Bi-exponential modelling of $$W^{^{\prime}}$$ reconstitution kinetics in trained cyclists

Purpose The aim of this study was to investigate the individual $$W^{^{\prime}}$$ W ′ reconstitution kinetics of trained cyclists following repeated bouts of incremental ramp exercise, and to determine an optimal mathematical model to describe $$W^{^{\prime}}$$ W ′ reconstitution. Methods Ten trained cyclists (age 41 ± 10 years; mass 73.4 ± 9.9 kg; $$\dot{V}{\text{O}}_{2\max }$$ V ˙ O 2 max 58.6 ± 7.1 mL kg min−1) completed three incremental ramps (20 W min−1) to the limit of tolerance with varying recovery durations (15–360 s) on 5–9 occasions. $$W^{^{\prime}}$$ W ′ reconstitution was measured following the first and second recovery periods against which mono-exponential and bi-exponential models were compared with adjusted R2 and bias-corrected Akaike information criterion (AICc). Results A bi-exponential model outperformed the mono-exponential model of $$W^{^{\prime}}$$ W ′ reconstitution (AICc 30.2 versus 72.2), fitting group mean data well (adjR2 = 0.999) for the first recovery when optimised with parameters of fast component (FC) amplitude = 50.67%; slow component (SC) amplitude = 49.33%; time constant (τ)FC = 21.5 s; τSC = 388 s. Following the second recovery, W′ reconstitution reduced by 9.1 ± 7.3%, at 180 s and 8.2 ± 9.8% at 240 s resulting in an increase in the modelled τSC to 716 s with τFC unchanged. Individual bi-exponential models also fit well (adjR2 = 0.978 ± 0.017) with large individual parameter variations (FC amplitude 47.7 ± 17.8%; first recovery: (τ)FC = 22.0 ± 11.8 s; (τ)SC = 377 ± 100 s; second recovery: (τ)FC = 16.3.0 ± 6.6 s; (τ)SC = 549 ± 226 s). Conclusions W′ reconstitution kinetics were best described by a bi-exponential model consisting of distinct fast and slow phases. The amplitudes of the FC and SC remained unchanged with repeated bouts, with a slowing of W′ reconstitution confined to an increase in the time constant of the slow component.

Stochastic rectification of fast oscillations on slow manifold closures

The problems of identifying the slow component (e.g., for weather forecast initialization) and of characterizing slow–fast interactions are central to geophysical fluid dynamics. In this study, the related rectification problem of slow manifold closures is addressed when breakdown of slow-to-fast scales deterministic parameterizations occurs due to explosive emergence of fast oscillations on the slow, geostrophic motion. For such regimes, it is shown on the Lorenz 80 model that if 1) the underlying manifold provides a good approximation of the optimal nonlinear parameterization that averages out the fast variables and 2) the residual dynamics off this manifold is mainly orthogonal to it, then no memory terms are required in the Mori–Zwanzig full closure. Instead, the noise term is key to resolve, and is shown to be, in this case, well modeled by a state-independent noise, obtained by means of networks of stochastic nonlinear oscillators. This stochastic parameterization allows, in turn, for rectifying the momentum-balanced slow manifold, and for accurate recovery of the multiscale dynamics. The approach is promising to be further applied to the closure of other more complex slow–fast systems, in strongly coupled regimes.

Effect of channel assembly (KCNQ1 or KCNQ1 + KCNE1) on the response of zebrafish IKs to IKs inhibitors and activators

