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1
Gabriel, S. E., E. M. Price, R. C. Boucher i M. J. Stutts. "Small linear chloride channels are endogenous to nonepithelial cells". American Journal of Physiology-Cell Physiology 263, nr 3 (1.09.1992): C708—C713. http://dx.doi.org/10.1152/ajpcell.1992.263.3.c708.
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We used both single-channel and whole cell patch-clamp techniques to characterize chloride channels and currents endogenous to Sf9 cells, 3T3 fibroblasts, and Chinese hamster ovary cells. In cell-attached patches from these cell types, anion channels were observed with low ohmic conductance (4-11 ps), linear current-voltage relationships, and little time- or voltage-dependent behavior. These channels are very similar to the Cl- channels reported to appear concomitant with the expression of cystic fibrosis transmembrane conductance regulator (CFTR) in these cell lines. The presence of such endogenous channels suggests either that low levels of CFTR are present in all of these cell lines prior to transfection or that an endogenous non-CFTR channel is present in these cell types. Our results suggest that at least some of the channel behaviors attributed to expressed, recombinant CFTR in previous studies may have been due to these endogenous Cl- channels.
2
Tu, Wanzhu, i J. Howard Pratt. "Small Potassium Channels". Hypertension 68, nr 3 (wrzesień 2016): 542–43. http://dx.doi.org/10.1161/hypertensionaha.116.07938.
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Oh, Y., i D. J. Benos. "Single-channel characteristics of a purified bovine renal amiloride-sensitive Na+ channel in planar lipid bilayers". American Journal of Physiology-Cell Physiology 264, nr 6 (1.06.1993): C1489—C1499. http://dx.doi.org/10.1152/ajpcell.1993.264.6.c1489.
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We have purified an amiloride-inhibitable Na+ channel protein from bovine renal papillae using ion-exchange and immunoaffinity chromatography. In the present study, these purified Na+ channels were reconstituted into planar lipid bilayers, and their single-channel characteristics were studied. We observed both large- and small-conductance Na(+)-selective ion channels in planar lipid bilayers. Single-channel conductance for the large- and small-conductance channels saturated as a function of Na+ concentration. These relations could be fitted by a simple Langmuir isotherm with a Michaelis constant of 55 and 45 mM and a maximum open-state conductance of 56 or 8.4 pS, respectively. Both channels were perfectly cation selective, with a Na(+)-to-K+ permeability ratio of 6.7:1 for the large channel and 7.8:1 for the small channel, and their open single-channel current-voltage relations were linear when bathed with symmetrical Na+ solutions. The percent open time of the reconstituted large or small channels varied between 10 and 50% or 1 and 20%, respectively. After application of amiloride, both the large- and small-conductance Na+ channels were inhibited in a dose-dependent manner.
4
Brown, Brandon M., Heesung Shim, Palle Christophersen i Heike Wulff. "Pharmacology of Small- and Intermediate-Conductance Calcium-Activated Potassium Channels". Annual Review of Pharmacology and Toxicology 60, nr 1 (6.01.2020): 219–40. http://dx.doi.org/10.1146/annurev-pharmtox-010919-023420.
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The three small-conductance calcium-activated potassium (KCa2) channels and the related intermediate-conductance KCa3.1 channel are voltage-independent K+ channels that mediate calcium-induced membrane hyperpolarization. When intracellular calcium increases in the channel vicinity, it calcifies the flexible N lobe of the channel-bound calmodulin, which then swings over to the S4-S5 linker and opens the channel. KCa2 and KCa3.1 channels are highly druggable and offer multiple binding sites for venom peptides and small-molecule blockers as well as for positive- and negative-gating modulators. In this review, we briefly summarize the physiological role of KCa channels and then discuss the pharmacophores and the mechanism of action of the most commonly used peptidic and small-molecule KCa2 and KCa3.1 modulators. Finally, we describe the progress that has been made in advancing KCa3.1 blockers and KCa2.2 negative- and positive-gating modulators toward the clinic for neurological and cardiovascular diseases and discuss the remaining challenges.
5
Zhang, Xiao-Dong, Phung N. Thai, Deborah K. Lieu i Nipavan Chiamvimonvat. "Cardiac small-conductance calcium-activated potassium channels in health and disease". Pflügers Archiv - European Journal of Physiology 473, nr 3 (23.02.2021): 477–89. http://dx.doi.org/10.1007/s00424-021-02535-0.
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AbstractSmall-conductance Ca2+-activated K+ (SK, KCa2) channels are encoded by KCNN genes, including KCNN1, 2, and 3. The channels play critical roles in the regulation of cardiac excitability and are gated solely by beat-to-beat changes in intracellular Ca2+. The family of SK channels consists of three members with differential sensitivity to apamin. All three isoforms are expressed in human hearts. Studies over the past two decades have provided evidence to substantiate the pivotal roles of SK channels, not only in healthy heart but also with diseases including atrial fibrillation (AF), ventricular arrhythmia, and heart failure (HF). SK channels are prominently expressed in atrial myocytes and pacemaking cells, compared to ventricular cells. However, the channels are significantly upregulated in ventricular myocytes in HF and pulmonary veins in AF models. Interests in cardiac SK channels are further fueled by recent studies suggesting the possible roles of SK channels in human AF. Therefore, SK channel may represent a novel therapeutic target for atrial arrhythmias. Furthermore, SK channel function is significantly altered by human calmodulin (CaM) mutations, linked to life-threatening arrhythmia syndromes. The current review will summarize recent progress in our understanding of cardiac SK channels and the roles of SK channels in the heart in health and disease.
6
Han, Ye, Kyle Lyman, Matt Clutter, Gary E. Schiltz, Quratul-Ain Ismail, Diego Bleifuss Prados, Chi-Hao Luan i Dane M. Chetkovich. "Identification of Small-Molecule Inhibitors of Hyperpolarization-Activated Cyclic Nucleotide–Gated Channels". Journal of Biomolecular Screening 20, nr 9 (4.06.2015): 1124–31. http://dx.doi.org/10.1177/1087057115589590.
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Hyperpolarization-activated cyclic nucleotide–gated (HCN) channels function in the brain to limit neuronal excitability. Limiting the activity of these channels has been proposed as a therapy for major depressive disorder, but the critical role of HCN channels in cardiac pacemaking has limited efforts to develop therapies directed at the channel. Previous studies indicated that the function of HCN is tightly regulated by its auxiliary subunit, tetratricopeptide repeat–containing Rab8b interacting protein (TRIP8b), which is not expressed in the heart. To target the function of the HCN channel in the brain without affecting the channel’s function in the heart, we propose disrupting the interaction between HCN and TRIP8b. We developed a high-throughput fluorescence polarization (FP) assay to identify small molecules capable of disrupting this interaction. We used this FP assay to screen a 20,000-compound library and identified a number of active compounds. The active compounds were validated using an orthogonal AlphaScreen assay to identify one compound (0.005%) as the first confirmed hit for inhibiting the HCN-TRIP8b interaction. Identifying small molecules capable of disrupting the interaction between HCN and TRIP8b should enable the development of new research tools and small-molecule therapies that could benefit patients with depression.
7
Bruening-Wright, Andrew, Wei-Sheng Lee, John P. Adelman i James Maylie. "Evidence for a Deep Pore Activation Gate in Small Conductance Ca2+-activated K+ Channels". Journal of General Physiology 130, nr 6 (12.11.2007): 601–10. http://dx.doi.org/10.1085/jgp.200709828.
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Small conductance calcium-gated potassium (SK) channels share an overall topology with voltage-gated potassium (Kv) channels, but are distinct in that they are gated solely by calcium (Ca2+), not voltage. For Kv channels there is strong evidence for an activation gate at the intracellular end of the pore, which was not revealed by substituted cysteine accessibility of the homologous region in SK2 channels. In this study, the divalent ions cadmium (Cd2+) and barium (Ba2+), and 2-aminoethyl methanethiosulfonate (MTSEA) were used to probe three sites in the SK2 channel pore, each intracellular to (on the selectivity filter side of) the region that forms the intracellular activation gate of voltage-gated ion channels. We report that Cd2+ applied to the intracellular side of the membrane can modify a cysteine introduced to a site (V391C) just intracellular to the putative activation gate whether channels are open or closed. Similarly, MTSEA applied to the intracellular side of the membrane can access a cysteine residue (A384C) that, based on homology to potassium (K) channel crystal structures (i.e., the KcsA/MthK model), resides one amino acid intracellular to the glycine gating hinge. Cd2+ and MTSEA modify with similar rates whether the channels are open or closed. In contrast, Ba2+ applied to the intracellular side of the membrane, which is believed to block at the intracellular end of the selectivity filter, blocks open but not closed channels when applied to the cytoplasmic face of rSK2 channels. Moreover, Ba2+ is trapped in SK2 channels when applied to open channels that are subsequently closed. Ba2+ pre-block slows MTSEA modification of A384C in open but not in closed (Ba2+-trapped) channels. The findings suggest that the SK channel activation gate resides deep in the vestibule of the channel, perhaps in the selectivity filter itself.
