ML277 specifically enhances the fully activated open state of KCNQ1 by modulating VSD-pore coupling

Upon membrane depolarization, the KCNQ1 potassium channel opens at the intermediate (IO) and activated (AO) states of the stepwise voltage-sensing domain (VSD) activation. In the heart, KCNQ1 associates with KCNE1 subunits to form

GBHT: Gradient Boosting Histogram Transform for Density Estimation

In this paper, we propose a density estimation algorithm called \textit{Gradient Boosting Histogram Transform} (GBHT), where we adopt the \textit{Negative Log Likelihood} as the loss function to make the boosting procedure available for the unsupervised tasks. From a learning theory viewpoint, we first prove fast convergence rates for GBHT with the smoothness assumption that the underlying density function lies in the space $C^{0,\alpha}$. Then when the target density function lies in spaces $C^{1,\alpha}$, we present an upper bound for GBHT which is smaller than the lower bound of its corresponding base learner, in the sense of convergence rates. To the best of our knowledge, we make the first attempt to theoretically explain why boosting can enhance the performance of its base learners for density estimation problems. In experiments, we not only conduct performance comparisons with the widely used KDE, but also apply GBHT to anomaly detection to showcase a further application of GBHT.Comment: Accepted to ICML2021. arXiv admin note: text overlap with arXiv:2106.0198

Effects of Multiple Metal Binding Sites on Calcium and Magnesium-dependent Activation of BK Channels

BK channels are activated by physiological concentrations of intracellular Ca2+ and Mg2+ in a variety of cells. Previous studies have identified two sites important for high-affinity Ca2+ sensing between [Ca2+]i of 0.1–100 μM and a site important for Mg2+ sensing between [Mg2+]i of 0.1–10 mM. BK channels can be also activated by Ca2+ and Mg2+ at concentrations >10 mM so that the steady-state conductance and voltage (G-V) relation continuously shifts to more negative voltage ranges when [Mg2+]i increases from 0.1–100 mM. We demonstrate that a novel site is responsible for metal sensing at concentrations ≥10 mM, and all four sites affect channel activation independently. As a result, the contributions of these sites to channel activation are complex, depending on the combination of Ca2+ and Mg2+ concentrations. Here we examined the effects of each of these sites on Ca2+ and Mg2+-dependent activation and the data are consistent with the suggestion that these sites are responsible for metal binding. We provide an allosteric model for quantitative estimation of the contributions that each of these putative binding sites makes to channel activation at any [Ca2+]i and [Mg2+]i

The NH2 Terminus of RCK1 Domain Regulates Ca2+-dependent BKCa Channel Gating

Large conductance, voltage- and Ca2+-activated K+ (BKCa) channels regulate blood vessel tone, synaptic transmission, and hearing owing to dual activation by membrane depolarization and intracellular Ca2+. Similar to an archeon Ca2+-activated K+ channel, MthK, each of four α subunits of BKCa may contain two cytosolic RCK domains and eight of which may form a gating ring. The structure of the MthK channel suggests that the RCK domains reorient with one another upon Ca2+ binding to change the gating ring conformation and open the activation gate. Here we report that the conformational changes of the NH2 terminus of RCK1 (AC region) modulate BKCa gating. Such modulation depends on Ca2+ occupancy and activation states, but is not directly related to the Ca2+ binding sites. These results demonstrate that AC region is important in the allosteric coupling between Ca2+ binding and channel opening. Thus, the conformational changes of the AC region within each RCK domain is likely to be an important step in addition to the reorientation of RCK domains leading to the opening of the BKCa activation gate. Our observations are consistent with a mechanism for Ca2+-dependent activation of BKCa channels such that the AC region inhibits channel activation when the channel is at the closed state in the absence of Ca2+; Ca2+ binding and depolarization relieve this inhibition

Ultrasound modulates ion channel currents

Transcranial focused ultrasound (US) has been demonstrated to stimulate neurons in animals and humans, but the mechanism of this effect is unknown. It has been hypothesized that US, a mechanical stimulus, may mediate cellular discharge by activating mechanosensitive ion channels embedded within cellular membranes. To test this hypothesis, we expressed potassium and sodium mechanosensitive ion channels (channels of the two-pore-domain potassium family (K2P) including TREK-1, TREK-2, TRAAK; Na(V)1.5) in the Xenopus oocyte system. Focused US (10 MHz, 0.3–4.9 W/cm(2)) modulated the currents flowing through the ion channels on average by up to 23%, depending on channel and stimulus intensity. The effects were reversible upon repeated stimulation and were abolished when a channel blocker (ranolazine to block Na(V)1.5, BaCl(2) to block K2P channels) was applied to the solution. These data reveal at the single cell level that focused US modulates the activity of specific ion channels to mediate transmembrane currents. These findings open doors to investigations of the effects of  US on ion channels expressed in neurons, retinal cells, or cardiac cells, which may lead to important medical applications. The findings may also pave the way to the development of sonogenetics: a non-invasive, US-based analogue of optogenetics

Enhancing ocean environment prediction in Yellow Sea through targeted observation using ocean acoustic tomography

Ocean Acoustic Tomography (OAT) is an efficient and economical marine acoustic observation technique. Targeted observation is an appealing procedure to reduce the uncertainty of ocean environment prediction through additional observation. This study aimed to assess the validity of OAT as an observation method for targeted observation. OAT based on Niche Genetic Algorithm was employed to extract sound speed and temperature profiles from acoustic transmission time, utilizing data from the 2019 Yellow Sea experiment. The inversion results were compared with measurement data, which are found to be accurate and reliable. To further evaluate OAT as targeted observation method, the vertical bias structure of OAT was added on synchronous measurement data in the sensitive area of targeted observation to simulate OAT observation in sensitive area. This simulated data was then incorporated into a 3D-Var assimilation system to improve the short-term prediction of the target region. Comparing the predictions derived with the measurement data at the verification time, it shows that the simulated OAT observation improved the quality of target region prediction, indicating that OAT can be an effective observation method for targeted observation. An Observing System Simulation Experiment was conducted to assess the impact of OAT characteristics on prediction improvement. The results show that both adding observation nodes and extending the observation duration have positive effects, while extending the observation duration performs better

Intelligence of Astronomical Optical Telescope: Present Status and Future Perspectives

Artificial intelligence technology has been widely used in astronomy, and new artificial intelligence technologies and application scenarios are constantly emerging. There have been a large number of papers reviewing the application of artificial intelligence technology in astronomy. However, relevant articles seldom mention telescope intelligence separately, and it is difficult to understand the current development status and research hotspots of telescope intelligence from these papers. This paper combines the development history of artificial intelligence technology and the difficulties of critical technologies of telescopes, comprehensively introduces the development and research hotspots of telescope intelligence, then conducts statistical analysis on various research directions of telescope intelligence and defines the research directions' merits. All kinds of research directions are evaluated, and the research trend of each telescope's intelligence is pointed out. Finally, according to the advantages of artificial intelligence technology and the development trend of telescopes, future research hotspots of telescope intelligence are given.Comment: 19 pages, 6 figure, for questions or comments, please email [email protected]

Calmodulin acts as a state-dependent switch to control a cardiac potassium channel opening

Calmodulin (CaM) and phosphatidylinositol 4,5-bisphosphate (PI