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Sample records for doubly selective channels

  1. Block Transmissions over Doubly Selective Channels: Iterative Channel Estimation and Turbo Equalization

    NASA Astrophysics Data System (ADS)

    Fang, Kun; Rugini, Luca; Leus, Geert

    2010-12-01

    Modern wireless communication systems require high transmission rates, giving rise to frequency selectivity due to multipath propagation. In addition, high-mobility terminals and scatterers induce Doppler shifts that introduce time selectivity. Therefore, advanced techniques are needed to accurately model the time- and frequency-selective (i.e., doubly selective) channels and to counteract the related performance degradation. In this paper, we develop new receivers for orthogonal frequency-division multiplexing (OFDM) systems and single-carrier (SC) systems in doubly selective channels by embedding the channel estimation task within low-complexity block turbo equalizers. Linear minimum mean-squared error (MMSE) pilot-assisted channel estimators are presented, and the soft data estimates from the turbo equalizers are used to improve the quality of the channel estimates.

  2. Entropy production of doubly stochastic quantum channels

    NASA Astrophysics Data System (ADS)

    Müller-Hermes, Alexander; Stilck França, Daniel; Wolf, Michael M.

    2016-02-01

    We study the entropy increase of quantum systems evolving under primitive, doubly stochastic Markovian noise and thus converging to the maximally mixed state. This entropy increase can be quantified by a logarithmic-Sobolev constant of the Liouvillian generating the noise. We prove a universal lower bound on this constant that stays invariant under taking tensor-powers. Our methods involve a new comparison method to relate logarithmic-Sobolev constants of different Liouvillians and a technique to compute logarithmic-Sobolev inequalities of Liouvillians with eigenvectors forming a projective representation of a finite abelian group. Our bounds improve upon similar results established before and as an application we prove an upper bound on continuous-time quantum capacities. In the last part of this work we study entropy production estimates of discrete-time doubly stochastic quantum channels by extending the framework of discrete-time logarithmic-Sobolev inequalities to the quantum case.

  3. Entropy production of doubly stochastic quantum channels

    SciTech Connect

    Müller-Hermes, Alexander; Stilck França, Daniel Wolf, Michael M.

    2016-02-15

    We study the entropy increase of quantum systems evolving under primitive, doubly stochastic Markovian noise and thus converging to the maximally mixed state. This entropy increase can be quantified by a logarithmic-Sobolev constant of the Liouvillian generating the noise. We prove a universal lower bound on this constant that stays invariant under taking tensor-powers. Our methods involve a new comparison method to relate logarithmic-Sobolev constants of different Liouvillians and a technique to compute logarithmic-Sobolev inequalities of Liouvillians with eigenvectors forming a projective representation of a finite abelian group. Our bounds improve upon similar results established before and as an application we prove an upper bound on continuous-time quantum capacities. In the last part of this work we study entropy production estimates of discrete-time doubly stochastic quantum channels by extending the framework of discrete-time logarithmic-Sobolev inequalities to the quantum case.

  4. Fast estimation of sparse doubly spread acoustic channels.

    PubMed

    Zeng, Wen-Jun; Xu, Wen

    2012-01-01

    The estimation of doubly spread underwater acoustic channels is addressed. By exploiting the sparsity in the delay-Doppler domain, this paper proposes a fast projected gradient method (FPGM) that can handle complex-valued data for estimating the delay-Doppler spread function of a time-varying channel. The proposed FPGM formulates the sparse channel estimation as a complex-valued convex optimization using an [script-l](1)-norm constraint. Conventional approaches to complex-valued optimization split the complex variables into their real and imaginary parts; this doubles the dimension compared with the original problem and may break the special data structure. Unlike the conventional methods, the proposed method directly handles the complex variables as a whole without splitting them into real numbers; hence the dimension will not increase. By exploiting the block Toeplitz-like structure of the coefficient matrix, the computational complexity of the FPGM is reduced to O(LNlogN), where L is the dimension of the Doppler shift and N is the signal length. Simulation results verify the accuracy and efficiency of the FPGM, indicating that is robust to parameter selection and is orders-of-magnitude faster than standard convex optimization algorithms. The Kauai experimental data processing results are also provided to demonstrate the performance of the proposed algorithm.

  5. Fully Coupled Channel Approach to Doubly Strange s-Shell Hypernuclei

    SciTech Connect

    Nemura, H.; Shinmura, S.; Akaishi, Y.; Myint, Khin Swe

    2005-05-27

    We describe ab initio calculations of doubly strange, S=-2, s-shell hypernuclei ({sub {lambda}}{sub {lambda}}{sup 4}H, {sub {lambda}}{sub {lambda}}{sup 5}H, {sub {lambda}}{sub {lambda}}{sup 5}He, and {sub {lambda}}{sub {lambda}}{sup 6}He) as a first attempt to explore the few-body problem of the full-coupled channel scheme for these systems. The wave function includes {lambda}{lambda}, {lambda}{sigma}, N{xi}, and {sigma}{sigma} channels. Minnesota NN, D2{sup '} YN, and simulated YY potentials based on the Nijmegen hard-core model are used. Bound-state solutions of these systems are obtained. We find that a set of phenomenological B{sub 8}B{sub 8} interactions among the octet baryons in S=0,-1, and -2 sectors, which is consistent with all of the available experimental binding energies of S=0,-1, and -2 s-shell (hyper)nuclei, can predict a particle stable bound state of {sub {lambda}}{sub {lambda}}{sup 4}H. For {sub {lambda}}{sub {lambda}}{sup 5}H and {sub {lambda}}{sub {lambda}}{sup 5}He, {lambda}N-{sigma}N and {xi}N-{lambda}{sigma} potentials significantly affect the net {lambda}{lambda}-N{xi} coupling, and a large {xi} probability is obtained even for a weaker {lambda}{lambda}-N{xi} potential.

  6. Selecting Channels for Institutional Public Relations.

    ERIC Educational Resources Information Center

    Schwartz, Donald F.; Glynn, Carroll J.

    1989-01-01

    Examines communication decision-making in organizations by looking at the extent to which public relations executives have control over channel selection for the media mix in an overall public relations program. Shows a variety of structures and procedures for channel selection decisions in United States organizations. (SR)

  7. Image Discrimination Models With Stochastic Channel Selection

    NASA Technical Reports Server (NTRS)

    Ahumada, Albert J., Jr.; Beard, Bettina L.; Null, Cynthia H. (Technical Monitor)

    1995-01-01

    Many models of human image processing feature a large fixed number of channels representing cortical units varying in spatial position (visual field direction and eccentricity) and spatial frequency (radial frequency and orientation). The values of these parameters are usually sampled at fixed values selected to ensure adequate overlap considering the bandwidth and/or spread parameters, which are usually fixed. Even high levels of overlap does not always ensure that the performance of the model will vary smoothly with image translation or scale changes. Physiological measurements of bandwidth and/or spread parameters result in a broad distribution of estimated parameter values and the prediction of some psychophysical results are facilitated by the assumption that these parameters also take on a range of values. Selecting a sample of channels from a continuum of channels rather than using a fixed set can make model performance vary smoothly with changes in image position, scale, and orientation. It also facilitates the addition of spatial inhomogeneity, nonlinear feature channels, and focus of attention to channel models.

  8. HCN Channels Modulators: The Need for Selectivity

    PubMed Central

    Romanelli, Maria Novella; Sartiani, Laura; Masi, Alessio; Mannaioni, Guido; Manetti, Dina; Mugelli, Alessandro; Cerbai, Elisabetta

    2016-01-01

    Hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels, the molecular correlate of the hyperpolarization-activated current (If/Ih), are membrane proteins which play an important role in several physiological processes and various pathological conditions. In the Sino Atrial Node (SAN) HCN4 is the target of ivabradine, a bradycardic agent that is, at the moment, the only drug which specifically blocks If. Nevertheless, several other pharmacological agents have been shown to modulate HCN channels, a property that may contribute to their therapeutic activity and/or to their side effects. HCN channels are considered potential targets for developing drugs to treat several important pathologies, but a major issue in this field is the discovery of isoform-selective compounds, owing to the wide distribution of these proteins into the central and peripheral nervous systems, heart and other peripheral tissues. This survey is focused on the compounds that have been shown, or have been designed, to interact with HCN channels and on their binding sites, with the aim to summarize current knowledge and possibly to unveil useful information to design new potent and selective modulators. PMID:26975509

  9. Structure and selectivity in bestrophin ion channels

    SciTech Connect

    Yang, Tingting; Liu, Qun; Kloss, Brian; Bruni, Renato; Kalathur, Ravi C.; Guo, Youzhong; Kloppmann, Edda; Rost, Burkhard; Colecraft, Henry M.; Hendrickson, Wayne A.

    2014-09-25

    Human bestrophin 1 (hBest1) is a calcium-activated chloride channel from the retinal pigment epithelium, where it can suffer mutations associated with vitelliform macular degeneration, or Best disease. We describe the structure of a bacterial homolog (KpBest) of hBest1 and functional characterizations of both channels. KpBest is a pentamer that forms a five-helix transmembrane pore, closed by three rings of conserved hydrophobic residues, and has a cytoplasmic cavern with a restricted exit. From electrophysiological analysis of structure-inspired mutations in KpBest and hBest1, we find a subtle control of ion selectivity in the bestrophins, including reversal of anion/cation selectivity, and dramatic activation by mutations at the exit restriction. Lastly, a homology model of hBest1 shows the locations of disease-causing mutations and suggests possible roles in regulation.

  10. Structure and selectivity in bestrophin ion channels

    DOE PAGES

    Yang, Tingting; Liu, Qun; Kloss, Brian; ...

    2014-09-25

    Human bestrophin 1 (hBest1) is a calcium-activated chloride channel from the retinal pigment epithelium, where it can suffer mutations associated with vitelliform macular degeneration, or Best disease. We describe the structure of a bacterial homolog (KpBest) of hBest1 and functional characterizations of both channels. KpBest is a pentamer that forms a five-helix transmembrane pore, closed by three rings of conserved hydrophobic residues, and has a cytoplasmic cavern with a restricted exit. From electrophysiological analysis of structure-inspired mutations in KpBest and hBest1, we find a subtle control of ion selectivity in the bestrophins, including reversal of anion/cation selectivity, and dramatic activationmore » by mutations at the exit restriction. Lastly, a homology model of hBest1 shows the locations of disease-causing mutations and suggests possible roles in regulation.« less

  11. Amiloride Selectively Blocks the Low Threshold (T) Calcium Channel

    NASA Astrophysics Data System (ADS)

    Tang, Cha-Min; Presser, Fernando; Morad, Martin

    1988-04-01

    More than one type of voltage-gated calcium channel has been identified in muscle cells and neurons. Many specific organic and inorganic blockers of the conventional, slowly inactivating high threshold (L) calcium channel have been reported. No specific blockers of the low threshold (T) channel have been as yet identified. Amiloride, a potassium sparing diuretic, has now been shown to selectively block the low threshold calcium channel in mouse neuroblastoma and chick dorsal root ganglion neurons. The selective blockade of the T-type calcium channel will allow identification of this channel in different tissues and characterization of its specific physiological role.

  12. Channel selective tunnelling through a nanographene assembly.

    PubMed

    Wong, H S; Feng, X; Müllen, K; Chandrasekhar, N; Durkan, C

    2012-03-09

    We report selective tunnelling through a nanographene intermolecular tunnel junction achieved via scanning tunnelling microscope tip functionalization with hexa-peri-hexabenzocoronene (HBC) molecules. This leads to an offset in the alignment between the energy levels of the tip and the molecular assembly, resulting in the imaging of a variety of distinct charge density patterns in the HBC assembly, not attainable using a bare metallic tip. Different tunnelling channels can be selected by the application of an electric field in the tunnelling junction, which changes the condition of the HBC on the tip. Density functional theory-based calculations relate the imaged HBC patterns to the calculated molecular orbitals at certain energy levels. These patterns bear a close resemblance to the π-orbital states of the HBC molecule calculated at the relevant energy levels, mainly below the Fermi energy of HBC. This correlation demonstrates the ability of an HBC functionalized tip as regards accessing an energy range that is restricted to the usual operating bias range around the Fermi energy with a normal metallic tip at room temperature. Apart from relating to molecular orbitals, some patterns could also be described in association with the Clar aromatic sextet formula. Our observations may help pave the way towards the possibility of controlling charge transport between organic interfaces.