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Potts, Donald F., i Bruce K. M. Anderson. "Organic Debris and the Management of Small Stream Channels". Western Journal of Applied Forestry 5, nr 1 (1.01.1990): 25–28. http://dx.doi.org/10.1093/wjaf/5.1.25.
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Abstract Longitudinal profiles, riparian and in-channel debris loads, and sediment storage were measured in eight reaches of first- to third-order, snowmelt-dominated, intermittent, and perennial streams in western Montana. Low-order channels tended to concentrate debris. Organic matter providedover 60% of total sediment storage in all study reaches. We suggest that Streamside Management Zones (SMZs) be extended to include intermittent channels and possibly the lowest portions of ephemeral channels in anticipation of their activation. Predisturbance appraisal of downed woody fuelsin these SMZs is recommended to provide a target debris loading during site preparation, thus ensuring a steady-state supply of organic materials to maintain channel stabdity following timber harvest. West. J. Appl. For. 5(1):25-28.
9
LeRoux, M. N., T. M. Schmit, M. Roth i D. H. Streeter. "Evaluating marketing channel options for small-scale fruit and vegetable producers". Renewable Agriculture and Food Systems 25, nr 1 (15.01.2010): 16–23. http://dx.doi.org/10.1017/s1742170509990275.
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AbstractAn analytical framework and ranking system is developed to summarize the primary factors affecting marketing channel performance and to prioritize those channels with the greatest opportunity for success. An application of the model is conducted using case-study evidence from four small-scale diversified vegetable crop producers in Central New York. The relative costs and benefits of alternative wholesale and direct marketing channels are investigated, including how the factors of risk, owner and paid labor, profits, lifestyle preferences and sales volume interact to impact optimal market channel selection. Given the highly perishable nature of the crops grown, along with the risks and potential sales volume of particular channels, a combination of different marketing channels is needed to maximize overall firm performance.
10
Wells, William. "Big DNA, small channels". Genome Biology 1 (2000): spotlight—20000516–02. http://dx.doi.org/10.1186/gb-spotlight-20000516-02.
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Orfali, Razan, Ali AlFaiz, Mohammad Asikur Rahman, Liz Lau, Young-Woo Nam i Miao Zhang. "KCa2 and KCa3.1 Channels in the Airways: A New Therapeutic Target". Biomedicines 11, nr 7 (21.06.2023): 1780. http://dx.doi.org/10.3390/biomedicines11071780.
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K+ channels are involved in many critical functions in lung physiology. Recently, the family of Ca2+-activated K+ channels (KCa) has received more attention, and a massive amount of effort has been devoted to developing selective medications targeting these channels. Within the family of KCa channels, three small-conductance Ca2+-activated K+ (KCa2) channel subtypes, together with the intermediate-conductance KCa3.1 channel, are voltage-independent K+ channels, and they mediate Ca2+-induced membrane hyperpolarization. Many KCa2 channel members are involved in crucial roles in physiological and pathological systems throughout the body. In this article, different subtypes of KCa2 and KCa3.1 channels and their functions in respiratory diseases are discussed. Additionally, the pharmacology of the KCa2 and KCa3.1 channels and the link between these channels and respiratory ciliary regulations will be explained in more detail. In the future, specific modulators for small or intermediate Ca2+-activated K+ channels may offer a unique therapeutic opportunity to treat muco-obstructive lung diseases.
12
Belozerov, Vladimir I., i Aleksandr S. Gorbach. "Investigation of the critical heat flux in small-diameter channels". Nuclear Energy and Technology 7, nr 1 (30.03.2021): 73–78. http://dx.doi.org/10.3897/nucet.7.65754.
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The paper describes experimental studies into the hydrodynamics and heat exchange in a forced water flow in small-diameter channels at low pressures. The timeliness of the studies has been defined by the growing interest in small-size heat exchangers. Small-diameter channels are actively used in components of compact heat exchangers for present-day engineering development applications. The major difficulty involved in investigation of heat-transfer processes in small-diameter channels consists in the absence of common methodologies to calculate coefficients of hydraulic resistance and heat transfer in a two-phase flow. The channel size influences the heat exchange and hydrodynamics of a two-phase flow as one of the determining parameters since the existing internal scales (vapor bubble size, liquid droplet diameter, film thickness) may become commensurable with the channel diameter, this leading potentially to different flow conditions. It is evident that one cannot justifiably expect a change in the momentum and energy transfer regularities in single-phase flows as the channel size is reduced for as long as the continuum approximation remains valid. The authors have analyzed the experiments undertaken by Russian scientists to investigate the distribution of thermal-hydraulic parameters in channels with a small cross-section in the entire variation range of the flow parameters in the channel up to the critical heat flux conditions when the wall temperature increases sharply as the thermal load grows slowly. The experimental critical heat flux data obtained by Russian and foreign authors has been compared.
13
Wu, Wei, Frank B. Sachse, Alison Gardner i Michael C. Sanguinetti. "Stoichiometry of altered hERG1 channel gating by small molecule activators". Journal of General Physiology 143, nr 4 (17.03.2014): 499–512. http://dx.doi.org/10.1085/jgp.201311038.
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Voltage-gated K+ channels are tetramers formed by coassembly of four identical or highly related subunits. All four subunits contribute to formation of the selectivity filter, the narrowest region of the channel pore which determines K+ selective conductance. In some K+ channels, the selectivity filter can undergo a conformational change to reduce K+ flux by a mechanism called C-type inactivation. In human ether-a-go-go–related gene 1 (hERG1) K+ channels, C-type inactivation is allosterically inhibited by ICA-105574, a substituted benzamide. PD-118057, a 2-(phenylamino) benzoic acid, alters selectivity filter gating to enhance open probability of channels. Both compounds bind to a hydrophobic pocket located between adjacent hERG1 subunits. Accordingly, a homotetrameric channel contains four identical activator binding sites. Here we determine the number of binding sites required for maximal drug effect and determine the role of subunit interactions in the modulation of hERG1 gating by these compounds. Concatenated tetramers were constructed to contain a variable number (zero to four) of wild-type and mutant hERG1 subunits, either L646E to inhibit PD-118057 binding or F557L to inhibit ICA-105574 binding. Enhancement of hERG1 channel current magnitude by PD-118057 and attenuated inactivation by ICA-105574 were mediated by cooperative subunit interactions. Maximal effects of the both compounds required the presence of all four binding sites. Understanding how hERG1 agonists allosterically modify channel gating may facilitate mechanism-based drug design of novel agents for treatment of long QT syndrome.
14
Sundukov, Evgeny Y., Boris M. Shifrin i Veronika E. Sundukova. "Construction of multichannelmagnetolevitation systems". Modern Transportation Systems and Technologies 7, nr 3 (30.09.2021): 120–30. http://dx.doi.org/10.17816/transsyst202173120-130.
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Background: It is proposed to set a traveling magnetic field in a special control channel (beam, pipe), coupled with several controlled channels - small-sized maglev systems in which levitation of transport modules is carried out.
Aim: to interface the control channel with several controlled channels (up to four) small-sized maglev systems. In this case, the control channel will be located in the center, and the controlled channels at the top, right, bottom, left.
Methods: 3D-modeling, layout, spatial composition, patent search.
Results: The traveling magnetic field in the control channel is created by a moving sequence of interacting magnetic field sources the movers, which interact too with magnetic field sources of transport modules the fellow travelers, levitating in the controlled channels through sources of a constant magnetic field. The structure is installed on arched supports that uniformly distribute the load over the support surface. A model of a two-channel system with a lower location of a controlled channel has been developed.
Conclusion: The small-sized maglev systems can form a multi-channel transport system.
15
Anderson, C. S., R. MacKinnon, C. Smith i C. Miller. "Charybdotoxin block of single Ca2+-activated K+ channels. Effects of channel gating, voltage, and ionic strength." Journal of General Physiology 91, nr 3 (1.03.1988): 317–33. http://dx.doi.org/10.1085/jgp.91.3.317.
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Charybdotoxin (CTX), a small, basic protein from scorpion venom, strongly inhibits the conduction of K ions through high-conductance, Ca2+-activated K+ channels. The interaction of CTX with Ca2+-activated K+ channels from rat skeletal muscle plasma membranes was studied by inserting single channels into uncharged planar phospholipid bilayers. CTX blocks K+ conduction by binding to the external side of the channel, with an apparent dissociation constant of approximately 10 nM at physiological ionic strength. The dwell-time distributions of both blocked and unblocked states are single-exponential. The toxin association rate varies linearly with the CTX concentration, and the dissociation rate is independent of it. CTX is competent to block both open and closed channels; the association rate is sevenfold faster for the open channel, while the dissociation rate is the same for both channel conformations. Membrane depolarization enhances the CTX dissociation rate e-fold/28 mV; if the channel's open probability is maintained constant as voltage varies, then the toxin association rate is voltage independent. Increasing the external solution ionic strength from 20 to 300 mM (with K+, Na+, or arginine+) reduces the association rate by two orders of magnitude, with little effect on the dissociation rate. We conclude that CTX binding to the Ca2+-activated K+ channel is a bimolecular process, and that the CTX interaction senses both voltage and the channel's conformational state. We further propose that a region of fixed negative charge exists near the channel's CTX-binding site.
