Physiological effects of different oxygen flow rates and ambient temperatures on pressure-suited subjects performing work at altitude

Physiological effects of oxygen flow rates and ambient temperatures on pressure-suited subjects performing work in altitude chambe

Using Group Model Building to Understand Factors That Influence Childhood Obesity in an Urban Environment

Background: Despite increased attention, conventional views of obesity are based upon individual behaviors, and children and parents living with obesity are assumed to be the primary problem solvers. Instead of focusing exclusively on individual reduction behaviors for childhood obesity, greater focus should be placed on better understanding existing community systems and their effects on obesity. The Milwaukee Childhood Obesity Prevention Project is a community-based coalition established to develop policy and environmental change strategies to impact childhood obesity in Milwaukee, Wisconsin. The coalition conducted a Group Model Building exercise to better understand root causes of childhood obesity in its community. Methods: Group Model Building is a process by which a group systematically engages in model construction to better understand the systems that are in place. It helps participants make their mental models explicit through a careful and consistent process to test assumptions. This process has 3 main components: (1) assembling a team of participants; (2) conducting a behavior-over-time graphs exercise; and (3) drawing the causal loop diagram exercise. Results: The behavior-over-time graph portion produced 61 graphs in 10 categories. The causal loop diagram yielded 5 major themes and 7 subthemes. Conclusions: Factors that influence childhood obesity are varied, and it is important to recognize that no single solution exists. The perspectives from this exercise provided a means to create a process for dialogue and commitment by stakeholders and partnerships to build capacity for change within the community

Mg2+ binding to open and closed states can activate BK channels provided that the voltage sensors are elevated

BK channels are activated by intracellular Ca2+ and Mg2+ as well as by depolarization. Such activation is possible because each of the four subunits has two high-affinity Ca2+ sites, one low-affinity Mg2+ site, and a voltage sensor. This study further investigates the mechanism of Mg2+ activation by using single-channel recording to determine separately the action of Mg2+ on the open and closed states of the channel. To limit Mg2+ action to the Mg2+ sites, the two high-affinity Ca2+ sites are disabled by mutation. When the voltage is stepped from negative holding potentials to +100 mV, we find that 10 mM Mg2+ decreases the mean closed latency to the first channel opening 2.1-fold, decreases the mean closed interval duration 8.7-fold, increases mean burst duration 10.1-fold, increases the number of openings per burst 4.4-fold, and increases mean open interval duration 2.3-fold. Hence, Mg2+ can bind to closed BK channels, increasing their opening rates, and to open BK channels, decreasing their closing rates. To explore the relationship between Mg2+ action and voltage sensor activation, we record single-channel activity in macropatches containing hundreds of channels. Open probability (Po) is dramatically increased by 10 mM Mg2+ when voltage sensors are activated with either depolarization or the mutation R210C. The increased Po arises from large decreases in mean closed interval durations and moderate increases in mean open interval durations. In contrast, 10 mM Mg2+ has no detectable effects on Po or interval durations when voltage sensors are deactivated with very negative potentials or the mutation R167E. These observations are consistent with a model in which Mg2+ can bind to and alter the gating of both closed and open states to increase Po, provided that one or more voltage sensors are activated

Population pharmacokinetics of NNZ-2566 in healthy subjects

NNZ-2566 is a novel, small molecule being developed as a treatment for cognitive impairment in different CNS conditions, including Rett and Fragile-X syndrome, both of which are associated with moderate to severe neurodevelopmental disorder. In current study we characterise the population pharmacokinetics of NNZ-2566 after administration of single and repeated ascending doses to healthy subjects. A meta-analytical approach was used to analyse pharmacokinetic data from 3 different studies, in which a total of 61 healthy subjects (median age 23years, range 19 to 38) were treated with NNZ-2566. Doses of NNZ-2566 ranged from 6.0 to 100mg/kg after oral administration and from 0.1 to 30mg/kg after intravenous administration. A two-compartment model with first order absorption and elimination was found to best describe the pharmacokinetics of NNZ-2566. Inter-individual variability was identified in clearance, absorption rate, central volume of distribution, peripheral volume of distribution and inter-compartmental clearance. Population predicted clearance and central volume of distribution were 10.35L/h and 20.23L, respectively. No accumulation, metabolic inhibition or induction was observed during the course of treatment. Dose proportionality was observed across the dose range evaluated in healthy subjects. In addition, oral bioavailability appeared to vary with food intake. The relatively short half-life of 1.4h suggests the need for a twice or three times daily regimen to maintain relevant systemic levels of NNZ-2566 in plasma

Deletion of cytosolic gating ring decreases gate and voltage sensor coupling in BK channels

Large conductance Ca(2+)-activated K(+) channels (BK channels) gate open in response to both membrane voltage and intracellular Ca(2+). The channel is formed by a central pore-gate domain (PGD), which spans the membrane, plus transmembrane voltage sensors and a cytoplasmic gating ring that acts as a Ca(2+) sensor. How these voltage and Ca(2+) sensors influence the common activation gate, and interact with each other, is unclear. A previous study showed that a BK channel core lacking the entire cytoplasmic gating ring (Core-MT) was devoid of Ca(2+) activation but retained voltage sensitivity (Budelli et al. 2013. Proc. Natl. Acad. Sci. USA. http://dx.doi.org/10.1073/pnas.1313433110). In this study, we measure voltage sensor activation and pore opening in this Core-MT channel over a wide range of voltages. We record gating currents and find that voltage sensor activation in this truncated channel is similar to WT but that the coupling between voltage sensor activation and gating of the pore is reduced. These results suggest that the gating ring, in addition to being the Ca(2+) sensor, enhances the effective coupling between voltage sensors and the PGD. We also find that removal of the gating ring alters modulation of the channels by the BK channel’s β1 and β2 subunits