  13. AVHRR channel selection for land cover classification

    USGS Publications Warehouse

    Maxwell, S.K.; Hoffer, R.M.; Chapman, P.L.

    2002-01-01

    Mapping land cover of large regions often requires processing of satellite images collected from several time periods at many spectral wavelength channels. However, manipulating and processing large amounts of image data increases the complexity and time, and hence the cost, that it takes to produce a land cover map. Very few studies have evaluated the importance of individual Advanced Very High Resolution Radiometer (AVHRR) channels for discriminating cover types, especially the thermal channels (channels 3, 4 and 5). Studies rarely perform a multi-year analysis to determine the impact of inter-annual variability on the classification results. We evaluated 5 years of AVHRR data using combinations of the original AVHRR spectral channels (1-5) to determine which channels are most important for cover type discrimination, yet stabilize inter-annual variability. Particular attention was placed on the channels in the thermal portion of the spectrum. Fourteen cover types over the entire state of Colorado were evaluated using a supervised classification approach on all two-, three-, four- and five-channel combinations for seven AVHRR biweekly composite datasets covering the entire growing season for each of 5 years. Results show that all three of the major portions of the electromagnetic spectrum represented by the AVHRR sensor are required to discriminate cover types effectively and stabilize inter-annual variability. Of the two-channel combinations, channels 1 (red visible) and 2 (near-infrared) had, by far, the highest average overall accuracy (72.2%), yet the inter-annual classification accuracies were highly variable. Including a thermal channel (channel 4) significantly increased the average overall classification accuracy by 5.5% and stabilized interannual variability. Each of the thermal channels gave similar classification accuracies; however, because of the problems in consistently interpreting channel 3 data, either channel 4 or 5 was found to be a more

  14. Mojave Toxin: A Selective Ca(++) Channel Antagonist

    DTIC Science & Technology

    1988-07-01

    other than maitotoxin, blocking 3H-nitrendipine binding to the high affinity dihydropyridine receptor associated with the Ca++ channel, as well as... dihydropyridine receptors in rat synaptic membranes suggests that this toxin may be a useful proble of the Ca++ channel complex. It is not certain whether MoTX has...increase in intracellular Ca++ resulting from the binding of the toxin to dihydropyridine receptors coupled to Ca++ channels. The resolution of this

  15. A review of channel selection algorithms for EEG signal processing

    NASA Astrophysics Data System (ADS)

    Alotaiby, Turky; El-Samie, Fathi E. Abd; Alshebeili, Saleh A.; Ahmad, Ishtiaq

    2015-12-01

    Digital processing of electroencephalography (EEG) signals has now been popularly used in a wide variety of applications such as seizure detection/prediction, motor imagery classification, mental task classification, emotion classification, sleep state classification, and drug effects diagnosis. With the large number of EEG channels acquired, it has become apparent that efficient channel selection algorithms are needed with varying importance from one application to another. The main purpose of the channel selection process is threefold: (i) to reduce the computational complexity of any processing task performed on EEG signals by selecting the relevant channels and hence extracting the features of major importance, (ii) to reduce the amount of overfitting that may arise due to the utilization of unnecessary channels, for the purpose of improving the performance, and (iii) to reduce the setup time in some applications. Signal processing tools such as time-domain analysis, power spectral estimation, and wavelet transform have been used for feature extraction and hence for channel selection in most of channel selection algorithms. In addition, different evaluation approaches such as filtering, wrapper, embedded, hybrid, and human-based techniques have been widely used for the evaluation of the selected subset of channels. In this paper, we survey the recent developments in the field of EEG channel selection methods along with their applications and classify these methods according to the evaluation approach.

  16. Potassium-selective block of barium permeation through single KcsA channels.

    PubMed

    Piasta, Kene N; Theobald, Douglas L; Miller, Christopher

    2011-10-01

    Ba(2+), a doubly charged analogue of K(+), specifically blocks K(+) channels by virtue of electrostatic stabilization in the permeation pathway. Ba(2+) block is used here as a tool to determine the equilibrium binding affinity for various monovalent cations at specific sites in the selectivity filter of a noninactivating mutant of KcsA. At high concentrations of external K(+), the block-time distribution is double exponential, marking at least two Ba(2+) sites in the selectivity filter, in accord with a Ba(2+)-containing crystal structure of KcsA. By analyzing block as a function of extracellular K(+), we determined the equilibrium dissociation constant of K(+) and of other monovalent cations at an extracellular site, presumably S1, to arrive at a selectivity sequence for binding at this site: Rb(+) (3 µM) > Cs(+) (23 µM) > K(+) (29 µM) > NH(4)(+) (440 µM) > Na(+) and Li(+) (>1 M). This represents an unusually high selectivity for K(+) over Na(+), with |ΔΔG(0)| of at least 7 kcal mol(-1). These results fit well with other kinetic measurements of selectivity as well as with the many crystal structures of KcsA in various ionic conditions.

  17. Quantum Interference and Selectivity through Biological Ion Channels

    PubMed Central

    Salari, Vahid; Naeij, Hamidreza; Shafiee, Afshin

    2017-01-01

    The mechanism of selectivity in ion channels is still an open question in biology for more than half a century. Here, we suggest that quantum interference can be a solution to explain the selectivity mechanism in ion channels since interference happens between similar ions through the same size of ion channels. In this paper, we simulate two neighboring ion channels on a cell membrane with the famous double-slit experiment in physics to investigate whether there is any possibility of matter-wave interference of ions via movement through ion channels. Our obtained decoherence timescales indicate that the quantum states of ions can only survive for short times, i.e. ≈100 picoseconds in each channel and ≈17–53 picoseconds outside the channels, giving the result that the quantum interference of ions seems unlikely due to environmental decoherence. However, we discuss our results and raise few points, which increase the possibility of interference. PMID:28134331

  18. Quantum Interference and Selectivity through Biological Ion Channels

    NASA Astrophysics Data System (ADS)

    Salari, Vahid; Naeij, Hamidreza; Shafiee, Afshin

    2017-01-01

    The mechanism of selectivity in ion channels is still an open question in biology for more than half a century. Here, we suggest that quantum interference can be a solution to explain the selectivity mechanism in ion channels since interference happens between similar ions through the same size of ion channels. In this paper, we simulate two neighboring ion channels on a cell membrane with the famous double-slit experiment in physics to investigate whether there is any possibility of matter-wave interference of ions via movement through ion channels. Our obtained decoherence timescales indicate that the quantum states of ions can only survive for short times, i.e. ≈100 picoseconds in each channel and ≈17–53 picoseconds outside the channels, giving the result that the quantum interference of ions seems unlikely due to environmental decoherence. However, we discuss our results and raise few points, which increase the possibility of interference.

  19. Equilibrium selectivity alone does not create K+-selective ion conduction in K+ channels

    NASA Astrophysics Data System (ADS)

    Liu, Shian; Lockless, Steve W.

    2013-11-01

    Potassium (K+) channels are selective for K+ over Na+ ions during their transport across membranes. We and others have previously shown that tetrameric K+ channels are primarily occupied by K+ ions in their selectivity filters under physiological conditions, demonstrating the channel’s intrinsic equilibrium preference for K+ ions. Based on this observation, we hypothesize that the preference for K+ ions over Na+ ions in the filter determines its selectivity during ion conduction. Here, we ask whether non-selective cation channels, which share an overall structure and similar individual ion-binding sites with K+ channels, have an ion preference at equilibrium. The variants of the non-selective Bacillus cereus NaK cation channel we examine are all selective for K+ over Na+ ions at equilibrium. Thus, the detailed architecture of the K+ channel selectivity filter, and not only its equilibrium ion preference, is fundamental to the generation of selectivity during ion conduction.

  20. Physical origin of selectivity in ionic channels of biological membranes.

    PubMed Central

    Laio, A; Torre, V

    1999-01-01

    This paper shows that the selectivity properties of monovalent cation channels found in biological membranes can originate simply from geometrical properties of the inner core of the channel without any critical contribution from electrostatic interactions between the permeating ions and charged or polar groups. By using well-known techniques of statistical mechanics, such as the Langevin equations and Kramer theory of reaction rates, a theoretical equation is provided relating the permeability ratio PB/PA between ions A and B to simple physical properties, such as channel geometry, thermodynamics of ion hydration, and electrostatic interactions between the ion and charged (or polar) groups. Diffusive corrections and recrossing rates are also considered and evaluated. It is shown that the selectivity found in usual K+, gramicidin, Na+, cyclic nucleotide gated, and end plate channels can be explained also in the absence of any charged or polar group. If these groups are present, they significantly change the permeability ratio only if the ion at the selectivity filter is in van der Waals contact with them, otherwise these groups simply affect the channel conductance, lowering the free energy barrier of the same amount for the two ions, thus explaining why single channel conductance, as it is experimentally observed, can be very different in channels sharing the same selectivity sequence. The proposed theory also provides an estimate of channel minimum radius for K+, gramicidin, Na+, and cyclic nucleotide gated channels. PMID:9876129

  1. Monte Carlo study of gating and selection in potassium channels

    NASA Astrophysics Data System (ADS)

    Andreucci, Daniele; Bellaveglia, Dario; Cirillo, Emilio N. M.; Marconi, Silvia

    2011-08-01

    The study of selection and gating in potassium channels is a very important issue in modern biology. Indeed, such structures are known in essentially all types of cells in all organisms where they play many important functional roles. The mechanism of gating and selection of ionic species is not clearly understood. In this paper we study a model in which gating is obtained via an affinity-switching selectivity filter. We discuss the dependence of selectivity and efficiency on the cytosolic ionic concentration and on the typical pore open state duration. We demonstrate that a simple modification in the way in which the selectivity filter is modeled yields larger channel efficiency.

  2. Drosotoxin, a selective inhibitor of tetrodotoxin-resistant sodium channels.

    PubMed

    Zhu, Shunyi; Gao, Bin; Deng, Meichun; Yuan, Yuzhe; Luo, Lan; Peigneur, Steve; Xiao, Yucheng; Liang, Songping; Tytgat, Jan

    2010-10-15

    The design of animal toxins with high target selectivity has long been a goal in protein engineering. Based on evolutionary relationship between the Drosophila antifungal defensin (drosomycin) and scorpion depressant Na(+) channel toxins, we exploited a strategy to create a novel chimeric molecule (named drosotoxin) with high selectivity for channel subtypes, which was achieved by using drosomycin to substitute the structural core of BmKITc, a depressant toxin acting on both insect and mammalian Na(+) channels. Recombinant drosotoxin selectively inhibited tetrodotoxin-resistant (TTX-R) Na(+) channels in rat dorsal root ganglion (DRG) neurons with a 50% inhibitory concentration (IC(50)) of 2.6+/-0.5muM. This chimeric peptide showed no activity on K(+), Ca(2+) and TTX-sensitive (TTX-S) Na(+) channels in rat DRG neurons and Drosophila para/tipE channels at micromolar concentrations. Drosotoxin represents the first chimeric toxin and example of a non-toxic core scaffold with high selectivity on mammalian TTX-R Na(+) channels.