ABSTRACTIn cardiac myocytes, the slow component of the delayed rectifier K+ current (IKs) ensures repolarization of action potential during beta-adrenergic activation or when other repolarizing K+ currents fail. As a key factor of cardiac repolarization IKs should be present in model species used for cardiovascular drug screening, preferably with pharmacological characteristics similar to those of the human IKs. To this end, we investigated the effects of inhibitors and activators of the IKs on KCNQ1 and KCNQ1+KCNE1 channels of the zebrafish, an important model species, in Chinese hamster ovary cells. Inhibitors of IKs, chromanol 293B and HMR-1556, inhibited zebrafish IKs channels with approximately similar potency as that of mammalian IKs. Chromanol 293B concentration for half-maximal inhibition (IC50) of zebrafish IKs was at 13.1±5.8 and 13.4±2.8 μM for KCNQ1 and KCNQ1+KCNE1 channels, respectively. HMR-1556 was a more potent inhibitor of zebrafish IKs with IC50=0.1±0.1 μM and 1.5±0.8 μM for KCNQ1 and KCNQ1+KCNE1 channels, respectively. R-L3 and mefenamic acid, generally identified as IKs activators, both inhibited zebrafish IKs. R-L3 almost completely inhibited zebrafish IKs generated by KCNQ1 and KCNQ1+KCNE1 channels with similar affinity (IC50 1.1±0.4 and 1.0±0.4 μM, respectively). Mefenamic acid partially blocked zebrafish KCNQ1 (IC50=9.5±4.8 μM) and completely blocked KCNQ1+KCNE1 channels (IC50=3.3±1.8 μM). Although zebrafish IKs responds to IKs inhibitors in the same way as mammalian IKs, its response to activators is atypical, probably due to the differences in the binding domain of KCNE1 to KCNQ1. Therefore, care must be taken when translating the results from zebrafish to humans.

Effective Accentuation of Voltage-Gated Sodium Current Caused by Apocynin (4′-Hydroxy-3′-methoxyacetophenone), a Known NADPH-Oxidase Inhibitor

Apocynin (aPO, 4′-Hydroxy-3′-methoxyacetophenone) is a cell-permeable, anti-inflammatory phenolic compound that acts as an inhibitor of NADPH-dependent oxidase (NOX). However, the mechanisms through which aPO can interact directly with plasmalemmal ionic channels to perturb the amplitude or gating of ionic currents in excitable cells remain incompletely understood. Herein, we aimed to investigate any modifications of aPO on ionic currents in pituitary GH3 cells or murine HL-1 cardiomyocytes. In whole-cell current recordings, GH3-cell exposure to aPO effectively stimulated the peak and late components of voltage-gated Na+ current (INa) with different potencies. The EC50 value of aPO required for its differential increase in peak or late INa in GH3 cells was estimated to be 13.2 or 2.8 μM, respectively, whereas the KD value required for its retardation in the slow component of current inactivation was 3.4 μM. The current–voltage relation of INa was shifted slightly to more negative potential during cell exposure to aPO (10 μM); however, the steady-state inactivation curve of the current was shifted in a rightward direction in its presence. Recovery of peak INa inactivation was increased in the presence of 10 μM aPO. In continued presence of aPO, further application of rufinamide or ranolazine attenuated aPO-stimulated INa. In methylglyoxal- or superoxide dismutase-treated cells, the stimulatory effect of aPO on peak INa remained effective. By using upright isosceles-triangular ramp pulse of varying duration, the amplitude of persistent INa measured at low or high threshold was enhanced by the aPO presence, along with increased hysteretic strength appearing at low or high threshold. The addition of aPO (10 μM) mildly inhibited the amplitude of erg-mediated K+ current. Likewise, in HL-1 murine cardiomyocytes, the aPO presence increased the peak amplitude of INa as well as decreased the inactivation or deactivation rate of the current, and further addition of ranolazine or esaxerenone attenuated aPO-accentuated INa. Altogether, this study provides a distinctive yet unidentified finding that, despite its effectiveness in suppressing NOX activity, aPO may directly and concertedly perturb the amplitude, gating and voltage-dependent hysteresis of INa in electrically excitable cells. The interaction of aPO with ionic currents may, at least in part, contribute to the underlying mechanisms through which it affects neuroendocrine, endocrine or cardiac function.

Effects of Blood Flow Restriction on O2 Muscle Extraction and O2 Pulmonary Uptake Kinetics During Heavy Exercise