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Thompson, Jill, i Ted Begenisich. "Membrane-delimited Inhibition of Maxi-K Channel Activity by the Intermediate Conductance Ca2+-activated K Channel". Journal of General Physiology 127, nr 2 (17.01.2006): 159–69. http://dx.doi.org/10.1085/jgp.200509457.
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The complexity of mammalian physiology requires a diverse array of ion channel proteins. This diversity extends even to a single family of channels. For example, the family of Ca2+-activated K channels contains three structural subfamilies characterized by small, intermediate, and large single channel conductances. Many cells and tissues, including neurons, vascular smooth muscle, endothelial cells, macrophages, and salivary glands express more than a single class of these channels, raising questions about their specific physiological roles. We demonstrate here a novel interaction between two types of Ca2+-activated K channels: maxi-K channels, encoded by the KCa1.1 gene, and IK1 channels (KCa3.1). In both native parotid acinar cells and in a heterologous expression system, activation of IK1 channels inhibits maxi-K activity. This interaction was independent of the mode of activation of the IK1 channels: direct application of Ca2+, muscarinic receptor stimulation, or by direct chemical activation of the IK1 channels. The IK1-induced inhibition of maxi-K activity occurred in small, cell-free membrane patches and was due to a reduction in the maxi-K channel open probability and not to a change in the single channel current level. These data suggest that IK1 channels inhibit maxi-K channel activity via a direct, membrane-delimited interaction between the channel proteins. A quantitative analysis indicates that each maxi-K channel may be surrounded by four IK1 channels and will be inhibited if any one of these IK1 channels opens. This novel, regulated inhibition of maxi-K channels by activation of IK1 adds to the complexity of the properties of these Ca2+-activated K channels and likely contributes to the diversity of their functional roles.
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Chen, Pei-Chun, Erik M. Olson, Qing Zhou, Yelena Kryukova, Heidi M. Sampson, David Y. Thomas i Show-Ling Shyng. "Carbamazepine as a Novel Small Molecule Corrector of Trafficking-impaired ATP-sensitive Potassium Channels Identified in Congenital Hyperinsulinism". Journal of Biological Chemistry 288, nr 29 (6.06.2013): 20942–54. http://dx.doi.org/10.1074/jbc.m113.470948.
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ATP-sensitive potassium (KATP) channels consisting of sulfonylurea receptor 1 (SUR1) and the potassium channel Kir6.2 play a key role in insulin secretion by coupling metabolic signals to β-cell membrane potential. Mutations in SUR1 and Kir6.2 that impair channel trafficking to the cell surface lead to loss of channel function and congenital hyperinsulinism. We report that carbamazepine, an anticonvulsant, corrects the trafficking defects of mutant KATP channels previously identified in congenital hyperinsulinism. Strikingly, of the 19 SUR1 mutations examined, only those located in the first transmembrane domain of SUR1 responded to the drug. We show that unlike that reported for several other protein misfolding diseases, carbamazepine did not correct KATP channel trafficking defects by activating autophagy; rather, it directly improved the biogenesis efficiency of mutant channels along the secretory pathway. In addition to its effect on channel trafficking, carbamazepine also inhibited KATP channel activity. Upon subsequent removal of carbamazepine, however, the function of rescued channels was recovered. Importantly, combination of the KATP channel opener diazoxide and carbamazepine led to enhanced mutant channel function without carbamazepine washout. The corrector effect of carbamazepine on mutant KATP channels was also demonstrated in rat and human β-cells with an accompanying increase in channel activity. Our findings identify carbamazepine as a novel small molecule corrector that may be used to restore KATP channel expression and function in a subset of congenital hyperinsulinism patients.
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Tenma, Taro, Hirofumi Mitsuyama, Masaya Watanabe, Naoya Kakutani, Yutaro Otsuka, Kazuya Mizukami, Rui Kamada i in. "Small-conductance Ca2+-activated K+ channel activation deteriorates hypoxic ventricular arrhythmias via CaMKII in cardiac hypertrophy". American Journal of Physiology-Heart and Circulatory Physiology 315, nr 2 (1.08.2018): H262—H272. http://dx.doi.org/10.1152/ajpheart.00636.2017.
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The molecular and electrophysiological mechanisms of acute ischemic ventricular arrhythmias in hypertrophied hearts are not well known. We hypothesized that small-conductance Ca2+-activated K+ (SK) channels are activated during hypoxia via the Ca2+/calmodulin-dependent protein kinase II (CaMKII)-dependent pathway. We used normotensive Wistar-Kyoto (WKY) rats and spontaneous hypertensive rats (SHRs) as a model of cardiac hypertrophy. The inhibitory effects of SK channels and ATP-sensitive K+ channels on electrophysiological changes and genesis of arrhythmias during simulated global hypoxia (GH) were evaluated. Hypoxia-induced abbreviation of action potential duration (APD) occurred earlier in ventricles from SHRs versus. WKY rats. Apamin, a SK channel blocker, prevented this abbreviation in SHRs in both the early and delayed phase of GH, whereas in WKY rats only the delayed phase was prevented. In contrast, SHRs were less sensitive to glibenclamide, a ATP-sensitive K+ channel blocker, which inhibited the APD abbreviation in both phases of GH in WKY rats. SK channel blockers (apamin and UCL-1684) reduced the incidence of hypoxia-induced sustained ventricular arrhythmias in SHRs but not in WKY rats. Among three SK channel isoforms, SK2 channels were directly coimmunoprecipitated with CaMKII phosphorylated at Thr286 (p-CaMKII). We conclude that activation of SK channels leads to the APD abbreviation and sustained ventricular arrhythmias during simulated hypoxia, especially in hypertrophied hearts. This mechanism may result from p-CaMKII-bound SK2 channels and reveal new molecular targets to prevent lethal ventricular arrhythmias during acute hypoxia in cardiac hypertrophy. NEW & NOTEWORTHY We now show a new pathophysiological role of small-conductance Ca2+-activated K+ channels, which shorten the action potential duration and induce ventricular arrhythmias during hypoxia. We also demonstrate that small-conductance Ca2+-activated K+ channels interact with phosphorylated Ca2+/calmodulin-dependent protein kinase II at Thr286 in hypertrophied hearts.
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Parsegian, V. A., S. M. Bezrukov i I. Vodyanoy. "Watching small molecules move: Interrogating ionic channels using neutral solutes". Bioscience Reports 15, nr 6 (1.12.1995): 503–14. http://dx.doi.org/10.1007/bf01204353.
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Whether they are small enough to wriggle through the current-carrying part of an ionic channel or big enough to be kept outside and thus able to exert an osmotic stress on the channel space, polymers interact with channels in several instructive ways. The osmotic stress of excluded polymers allows one to measure the number of water molecules that come out of the channel in transitions between various “open” to “closed” states. The loss of osmotic activity, due to the partial or completely unrestricted admission of small polymers becomes a measure of the transfer probabilities of polymers from solution to small cavities; it provides an opportunity to study polymer conformation in a perfectly sieved preparation. Current fluctuations due to the partial blockage by a transient polymer are converted into estimates of times of passage and diffusion constants of polymers in channels. These estimates show how a channel whose functional states last for milliseconds is able to average over the interactions with polymers, interactions that last only microseconds. One sees clearly that in this averaging, the macromolecular channel is large enough to react like a macroscopic object to the chemical potentials of the species that modulate its activity.
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Illés, Gabriella. "Expansion of the small cable television counterparts of market leading commercial channels in view of Hungarian regional and social aspects". Acta Agraria Debreceniensis, nr 58 (8.04.2014): 107–10. http://dx.doi.org/10.34101/actaagrar/58/1981.
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Currently, there are 102 Hungarian-language television channels in Hungary. TV2 Hungary is the second largest commercial television channel. Current trends in the television market in Europe indicate that large channels are expanding their portfolios while at the same time selling their smaller units. This trend has now affected Hungary as well.
After having TV2 for 16 years, MTM-SBS Television Ltd. eventually expanded its portfolio with three new cable channels. The first new channel was FEM3, a channel directed at women, which was launched on January 1, 2010. A year later, the male channel, PRO4, was launched and finally, SuperTV2, primarily a premium entertainment channel, was launched on November 2, 2012. Although the main channel, TV2, remained free, the new pay channels on cable received a significant amount of investment from venture capitalists and Pro7Sat1 for the development of new content.
SuperTV2 is a premium channel. When the channel was launched, the goal was to target those viewers who had turned away from watching the increasingly less-sophisticated content on the commercial channels as well as those who were not drawn to the programming on public television. When the viewer stats were examined, the channel had proven itself. The premium brand of Super TV2 was successful in attracting new viewers and consumers and within a year it had gained a strong foothold over more than 100 other Hungarian-language channels.
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Vyas, Vivek K., Palak Parikh, Jonali Ramani i Manjunath Ghate. "Medicinal Chemistry of Potassium Channel Modulators: An Update of Recent Progress (2011-2017)". Current Medicinal Chemistry 26, nr 12 (1.07.2019): 2062–84. http://dx.doi.org/10.2174/0929867325666180430152023.