  3. Anion conductance selectivity mechanism of the CFTR chloride channel.

    PubMed

    Linsdell, Paul

    2016-04-01

    All ion channels are able to discriminate between substrate ions to some extent, a process that involves specific interactions between permeant anions and the so-called selectivity filter within the channel pore. In the cystic fibrosis transmembrane conductance regulator (CFTR) anion-selective channel, both anion relative permeability and anion relative conductance are dependent on anion free energy of hydration--anions that are relatively easily dehydrated tend to show both high permeability and low conductance. In the present work, patch clamp recording was used to investigate the relative conductance of different anions in CFTR, and the effect of mutations within the channel pore. In constitutively-active E1371Q-CFTR channels, the anion conductance sequence was Cl(-) > NO3(-) > Br(-) > formate > SCN(-) > I(-). A mutation that disrupts anion binding in the inner vestibule of the pore (K95Q) disrupted anion conductance selectivity, such that anions with different permeabilities showed almost indistinguishable conductances. Conversely, a mutation at the putative narrowest pore region that is known to disrupt anion permeability selectivity (F337A) had minimal effects on anion relative conductance. Ion competition experiments confirmed that relatively tight binding of permeant anions resulted in relatively low conductance. These results suggest that the relative affinity of ion binding in the inner vestibule of the pore controls the relative conductance of different permeant anions in CFTR, and that the pore has two physically distinct anion selectivity filters that act in series to control anion conductance selectivity and anion permeability selectivity respectively.

  4. Principles Governing Metal Ion Selectivity in Ion Channel Proteins

    NASA Astrophysics Data System (ADS)

    Lim, Carmay

    2014-03-01

    Our research interests are to (i) unravel the principles governing biological processes and use them to identify novel drug targets and guide drug design, and (ii) develop new methods for studying macromolecular interactions. This talk will provide an overview of our work in these two areas and an example of how our studies have helped to unravel the principles underlying the conversion of Ca2+-selective to Na+-selective channels. Ion selectivity of four-domain voltage-gated Ca2+(Cav) and sodium (Nav) channels, which is controlled by the selectivity filter (SF, the narrowest region of an open pore), is crucial for electrical signaling. Over billions of years of evolution, mutation of the Glu from domain II/III in the EEEE/DEEA SF of Ca2+-selective Cav channels to Lys made these channels Na+-selective. This talk will delineate the physical principles why Lys is sufficient for Na+/Ca2+selectivity and why the DEKA SF is more Na+-selective than the DKEA one.

  5. Structural correlates of selectivity and inactivation in potassium channels

    PubMed Central

    McCoy, Jason G.; Nimigean, Crina M.

    2011-01-01

    Potassium channels are involved in a tremendously diverse range of physiological applications requiring distinctly different functional properties. Not surprisingly, the amino acid sequences for these proteins are diverse as well, except for the region that has been ordained the “selectivity filter”. The goal of this review is to examine our current understanding of the role of the selectivity filter and regions adjacent to it in specifying selectivity as well as its role in gating/inactivation and possible mechanisms by which these processes are coupled. Our working hypothesis is that an amino acid network behind the filter modulates selectivity in channels with the same signature sequence while at the same time affecting channel inactivation properties. PMID:21958666

  6. Potent inhibition of native TREK-1 K+ channels by selected dihydropyridine Ca2+ channel antagonists.

    PubMed

    Liu, Haiyan; Enyeart, Judith A; Enyeart, John J

    2007-10-01

    Bovine adrenal zona fasciculata (AZF) cells express bTREK-1 background K+ channels that set the resting membrane potential. Whole-cell and single-channel patch-clamp recording were used to compare five Ca2+ channel antagonists with respect to their potency as inhibitors of native bTREK-1 K+ channels. The dihydropyridine (DHP) Ca2+ channel antagonists amlodipine and niguldipine potently and specifically inhibited bTREK-1 with IC50 values of 0.43 and 0.75 microM, respectively. The other Ca2+ channel antagonists, including the DHP nifedipine, the diphenyldiperazine flunarizine, and the cannabinoid anandamide were less potent, with IC50 values of 8.18, 2.48, and 5.07 microM, respectively. Additional studies with the highly prescribed antihypertensive amlodipine showed that inhibition of bTREK-1 by this agent was voltage-independent and specific. At concentrations that produced near complete block of bTREK-1, amlodipine inhibited voltage-gated Kv1.4 K+ and T-type Ca2+ currents in AZF cells by less than 10%. At the single-channel level, amlodipine reduced bTREK-1 open probability without altering the unitary conductance. The results demonstrate that selected DHP L-type Ca2+ channel antagonists potently inhibit native bTREK-1 K+ channels, whereas other Ca2+ channel antagonists also inhibit bTREK-1 at higher concentrations. Collectively, organic Ca2+ channel antagonists make up the most potent class of TREK-1 inhibitors yet described. Because TREK-1 K+ channels are widely expressed in the central nervous and cardiovascular systems, it is possible that some of the therapeutic or toxic effects of frequently prescribed drugs such as amlodipine may be due to their interaction with TREK-1 K+ rather L-type Ca2+ channels.

  7. Doubly fed induction machine

    DOEpatents

    Skeist, S. Merrill; Baker, Richard H.

    2005-10-11

    An electro-mechanical energy conversion system coupled between an energy source and an energy load including an energy converter device having a doubly fed induction machine coupled between the energy source and the energy load to convert the energy from the energy source and to transfer the converted energy to the energy load and an energy transfer multiplexer coupled to the energy converter device to control the flow of power or energy through the doubly fed induction machine.

  8. Modulation of mechanosensitive calcium-selective cation channels by temperature

    NASA Technical Reports Server (NTRS)

    Ding, J. P.; Pickard, B. G.

    1993-01-01

    Gating of associations of mechanosensitive Ca(2+)-selective cation co-channels in the plasmalemma of onion epidermis has a strong and unusual temperature dependence. Tension-dependent activity rises steeply as temperature is lowered from 25 degrees C to about 6 degrees C, but drops to a low level at about 5 degrees C. Under the conditions tested (with Mg2+ and K+ at the cytosolic face of outside-out membrane patches), promotion results both from more bursting at all observed linkage levels and from longer duration of bursts of co-channels linked as quadruplets and quintuplets. Co-channel conductance decreases linearly, but only modestly, with declining temperature. It is proposed that these and related mechanosensitive channels may participate in a variety of responses to temperature, including thermonasty, thermotropism, hydrotropism, and both cold damage and cold acclimation.

  9. Sodium channel selectivity filter regulates antiarrhythmic drug binding

    PubMed Central

    Sunami, Akihiko; Dudley, Samuel C.; Fozzard, Harry A.

    1997-01-01

    Local anesthetic antiarrhythmic drugs block Na+ channels and have important clinical uses. However, the molecular mechanism by which these drugs block the channel has not been established. The family of drugs is characterized by having an ionizable amino group and a hydrophobic tail. We hypothesized that the charged amino group of the drug may interact with charged residues in the channel’s selectivity filter. Mutation of the putative domain III selectivity filter residue of the adult rat skeletal muscle Na+ channel (μ1) K1237E increased resting lidocaine block, but no change was observed in block by neutral analogs of lidocaine. An intermediate effect on the lidocaine block resulted from K1237S and there was no effect from K1237R, implying an electrostatic effect of Lys. Mutation of the other selectivity residues, D400A (domain I), E755A (domain II), and A1529D (domain IV) allowed block by externally applied quaternary membrane-impermeant derivatives of lidocaine (QX314 and QX222) and accelerated recovery from block by internal QX314. Neo-saxitoxin and tetrodotoxin, which occlude the channel pore, reduced the amount of QX314 bound in D400A and A1529D, respectively. Block by outside QX314 in E755A was inhibited by mutation of residues in transmembrane segment S6 of domain IV that are thought to be part of an internal binding site. The results demonstrate that the Na+ channel selectivity filter is involved in interactions with the hydrophilic part of the drugs, and it normally limits extracellular access to and escape from their binding site just within the selectivity filter. Participation of the selectivity ring in antiarrhythmic drug binding and access locates this structure adjacent to the S6 segment. PMID:9391164

  10. Performance of Digital Communications over Selective Fading Channels.

    DTIC Science & Technology

    1983-09-01

    J. G. Proakis , Digital Communications, McGraw-Hill, New York, 1983. ’ [45] R. D. Gitlin, E. Y. Ho and 3. E. Mazo, "Passband equalization of...7 D-A142 427 PERFORNANCE OF DIGITAL COMMUNICATIONS OVER SELECTIVE 1/2 FADING CHRNNELS(U) ILLINOIS UNIV AT URBANA COORDINATED SCIENCE LAB F D GARBER...PERIOD COVERED Technical Report PERFORMANCE OF DIGITAL COMMUNICATIONS OVER 6. PERFORMING ORG. REPORT NUMBER SELECTIVE FADING CHANNELS R-998; UILU-ENG

  11. Gating of a pH-Sensitive K2P Potassium Channel by an Electrostatic Effect of Basic Sensor Residues on the Selectivity Filter

    PubMed Central

    Zúñiga, Leandro; Márquez, Valeria; González-Nilo, Fernando D.; Chipot, Christophe; Cid, L. Pablo; Sepúlveda, Francisco V.; Niemeyer, María Isabel

    2011-01-01

    K+ channels share common selectivity characteristics but exhibit a wide diversity in how they are gated open. Leak K2P K+ channels TASK-2, TALK-1 and TALK-2 are gated open by extracellular alkalinization. The mechanism for this alkalinization-dependent gating has been proposed to be the neutralization of the side chain of a single arginine (lysine in TALK-2) residue near the pore of TASK-2, which occurs with the unusual pKa of 8.0. We now corroborate this hypothesis by transplanting the TASK-2 extracellular pH (pHo) sensor in the background of a pHo-insensitive TASK-3 channel, which leads to the restitution of pHo-gating. Using a concatenated channel approach, we also demonstrate that for TASK-2 to open, pHo sensors must be neutralized in each of the two subunits forming these dimeric channels with no apparent cross-talk between the sensors. These results are consistent with adaptive biasing force analysis of K+ permeation using a model selectivity filter in wild-type and mutated channels. The underlying free-energy profiles confirm that either a doubly or a singly charged pHo sensor is sufficient to abolish ion flow. Atomic detail of the associated mechanism reveals that, rather than a collapse of the pore, as proposed for other K2P channels gated at the selectivity filter, an increased height of the energetic barriers for ion translocation accounts for channel blockade at acid pHo. Our data, therefore, strongly suggest that a cycle of protonation/deprotonation of pHo-sensing arginine 224 side chain gates the TASK-2 channel by electrostatically tuning the conformational stability of its selectivity filter. PMID:21283586

  12. Gating of a pH-sensitive K(2P) potassium channel by an electrostatic effect of basic sensor residues on the selectivity filter.

    PubMed

    Zúñiga, Leandro; Márquez, Valeria; González-Nilo, Fernando D; Chipot, Christophe; Cid, L Pablo; Sepúlveda, Francisco V; Niemeyer, María Isabel

    2011-01-25

    K(+) channels share common selectivity characteristics but exhibit a wide diversity in how they are gated open. Leak K(2P) K(+) channels TASK-2, TALK-1 and TALK-2 are gated open by extracellular alkalinization. The mechanism for this alkalinization-dependent gating has been proposed to be the neutralization of the side chain of a single arginine (lysine in TALK-2) residue near the pore of TASK-2, which occurs with the unusual pK(a) of 8.0. We now corroborate this hypothesis by transplanting the TASK-2 extracellular pH (pH(o)) sensor in the background of a pH(o)-insensitive TASK-3 channel, which leads to the restitution of pH(o)-gating. Using a concatenated channel approach, we also demonstrate that for TASK-2 to open, pH(o) sensors must be neutralized in each of the two subunits forming these dimeric channels with no apparent cross-talk between the sensors. These results are consistent with adaptive biasing force analysis of K(+) permeation using a model selectivity filter in wild-type and mutated channels. The underlying free-energy profiles confirm that either a doubly or a singly charged pH(o) sensor is sufficient to abolish ion flow. Atomic detail of the associated mechanism reveals that, rather than a collapse of the pore, as proposed for other K(2P) channels gated at the selectivity filter, an increased height of the energetic barriers for ion translocation accounts for channel blockade at acid pH(o). Our data, therefore, strongly suggest that a cycle of protonation/deprotonation of pH(o)-sensing arginine 224 side chain gates the TASK-2 channel by electrostatically tuning the conformational stability of its selectivity filter.

