Differential lipid dependence of function of bacterial sodium channel homologues

The lipid bilayer is important for maintaining the integrity of cellular compartments and plays a vital role in maintaining the hydrophobic/charged interactions necessary for structure, conformational flexibility and function. Despite the intimate relationship between ion channels and the membranes in which they are embedded, challenges resulting from the dynamic and complex nature of cellular membranes have limited our ability to address the functional role of these interactions. To directly assess lipid dependence of activity, we examined channel function ofthree purified bacterial sodium channel orthologues (NaChBac, NavMs, and NavSp) by cumulative 22Na+ uptake into proteoliposomes containing a 3:1 ratio of POPE and another glycerophospholipid (POPC, POPG, POPS, Cardiolipin (CL), POPA, or PI). We observed a unique lipid dependence for each homologue tested. Common to each was a low level of activity above background (uptake into protein free liposomes) when the second lipid was a zwitterionic lipid such as POPE and POPC. Maximal activity for full-length NaChBac and NavMs proteins was observed in POPE + POPG liposomes. On the other hand, full-length NavSp channels possessed a different lipid dependence, with maximal activity in liposomes containing POPE + PI. No strong lipid dependence was observed for pore-only constructs of NavMs or NavSp, that lacked the S1-S4 segments, suggesting that the lipid dependence of sodium channels may arise from their abilities to affect the voltage-sensing domains. The effect may be maximized by specific lipid-protein interactions that are uniquely favourable in each homologue, giving rise to differing lipid dependences

Frail young adult cancer survivors experience poor health-related quality of life

Background: Young adult cancer survivors experience frailty and decreased muscle mass at rates equivalent to much older noncancer populations, which indicate accelerated aging. Although frailty and low muscle mass can be identified in survivors, their implications for health-related quality of life are not well understood. Methods: Through a cross-sectional analysis of young adult cancer survivors, frailty was assessed with the Fried frailty phenotype and skeletal muscle mass in relation to functional and quality of life outcomes measured by the Medical Outcomes Survey Short-Form 36 (SF-36). z tests compared survivors with US population means, and multivariable linear regression models estimated mean SF-36 scores by frailty and muscle mass with adjustments made for comorbidities, sex, and time from treatment. Results: Sixty survivors (median age, 21 years; range, 18-29) participated in the study. Twenty-five (42%) had low muscle mass, and 25 were either frail or prefrail. Compared with US population means, survivors reported worse health and functional impairments across SF-36 domains that were more common among survivors with (pre)frailty or low muscle mass. In multivariable linear modeling, (pre)frail survivors (vs nonfrail) exhibited lower mean scores for general health (−9.1; P =.05), physical function (−14.9; P <.01), and overall physical health (−5.6; P =.02) independent of comorbid conditions. Conclusions: Measures of frailty and skeletal muscle mass identify subgroups of young adult cancer survivors with significantly impaired health, functional status, and quality of life independent of medical comorbidities. Identifying survivors with frailty or low muscle mass may provide opportunities for interventions to prevent functional and health declines or to reverse this process. Lay Summary: Young adult cancer survivors age more quickly than peers without cancer, which is evidenced by a syndrome of decreased resilience known as frailty. The relationship between frailty (and one of its common components, decreased muscle mass) and quality of life among young adult cancer survivors was examined. Measuring decreased muscle mass and frailty identifies young survivors with poor quality of life, including worse general health, fatigue, physical function, and overall physical health, compared with nonfrail survivors. Interventions to address components of frailty (low muscle mass and weakness) may improve function and quality of life among young adult cancer survivors

Arrhythmogenic mechanisms in the isolated perfused hypokalaemic murine heart

AIM: Hypokalaemia is associated with a lethal form of ventricular tachycardia (VT), torsade de pointes, through pathophysiological mechanisms requiring clarification. METHODS: Left ventricular endocardial and epicardial monophasic action potentials were compared in isolated mouse hearts paced from the right ventricular epicardium perfused with hypokalaemic (3 and 4 mm [K(+)](o)) solutions. Corresponding K(+) currents were compared in whole-cell patch-clamped epicardial and endocardial myocytes. RESULTS: Hypokalaemia prolonged epicardial action potential durations (APD) from mean APD(90)s of 37.2 ± 1.7 ms (n = 7) to 58.4 ± 4.1 ms (n =7) and 66.7 ± 2.1 ms (n = 11) at 5.2, 4 and 3 mm [K(+)](o) respectively. Endocardial APD(90)s correspondingly increased from 51.6 ± 1.9 ms (n = 7) to 62.8 ± 2.8 ms (n = 7) and 62.9 ± 5.9 ms (n = 11) giving reductions in endocardial–epicardial differences, ΔAPD(90), from 14.4 ± 2.6 to 4.4 ± 5.0 and −3.4 ± 6.0 ms respectively. Early afterdepolarizations (EADs) occurred in epicardia in three of seven spontaneously beating hearts at 4 mm [K(+)](o) with triggered beats followed by episodes of non-sustained VT in nine of 11 preparations at 3 mm. Programmed electrical stimulation never induced arrhythmic events in preparations perfused with normokalemic solutions yet induced VT in two of seven and nine of 11 preparations at 4 and 3 mm [K(+)](o) respectively. Early outward K(+) current correspondingly fell from 73.46 ± 8.45 to 61.16±6.14 pA/pF in isolated epicardial but not endocardial myocytes (n = 9) (3 mm [K(+)](o)). CONCLUSIONS: Hypokalaemic mouse hearts recapitulate the clinical arrhythmogenic phenotype, demonstrating EADs and triggered beats that might initiate VT on the one hand and reduced transmural dispersion of repolarization reflected in ΔAPD(90) suggesting arrhythmogenic substrate on the other

Pion contamination in the MICE muon beam

The international Muon Ionization Cooling Experiment (MICE) will perform a systematic investigation of ionization cooling with muon beams of momentum between 140 and 240\,MeV/c at the Rutherford Appleton Laboratory ISIS facility. The measurement of ionization cooling in MICE relies on the selection of a pure sample of muons that traverse the experiment. To make this selection, the MICE Muon Beam is designed to deliver a beam of muons with less than $\sim$1\% contamination. To make the final muon selection, MICE employs a particle-identification (PID) system upstream and downstream of the cooling cell. The PID system includes time-of-flight hodoscopes, threshold-Cherenkov counters and calorimetry. The upper limit for the pion contamination measured in this paper is $f_\pi < 1.4\%$ at 90\% C.L., including systematic uncertainties. Therefore, the MICE Muon Beam is able to meet the stringent pion-contamination requirements of the study of ionization cooling.Department of Energy and National Science Foundation (U.S.A.), the Instituto Nazionale di Fisica Nucleare (Italy), the Science and Technology Facilities Council (U.K.), the European Community under the European Commission Framework Programme 7 (AIDA project, grant agreement no. 262025, TIARA project, grant agreement no. 261905, and EuCARD), the Japan Society for the Promotion of Science and the Swiss National Science Foundation, in the framework of the SCOPES programme

Erratum: "A Gravitational-wave Measurement of the Hubble Constant Following the Second Observing Run of Advanced LIGO and Virgo" (2021, ApJ, 909, 218)

[no abstract available