catheter days of use were monitored across 6364 patients. Patient characteristics were similar across baseline and intervention phases. 315 CRBSIs occurred (158 in the baseline phase and 157 in the intervention phase), with a rate of 0.21 per 1000 days of catheter use in the baseline phase and 0.29 per 1000 days in the intervention phase, giving an incidence rate ratio of 1.37 (95% confidence interval 0.85 to 2.21; P=0.20). This translates to one in 10 patients who undergo dialysis for a year with a catheter experiencing an episode of CRBSI. CONCLUSIONS: Among patients who require a haemodialysis catheter, the implementation of a multifaceted intervention did not reduce the rate of CRBSI. Multifaceted interventions to prevent CRBSI might not be effective in clinical practice settings. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry ACTRN12616000830493

Structure of the Janus Protein Human CLIC2

Chloride intracellular channel (CLIC) proteins possess the remarkable property of being able to convert from a water-soluble state to a membrane channel state. We determined the three-dimensional structure of human CLIC2 in its water-soluble form by X-ray crystallography at 1.8-Å resolution from two crystal forms. In contrast to the previously characterized CLIC1 protein, which forms a possibly functionally important disulfide-induced dimer under oxidizing conditions, we show that CLIC2 possesses an intramolecular disulfide and that the protein remains monomeric irrespective of redox conditions. Site-directed mutagenesis studies show that removal of the intramolecular disulfide or introduction of cysteine residues in CLIC2, equivalent to those that form the intramolecular disulfide in CLIC1, does not cause dimer formation under oxidizing conditions.We also show that CLIC2 forms pH-dependent chloride channels in vitro with higher channel activity at low pH levels and that the channels are subject to redox regulation. In both crystal forms, we observed an extended loop region from the C-terminal domain, called the foot loop, inserting itself into an interdomain crevice of a neighboring molecule. The equivalent region in the structurally related glutathione transferase superfamily corresponds to the active site. This so-called foot-in-mouth interaction suggests that CLIC2 might recognize other proteins such as the ryanodine receptor through a similar interaction

Potential health effects of dietary nitrate supplementation in aging and chronic degenerative disease

In the United States, latest projections indicate the number of adults 65 years of age and older is expected to double by 2050. Given that increased oxidative stress is a hallmark of aging, it is understandable that waning nitric oxide and chronic degenerative disease arise in tandem. To this end, translational evidence-based strategies are needed to mitigate the impending toll on personal and public health. Dietary nitrate supplementation, particularly in the form of beetroot juice, is an active area of inquiry that has gained considerable attention in recent years. Compelling evidence has revealed beetroot juice can elicit potent physiological responses that may offer associated health benefits for multiple clinical disorders including hypertension, dementia, and sarcopenia. Even in the absence of overt disease, age-related impairments in cardiovascular and skeletal muscle function may uniquely benefit from beetroot juice supplementation as evidence has shown blood pressure lowering effects and improved muscle function/contractility – presumably from increased nitric oxide bioavailability. This, in turn, presents a practical opportunity for susceptible populations to support ease of movement and exercise tolerance, both of which may promote free-living physical activity. A theoretical rationale details the potential health effects of dietary nitrate supplementation, wherein a working framework hypothesizes beetroot juice consumption prior to structured exercise training may offer synergistic benefits to aid healthy aging and independent-living among older adults

Bariatric Surgery–Induced Cardiac and Lipidomic Changes in Obesity‐Related Heart Failure with Preserved Ejection Fraction

Objective To determine the effects of gastric bypass on myocardial lipid deposition and function and the plasma lipidome in women with obesity and heart failure with preserved ejection fraction (HFpEF). Methods A primary cohort (N = 12) with HFpEF and obesity underwent echocardiography and magnetic resonance spectroscopy both before and 3 months and 6 months after bariatric surgery. Plasma lipidomic analysis was performed before surgery and 3 months after surgery in the primary cohort and were confirmed in a validation cohort (N = 22). Results After surgery‐induced weight loss, Minnesota Living with Heart Failure questionnaire scores, cardiac mass, and liver fat decreased (P < 0.02, P < 0.001, and P = 0.007, respectively); echo‐derived e′ increased (P = 0.03), but cardiac fat was unchanged. Although weight loss was associated with decreases in many plasma ceramide and sphingolipid species, plasma lipid and cardiac function changes did not correlate. Conclusions Surgery‐induced weight loss in women with HFpEF and obesity was associated with improved symptoms, reverse cardiac remodeling, and improved relaxation. Although weight loss was associated with plasma sphingolipidome changes, cardiac function improvement was not associated with lipidomic or myocardial triglyceride changes. The results of this study suggest that gastric bypass ameliorates obesity‐related HFpEF and that cardiac fat deposition and lipidomic changes may not be critical to its pathogenesis

Initiation of Dialysis Is Associated With Impaired Cardiovascular Functional Capacity

Background The transition to dialysis period carries a substantial increased cardiovascular risk in patients with chronic kidney disease. Despite this, alterations in cardiovascular functional capacity during this transition are largely unknown. The present study therefore sought to assess ventilatory exercise response measures in patients within 1 year of initiating dialysis. Methods and Results We conducted a cross‐sectional study of 241 patients with chronic kidney disease stage 5 from the CAPER (Cardiopulmonary Exercise Testing in Renal Failure) study and from the intradialytic low‐frequency electrical muscle stimulation pilot randomized controlled trial cohorts. Patients underwent cardiopulmonary exercise testing and echocardiography. Of the 241 patients (age, 48.9 [15.0] years; 154 [63.9%] men), 42 were predialytic (mean estimated glomerular filtration rate, 14 mL·min −1 ·1.73 m −2 ), 54 had a dialysis vintage ≤12 months, and 145 had a dialysis vintage &gt;12 months. Dialysis vintage ≤12 months exhibited a significantly impaired cardiovascular functional capacity, as assessed by oxygen uptake at peak exercise (18.7 [5.8] mL·min −1 ·kg −1 ) compared with predialysis (22.7 [5.2] mL·min −1 ·kg −1 ; P &lt;0.001). Dialysis vintage ≤12 months also exhibited reduced peak workload, impaired peak heart rate, reduced circulatory power, and increased left ventricular mass index ( P &lt;0.05 for all) compared with predialysis. After excluding those with prior kidney transplant, dialysis vintage &gt;12 months exhibited a lower oxygen uptake at peak exercise (17.0 [4.9] mL·min −1 ·kg −1 ) compared with dialysis vintage ≤12 months (18.9 [5.9] mL·min −1 ·kg −1 ; P =0.033). Conclusions Initiating dialysis is associated with a significant impairment in oxygen uptake at peak exercise and overall decrements in ventilatory and hemodynamic exercise responses that predispose patients to functional dependence. The magnitude of these changes is comparable to the differences between low‐risk New York Heart Association class I and higher‐risk New York Heart Association class II to IV heart failure