  13. Mechanosensory calcium-selective cation channels in epidermal cells

    NASA Technical Reports Server (NTRS)

    Ding, J. P.; Pickard, B. G.

    1993-01-01

    This paper explores the properties and likely functions of an epidermal Ca(2+)-selective cation channel complex activated by tension. As many as eight or nine linked or linkable equivalent conductance units or co-channels can open together. Open time for co-channel quadruplets and quintuplets tends to be relatively long with millimolar Mg2+ (but not millimolar Ca2+) at the cytosolic face of excised plasma membrane. Sensitivity to tension is regulated by transmembrane voltage and temperature. Under some circumstances channel activity is sychronized in rhythmic pulses. Certain lanthanides and a cytoskeleton-disturbing herbicide that inhibit gravitropic reception act on the channel system at low concentrations. Specifically, ethyl-N-phenylcarbamate promotes tension-dependent activity at micromolar levels. With moderate suction, Gd3+ provided at about 0.5 micromole at the extracellular face of the membrane promotes for several seconds but may then become inhibitory. Provision at 1-2 micromoles promotes and subsequently inhibits more vigorously (often abruptly and totally), and at high levels inhibits immediately. La3+, a poor gravitropic inhibitor, acts similarly but much more gradually and only at much higher concentrations. These properties, particularly these susceptibilities to modulation, indicate that in vivo the mechanosensitive channel must be mechanosensory and mechanoregulatory. It could serve to transduce the shear forces generated in the integrated wall-membrane-cytoskeleton system during turgor changes and cell expansion as well as transducing the stresses induced by gravity, touch and flexure. In so far as such transduction is modulated by voltage and temperature, the channels would also be sensors for these modalities as long as the wall-membrane-cytoskeleton system experiences mechanical stress.

  14. The structure and regulation of magnesium selective ion channels.

    PubMed

    Payandeh, Jian; Pfoh, Roland; Pai, Emil F

    2013-11-01

    The magnesium ion (Mg(2+)) is the most abundant divalent cation within cells. In man, Mg(2+)-deficiency is associated with diseases affecting the heart, muscle, bone, immune, and nervous systems. Despite its impact on human health, little is known about the molecular mechanisms that regulate magnesium transport and storage. Complete structural information on eukaryotic Mg(2+)-transport proteins is currently lacking due to associated technical challenges. The prokaryotic MgtE and CorA magnesium transport systems have recently succumbed to structure determination by X-ray crystallography, providing first views of these ubiquitous and essential Mg(2+)-channels. MgtE and CorA are unique among known membrane protein structures, each revealing a novel protein fold containing distinct arrangements of ten transmembrane-spanning α-helices. Structural and functional analyses have established that Mg(2+)-selectivity in MgtE and CorA occurs through distinct mechanisms. Conserved acidic side-chains appear to form the selectivity filter in MgtE, whereas conserved asparagines coordinate hydrated Mg(2+)-ions within the selectivity filter of CorA. Common structural themes have also emerged whereby MgtE and CorA sense and respond to physiologically relevant, intracellular Mg(2+)-levels through dedicated regulatory domains. Within these domains, multiple primary and secondary Mg(2+)-binding sites serve to staple these ion channels into their respective closed conformations, implying that Mg(2+)-transport is well guarded and very tightly regulated. The MgtE and CorA proteins represent valuable structural templates to better understand the related eukaryotic SLC41 and Mrs2-Alr1 magnesium channels. Herein, we review the structure, function and regulation of MgtE and CorA and consider these unique proteins within the expanding universe of ion channel and transporter structural biology.

  15. Deciphering Subtype-Selective Modulations in TRPA1 Biosensor Channels.

    PubMed

    Kozai, Daisuke; Sakaguchi, Reiko; Ohwada, Tomohiko; Mori, Yasuo

    2015-01-01

    The transient receptor potential (TRP) proteins are a family of ion channels that act as cellular sensors. Several members of the TRP family are sensitive to oxidative stress mediators. Among them, TRPA1 is remarkably susceptible to various oxidants, and is known to mediate neuropathic pain and respiratory, vascular and gastrointestinal functions, making TRPA1 an attractive therapeutic target. Recent studies have revealed a number of modulators (both activators and inhibitors) that act on TRPA1. Endogenous mediators of oxidative stress and exogenous electrophiles activate TRPA1 through oxidative modification of cysteine residues. Non-electrophilic compounds also activate TRPA1. Certain non-electrophilic modulators may act on critical non-cysteine sites in TRPA1. However, a method to achieve selective modulation of TRPA1 by small molecules has not yet been established. More recently, we found that a novel N-nitrosamine compound activates TRPA1 by S-nitrosylation (the addition of a nitric oxide (NO) group to cysteine thiol), and does so with significant selectivity over other NO-sensitive TRP channels. It is proposed that this subtype selectivity is conferred through synergistic effects of electrophilic cysteine transnitrosylation and molecular recognition of the non-electrophilic moiety on the N-nitrosamine. In this review, we describe the molecular pharmacology of these TRPA1 modulators and discuss their modulatory mechanisms.

  16. Protein structure and ionic selectivity in calcium channels: Selectivity filter size, not shape, matters

    PubMed Central

    Malasics, Attila; Gillespie, Dirk; Nonner, Wolfgang; Henderson, Douglas; Eisenberg, Bob; Boda, Dezső

    2009-01-01

    Calcium channels have highly charged selectivity filters (4 COO− groups) that attract cations in to balance this charge and minimize free energy, forcing the cations (Na+ and Ca2+) to compete for space in the filter. A reduced model was developed to better understand the mechanism of ion selectivity in calcium channels. The charge/space competition (CSC) mechanism implies that Ca2+ is more efficient in balancing the charge of the filter because it provides twice the charge as Na+ while occupying the same space. The CSC mechanism further implies that the main determinant of Ca2+ vs. Na+ selectivity is the density of charged particles in the selectivity filter, i.e., the volume of the filter (after fixing the number of charged groups in the filter). In this paper we test this hypothesis by changing filter length and/or radius (shape) of the cylindrical selectivity filter of our reduced model. We show that varying volume and shape together has substantially stronger effects than varying shape alone with volume fixed. Our simulations show the importance of depletion zones of ions in determining channel conductance calculated with the integrated Nernst-Planck equation. We show that confining the protein side chains with soft or hard walls does not influence selectivity. PMID:19818330

  17. Apparatus and method for selectively channeling a fluid

    DOEpatents

    Rightley, Michael Joseph

    2008-01-01

    An apparatus for selectively channeling a high temperature fluid without chemically reacting with the fluid. The apparatus includes an inlet and a membrane positioned adjacent to the inlet, each composed of a chemically inert material. The membrane is formed by compressive preloading techniques. The apparatus further includes a seat disposed on the inlet adjacent to the membrane. The seat is composed of a heat resistant and chemically inert material. Operation of the apparatus requires that the temperature of the fluid remains below the chemical characteristic melting point of the seat. The apparatus further includes an actuator coupled to the membrane for rendering the membrane in an open and a closed position with respect to the seat. Specifically, the actuator supplies a load in the normal direction to the membrane to selectively engage the membrane in a plurality of predetermined configurations. Operatively, the apparatus receives the fluid at the inlet. The fluid is received at a high temperature and is directed from the inlet to the membrane. In the closed position, the actuator engages the membrane to prevent the fluid from flowing from the inlet between the membrane and the seat. Alternatively, in the open position, the actuator engages the membrane to permit fluid flow from the inlet between the membrane and the seat to at least one outlet provided by the apparatus. In one exemplary embodiment, the fluid may be discharged from the at least one outlet to a sensor in fluid communication with the at least one outlet. Accordingly, the sensor may measure the fluid channeled through the heat resistant and chemically inert environment provided by the apparatus.

  18. Calcium ions open a selectivity filter gate during activation of the MthK potassium channel.

    PubMed

    Posson, David J; Rusinova, Radda; Andersen, Olaf S; Nimigean, Crina M

    2015-09-23

    Ion channel opening and closing are fundamental to cellular signalling and homeostasis. Gates that control K(+) channel activity were found both at an intracellular pore constriction and within the selectivity filter near the extracellular side but the specific location of the gate that opens Ca(2+)-activated K(+) channels has remained elusive. Using the Methanobacterium thermoautotrophicum homologue (MthK) and a stopped-flow fluorometric assay for fast channel activation, we show that intracellular quaternary ammonium blockers bind to closed MthK channels. Since the blockers are known to bind inside a central channel cavity, past the intracellular entryway, the gate must be within the selectivity filter. Furthermore, the blockers access the closed channel slower than the open channel, suggesting that the intracellular entryway narrows upon pore closure, without preventing access of either the blockers or the smaller K(+). Thus, Ca(2+)-dependent gating in MthK occurs at the selectivity filter with coupled movement of the intracellular helices.

  19. Calcium ions open a selectivity filter gate during activation of the MthK potassium channel

    NASA Astrophysics Data System (ADS)

    Posson, David J.; Rusinova, Radda; Andersen, Olaf S.; Nimigean, Crina M.

    2015-09-01

    Ion channel opening and closing are fundamental to cellular signalling and homeostasis. Gates that control K+ channel activity were found both at an intracellular pore constriction and within the selectivity filter near the extracellular side but the specific location of the gate that opens Ca2+-activated K+ channels has remained elusive. Using the Methanobacterium thermoautotrophicum homologue (MthK) and a stopped-flow fluorometric assay for fast channel activation, we show that intracellular quaternary ammonium blockers bind to closed MthK channels. Since the blockers are known to bind inside a central channel cavity, past the intracellular entryway, the gate must be within the selectivity filter. Furthermore, the blockers access the closed channel slower than the open channel, suggesting that the intracellular entryway narrows upon pore closure, without preventing access of either the blockers or the smaller K+. Thus, Ca2+-dependent gating in MthK occurs at the selectivity filter with coupled movement of the intracellular helices.

  20. Arizona Canal Diversion Channel Selection of Roughness Coefficients for Designing the Concrete-Lined Channel.

    DTIC Science & Technology

    1985-09-01

    CHANNEL STABILIZATION Technical Report Title Date 1 Symposium on Channel Stabilization Problems Volume 1 Sep 1983 Volume 2 May 1964 Volume 3 Jun 1965...Volume 4 Feb 1966 2 Review of Research on Channel Stabilization of the Sep 1963 Mississippi River, 1931-1962 3 Effect of Water Temperature on... Effects on Stage-Discharge Relations Sep 1969 * in Large Alluvial Rivers 7 State of Knowledge of Channel Stabilization in Major Oct 1969 Alluvial

  1. Molecular determinants of anion selectivity in the cystic fibrosis transmembrane conductance regulator chloride channel pore.