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Background: Potassium (K+) channels participate in many physiological processes, cardiac function, cell proliferation, neuronal signaling, muscle contractility, immune function, hormone secretion, osmotic pressure, changes in gene expression, and are involved in critical biological functions, and in a variety of diseases. Potassium channels represent a large family of tetrameric membrane proteins. Potassium channels activation reduces excitability, whereas channel inhibition increases excitability. Objective: Small molecule K+ channel activators and inhibitors interact with voltage-gated, inward rectifying, and two-pore tandem potassium channels. Due to their involvement in biological functions, and in a variety of diseases, small molecules as potassium channel modulators have received great scientific attention. Methods: : In this review, we have compiled the literature, patents and patent applications (2011 to 2017) related to different chemical classes of potassium channel openers and blockers as therapeutic agents for the treatment of various diseases. Many different chemical classes of selective small molecule have emerged as potassium channel modulators over the past years. Conclusion: This review discussed the current understanding of medicinal chemistry research in the field of potassium channel modulators to update the key advances in this field.
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Choi, Seok, Hyun Goo Kang, Mei Jin Wu, Han Yi Jiao, Dong Hoon Shin, Chansik Hong i Jae Yeoul Jun. "Effects of Ca2+-Activated Cl- Channel ANO1inhibitors on Pacemaker Activity in Interstitial Cells of Cajal". Cellular Physiology and Biochemistry 51, nr 6 (2018): 2887–99. http://dx.doi.org/10.1159/000496041.
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Background/Aims: Anoctamin1 (Ca2+-activated Cl- channel, ANO1) is a specific marker of the interstitial cells of Cajal (ICC) in the gastrointestinal tract, and are candidate proteins that can function as pacemaker channels. Recently, novel selective ANO1 inhibitors were discovered and used to study Ca2+-activated Cl- channels. Therefore, to investigate whether ANO1 channels function as pacemaker channels, selective ANO1 inhibitors were tested with respect to the pacemaker potentials in ICC. Methods: Whole-cell patch-clamp recording, RT-PCR, and intracellular Ca2+ ([Ca2+]i) imaging were performed in cultured ICC obtained from mice. Results: Though CaCCinh-A01 (5 µM), T16Ainh-A01 (5 µM), and MONNA (5 µM) (selective ANO1 inhibitors) blocked the generation of pacemaker potentials in colonic ICC, they did not do so in small intestinal ICC. Though nifulmic acid (10 µM) and DIDS (10 µM) (classical Ca2+-activated Cl- channel inhibitors) also had no effect in small intestinal ICC, they suppressed the generation of pacemaker potentials in colonic ICC. In addition, knockdown of ANO1 reduced the pacemaker potential frequency in colonic ICC alone. Though ANO1 inhibitors suppressed [Ca2+]i oscillations in colonic ICC, they did not do so in small intestinal ICC. T-type Ca2+ channels were expressed in the both the small intestinal and colonic ICC, but mibefradil (5 µM) and NiCl2 (30 µM) (T-type Ca2+ channel inhibitors) inhibited the generation of pacemaker potentials in colonic ICC alone. Conclusion: These results indicate that though ANO1 and T-type Ca2+ channels participate in generating pacemaker potentials in colonic ICC, they do not do so in small intestinal ICC. Therefore, the mechanisms underlying pacemaking in ICC might be different in the small intestine and the colon.
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Xiao, Zhang, i Wenzheng Wu. "Durability Analysis of Small Assembled Buildings in Irrigation Canal System". Scientific Programming 2022 (30.09.2022): 1–10. http://dx.doi.org/10.1155/2022/2202052.
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With the rapid development of agricultural economy, people are paying more and more attention to how to apply high-efficiency technologies that save resources to improve agricultural production efficiency, so water-saving irrigation technology has gradually developed. China’s agricultural irrigation technology is relatively backward. In addition to the inappropriate irrigation methods and irrigation systems, problems such as siltation, seepage, and frost heave damage in irrigation canals have seriously affected the durability and service life of the canals. The backward irrigation technology seriously restricts the development of agricultural water-saving irrigation. Compared with large irrigation channels, the fabricated reinforced concrete small irrigation channels studied in this paper are less prone to frost heave damage and infiltration problems, and have the advantages of standardized production, simple transportation and installation, and convenient maintenance. In order to study the durability issues such as the basic characteristics, frost heave damage, and service life of fabricated irrigation channels, this paper takes the channel concrete and the formed channel as the research objects, and discusses the research on the properties of the channel concrete through theoretical research, numerical analysis, experiments, and other methods. Strength properties, water penetration resistance, cyanide ion penetration resistance and frost resistance; simulate the seasonal frost heave failure process of the channel; finally, on the basis of the test data, the service life aims to explore the safety and applicability of the fabricated reinforced concrete irrigation channel during the design use period.
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Hinds, Bruce J. "Engineering small-ion transporter channels". Science 372, nr 6541 (29.04.2021): 459–60. http://dx.doi.org/10.1126/science.abh2618.
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Lavine, M. S. "APPLIED PHYSICS: Channels Writ Small". Science 300, nr 5622 (16.05.2003): 1055a—1055. http://dx.doi.org/10.1126/science.300.5622.1055a.
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Wokke, JHJ, i J. van Gijn. "Small channels and large trials". Lancet 350 (grudzień 1997): SIII14. http://dx.doi.org/10.1016/s0140-6736(97)90047-7.
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Helm, Carina, Marwan A. Hassan i David Reid. "Characterization of morphological units in a small, forested stream using close-range remotely piloted aircraft imagery". Earth Surface Dynamics 8, nr 4 (4.11.2020): 913–29. http://dx.doi.org/10.5194/esurf-8-913-2020.
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Abstract. Forested, gravel-bed streams possess complex channel morphologies which are difficult to objectively characterize. The spatial scale necessary to adequately capture variability in these streams is often unclear, as channels are governed by irregularly spaced features and episodic processes. This issue is compounded by the high cost and time-consuming nature of field surveys in these complex fluvial environments. In larger streams, remotely piloted aircraft (RPA) have proven to be effective tools for characterizing channels at high resolutions over large spatial extents, but to date their use in small, forested streams with closed forest canopies has been limited. This paper seeks to demonstrate an effective method for classifying channel morphological units in small, forested streams and for providing information on the spatial scale necessary to capture the dominant spatial morphological variability of these channels. This goal was achieved using easily extractable data from close-range RPA imagery collected under the forest canopy (flying height of 5–15 m above ground level; ma.g.l.) in a small (width of 10–15 m) stream along its 3 km of salmon-bearing channel. First, the accuracy and coverage of RPA for extracting channel data were investigated through a subcanopy survey. From these survey data, relevant cross-sectional variables (hydraulic radius, sediment texture, and channel slope) were extracted from high-resolution point clouds and digital elevation models (DEMs) of the channel and used to characterize channel unit morphology using a principal component analysis-clustering (PCA-clustering) technique. Finally, the length scale required to capture dominant morphological variability was investigated from an analysis of morphological diversity along the channel. The results demonstrate that subcanopy RPA surveys provide a viable alternative to traditional ground-based survey approaches for mapping morphological units, with 87 % coverage of the main channel stream bed achieved. The PCA-clustering analysis provided a comparatively objective means of classifying channel unit morphology with a correct classification rate of 85 %. An analysis of the morphological diversity along the surveyed channel indicates that reaches of at least 15 bankfull width equivalents are required to capture the channel's dominant morphological heterogeneity. Altogether, the results provide a precedent for using RPA to characterize the morphology and diversity of forested streams under dense canopies.
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Hirschberg, Birgit, James Maylie, John P. Adelman i Neil V. Marrion. "Gating of Recombinant Small-Conductance Ca-activated K+ Channels by Calcium". Journal of General Physiology 111, nr 4 (1.04.1998): 565–81. http://dx.doi.org/10.1085/jgp.111.4.565.
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Small-conductance Ca-activated K+ channels play an important role in modulating excitability in many cell types. These channels are activated by submicromolar concentrations of intracellular Ca2+, but little is known about the gating kinetics upon activation by Ca2+. In this study, single channel currents were recorded from Xenopus oocytes expressing the apamin-sensitive clone rSK2. Channel activity was detectable in 0.2 μM Ca2+ and was maximal above 2 μM Ca2+. Analysis of stationary currents revealed two open times and three closed times, with only the longest closed time being Ca dependent, decreasing with increasing Ca2+ concentrations. In addition, elevated Ca2+ concentrations resulted in a larger percentage of long openings and short closures. Membrane voltage did not have significant effects on either open or closed times. The open probability was ∼0.6 in 1 μM free Ca2+. A lower open probability of ∼0.05 in 1 μM Ca2+ was also observed, and channels switched spontaneously between behaviors. The occurrence of these switches and the amount of time channels spent displaying high open probability behavior was Ca2+ dependent. The two behaviors shared many features including the open times and the short and intermediate closed times, but the low open probability behavior was characterized by a different, long Ca2+-dependent closed time in the range of hundreds of milliseconds to seconds. Small-conductance Ca- activated K+ channel gating was modeled by a gating scheme consisting of four closed and two open states. This model yielded a close representation of the single channel data and predicted a macroscopic activation time course similar to that observed upon fast application of Ca2+ to excised inside-out patches.