This study aimed to determine the effects of three levels of blood flow restriction (BFR) on V˙O2 and O2 extraction kinetics during heavy cycling exercise transitions. Twelve healthy trained males completed two bouts of 10 min heavy intensity exercise without BFR (CON), with 40% or 50% BFR (BFR40 and BFR50, respectively). V˙O2 and tissue saturation index (TSI) were continuously measured and modelled using multiexponential functions. The time constant of the V˙O2 primary phase was significantly slowed in BFR40 (26.4 ± 2.0s; p < 0.001) and BFR50 (27.1 ± 2.1s; p = 0.001) compared to CON (19.0 ± 1.1s). The amplitude of the V˙O2 slow component was significantly increased (p < 0.001) with BFR in a pressure-dependent manner 3.6 ± 0.7, 6.7 ± 0.9 and 9.7 ± 1.0 ml·min−1·kg−1 for CON, BFR40, and BFR50, respectively. While no acceleration of the primary component of the TSI kinetics was observed, there was an increase (p < 0.001) of the phase 3 amplitude with BFR (CON −0.8 ± 0.3% VS BFR40 −2.9 ± 0.9%, CON VS BFR50 −2.8 ± 0.8%). It may be speculated that BFR applied during cycling exercise in the heavy intensity domain shifted the working muscles to an O2 dependent situation. The acceleration of the extraction kinetics could have reached a plateau, hence not permitting compensation for the slowdown of the blood flow kinetics, and slowing V˙O2 kinetics.

Effective Perturbations of the Amplitude, Gating, and Hysteresis of IK(DR) Caused by PT-2385, an HIF-2α Inhibitor

PT-2385 is currently regarded as a potent and selective inhibitor of hypoxia-inducible factor-2α (HIF-2α), with potential antineoplastic activity. However, the membrane ion channels changed by this compound are obscure, although it is reasonable to assume that the compound might act on surface membrane before entering the cell´s interior. In this study, we intended to explore whether it and related compounds make any adjustments to the plasmalemmal ionic currents of pituitary tumor (GH3) cells and human 13-06-MG glioma cells. Cell exposure to PT-2385 suppressed the peak or late amplitude of delayed-rectifier K+ current (IK(DR)) in a time- and concentration-dependent manner, with IC50 values of 8.1 or 2.2 µM, respectively, while the KD value in PT-2385-induced shortening in the slow component of IK(DR) inactivation was estimated to be 2.9 µM. The PT-2385-mediated block of IK(DR) in GH3 cells was little-affected by the further application of diazoxide, cilostazol, or sorafenib. Increasing PT-2385 concentrations shifted the steady-state inactivation curve of IK(DR) towards a more hyperpolarized potential, with no change in the gating charge of the current, and also prolonged the time-dependent recovery of the IK(DR) block. The hysteretic strength of IK(DR) elicited by upright or inverted isosceles-triangular ramp voltage was decreased during exposure to PT-2385; meanwhile, the activation energy involved in the gating of IK(DR) elicitation was noticeably raised in its presence. Alternatively, the presence of PT-2385 in human 13-06-MG glioma cells effectively decreased the amplitude of IK(DR). Considering all of the experimental results together, the effects of PT-2385 on ionic currents demonstrated herein could be non-canonical and tend to be upstream of the inhibition of HIF-2α. This action therefore probably contributes to down-streaming mechanisms through the changes that it or other structurally resemblant compounds lead to in the perturbations of the functional activities of pituitary cells or neoplastic astrocytes, in the case that in vivo observations occur.

Decadal and Multidecadal Variability in ERSSTv5 Global SST During 1879-2018

Decadal and multi-decadal variability in the ERSSTv5 global SST dataset are studied in terms of implicit fast (noise) and slow (signal) processes that affect variability on decadal time scales. Using a new method that better estimates the fast, or noise, component of decadal variability, estimates of the modes of variability in the slow component are possible. The fast component of decadal variability has a leading fast mode, which explains 62% of the variance, and it is shown that this fast variability, or decadal climate noise, is well represented by any of the indices associated with intra-decadal or interannual variability in the tropical Pacific Ocean.Three slow modes are identified, representing 69% of the slow multi-decadal variance, after removing the radiative forcing trend. These modes are shown to be related to variability in the Atlantic Multi-decadal Oscillation (AMO), and SST multi-decadal variability in the Central Western Pacific and in the Indian Ocean gyre region, respectively. The first and third slow modes represent two phases of a propagating mode with a period of about 80 years. The second slow mode represents multi-decadal variability of the Western Pacific Warm Pool which is less robust than the other two and shown to be weakly related to the AMO with a lag of about 30 years; fast variability in this region is related to the leading fast mode. Three regions of significant slow variability are identified south of Australia, south of Africa and near the Drake Passage in association with the Antarctic Circumpolar Current.