    PubMed Central

    Linsdell, P; Evagelidis, A; Hanrahan, J W

    2000-01-01

    Ionic selectivity in many cation channels is achieved over a short region of the pore known as the selectivity filter, the molecular determinants of which have been identified in Ca(2+), Na(+), and K(+) channels. However, a filter controlling selectivity among different anions has not previously been identified in any Cl(-) channel. In fact, because Cl(-) channels are only weakly selective among small anions, and because their selectivity has proved so resistant to site-directed mutagenesis, the very existence of a discrete anion selectivity filter has been called into question. Here we show that mutation of a putative pore-lining phenylalanine residue, F337, in the sixth membrane-spanning region of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel, dramatically alters the relative permeabilities of different anions in the channel. Specifically, mutations that reduce the size of the amino acid side chain present at this position virtually abolish the relationship between anion permeability and hydration energy, a relationship that characterizes the anion selectivity not only of wild-type CFTR, but of most classes of Cl(-) channels. These results suggest that the pore of CFTR may indeed contain a specialized region, analogous to the selectivity filter of cation channels, at which discrimination between different permeant anions takes place. Because F337 is adjacent to another amino acid residue, T338, which also affects anion selectivity in CFTR, we suggest that selectivity is predominantly determined over a physically discrete region of the pore located near these important residues. PMID:10827976

  2. Selectivity filter gating in large-conductance Ca(2+)-activated K+ channels.

    PubMed

    Thompson, Jill; Begenisich, Ted

    2012-03-01

    Membrane voltage controls the passage of ions through voltage-gated K (K(v)) channels, and many studies have demonstrated that this is accomplished by a physical gate located at the cytoplasmic end of the pore. Critical to this determination were the findings that quaternary ammonium ions and certain peptides have access to their internal pore-blocking sites only when the channel gates are open, and that large blocking ions interfere with channel closing. Although an intracellular location for the physical gate of K(v) channels is well established, it is not clear if such a cytoplasmic gate exists in all K(+) channels. Some studies on large-conductance, voltage- and Ca(2+)-activated K(+) (BK) channels suggest a cytoplasmic location for the gate, but other findings question this conclusion and, instead, support the concept that BK channels are gated by the pore selectivity filter. If the BK channel is gated by the selectivity filter, the interactions between the blocking ions and channel gating should be influenced by the permeant ion. Thus, we tested tetrabutyl ammonium (TBA) and the Shaker "ball" peptide (BP) on BK channels with either K(+) or Rb(+) as the permeant ion. When tested in K(+) solutions, both TBA and the BP acted as open-channel blockers of BK channels, and the BP interfered with channel closing. In contrast, when Rb(+) replaced K(+) as the permeant ion, TBA and the BP blocked both closed and open BK channels, and the BP no longer interfered with channel closing. We also tested the cytoplasmically gated Shaker K channels and found the opposite behavior: the interactions of TBA and the BP with these K(v) channels were independent of the permeant ion. Our results add significantly to the evidence against a cytoplasmic gate in BK channels and represent a positive test for selectivity filter gating.

  3. Selectivity filter gating in large-conductance Ca2+-activated K+ channels

    PubMed Central

    Thompson, Jill

    2012-01-01

    Membrane voltage controls the passage of ions through voltage-gated K (Kv) channels, and many studies have demonstrated that this is accomplished by a physical gate located at the cytoplasmic end of the pore. Critical to this determination were the findings that quaternary ammonium ions and certain peptides have access to their internal pore-blocking sites only when the channel gates are open, and that large blocking ions interfere with channel closing. Although an intracellular location for the physical gate of Kv channels is well established, it is not clear if such a cytoplasmic gate exists in all K+ channels. Some studies on large-conductance, voltage- and Ca2+-activated K+ (BK) channels suggest a cytoplasmic location for the gate, but other findings question this conclusion and, instead, support the concept that BK channels are gated by the pore selectivity filter. If the BK channel is gated by the selectivity filter, the interactions between the blocking ions and channel gating should be influenced by the permeant ion. Thus, we tested tetrabutyl ammonium (TBA) and the Shaker “ball” peptide (BP) on BK channels with either K+ or Rb+ as the permeant ion. When tested in K+ solutions, both TBA and the BP acted as open-channel blockers of BK channels, and the BP interfered with channel closing. In contrast, when Rb+ replaced K+ as the permeant ion, TBA and the BP blocked both closed and open BK channels, and the BP no longer interfered with channel closing. We also tested the cytoplasmically gated Shaker K channels and found the opposite behavior: the interactions of TBA and the BP with these Kv channels were independent of the permeant ion. Our results add significantly to the evidence against a cytoplasmic gate in BK channels and represent a positive test for selectivity filter gating. PMID:22371364

  4. A General Method of Selecting Quantum Channel for Bidirectional Quantum Teleportation

    NASA Astrophysics Data System (ADS)

    Fu, Hong-Zi; Tian, Xiu-Lao; Hu, Yang

    2014-06-01

    Based on tensor representation and Bell basis measurement in bidirectional quantum teleportation, a criterion that can be used to judge whether a four-qubit quantum state can be regarded as quantum channel or not in bidirectional teleportation is suggested and a theoretical scheme of bidirectional teleportation via four-qubit state as the quantum channel is proposed. In accordance with this criterion we give a general method of selecting quantum channel in bidirectional teleportation, which is determined by the channel parameter matrix R in the Bell basis measurement. This general method provide a theoretical basis for quantum channel selection in bidirectional quantum teleportation experiments.

  5. Tuning the ion selectivity of tetrameric cation channels by changing the number of ion binding sites

    SciTech Connect

    Derebe, Mehabaw G.; Sauer, David B.; Zeng, Weizhong; Alam, Amer; Shi, Ning; Jiang, Youxing

    2015-11-30

    Selective ion conduction across ion channel pores is central to cellular physiology. To understand the underlying principles of ion selectivity in tetrameric cation channels, we engineered a set of cation channel pores based on the nonselective NaK channel and determined their structures to high resolution. These structures showcase an ensemble of selectivity filters with a various number of contiguous ion binding sites ranging from 2 to 4, with each individual site maintaining a geometry and ligand environment virtually identical to that of equivalent sites in K{sup +} channel selectivity filters. Combined with single channel electrophysiology, we show that only the channel with four ion binding sites is K{sup +} selective, whereas those with two or three are nonselective and permeate Na{sup +} and K{sup +} equally well. These observations strongly suggest that the number of contiguous ion binding sites in a single file is the key determinant of the channel's selectivity properties and the presence of four sites in K{sup +} channels is essential for highly selective and efficient permeation of K{sup +} ions.

  6. Non-Equilibrium Dynamics Contribute to Ion Selectivity in the KcsA Channel

    PubMed Central

    Haas, Stephan; Farley, Robert A.

    2014-01-01

    The ability of biological ion channels to conduct selected ions across cell membranes is critical for the survival of both animal and bacterial cells. Numerous investigations of ion selectivity have been conducted over more than 50 years, yet the mechanisms whereby the channels select certain ions and reject others are not well understood. Here we report a new application of Jarzynski’s Equality to investigate the mechanism of ion selectivity using non-equilibrium molecular dynamics simulations of Na+ and K+ ions moving through the KcsA channel. The simulations show that the selectivity filter of KcsA adapts and responds to the presence of the ions with structural rearrangements that are different for Na+ and K+. These structural rearrangements facilitate entry of K+ ions into the selectivity filter and permeation through the channel, and rejection of Na+ ions. A mechanistic model of ion selectivity by this channel based on the results of the simulations relates the structural rearrangement of the selectivity filter to the differential dehydration of ions and multiple-ion occupancy and describes a mechanism to efficiently select and conduct K+. Estimates of the K+/Na+ selectivity ratio and steady state ion conductance for KcsA from the simulations are in good quantitative agreement with experimental measurements. This model also accurately describes experimental observations of channel block by cytoplasmic Na+ ions, the “punch through” relief of channel block by cytoplasmic positive voltages, and is consistent with the knock-on mechanism of ion permeation. PMID:24465882

  7. Ion-binding properties of a K+ channel selectivity filter in different conformations.

    PubMed

    Liu, Shian; Focke, Paul J; Matulef, Kimberly; Bian, Xuelin; Moënne-Loccoz, Pierre; Valiyaveetil, Francis I; Lockless, Steve W

    2015-12-08

    K(+) channels are membrane proteins that selectively conduct K(+) ions across lipid bilayers. Many voltage-gated K(+) (KV) channels contain two gates, one at the bundle crossing on the intracellular side of the membrane and another in the selectivity filter. The gate at the bundle crossing is responsible for channel opening in response to a voltage stimulus, whereas the gate at the selectivity filter is responsible for C-type inactivation. Together, these regions determine when the channel conducts ions. The K(+) channel from Streptomyces lividians (KcsA) undergoes an inactivation process that is functionally similar to KV channels, which has led to its use as a practical system to study inactivation. Crystal structures of KcsA channels with an open intracellular gate revealed a selectivity filter in a constricted conformation similar to the structure observed in closed KcsA containing only Na(+) or low [K(+)]. However, recent work using a semisynthetic channel that is unable to adopt a constricted filter but inactivates like WT channels challenges this idea. In this study, we measured the equilibrium ion-binding properties of channels with conductive, inactivated, and constricted filters using isothermal titration calorimetry (ITC). EPR spectroscopy was used to determine the state of the intracellular gate of the channel, which we found can depend on the presence or absence of a lipid bilayer. Overall, we discovered that K(+) ion binding to channels with an inactivated or conductive selectivity filter is different from K(+) ion binding to channels with a constricted filter, suggesting that the structures of these channels are different.

  8. Gating the Selectivity Filter in ClC Chloride Channels

    NASA Astrophysics Data System (ADS)

    Dutzler, Raimund; Campbell, Ernest B.; MacKinnon, Roderick

    2003-04-01

    ClC channels conduct chloride (Cl-) ions across cell membranes and thereby govern the electrical activity of muscle cells and certain neurons, the transport of fluid and electrolytes across epithelia, and the acidification of intracellular vesicles. The structural basis of ClC channel gating was studied. Crystal structures of wild-type and mutant Escherichia coli ClC channels bound to a monoclonal Fab fragment reveal three Cl- binding sites within the 15-angstrom neck of an hourglass-shaped pore. The Cl- binding site nearest the extracellular solution can be occupied either by a Cl- ion or by a glutamate carboxyl group. Mutations of this glutamate residue in Torpedo ray ClC channels alter gating in electrophysiological assays. These findings reveal a form of gating in which the glutamate carboxyl group closes the pore by mimicking a Cl- ion.

  9. Modified kinetics and selectivity of sodium channels in frog skeletal muscle fibers treated with aconitine

    PubMed Central

    1982-01-01

    The effect of the plant alkaloid aconitine on sodium channel kinetics, ionic selectivity, and blockage by protons and tetrodotoxin (TTX) has been studied in frog skeletal muscle. Treatment with 0.25 or 0.3 mM aconitine alters sodium channels so that the threshold of activation is shifted 40-50 mV in the hyperpolarized direction. In contrast to previous results in frog nerve, inactivation is complete for depolarizations beyond about -60 mV. After aconitine treatment, the steady state level of inactivation is shifted approximately 20 mV in the hyperpolarizing direction. Concomitant with changes in channel kinetics, the relative permeability of the sodium channel to NH4,K, and Cs is increased. This altered selectivity is not accompanied by altered block by protons or TTX. The results suggest that sites other than those involved in channel block by protons and TTX are important in determining sodium channel selectivity. PMID:6294221

  10. Channel selection for simultaneous and proportional myoelectric prosthesis control of multiple degrees-of-freedom

    NASA Astrophysics Data System (ADS)

    Hwang, Han-Jeong; Hahne, Janne Mathias; Müller, Klaus-Robert

    2014-10-01

    Objective. Recent studies have shown the possibility of simultaneous and proportional control of electrically powered upper-limb prostheses, but there has been little investigation on optimal channel selection. The objective of this study is to find a robust channel selection method and the channel subsets most suitable for simultaneous and proportional myoelectric prosthesis control of multiple degrees-of-freedom (DoFs). Approach. Ten able-bodied subjects and one person with congenital upper-limb deficiency took part in this study, and performed wrist movements with various combinations of two DoFs (flexion/extension and radial/ulnar deviation). During the experiment, high density electromyographic (EMG) signals and the actual wrist angles were recorded with an 8 × 24 electrode array and a motion tracking system, respectively. The wrist angles were estimated from EMG features with ridge regression using the subsets of channels chosen by three different channel selection methods: (1) least absolute shrinkage and selection operator (LASSO), (2) sequential feature selection (SFS), and (3) uniform selection (UNI). Main results. SFS generally showed higher estimation accuracy than LASSO and UNI, but LASSO always outperformed SFS in terms of robustness, such as noise addition, channel shift and training data reduction. It was also confirmed that about 95% of the original performance obtained using all channels can be retained with only 12 bipolar channels individually selected by LASSO and SFS. Significance. From the analysis results, it can be concluded that LASSO is a promising channel selection method for accurate simultaneous and proportional prosthesis control. We expect that our results will provide a useful guideline to select optimal channel subsets when developing clinical myoelectric prosthesis control systems based on continuous movements with multiple DoFs.