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Ge, Yan, Wenqiu Wu, Yemin Zhang i Chencheng Zhao. "Comparison of Terahertz channel and SAGINs channel of 6G channels". Applied and Computational Engineering 5, nr 1 (14.06.2023): 771–78. http://dx.doi.org/10.54254/2755-2721/5/20230701.
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This paper is mainly about researching some different types of 6G channels. The article introduces two common types of 6G channels: Terahertz channel and SAGINs channel, and studies and summarizes their advantages, problems, and development prospects, and compares them. The paper also introduces three small-scale 6G channel models.
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Pozdnyakov, Ilya, Olga Matantseva i Sergei Skarlato. "Consensus channelome of dinoflagellates revealed by transcriptomic analysis sheds light on their physiology". Algae 36, nr 4 (15.12.2021): 315–26. http://dx.doi.org/10.4490/algae.2021.36.12.2.
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Ion channels are membrane protein complexes mediating passive ion flux across the cell membranes. Every organism has a certain set of ion channels that define its physiology. Dinoflagellates are ecologically important microorganisms characterized by effective physiological adaptability, which backs up their massive proliferations that often result in harmful blooms (red tides). In this study, we used a bioinformatics approach to identify homologs of known ion channels that belong to 36 ion channel families. We demonstrated that the versatility of the dinoflagellate physiology is underpinned by a high diversity of ion channels including homologs of animal and plant proteins, as well as channels unique to protists. The analysis of 27 transcriptomes allowed reconstructing a consensus ion channel repertoire (channelome) of dinoflagellates including the members of 31 ion channel families: inwardly-rectifying potassium channels, two-pore domain potassium channels, voltage-gated potassium channels (Kv), tandem Kv, cyclic nucleotide-binding domain-containing channels (CNBD), tandem CNBD, eukaryotic ionotropic glutamate receptors, large-conductance calcium-activated potassium channels, intermediate/small-conductance calcium-activated potassium channels, eukaryotic single-domain voltage-gated cation channels, transient receptor potential channels, two-pore domain calcium channels, four-domain voltage-gated cation channels, cation and anion Cys-loop receptors, small-conductivity mechanosensitive channels, large-conductivity mechanosensitive channels, voltage-gated proton channels, inositole-1,4,5- trisphosphate receptors, slow anion channels, aluminum-activated malate transporters and quick anion channels, mitochondrial calcium uniporters, voltage-dependent anion channels, vesicular chloride channels, ionotropic purinergic receptors, animal volage-insensitive cation channels, channelrhodopsins, bestrophins, voltage-gated chloride channels H+/Cl- exchangers, plant calcium-permeable mechanosensitive channels, and trimeric intracellular cation channels. Overall, dinoflagellates represent cells able to respond to physical and chemical stimuli utilizing a wide range of Gprotein coupled receptors- and Ca2+-dependent signaling pathways. The applied approach not only shed light on the ion channel set in dinoflagellates, but also provided the information on possible molecular mechanisms underlying vital cellular processes dependent on the ion transport.
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Mulyana, Ig Jaka, Ivan Gunawan, Dian Trihastuti, Yehezkiel Prakoso Putra Yunen i Dwi Agustin Nuriani Sirodj. "ONLINE PRICING FOR SMALL MEDIUM ENTERPRISES’ PRODUCTS IN THE EX-LOCALIZATION OF DOLLY SURABAYA". J@ti Undip: Jurnal Teknik Industri 16, nr 3 (1.10.2021): 169–76. http://dx.doi.org/10.14710/jati.16.3.169-176.
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Numerous Small and Medium Enterprises (SMEs) do not have a basic method in pricing decisions. Many times, this decision comes up based on an intuitive probe instead of a detailed analysis. This could lead to marketing problems, which may result in disruptions of financial liquidity. This also applies to SMEs wishing to sell products through the online channel. They need a proper pricing strategy, considering its different marketing strategies. Sales made through both offline channels (conventional stores) and online channels are known as Dual-Channel Supply Chain (DCSC). It is argued that the pricing decision at DCSC needs to consider consumer preferences in selecting the sales channel. One assumption commonly adopted in the DCSC pricing model is that the lost value if consumers purchase products through online channels. Therefore, the pricing decision for the online channel should be cheaper than the price on the offline channel. This study aims to assist SMEs in the ex-localization of Dolly in Surabaya in determining the price of products to be sold through online channels. Three types of products: batik, chips, and leather shoes were selected as research samples to represent the product groups: craft, fashion, and processed food. This study proposes an optimal online price strategy through experiments with a mathematical model. Model parameters, namely consumer preferences in choosing sales channels, are obtained through surveys. Apart from that, surveys are also used to reveal which platforms consumers are interested in shopping online. Shopee and Instagram were chosen by respondents as the most popular marketplaces and social media for online shopping. Finally, the online prices proposed for the batik product are IDR 82,500-IDR 66,000; chips Rp7,620-Rp6,336; and leather shoes Rp.103,800-Rp82,200.
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Här, Kristina, Natalia N. Lysenko, Daniela Dimitrova, Torsten Schlüter, Olga Zavaritskaya, Andrej G. Kamkin, Mitko Mladenov i in. "Kv2.1 Channels Prevent Vasomotion and Safeguard Myogenic Reactivity in Rat Small Superior Cerebellar Arteries". Cells 12, nr 15 (2.08.2023): 1989. http://dx.doi.org/10.3390/cells12151989.
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Vascular smooth muscle voltage-gated potassium (Kv) channels have been proposed to contribute to myogenic autoregulation. Surprisingly, in initial experiments, we observed that the Kv2 channel inhibitor stromatoxin induced vasomotion without affecting myogenic tone. Thus, we tested the hypothesis that Kv2 channels contribute to myogenic autoregulation by fine-tuning the myogenic response. Expression of Kv2 channel mRNA was determined using real-time PCR and ‘multiplex’ single-cell RT-PCR. Potassium currents were measured using the patch-clamp technique. Contractile responses of intact arteries were studied using isobaric myography. Expression of Kv2.1 but not Kv2.2 channels was detected in intact rat superior cerebellar arteries and in single smooth muscle cells. Stromatoxin, a high-affinity inhibitor of Kv2 channels, reduced smooth muscle Kv currents by 61% at saturating concentrations (EC50 36 nmol/L). Further, stromatoxin (10–100 nmol/L) induced pronounced vasomotion in 48% of the vessels studied. In vessels not exhibiting vasomotion, stromatoxin did not affect myogenic reactivity. Notably, in vessels exhibiting stromatoxin-induced vasomotion, pressure increases evoked two effects: First, they facilitated the occurrence of random vasodilations and/or vasoconstrictions, disturbing the myogenic response (24% of the vessels). Second, they modified the vasomotion by decreasing its amplitude and increasing its frequency, thereby destabilizing myogenic tone (76% of the vessels). Our study demonstrates that (i) Kv2.1 channels are the predominantly expressed Kv channels in smooth muscle cells of rat superior cerebellar arteries, and (ii) Kv2.1 channels provide a novel type of negative feedback mechanism in myogenic autoregulation by preventing vasomotion and thereby safeguarding the myogenic response.
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Falk, Matthias M., Susan M. Baker, Anna M. Gumpert, Dominique Segretain i Robert W. Buckheit. "Gap Junction Turnover Is Achieved by the Internalization of Small Endocytic Double-Membrane Vesicles". Molecular Biology of the Cell 20, nr 14 (15.07.2009): 3342–52. http://dx.doi.org/10.1091/mbc.e09-04-0288.
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Double-membrane–spanning gap junction (GJ) channels cluster into two-dimensional arrays, termed plaques, to provide direct cell-to-cell communication. GJ plaques often contain circular, channel-free domains (∼0.05–0.5 μm in diameter) identified >30 y ago and termed nonjunctional membrane (NM) domains. We show, by expressing the GJ protein connexin43 (Cx43) tagged with green fluorescent protein, or the novel photoconvertible fluorescent protein Dendra2, that NM domains appear to be remnants generated by the internalization of small GJ channel clusters that bud over time from central plaque areas. Channel clusters internalized within seconds forming endocytic double-membrane GJ vesicles (∼0.18–0.27 μm in diameter) that were degraded by lysosomal pathways. Surprisingly, NM domains were not repopulated by surrounding channels and instead remained mobile, fused with each other, and were expelled at plaque edges. Quantification of internalized, photoconverted Cx43-Dendra2 vesicles indicated a GJ half-life of 2.6 h that falls within the estimated half-life of 1–5 h reported for GJs. Together with previous publications that revealed continuous accrual of newly synthesized channels along plaque edges and simultaneous removal of channels from plaque centers, our data suggest how the known dynamic channel replenishment of functional GJ plaques can be achieved. Our observations may have implications for the process of endocytic vesicle budding in general.
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Chazarreta, Javier, Monica Susana Hoffmeyer, Diana G. Cuadrado i Anabela Anahí Berasategui. "Tidal effects on short-term mesozooplankton distribution in small channels of a temperate-turbid estuary, Southwestern Atlantic". Brazilian Journal of Oceanography 63, nr 2 (czerwiec 2015): 83–92. http://dx.doi.org/10.1590/s1679-87592015076806302.