Coupling and cooperativity in voltage activation of a limited-state BK channel gating in saturating Ca2+

Voltage-dependent gating mechanisms of large conductance Ca2+ and voltage-activated (BK) channels were investigated using two-dimensional maximum likelihood analysis of single-channel open and closed intervals. To obtain sufficient data at negative as well as positive voltages, single-channel currents were recorded at saturating Ca2+ from BK channels mutated to remove the RCK1 Ca2+ and Mg2+ sensors. The saturating Ca2+ acting on the Ca2+ bowl sensors of the resulting BKB channels increased channel activity while driving the gating into a reduced number of states, simplifying the model. Five highly constrained idealized gating mechanisms based on extensions of the Monod-Wyman-Changeux model for allosteric proteins were examined. A 10-state model without coupling between the voltage sensors and the opening/closing transitions partially described the voltage dependence of Po but not the single-channel kinetics. With allowed coupling, the model gave improved descriptions of Po and approximated the single-channel kinetics; each activated voltage sensor increased the opening rate approximately an additional 23-fold while having little effect on the closing rate. Allowing cooperativity among voltage sensors further improved the description of the data: each activated voltage sensor increased the activation rate of the remaining voltage sensors approximately fourfold, with little effect on the deactivation rate. The coupling factor was decreased in models with cooperativity from ∼23 to ∼18. Whether the apparent cooperativity among voltage sensors arises from imposing highly idealized models or from actual cooperativity will require additional studies to resolve. For both cooperative and noncooperative models, allowing transitions to five additional brief (flicker) closed states further improved the description of the data. These observations show that the voltage-dependent single-channel kinetics of BKB channels can be approximated by highly idealized allosteric models in which voltage sensor movement increases Po mainly through an increase in channel opening rates, with limited effects on closing rates

Comparable patencies of the radial artery and right internal thoracic artery or saphenous vein beyond 5 years: Results from the Radial Artery Patency and Clinical Outcomes trial

ObjectiveTo investigate the optimum conduit for coronary targets other than the left anterior descending artery, we evaluated long-term patencies and clinical outcomes of the radial artery, right internal thoracic artery, and saphenous vein through the Radial Artery Patency and Clinical Outcomes trial.MethodsAs part of a 10-year prospective, randomized, single-center trial, patients undergoing primary coronary surgery were allocated to the radial artery (n = 198) or free right internal thoracic artery (n = 196) if aged less than 70 years (group 1), or radial artery (n = 113) or saphenous vein (n = 112) if aged at least 70 years (group 2). All patients received a left internal thoracic artery to the left anterior descending, and the randomized conduit was used to graft the second largest target. Protocol-directed angiography has been performed at randomly assigned intervals, weighted toward the end of the study period. Grafts are defined as failed if there was occlusion, string sign, or greater than 80% stenosis, independently reported by 3 assessors. Analysis is by intention to treat.ResultsAt mean follow up of 5.5 years, protocol angiography has been performed in groups 1 and 2 in 237 and 113 patients, respectively. There are no significant differences within each group in preoperative comorbidity, age, or urgency. Patencies were similar for either of the 2 conduits in each group (log rank analysis, P = .06 and P = .54, respectively). The differences in estimated 5-year patencies were 6.6% (radial minus right internal thoracic artery) in group 1 and 2.9% (radial minus saphenous vein graft) in group 2.ConclusionAt mean 5-year angiography in largely asymptomatic patients, the selection of arterial or venous conduit for the second graft has not significantly affected patency. This finding offers surgeons, for now, enhanced flexibility in planning revascularization

Global oceanic production of nitrous oxide

We use transient time distributions calculated from tracer data together with in situ measurements of nitrous oxide (N2O) to estimate the concentration of biologically produced N2O and N2O production rates in the ocean on a global scale. Our approach to estimate the N2O production rates integrates the effects of potentially varying production and decomposition mechanisms along the transport path of a water mass.We estimate that the oceanic N2O production is dominated by nitrification with a contribution of only approximately 7 per cent by denitrification. This indicates that previously used approaches have overestimated the contribution by denitrification. Shelf areas may account for only a negligible fraction of the global production; however, estuarine sources and coastal upwelling of N2O are not taken into account in our study. The largest amount of subsurface N2O is produced in the upper 500 m of the water column. The estimated global annual subsurface N2O production ranges from 3.1+/-0.9 to 3.4+/-0.9 Tg N yr^-1. This is in agreement with estimates of the global N2O emissions to the atmosphere and indicates that a N2O source in the mixed layer is unlikely. The potential future development of the oceanic N2O source in view of the ongoing changes of the ocean environment (deoxygenation, warming, eutrophication and acidification) is discussed