  11. Mechanism for Selectivity-inactivation Coupling in KcsA Potassium Channels

    SciTech Connect

    W Cheng; J McCoy; A Thompson; C Nichols; C Nimigean

    2011-12-31

    Structures of the prokaryotic K{sup +} channel, KcsA, highlight the role of the selectivity filter carbonyls from the GYG signature sequence in determining a highly selective pore, but channels displaying this sequence vary widely in their cation selectivity. Furthermore, variable selectivity can be found within the same channel during a process called C-type inactivation. We investigated the mechanism for changes in selectivity associated with inactivation in a model K{sup +} channel, KcsA. We found that E71A, a noninactivating KcsA mutant in which a hydrogen-bond behind the selectivity filter is disrupted, also displays decreased K{sup +} selectivity. In E71A channels, Na{sup +} permeates at higher rates as seen with {sup 86}Rb{sup +} and {sup 22}Na{sup +} flux measurements and analysis of intracellular Na{sup +} block. Crystal structures of E71A reveal that the selectivity filter no longer assumes the 'collapsed,' presumed inactivated, conformation in low K{sup +}, but a 'flipped' conformation, that is also observed in high K{sup +}, high Na{sup +}, and even Na{sup +} only conditions. The data reveal the importance of the E71-D80 interaction in both favoring inactivation and maintaining high K{sup +} selectivity. We propose a molecular mechanism by which inactivation and K{sup +} selectivity are linked, a mechanism that may also be at work in other channels containing the canonical GYG signature sequence.

  12. Sub-surface channels in sapphire made by ultraviolet picosecond laser irradiation and selective etching.

    PubMed

    Moser, Rüdiger; Ojha, Nirdesh; Kunzer, Michael; Schwarz, Ulrich T

    2011-11-21

    We demonstrate the realization of sub-surface channels in sapphire prepared by ultraviolet picosecond laser irradiation and subsequent selective wet etching. By optimizing the pulse energy and the separation between individual laser pulses, an optimization of channel length can be achieved with an aspect ratio as high as 3200. Due to strong variation in channel length, further investigation was done to improve the reproducibility. By multiple irradiations the standard deviation of the channel length could be reduced to 2.2%. The achieved channel length together with the high reproducibility and the use of a commercial picosecond laser system makes the process attractive for industrial application.

  13. Ion Permeation Through a Cl--Selective Channel Designed from a CLC Cl-/H+ Exchanger

    SciTech Connect

    Jayaram,H.; Accardi, A.; Wu, F.; Williams, C.; Miller, C.

    2008-01-01

    The CLC family of Cl--transporting proteins includes both Cl- channels and Cl-/H+ exchange transporters. CLC-ec1, a structurally known bacterial homolog of the transporter subclass, exchanges two Cl- ions per proton with strict, obligatory stoichiometry. Point mutations at two residues, Glu148 and Tyr445, are known to impair H+ movement while preserving Cl- transport. In the x-ray crystal structure of CLC-ec1, these residues form putative 'gates' flanking an ion-binding region. In mutants with both of the gate-forming side chains reduced in size, H+ transport is abolished, and unitary Cl- transport rates are greatly increased, well above values expected for transporter mechanisms. Cl- transport rates increase as side-chain volume at these positions is decreased. The crystal structure of a doubly ungated mutant shows a narrow conduit traversing the entire protein transmembrane width. These characteristics suggest that Cl- flux through uncoupled, ungated CLC-ec1 occurs via a channel-like electrodiffusion mechanism rather than an alternating-exposure conformational cycle that has been rendered proton-independent by the gate mutations.

  14. Squalyl Crown Ether Self-Assembled Conjugates: An Example of Highly Selective Artificial K(+) Channels.

    PubMed

    Sun, Zhanhu; Gilles, Arnaud; Kocsis, Istvan; Legrand, Yves-Marie; Petit, Eddy; Barboiu, Mihail

    2016-02-01

    The natural KcsA K(+) channel, one of the best-characterized biological pore structures, conducts K(+) cations at high rates while excluding Na(+) cations. The KcsA K(+) channel is of primordial inspiration for the design of artificial channels. Important progress in improving conduction activity and K(+) /Na(+) selectivity has been achieved with artificial ion-channel systems. However, simple artificial systems exhibiting K(+) /Na(+) selectivity and mimicking the biofunctions of the KcsA K(+) channel are unknown. Herein, an artificial ion channel formed by H-bonded stacks of squalyl crown ethers, in which K(+) conduction is highly preferred to Na(+) conduction, is reported. The K(+) -channel behavior is interpreted as arising from discreet stacks of dimers resulting in the formation of oligomeric channels, in which transport of cations occurs through macrocycles mixed with dimeric carriers undergoing dynamic exchange within the bilayer membrane. The present highly K(+) -selective macrocyclic channel can be regarded as a biomimetic alternative to the KcsA channel.

  15. Kv1 channels selectively prevent dendritic hyperexcitability in rat Purkinje cells

    PubMed Central

    Khavandgar, Simin; Walter, Joy T; Sageser, Kristin; Khodakhah, Kamran

    2005-01-01

    Purkinje cells, the sole output of the cerebellar cortex, encode the timing signals required for motor coordination in their firing rate and activity pattern. Dendrites of Purkinje cells express a high density of P/Q-type voltage-gated calcium channels and fire dendritic calcium spikes. Here we show that dendritic subthreshold Kv1.2 subunit-containing Kv1 potassium channels prevent generation of random spontaneous calcium spikes. With Kv1 channels blocked, dendritic calcium spikes drive bursts of somatic sodium spikes and prevent the cell from faithfully encoding motor timing signals. The selective dendritic function of Kv1 channels in Purkinje cells allows them to effectively suppress dendritic hyperexcitability without hindering the generation of somatic action potentials. Further, we show that Kv1 channels also contribute to dendritic integration of parallel fibre synaptic input. Kv1 channels are often targeted to soma and axon and the data presented support a major dendritic function for these channels. PMID:16210348

  16. Use of color-coded sleeve shutters accelerates oscillograph channel selection

    NASA Technical Reports Server (NTRS)

    Bouchlas, T.; Bowden, F. W.

    1967-01-01

    Sleeve-type shutters mechanically adjust individual galvanometer light beams onto or away from selected channels on oscillograph papers. In complex test setups, the sleeve-type shutters are color coded to separately identify each oscillograph channel. This technique could be used on any equipment using tubular galvanometer light sources.

  17. Apparent phosphorus availabilities of selected traditional and alternative feedstuffs for channel catfish

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A digestibility trial with channel catfish Ictalurus punctatus was conducted to determine apparent availability coefficients (AACs) of phosphorus for selected common feedstuffs: soybean meal, cottonseed meal, wheat middlings, corn gluten feed (CGF), and corn distillers dried grains with solubles (DD...

  18. Selection of Inhibitor-Resistant Viral Potassium Channels Identifies a Selectivity Filter Site that Affects Barium and Amantadine Block

    PubMed Central

    Fujiwara, Yuichiro; Arrigoni, Cristina; Domigan, Courtney; Ferrara, Giuseppina; Pantoja, Carlos; Thiel, Gerhard; Moroni, Anna; Minor, Daniel L.

    2009-01-01

    Background Understanding the interactions between ion channels and blockers remains an important goal that has implications for delineating the basic mechanisms of ion channel function and for the discovery and development of ion channel directed drugs. Methodology/Principal Findings We used genetic selection methods to probe the interaction of two ion channel blockers, barium and amantadine, with the miniature viral potassium channel Kcv. Selection for Kcv mutants that were resistant to either blocker identified a mutant bearing multiple changes that was resistant to both. Implementation of a PCR shuffling and backcrossing procedure uncovered that the blocker resistance could be attributed to a single change, T63S, at a position that is likely to form the binding site for the inner ion in the selectivity filter (site 4). A combination of electrophysiological and biochemical assays revealed a distinct difference in the ability of the mutant channel to interact with the blockers. Studies of the analogous mutation in the mammalian inward rectifier Kir2.1 show that the T→S mutation affects barium block as well as the stability of the conductive state. Comparison of the effects of similar barium resistant mutations in Kcv and Kir2.1 shows that neighboring amino acids in the Kcv selectivity filter affect blocker binding. Conclusions/Significance The data support the idea that permeant ions have an integral role in stabilizing potassium channel structure, suggest that both barium and amantadine act at a similar site, and demonstrate how genetic selections can be used to map blocker binding sites and reveal mechanistic features. PMID:19834614

  19. Morpholin-2-one derivatives as novel selective T-type Ca2+ channel blockers.

    PubMed

    Ku, Il Whea; Cho, Sangwon; Doddareddy, Munikumar Reddy; Jang, Min Seok; Keum, Gyochang; Lee, Jung-Ha; Chung, Bong Young; Kim, Youseung; Rhim, Hyewhon; Kang, Soon Bang

    2006-10-01

    Morpholin-2-one-5-carboxamide derivatives were prepared by using the one-pot Ugi multicomponent reaction and evaluated for blocking effects on T- and N-type Ca(2+) channels. Among them, compound 5i produced the highest potency (IC(50)=0.45+/-0.02 microM), while compounds 5d, 5f, 5k, 5n, 5o, and 6m produced relatively high potency as well as selectivity on T-type Ca(2+) channels. These novel scaffolds showed potent and selective T-type Ca(2+) channel blocking activities.

  20. Enhancement of transport selectivity through nano-channels by non-specific competition.

    PubMed

    Zilman, Anton; Di Talia, Stefano; Jovanovic-Talisman, Tijana; Chait, Brian T; Rout, Michael P; Magnasco, Marcelo O

    2010-06-10

    The functioning of living cells requires efficient and selective transport of materials into and out of the cell, and between different cellular compartments. Much of this transport occurs through nano-scale channels that do not require large scale molecular re-arrangements (such as transition from a 'closed' to an 'open' state) and do not require a direct input of metabolic energy during transport. Nevertheless, these 'always open' channels are highly selective and pass only their cognate molecules, while efficiently excluding all others; indeed, these channels can efficiently transport specific molecules even in the presence of a vast excess of non-specific molecules. Such biological transporters have inspired the creation of artificial nano-channels. These channels can be used as nano-molecular sorters, and can also serve as testbeds for examining modes of biological transport. In this paper, we propose a simple kinetic mechanism that explains how the selectivity of such 'always open' channels can be based on the exclusion of non-specific molecules by specific ones, due to the competition for limited space inside the channel. The predictions of the theory account for the behavior of the nuclear pore complex and of artificial nanopores that mimic its function. This theory provides the basis for future work aimed at understanding the selectivity of various biological transport phenomena.

  1. Enhancement of Transport Selectivity through Nano-Channels by Non-Specific Competition

    PubMed Central

    Zilman, Anton; Di Talia, Stefano; Jovanovic-Talisman, Tijana; Chait, Brian T.; Rout, Michael P.; Magnasco, Marcelo O.