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Abstract The short-term variability of mesozooplankton distribution and physicochemical variables was examined in two different channels of the Bahía Blanca Estuary, Argentina, during two tidal cycles. All the physicochemical measurements and mesozooplankton sampling were performed at a fixed site during approximately 22-23 h at 3-h intervals. Pumps were used to obtain surface and bottom mesozooplankton samples and the water speed of each stratum was measured with an Acoustic Doppler Current Profiler (ADCP). In all, 23 mesozooplanktonic taxa belonging to four phyla (Arthropoda, Annelida, Echinodermata and Chordata) were identified. The most abundant taxa during the two tidal cycles were Balanus glandula larvae, Eurytemora americana and Acartia tonsa. A discernible variability in the water conditions and vertical mesozooplankton distribution (VMD) different from that known for the estuary's main channel, was found in the other two selected channels. VMD varied during the tidal cycle in both channels in accordance with the channel's geomorphology and water dynamic characteristics of each of them. The variation of the abundance of the different taxa during ebb and flood currents might indicate the existence of a tidal vertical migration of the mesozooplankton as a response to particular dynamic water conditions.
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Dvorak, Nolan M., Paul A. Wadsworth, Pingyuan Wang, Jia Zhou i Fernanda Laezza. "Development of Allosteric Modulators of Voltage-Gated Na+ Channels: A Novel Approach for an Old Target". Current Topics in Medicinal Chemistry 21, nr 10 (17.06.2021): 841–48. http://dx.doi.org/10.2174/1568026621666210525105359.
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Given their primacy in governing the action potential (AP) of excitable cells, voltage-gated Na+ (Nav) channels are important pharmacological targets of therapeutics for a diverse array of clinical indications. Despite historically being a traditional drug target, therapeutics targeting Nav channels lack isoform selectivity, giving rise to off-target side effects. To develop isoform-selective modulators of Nav channels with improved target-specificity, the identification and pharmacological targeting of allosteric sites that display structural divergence among Nav channel isoforms represents an attractive approach. Despite the high homology among Nav channel α subunit isoforms (Nav1.1-Nav1.9), there is considerable amino acid sequence divergence among their constituent C-terminal domains (CTD), which enables structurally and functionally specific protein: protein interactions (PPI) with auxiliary proteins. Although pharmacological targeting of such PPI interfaces between the CTDs of Nav channels and auxiliary proteins represents an innovate approach for developing isoform-selective modulators of Nav channels, appreciable modulation of PPIs using small molecules has conventionally been difficult to achieve. After briefly discussing the challenges of modulating PPIs using small molecules, this current frontier review that follows subsequently expounds on approaches for circumventing such difficulties in the context of developing small molecule modulators of PPIs between transmembrane ion channels and their auxiliary proteins. In addition to broadly discussing such approaches, the implementation of such approaches is specifically discussed in the context of developing small molecule modulators between the CTD of Nav channels and auxiliary proteins. Developing allosteric modulators of ion channels by targeting their PPI interfaces with auxiliary proteins represents an innovative and promising strategy in ion channel drug discovery that could expand the “druggable genome” and usher in first-in-class PPI-targeting therapeutics for a multitude of channelopathies.
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Parwati, Mian Ida, Surni Surni i Muhammad Syukri. "Analysis of Milkfish Marketing in Ranooha Raya Village, Moramo District, South Konawe Regency". Tekper : Jurnal Teknologi dan Manajemen Industri Pertanian 2, nr 2 (7.06.2022): 136. http://dx.doi.org/10.33772/tekper.v2i2.20779.
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The aims of this research are (1) to determine the marketing channels of milkfish; (2) to determine the level of marketing efficiency of milkfish. This research will be conducted from September to December 2020 in Raooha Raya Village, Moramo District, South Konawe Regency. Data collection techniques are by way of interviews—primary and secondary data. Data analysis is to determine the marketing channels of fish in the Moramo sub-district using descriptive analysis. The results showed that the marketing channel of milkfish in the village of Ranooha Raya consisted of 2 channels, namely marketing channel one from farmers- wholesalers- small traders- consumers, marketing channel two from farmers- small traders- consumers. Then the marketing margin of milkfish on channels I and II is the same, namely Rp. 2,000. The thing that causes the similarity of marketing margins for each channel is because, in Moramo District, farmers there determine the price where the price applies to each marketing agency.
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Chen, Xingjuan, Degang Liu, Donghui Zhou, Yubing Si, David Xu, Christopher W. Stamatkin, Mona K. Ghozayel i in. "Small-molecule CaVα1⋅CaVβ antagonist suppresses neuronal voltage-gated calcium-channel trafficking". Proceedings of the National Academy of Sciences 115, nr 45 (24.10.2018): E10566—E10575. http://dx.doi.org/10.1073/pnas.1813157115.
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Extracellular calcium flow through neuronal voltage-gated CaV2.2 calcium channels converts action potential-encoded information to the release of pronociceptive neurotransmitters in the dorsal horn of the spinal cord, culminating in excitation of the postsynaptic central nociceptive neurons. The CaV2.2 channel is composed of a pore-forming α1subunit (CaVα1) that is engaged in protein–protein interactions with auxiliary α2/δ and β subunits. The high-affinity CaV2.2α1⋅CaVβ3protein–protein interaction is essential for proper trafficking of CaV2.2 channels to the plasma membrane. Here, structure-based computational screening led to small molecules that disrupt the CaV2.2α1⋅CaVβ3protein–protein interaction. The binding mode of these compounds reveals that three substituents closely mimic the side chains of hot-spot residues located on the α-helix of CaV2.2α1. Site-directed mutagenesis confirmed the critical nature of a salt-bridge interaction between the compounds and CaVβ3Arg-307. In cells, compounds decreased trafficking of CaV2.2 channels to the plasma membrane and modulated the functions of the channel. In a rodent neuropathic pain model, the compounds suppressed pain responses. Small-molecule α-helical mimetics targeting ion channel protein–protein interactions may represent a strategy for developing nonopioid analgesia and for treatment of other neurological disorders associated with calcium-channel trafficking.
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Tošović-Stevanović, Aleksandra, Vladimir Ristanović, Dragan Ćalović, Goran Lalić, Milena Žuža i Gorica Cvijanović. "Small Farm Business Analysis Using the AHP Model for Efficient Assessment of Distribution Channels". Sustainability 12, nr 24 (15.12.2020): 10479. http://dx.doi.org/10.3390/su122410479.
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Distribution of agricultural products from the aspect of farms is a continuous issue. Efficient application of the distribution model should provide a farm owner with regular income, as well as with a competitive advantage. Assessment of distribution channels in the context of an agricultural producer is subject to multi-criteria decisions, including both qualitative and quantitative factors. The aim of this paper is to develop a model which enables a structured analysis and an efficient assessment of distribution channels. The methodology based on the Analytical Hierarchy Process (AHP) will be a useful tool in setting various criteria for deciding on distribution channels, as well as a tool for managing a multi-variant qualitative assessment of data included in decision-making processes. The survey results show that the most important distribution channel for agricultural products is the channel of sales via processing plants (cooling and drying facilities, silos and agricultural combines), compared to sales through advertising (which significantly increased its share with the COVID-19 pandemic), sales through sales channels or at farmers’ markets.
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Kuo, Ivana Y., Anthie Ellis, Victoria AL Seymour, Shaun L. Sandow i Caryl E. Hill. "Dihydropyridine-Insensitive Calcium Currents Contribute to Function of Small Cerebral Arteries". Journal of Cerebral Blood Flow & Metabolism 30, nr 6 (3.02.2010): 1226–39. http://dx.doi.org/10.1038/jcbfm.2010.11.
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Although dihydropyridines are widely used for the treatment of vasospasm, their effectiveness is questionable, suggesting that other voltage-dependent calcium channels (VDCCs) contribute to control of cerebrovascular tone. This study therefore investigated the role of dihydropyridine-insensitive VDCCs in cerebrovascular function. Using quantitative PCR and immunohistochemistry, we found mRNA and protein for L-type (CaV1.2) and T-type (CaV3.1 and CaV3.2) channels in adult rat basilar and middle cerebral arteries and their branches. Immunoelectron microscopy revealed both L- and T-type channels in smooth muscle cell (SMC) membranes. Using patch clamp electrophysiology, we found that a high-voltage-activated calcium current, showing T-type channel kinetics and insensitivity to nifedipine and nimodipine, comprised ∼20% of current in SMCs of the main arteries and ∼45% of current in SMCs from branches. Both components were abolished by the T-type antagonists mibefradil, NNC 55-0396, and efonidipine. Although nifedipine completely blocked vasoconstriction in pressurized basilar arteries, a nifedipine-insensitive constriction was found in branches and this increased in magnitude as vessel size decreased. We conclude that a heterogeneous population of VDCCs contributes to cerebrovascular function, with dihydropyridine-insensitive channels having a larger role in smaller vessels. Sensitivity of these currents to nonselective T-type channel antagonists suggests that these drugs may provide a more effective treatment for therapy-refractory cerebrovascular constriction.
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Garg, Vivek, Frank B. Sachse i Michael C. Sanguinetti. "Tuning of EAG K+ channel inactivation: Molecular determinants of amplification by mutations and a small molecule". Journal of General Physiology 140, nr 3 (27.08.2012): 307–24. http://dx.doi.org/10.1085/jgp.201210826.
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Ether-à-go-go (EAG) and EAG-related gene (ERG) K+ channels are close homologues but differ markedly in their gating properties. ERG1 channels are characterized by rapid and extensive C-type inactivation, whereas mammalian EAG1 channels were previously considered noninactivating. Here, we show that human EAG1 channels exhibit an intrinsic voltage-dependent slow inactivation that is markedly enhanced in rate and extent by 1–10 µM 3-nitro-N-(4-phenoxyphenyl) benzamide, or ICA105574 (ICA). This compound was previously reported to have the opposite effect on ERG1 channels, causing an increase in current magnitude by inhibition of C-type inactivation. The voltage dependence of 2 µM ICA-induced inhibition of EAG1 current was half-maximal at −73 mV, 62 mV negative to the half-point for channel activation. This finding suggests that current inhibition by the drug is mediated by enhanced inactivation and not open-channel block, where the voltage half-points for current inhibition and channel activation are predicted to overlap, as we demonstrate for clofilium and astemizole. The mutation Y464A in the S6 segment also induced inactivation of EAG1, with a time course and voltage dependence similar to that caused by 2 µM ICA. Several Markov models were investigated to describe gating effects induced by multiple concentrations of the drug and the Y464A mutation. Models with the smallest fit error required both closed- and open-state inactivation. Unlike typical C-type inactivation, the rate of Y464A- and ICA-induced inactivation was not decreased by external tetraethylammonium or elevated [K+]e. EAG1 channel inactivation introduced by Y464A was prevented by additional mutation of a nearby residue located in the S5 segment (F359A) or pore helix (L434A), suggesting a tripartite molecular model where interactions between single residues in S5, S6, and the pore helix modulate inactivation of EAG1 channels.
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Xu, Yu, Lucas Cantwell, Andrei I. Molosh, Leigh D. Plant, Dimitris Gazgalis, Stephanie D. Fitz, Erik T. Dustrude i in. "The small molecule GAT1508 activates brain-specific GIRK1/2 channel heteromers and facilitates conditioned fear extinction in rodents". Journal of Biological Chemistry 295, nr 11 (17.01.2020): 3614–34. http://dx.doi.org/10.1074/jbc.ra119.011527.
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G-protein–gated inwardly-rectifying K+ (GIRK) channels are targets of Gi/o-protein–signaling systems that inhibit cell excitability. GIRK channels exist as homotetramers (GIRK2 and GIRK4) or heterotetramers with nonfunctional homomeric subunits (GIRK1 and GIRK3). Although they have been implicated in multiple conditions, the lack of selective GIRK drugs that discriminate among the different GIRK channel subtypes has hampered investigations into their precise physiological relevance and therapeutic potential. Here, we report on a highly-specific, potent, and efficacious activator of brain GIRK1/2 channels. Using a chemical screen and electrophysiological assays, we found that this activator, the bromothiophene-substituted small molecule GAT1508, is specific for brain-expressed GIRK1/2 channels rather than for cardiac GIRK1/4 channels. Computational models predicted a GAT1508-binding site validated by experimental mutagenesis experiments, providing insights into how urea-based compounds engage distant GIRK1 residues required for channel activation. Furthermore, we provide computational and experimental evidence that GAT1508 is an allosteric modulator of channel–phosphatidylinositol 4,5-bisphosphate interactions. Through brain-slice electrophysiology, we show that subthreshold GAT1508 concentrations directly stimulate GIRK currents in the basolateral amygdala (BLA) and potentiate baclofen-induced currents. Of note, GAT1508 effectively extinguished conditioned fear in rodents and lacked cardiac and behavioral side effects, suggesting its potential for use in pharmacotherapy for post-traumatic stress disorder. In summary, our findings indicate that the small molecule GAT1508 has high specificity for brain GIRK1/2 channel subunits, directly or allosterically activates GIRK1/2 channels in the BLA, and facilitates fear extinction in a rodent model.
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Wachira, Murage Boniface, Eric Kiprotich Bett, Bernard Njehia i Charles Karani. "Analysis of Rice Marketing Channels Choices in Mwea Irrigation Scheme, Kirinyaga County, Kenya". American Journal of Economics and Business Innovation 2, nr 1 (22.02.2023): 29–38. http://dx.doi.org/10.54536/ajebi.v2i1.1238.
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The National Rice Development Strategy in (Kenya vision 2030) aims to improve food security, rural employment, and income for smallholder farmers in the Mwea irrigation scheme (MIS) through planned and intentional efforts. A study was conducted to identify major influences in choosing market avenues among rice farmers. The study used a sample size of 384 small-scale rice farmers to analyze the different rice marketing channels used in MIS, and to understand the factors that influence farmers’ choices of marketing channels. A pretested semi-structured questionnaire was used for data collection. Descriptive statistics were used to characterize the marketing channels, multinomial logit model was used to evaluate channel choices. The marketing channels were Channel 1: Farmer-Consumer (0.3%); Channel 2: Farmer-Brokers-Millers-Consumer (51.1%); Channel 3: Farmer-Brokers-Millers- Retailer-Consumer (42.3%); Channel 4: Farmer- Millers-Retailer-Consumer (62.72%) and Channel 5: Farmer- Millers- Wholesaler-Retailer-Consumer (37.28%). The most profitable channel was direct sales to consumers, which accounted for only 0.3% of total rice production in MIS. The study also found that factors such as education level, participation in marketing groups, distance to market, and age of the household head significantly influenced farmers’ choice of marketing channels. The study is critical in enriching literature on rice agricultural supply chains in Kenya. The study recommends policy considerations to protect small-scale farmers from exploitative brokers and suggests registering brokers to monitor their activities and set standards for fair practices, with the goal of regulating their activities to prevent exploitation of small-scale farmers in rice marketing.
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Bian, Xiaochun, Xiaoping Zhou i James J. Galligan. "R-type calcium channels in myenteric neurons of guinea pig small intestine". American Journal of Physiology-Gastrointestinal and Liver Physiology 287, nr 1 (lipiec 2004): G134—G142. http://dx.doi.org/10.1152/ajpgi.00532.2003.
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Currents carried by L-, N-, and P/Q-type calcium channels do not account for the total calcium current in myenteric neurons. This study identified all calcium channels expressed by guinea pig small intestinal myenteric neurons maintained in primary culture. Calcium currents were recorded using whole cell techniques. Depolarizations (holding potential = −70 mV) elicited inward currents that were blocked by CdCl2 (100 μM). Combined application of nifedipine (blocks L-type channels), Ω-conotoxin GVIA (blocks N-type channels), and Ω-agatoxin IVA (blocks P/Q-type channels) inhibited calcium currents by 56%. Subsequent addition of the R-type calcium channel antagonists, NiCl2 (50 μM) or SNX-482 (0.1 μM), abolished the residual calcium current. NiCl2 or SNX-482 alone inhibited calcium currents by 46%. The activation threshold for R-type calcium currents was −30 mV, the half-activation voltage was −5.2 ± 5 mV, and the voltage sensitivity was 17 ± 3 mV. R-type currents activated fully in 10 ms at 10 mV. R-type calcium currents inactivated in 1 s at 10 mV, and they inactivated (voltage sensitivity of 16 ± 1 mV) with a half-inactivation voltage of −76 ± 5 mV. These studies have accounted for all of the calcium channels in myenteric neurons. The data indicate that R-type calcium channels make the largest contribution to the total calcium current in myenteric neurons. The relatively positive half-activation voltage and rapid activation kinetics suggest that R-type channels could contribute to calcium entry during somal action potentials or during action potential-induced neurotransmitter release.
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Sancho, Maria, Bjorn O. Hald i Donald G. Welsh. "A stepwise approach to resolving small ionic currents in vascular tissue". American Journal of Physiology-Heart and Circulatory Physiology 318, nr 3 (1.03.2020): H632—H638. http://dx.doi.org/10.1152/ajpheart.00628.2019.
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Arterial membrane potential ( Vm) is set by an active interplay among ion channels whose principal function is to set contractility through the gating of voltage-operated Ca2+ channels. To garner an understanding of this electrical parameter, the activity of each channel must be established under near-physiological conditions, a significant challenge given their small magnitude. The inward rectifying K+ (KIR) channel is illustrative of the problem, as its outward “physiological” component is almost undetectable. This study describes a stepwise approach to dissect small ionic currents at physiological Vm using endothelial and smooth muscle cells freshly isolated from rat cerebral arteries. We highlight three critical steps, beginning with the voltage clamping of vascular cells bathed in physiological solutions while maintaining a giga-ohm seal. KIR channels are then inhibited (micromolar Ba2+) so that a difference current can be created, once Ba2+ traces are corrected for the changing seal resistance and subtle instrument drift, pulling the reversal potential rightward. The latter is a new procedure and entails the alignment of whole cell current traces at a voltage where KIR is silent and other channels exhibit limited activity. We subsequently introduced corrected and uncorrected currents into computer models of the arterial wall to show how these subtle adjustments markedly impact the importance of KIR in Vm and arterial tone regulation. We argue that this refined approach can be used on an array of vascular ion channels to build a complete picture of how they dynamically interact to set arterial tone in key organs like the brain. NEW & NOTEWORTHY This work describes a stepwise approach to resolve small ionic currents involved in controlling Vm in resistance arteries. Using this new methodology, we particularly resolved the outward component of the KIR current in native vascular cells, voltage clamped in near-physiological conditions. This novel approach can be applied to any other vascular currents and used to better interpret how vascular ion channels cooperate to control arterial tone.