    2010-01-01

    The functioning of living cells requires efficient and selective transport of materials into and out of the cell, and between different cellular compartments. Much of this transport occurs through nano-scale channels that do not require large scale molecular re-arrangements (such as transition from a ‘closed’ to an ‘open’ state) and do not require a direct input of metabolic energy during transport. Nevertheless, these ‘always open’ channels are highly selective and pass only their cognate molecules, while efficiently excluding all others; indeed, these channels can efficiently transport specific molecules even in the presence of a vast excess of non-specific molecules. Such biological transporters have inspired the creation of artificial nano-channels. These channels can be used as nano-molecular sorters, and can also serve as testbeds for examining modes of biological transport. In this paper, we propose a simple kinetic mechanism that explains how the selectivity of such ‘always open’ channels can be based on the exclusion of non-specific molecules by specific ones, due to the competition for limited space inside the channel. The predictions of the theory account for the behavior of the nuclear pore complex and of artificial nanopores that mimic its function. This theory provides the basis for future work aimed at understanding the selectivity of various biological transport phenomena. PMID:20548778

  2. Altered ion channel conductance and ionic selectivity induced by large imposed membrane potential pulse.

    PubMed Central

    Chen, W; Lee, R C

    1994-01-01

    The effects of large magnitude transmembrane potential pulses on voltage-gated Na and K channel behavior in frog skeletal muscle membrane were studied using a modified double vaseline-gap voltage clamp. The effects of electroconformational damage to ionic channels were separated from damage to lipid bilayer (electroporation). A 4 ms transmembrane potential pulse of -600 mV resulted in a reduction of both Na and K channel conductivities. The supraphysiologic pulses also reduced ionic selectivity of the K channels against Na+ ions, resulting in a depolarization of the membrane resting potential. However, TTX and TEA binding effects were unaltered. The kinetics of spontaneous reversal of the electroconformational damage of channel proteins was found to be dependent on the magnitude of imposed membrane potential pulse. These results suggest that muscle and nerve dysfunction after electrical shock may be in part caused by electroconformational damage to voltage-gated ion channels. PMID:7948676

  3. Study of Internal Channel Surface Roughnesses Manufactured by Selective Laser Melting in Aluminum and Titanium Alloys

    NASA Astrophysics Data System (ADS)

    Pakkanen, Jukka; Calignano, Flaviana; Trevisan, Francesco; Lorusso, Massimo; Ambrosio, Elisa Paola; Manfredi, Diego; Fino, Paolo

    2016-08-01

    Interest in additive manufacturing (AM) has gained considerable impetus over the past decade. One of the driving factors for AM success is the ability to create unique designs with intrinsic characteristics as, e.g., internal channels used for hydraulic components, cooling channels, and heat exchangers. However, a couple of the main problems in internal channels manufactured by AM technologies are the high surface roughness obtained and the distortion of the channel shape. There is still much to understand in these design aspects. In this study, a cylindrical geometry for internal channels to be built with different angles with respect to the building plane in AlSi10Mg and Ti6Al4V alloys by selective laser melting was considered. The internal surfaces of the channels produced in both materials were analyzed by means of a surface roughness tester and by optical and electron microscopy to evaluate the effects of the material and design choices.

  4. A novel channel selection method for multiple motion classification using high-density electromyography

    PubMed Central

    2014-01-01

    Background Selecting an appropriate number of surface electromyography (EMG) channels with desired classification performance and determining the optimal placement of EMG electrodes would be necessary and important in practical myoelectric control. In previous studies, several methods such as sequential forward selection (SFS) and Fisher-Markov selector (FMS) have been used to select the appropriate number of EMG channels for a control system. These exiting methods are dependent on either EMG features and/or classification algorithms, which means that when using different channel features or classification algorithm, the selected channels would be changed. In this study, a new method named multi-class common spatial pattern (MCCSP) was proposed for EMG selection in EMG pattern-recognition-based movement classification. Since MCCSP is independent on specific EMG features and classification algorithms, it would be more convenient for channel selection in developing an EMG control system than the exiting methods. Methods The performance of the proposed MCCSP method in selecting some optimal EMG channels (designated as a subset) was assessed with high-density EMG recordings from twelve mildly-impaired traumatic brain injury (TBI) patients. With the MCCSP method, a subset of EMG channels was selected and then used for motion classification with pattern recognition technique. In order to justify the performance of the MCCSP method against different electrode configurations, features and classification algorithms, two electrode configurations (unipolar and bipolar) as well as two EMG feature sets and two types of pattern recognition classifiers were considered in the study, respectively. And the performance of the proposed MCCSP method was compared with that of two exiting channel selection methods (SFS and FMS) in EMG control system. Results The results showed that in comparison with the previously used SFS and FMS methods, the newly proposed MCCSP method had better

  5. On Optimal Input Design and Model Selection for Communication Channels

    SciTech Connect

    Li, Yanyan; Djouadi, Seddik M; Olama, Mohammed M

    2013-01-01

    In this paper, the optimal model (structure) selection and input design which minimize the worst case identification error for communication systems are provided. The problem is formulated using metric complexity theory in a Hilbert space setting. It is pointed out that model selection and input design can be handled independently. Kolmogorov n-width is used to characterize the representation error introduced by model selection, while Gel fand and Time n-widths are used to represent the inherent error introduced by input design. After the model is selected, an optimal input which minimizes the worst case identification error is shown to exist. In particular, it is proven that the optimal model for reducing the representation error is a Finite Impulse Response (FIR) model, and the optimal input is an impulse at the start of the observation interval. FIR models are widely popular in communication systems, such as, in Orthogonal Frequency Division Multiplexing (OFDM) systems.

  6. Single voltage-dependent chloride-selective channels of large conductance in cultured rat muscle.

    PubMed Central

    Blatz, A L; Magleby, K L

    1983-01-01

    Single-channel currents of an anion-selective channel in the plasma membrane of cultured rat muscle cells (myotubes) were recorded with the patch-clamp technique (Hamill, O.P., A. Marty, E. Neher, B. Sakmann, and F.J. Sigworth, 1981. Pfluegers Arch. Eur. J. Physiol., 391:85-100). The channel is selective for Cl- over cations, and has an unusually large single-channel conductance of approximately 430 pS in symmetrical 143 mM KCl. The channel is often active at 0 mV, opening and closing spontaneously. When active, steps from 0 mV to either negative or positive membrane potentials close the channel to an apparent inactivated state. The mean effective time that a channel is open before it inactivates is approximately 1.19 s for steps to -30 mV and 0.48 s for steps to +30 mV. Returning the membrane potential to 0 mV results in recovery from inactivation. Calcium ions are not required for channel activity. PMID:6311302

  7. Selectivities of dihydropyridine derivatives in blocking Ca(2+) channel subtypes expressed in Xenopus oocytes.

    PubMed

    Furukawa, T; Yamakawa, T; Midera, T; Sagawa, T; Mori, Y; Nukada, T

    1999-11-01

    Some dihydropyridines (DHPs), such as amlodipine and cilnidipine, have been shown to block not only L-type but also N-type Ca(2+) channels; therefore, DHPs are no longer considered as L-type-specific Ca(2+) channel blockers. However, selectivity of DHPs for Ca(2+) channel subtypes including N-, P/Q-, and R-types are poorly understood. To address this issue at the molecular level, blocking effects of 10 DHPs (nifedipine, nilvadipine, barnidipine, nimodipine, nitrendipine, amlodipine, nicardipine, benidipine, felodipine, and cilnidipine) on four subtypes of Ca(2+) channels (L-, N-, P/Q-, and R-types) were investigated in the Xenopus oocyte expression system with the use of the two-microelectrode voltage-clamp technique. L-type Ca(2+) channels expressed as alpha(1C)alpha(2)beta(1a) combination were profoundly blocked by all DHPs examined, whereas blocking actions of these DHPs on R-type (alpha(1E)alpha(2)beta(1a)) channels were equally weak. In contrast, 5 of the 10 DHPs (amlodipine, benidipine, cilnidipine, nicardipine, and barnidipine) significantly blocked N-type (alpha(1B)alpha(2)beta(1a)) and P/Q-type (alpha(1A)alpha(2)beta(1a)) Ca(2+) channels. These selectivities of DHPs in blocking Ca(2+) channel subtypes would provide useful pharmacological and clinical information on the mode of action of the drugs including side effects and adverse effects.

  8. Hysteresis of KcsA potassium channel's activation- deactivation gating is caused by structural changes at the channel's selectivity filter.

    PubMed

    Tilegenova, Cholpon; Cortes, D Marien; Cuello, Luis G

    2017-03-21

    Mode-shift or hysteresis has been reported in ion channels. Voltage-shift for gating currents is well documented for voltage-gated cation channels (VGCC), and it is considered a voltage-sensing domain's (VSD) intrinsic property. However, uncoupling the Shaker K(+) channel's pore domain (PD) from the VSD prevented the mode-shift of the gating currents. Consequently, it was proposed that an open-state stabilization of the PD imposes a mechanical load on the VSD, which causes its mode-shift. Furthermore, the mode-shift displayed by hyperpolarization-gated cation channels is likely caused by structural changes at the channel's PD similar to those underlying C-type inactivation. To demonstrate that the PD of VGCC undergoes hysteresis, it is imperative to study its gating process in the absence of the VSD. A back-door strategy is to use KcsA (a K(+) channel from the bacteria Streptomyces lividans) as a surrogate because it lacks a VSD and exhibits an activation coupled to C-type inactivation. By directly measuring KcsA's activation gate opening and closing in conditions that promote or halt C-type inactivation, we have found (i) that KcsA undergoes mode-shift of gating when having K(+) as the permeant ion; (ii) that Cs(+) or Rb(+), known to halt C-inactivation, prevented mode-shift of gating; and (iii) that, in the total absence of C-type inactivation, KcsA's mode-shift was prevented. Finally, our results demonstrate that an allosteric communication causes KcsA's activation gate to "remember" the conformation of the selectivity filter, and hence KcsA requires a different amount of energy for opening than for closing.

  9. Picomolar, selective and subtype specific small-molecule inhibition of TRPC1/4/5 channels.

    PubMed

    Rubaiy, Hussein N; Ludlow, Melanie J; Henrot, Matthias; Gaunt, Hannah J; Miteva, Katarina; Cheung, Sin Yin; Tanahashi, Yasuyuki; Hamzah, Nurasyikin; Musialowski, Katie E; Blythe, Nicola M; Appleby, Hollie L; Bailey, Marc A; McKeown, Lynn; Taylor, Roger; Foster, Richard; Waldmann, Herbert; Nussbaumer, Peter; Christmann, Mathias; Bon, Robin S; Muraki, Katsuhiko; Beech, David J

    2017-03-21

    The concentration of free cytosolic Ca(2+) and the voltage across the plasma membrane are major determinants of cell function. Ca(2+)-permeable non-selective cationic channels are known to regulate these parameters but understanding of these channels remains inadequate. Here we focus on Transient Receptor Potential Canonical 4 and 5 proteins (TRPC4 and TRPC5) which assemble as homomers or heteromerize with TRPC1 to form Ca(2+)-permeable non-selective cationic channels in many mammalian cell types. Multiple roles have been suggested including in epilepsy, innate fear, pain and cardiac remodeling but limitations in tools to probe these channels have restricted progress. A key question is whether we can overcome these limitations and develop tools which are high-quality, reliable, easy to use and readily accessible for all investigators. Here, through chemical synthesis and studies of native and over-expressed channels by Ca(2+) and patch-clamp assays, we describe compound 31 (C31), a remarkable small-molecule inhibitor of TRPC1/4/5 channels. Its potency ranged from 9 to 1300 pM, depending on the TRPC1/4/5 subtype and activation mechanism. Other channel types investigated were unaffected, including TRPC3, TRPC6, TRPV1, TRPV4, TRPA1, TRPM2, TRPM8 and store-operated Ca(2+) entry mediated by Orai1. These findings suggest identification of an important experimental tool compound which has much higher potency for inhibiting TRPC1/4/5 channels than previously reported agents, impressive specificity, and graded subtype selectivity within the TRPC1/4/5 channel family. The compound should greatly facilitate future studies of these ion channels. We suggest naming this TRPC1/4/5-inhibitory compound Pico145.

  10. The role of solvation in the binding selectivity of the L-type calcium channel.

    PubMed

    Boda, Dezső; Henderson, Douglas; Gillespie, Dirk

    2013-08-07

    We present grand canonical Monte Carlo simulation results for a reduced model of the L-type calcium channel. While charged residues of the protein amino acids in the selectivity filter are treated explicitly, most of the degrees of freedom (including the rest of the protein and the solvent) are represented by their dielectric response, i.e., dielectric continua. The new aspect of this paper is that the dielectric coefficient in the channel is different from that in the baths. The ions entering the channel, thus, cross a dielectric boundary at the entrance of the channel. Simulating this case has been made possible by our recent methodological development [D. Boda, D. Henderson, B. Eisenberg, and D. Gillespie, J. Chem. Phys. 135, 064105 (2011)]. Our main focus is on the effect of solvation energy (represented by the Born energy) on monovalent vs. divalent ion selectivity in the channel. We find no significant change in selectivity by changing the dielectric coefficient in the channel because the larger solvation penalty is counterbalanced by the enhanced Coulomb attraction inside the channel as soon as we use the Born radii (fitted to experimental hydration energies) to compute the solvation penalty from the Born equation.