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Tuteja, Dipika, Danyan Xu, Valeriy Timofeyev, Ling Lu, Dipika Sharma, Zhao Zhang, Yanfang Xu i in. "Differential expression of small-conductance Ca2+-activated K+ channels SK1, SK2, and SK3 in mouse atrial and ventricular myocytes". American Journal of Physiology-Heart and Circulatory Physiology 289, nr 6 (grudzień 2005): H2714—H2723. http://dx.doi.org/10.1152/ajpheart.00534.2005.
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Small-conductance Ca2+-activated K+ channels (SK channels, KCa channels) have been reported in excitable cells, where they aid in integrating changes in intracellular Ca2+ with membrane potential. We recently reported for the first time the functional existence of SK2 (KCa2.2) channels in human and mouse cardiac myocytes. Here, we report cloning of SK1 (KCa2.1) and SK3 (KCa2.3) channels from mouse atria and ventricles using RT-PCR. Full-length transcripts and their variants were detected for both SK1 and SK3 channels. Variants of mouse SK1 channel (mSK1) differ mainly in the COOH-terminal structure, affecting a portion of the sixth transmembrane segment (S6) and the calmodulin binding domain (CaMBD). Mouse SK3 channel (mSK3) differs not only in the number of polyglutamine repeats in the NH2 terminus but also in the intervening sequences between the polyglutamine repeats. Full-length cardiac mSK1 and mSK3 show 99 and 91% nucleotide identity with those of mouse colon SK1 and SK3, respectively. Quantification of SK1, SK2, and SK3 transcripts between atria and ventricles was performed using real-time quantitative RT-PCR from single, isolated cardiomyocytes. SK1 transcript was found to be more abundant in atria compared with ventricles, similar to the previously reported finding for SK2 channel. In contrast, SK3 showed similar levels of expression in atria and ventricles. Together, our data are the first to indicate the presence of the three different isoforms of SK channels in heart and the differential expression of SK1 and SK2 in mouse atria and ventricles. Because of the marked differential expression of SK channel isoforms in heart, specific ligands for Ca2+-activated K+ currents may offer a unique therapeutic opportunity to modify atrial cells without interfering with ventricular myocytes.
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Ke, Wentao, Xiangdi Yu i Yutong Gao. "Neonatal exposure to sevoflurane caused learning and memory impairment via dysregulating SK2 channel endocytosis". Science Progress 104, nr 3 (lipiec 2021): 003685042110437. http://dx.doi.org/10.1177/00368504211043763.
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Numerous studies have demonstrated that anesthetics’ exposure to neonates imposes toxicity on the developing brain but the underlying mechanisms need to be further elucidated. Our present study aimed to explore the role of small conductance Ca2+-activated potassium channel type2 in memory and learning dysfunction caused by exposing neonates to sevoflurane. Postnatal day 7 Sprague-Dawley rats and hemagglutinin-tagged small conductance Ca2+-activated potassium channel type2 channel transfected COS-7 cells were exposed to sevoflurane and the trafficking of small conductance Ca2+-activated potassium channel type2 channels was analyzed; furthermore, memory and learning ability was analyzed by the Morris water maze test on postnatal day30–35 (juvenile period). Our results showed that sevoflurane exposure inhibited small conductance Ca2+-activated potassium channel type2 channel endocytosis in both hippocampi of postnatal day 7 rats and hemagglutinin-tagged small conductance Ca2+-activated potassium channel type2 channel transfected COS-7 cells and the memory and learning ability was impaired in the juvenile period after sevoflurane exposure to neonatal rats. Herein, our results demonstrated that exposing neonates to sevoflurane caused memory and learning impairment via dysregulating small conductance Ca2+-activated potassium channel type2 channels endocytosis.
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Wang, Yueyu, Jianjun Song, Xianying Dai i Tianlong Zhao. "Study on uniaxial stress intensity of MOS channels along different crystal planes induced by SiN-film". Materials Express 10, nr 10 (31.10.2020): 1753–57. http://dx.doi.org/10.1166/mex.2020.1803.
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The process conditions for depositing SiN film on small-sized MOS along different crystal face channels to introduce stress are the same. However, since the elastic stiffness coefficient of channel Si material is anisotropic, the stress intensity introduced in small-sized MOS channels along different crystal planes is different. It is necessary to consider it while designing and manufacturing small-sized strained MOS. In this paper, the uniaxial strained Si PMOS and NMOS with 40 nm channel along different crystal faces were produced by compressive stress and tensile stress SiN film respectively. Quantitative results of uniaxial stress intensity of MOS channel along different crystal planes induced by the same process SiN films were obtained by measuring device transfer characteristics and corresponding theoretical calculations. The results indicate that, for strained NMOS induced by the tensile stress SiN film, (100) and (110) crystal plane channels are subjected to 0.8 GPa and 1.6 GPa tensile stress; for strained PMOS induced by the compressive stress SiN film, (100), (110), and (111) crystal plane channels are subjected to compressive stresses of 1.1 GPa, 0.8 GPa and 1.6 Gpa, respectively.
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Taylor, Mark S., i Joseph N. Benoit. "Effect of milrinone on small mesenteric artery vasoconstriction: role of K+channels". American Journal of Physiology-Gastrointestinal and Liver Physiology 277, nr 1 (1.07.1999): G69—G78. http://dx.doi.org/10.1152/ajpgi.1999.277.1.g69.
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We examined whether milrinone-mediated attenuation of small mesenteric artery vasoconstriction results predominantly from the activation of vascular smooth muscle K+ channels. Resistance arteries (∼150 μm) were dissected from rat mesentery and were mounted on a wire myograph. Isometric force development in response to increasing concentrations of norepinephrine (NE) was monitored before and after treatment with the type 3 phosphodiesterase inhibitor milrinone. Milrinone significantly reduced NE-induced vasoconstriction, attenuating both NE sensitivity and maximal tension generation. Inhibition of ATP-sensitive K+channels or voltage-gated K+channels did not prevent the milrinone-induced attenuation of NE responses. Blockade of inwardly rectifying K+ channels or Ca2+-sensitive K+ channels prevented the milrinone-mediated reduction in NE sensitivity, but this effect was apparently due to direct enhancement of vasoconstrictor responsiveness rather than interference with the mechanism of milrinone action. In addition, milrinone elicited substantial relaxation in vessels preconstricted with 100 mM KCl. This effect was mimicked by the adenylyl cyclase activator forskolin and was reversed by the Rp diastereomer of cAMP, which is a cAMP-dependent protein kinase (PKA) inhibitor. Our results indicate that cAMP/PKA-mediated impairment of vasoconstriction may occur without the contribution of K+ channel regulation.
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Bernsteiner, Harald, Eva-Maria Zangerl-Plessl, Xingyu Chen i Anna Stary-Weinzinger. "Conduction through a narrow inward-rectifier K+ channel pore". Journal of General Physiology 151, nr 10 (11.09.2019): 1231–46. http://dx.doi.org/10.1085/jgp.201912359.
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Inwardly rectifying potassium (Kir) channels play a key role in controlling membrane potentials in excitable and unexcitable cells, thereby regulating a plethora of physiological processes. G-protein–gated Kir channels control heart rate and neuronal excitability via small hyperpolarizing outward K+ currents near the resting membrane potential. Despite recent breakthroughs in x-ray crystallography and cryo-EM, the gating and conduction mechanisms of these channels are poorly understood. MD simulations have provided unprecedented details concerning the gating and conduction mechanisms of voltage-gated K+ and Na+ channels. Here, we use multi-microsecond–timescale MD simulations based on the crystal structures of GIRK2 (Kir3.2) bound to phosphatidylinositol-4,5-bisphosphate to provide detailed insights into the channel’s gating dynamics, including insights into the behavior of the G-loop gate. The simulations also elucidate the elementary steps that underlie the movement of K+ ions through an inward-rectifier K+ channel under an applied electric field. Our simulations suggest that K+ permeation might occur via direct knock-on, similar to the mechanism recently shown for Kv channels.
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Hou, Shangwei, Stefan H. Heinemann i Toshinori Hoshi. "Modulation of BKCa Channel Gating by Endogenous Signaling Molecules". Physiology 24, nr 1 (luty 2009): 26–35. http://dx.doi.org/10.1152/physiol.00032.2008.
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Large-conductance Ca2+- and voltage-activated K+ (BKCa, MaxiK, or Slo1) channels are expressed in almost every tissue in our body and participate in many critical functions such as neuronal excitability, vascular tone regulation, and neurotransmitter release. The functional versatility of BKCa channels owes in part to the availability of a spectacularly wide array of biological modulators of the channel function. In this review, we focus on modulation of BKCa channels by small endogenous molecules, emphasizing their molecular mechanisms. The mechanistic information available from studies on the small naturally occurring modulators is expected to contribute to our understanding of the physiological and pathophysiological roles of BKCa channels.