  11. Lysine and the Na+/K+ Selectivity in Mammalian Voltage-Gated Sodium Channels

    PubMed Central

    Xia, Mengdie

    2016-01-01

    Voltage-gated sodium (Nav) channels are critical in the generation and transmission of neuronal signals in mammals. The crystal structures of several prokaryotic Nav channels determined in recent years inspire the mechanistic studies on their selection upon the permeable cations (especially between Na+ and K+ ions), a property that is proposed to be mainly determined by residues in the selectivity filter. However, the mechanism of cation selection in mammalian Nav channels lacks direct explanation at atomic level due to the difference in amino acid sequences between mammalian and prokaryotic Nav homologues, especially at the constriction site where the DEKA motif has been identified to determine the Na+/K+ selectivity in mammalian Nav channels but is completely absent in the prokaryotic counterparts. Among the DEKA residues, Lys is of the most importance since its mutation to Arg abolishes the Na+/K+ selectivity. In this work, we modeled the pore domain of mammalian Nav channels by mutating the four residues at the constriction site of a prokaryotic Nav channel (NavRh) to DEKA, and then mechanistically investigated the contribution of Lys in cation selection using molecular dynamics simulations. The DERA mutant was generated as a comparison to understand the loss of ion selectivity caused by the K-to-R mutation. Simulations and free energy calculations on the mutants indicate that Lys facilitates Na+/K+ selection by electrostatically repelling the cation to a highly Na+-selective location sandwiched by the carboxylate groups of Asp and Glu at the constriction site. In contrast, the electrostatic repulsion is substantially weakened when Lys is mutated to Arg, because of two intrinsic properties of the Arg side chain: the planar geometric design and the sparse charge distribution of the guanidine group. PMID:27584582

  12. Alternative splicing switches the divalent cation selectivity of TRPM3 channels.

    PubMed

    Oberwinkler, Johannes; Lis, Annette; Giehl, Klaus M; Flockerzi, Veit; Philipp, Stephan E

    2005-06-10

    TRPM3 is a poorly understood member of the large family of transient receptor potential (TRP) ion channels. Here we describe five novel splice variants of TRPM3, TRPM3alpha1-5. These variants are characterized by a previously unknown amino terminus of 61 residues. The differences between the five variants arise through splice events at three different sites. One of these splice sites might be located in the pore region of the channel as indicated by sequence alignment with other, better-characterized TRP channels. We selected two splice variants, TRPM3alpha1 and TRPM3alpha2, that differ only in this presumed pore region and analyzed their biophysical characteristics after heterologous expression in human embryonic kidney 293 cells. TRPM3alpha1 as well as TRPM3alpha2 induced a novel, outwardly rectifying cationic conductance that was tightly regulated by intracellular Mg(2+). However, these two variants are highly different in their ionic selectivity. Whereas TRPM3alpha1-encoded channels are poorly permeable for divalent cations, TRPM3alpha2-encoded channels are well permeated by Ca(2+) and Mg(2+). Additionally, we found that currents through TRPM3alpha2 are blocked by extracellular monovalent cations, whereas currents through TRPM3alpha1 are not. These differences unambiguously show that TRPM3 proteins constitute a pore-forming channel subunit and localize the position of the ion-conducting pore within the TRPM3 protein. Although the ionic selectivity of ion channels has traditionally been regarded as rather constant for a given channel-encoding gene, our results show that alternative splicing can be a mechanism to produce channels with very different selectivity profiles.

  13. A Wearable Channel Selection-Based Brain-Computer Interface for Motor Imagery Detection.

    PubMed

    Lo, Chi-Chun; Chien, Tsung-Yi; Chen, Yu-Chun; Tsai, Shang-Ho; Fang, Wai-Chi; Lin, Bor-Shyh

    2016-02-06

    Motor imagery-based brain-computer interface (BCI) is a communication interface between an external machine and the brain. Many kinds of spatial filters are used in BCIs to enhance the electroencephalography (EEG) features related to motor imagery. The approach of channel selection, developed to reserve meaningful EEG channels, is also an important technique for the development of BCIs. However, current BCI systems require a conventional EEG machine and EEG electrodes with conductive gel to acquire multi-channel EEG signals and then transmit these EEG signals to the back-end computer to perform the approach of channel selection. This reduces the convenience of use in daily life and increases the limitations of BCI applications. In order to improve the above issues, a novel wearable channel selection-based brain-computer interface is proposed. Here, retractable comb-shaped active dry electrodes are designed to measure the EEG signals on a hairy site, without conductive gel. By the design of analog CAR spatial filters and the firmware of EEG acquisition module, the function of spatial filters could be performed without any calculation, and channel selection could be performed in the front-end device to improve the practicability of detecting motor imagery in the wearable EEG device directly or in commercial mobile phones or tablets, which may have relatively low system specifications. Finally, the performance of the proposed BCI is investigated, and the experimental results show that the proposed system is a good wearable BCI system prototype.

  14. Evoked potential correlates of selective attention with multi-channel auditory inputs

    NASA Technical Reports Server (NTRS)

    Schwent, V. L.; Hillyard, S. A.

    1975-01-01

    Ten subjects were presented with random, rapid sequences of four auditory tones which were separated in pitch and apparent spatial position. The N1 component of the auditory vertex evoked potential (EP) measured relative to a baseline was observed to increase with attention. It was concluded that the N1 enhancement reflects a finely tuned selective attention to one stimulus channel among several concurrent, competing channels. This EP enhancement probably increases with increased information load on the subject.

  15. Second order statistics of selection combining receiver over κ-μ fading channels subject to co-channel interferences

    NASA Astrophysics Data System (ADS)

    Stefanović, Mihajlo; Panić, Stefan R.; Stefanović, DušAn; Nikolić, Bojana; Cvetković, Aleksandra

    2012-12-01

    Radio propagation performances in interference-limited faded environment are studied in this paper. Selection combining (SC) based on signal-to-interference ratio (SIR) overκ-μfading channels is performed. Probability density function (PDF) and cumulative distribution function (CDF) of the received SIR are determined. Based on the results obtained for PDF and CDF, infinite-series expressions are derived for the output level crossing rate (LCR) and average fade duration (AFD). These second order statistical measures are regarded as necessary for supporting technical documentation in every radio communication link design. Influences of various system parameters such as fading severity and the number of co-channel interferences affecting these measures are graphically presented and discussed.

  16. Non-selective voltage-activated cation channel in the human red blood cell membrane.

    PubMed

    Kaestner, L; Bollensdorff, C; Bernhardt, I

    1999-02-04

    Using the patch-clamp technique, a non-selective voltage-activated Na+ and K+ channel in the human red blood cell membrane was found. The channel operates only at positive membrane potentials from about +30 mV (inside positive) onwards. For sodium and potassium ions, similar conductances of about 21 pS were determined. Together with the recently described K+(Na+)/H+ exchanger, this channel is responsible for the increase of residual K+ and Na+ fluxes across the human red blood cell membrane when the cells are suspended in low ionic strength medium.

  17. The mechanosensory calcium-selective ion channel: key component of a plasmalemmal control centre?

    NASA Technical Reports Server (NTRS)

    Pickard, B. G.; Ding, J. P.

    1993-01-01

    Mechanosensory calcium-selective ion channels probably serve to detect not only mechanical stress but also electrical, thermal, and diverse chemical stimuli. Because all stimuli result in a common output, most notably a shift in second messenger calcium concentration, the channels are presumed to serve as signal integrators. Further, insofar as second messenger calcium in turn gives rise to mechanical, electrical, and diverse chemical changes, the channels are postulated to initiate regulatory feedbacks. It is proposed that the channels and the feedback loops play a wide range of roles in regulating normal plant function, as well as in mediating disturbance of normal function by environmental stressors and various pathogens. In developing evidence for the physiological performance of the channel, a model for a cluster of regulatory plasmalemmal proteins and cytoskeletal elements grouped around a set of wall-to-membrane and transmembrane linkers has proved useful. An illustration of how the model might operate is presented. It is founded on the demonstration that several xenobiotics interfere both with normal channel behaviour and with gravitropic reception. Accordingly, the first part of the illustration deals with how the channels and the control system within which they putatively operate might initiate gravitropism. Assuming that gravitropism is an asymmetric expression of growth, the activities of the channels and the plasmalemmal control system are extrapolated to account for regulation of both rate and allometry of cell expansion. Finally, it is discussed how light, hormones, redox agents and herbicides could in principle affect growth via the putative plasmalemmal control cluster or centre.

  18. Demonstration of arbitrary channel selection utilizing a pulse-injected semiconductor laser with a phase-locked loop.

    PubMed

    Juan, Yu-Shan; Lin, Fan-Yi

    2011-01-17

    An arbitrary channel selection system based on a pulse-injected semiconductor laser with a phase-locked loop (PLL) is experimentally demonstrated and characterized. Through optical injection from a tunable laser, channels formed by the frequency components of a microwave frequency comb generated in the pulse-injected semiconductor laser are individually selected and enhanced. Selections of a primary channel at the fundamental frequency of 1.2 GHz and a secondary channel in a range from 10.8 to 18 GHz are shown, where the selection is done by adjusting the injection strength from the tunable laser. Suppression ratios of 44.5 and 25.9 dB between the selected primary and secondary channels to the averaged magnitude of the unwanted channels are obtained, respectively. To show the spectral quality of the pulse-injected laser, a single sideband (SSB) phase noise of -60 dBc/kHz at an offset frequency of 25 kHz is measured. Moreover, the conversion gain between the primary and secondary channels and the crosstalk between the selected channels to the adjacent unwanted channels are also investigated. Without the need of expensive external modulators, arbitrary channel selection is realized in the proposed system where the channel spacing and selection can be continuously adjusted through tuning the controllable laser parameters.

  19. Sodium channel selectivity and conduction: prokaryotes have devised their own molecular strategy.

    PubMed

    Finol-Urdaneta, Rocio K; Wang, Yibo; Al-Sabi, Ahmed; Zhao, Chunfeng; Noskov, Sergei Y; French, Robert J

    2014-02-01

    Striking structural differences between voltage-gated sodium (Nav) channels from prokaryotes (homotetramers) and eukaryotes (asymmetric, four-domain proteins) suggest the likelihood of different molecular mechanisms for common functions. For these two channel families, our data show similar selectivity sequences among alkali cations (relative permeability, Pion/PNa) and asymmetric, bi-ionic reversal potentials when the Na/K gradient is reversed. We performed coordinated experimental and computational studies, respectively, on the prokaryotic Nav channels NaChBac and NavAb. NaChBac shows an "anomalous," nonmonotonic mole-fraction dependence in the presence of certain sodium-potassium mixtures; to our knowledge, no comparable observation has been reported for eukaryotic Nav channels. NaChBac's preferential selectivity for sodium is reduced either by partial titration of its highly charged selectivity filter, when extracellular pH is lowered from 7.4 to 5.8, or by perturbation-likely steric-associated with a nominally electro-neutral substitution in the selectivity filter (E191D). Although no single molecular feature or energetic parameter appears to dominate, our atomistic simulations, based on the published NavAb crystal structure, revealed factors that may contribute to the normally observed selectivity for Na over K. These include: (a) a thermodynamic penalty to exchange one K(+) for one Na(+) in the wild-type (WT) channel, increasing the relative likelihood of Na(+) occupying the binding site; (b) a small tendency toward weaker ion binding to the selectivity filter in Na-K mixtures, consistent with the higher conductance observed with both sodium and potassium present; and (c) integrated 1-D potentials of mean force for sodium or potassium movement that show less separation for the less selective E/D mutant than for WT. Overall, tight binding of a single favored ion to the selectivity filter, together with crucial inter-ion interactions within the pore, suggests

  20. High spin spectroscopy near the N=Z line: Channel selection and excitation energy systematics

    SciTech Connect

    Svensson, C.E.; Cameron, J.A.; Flibotte, S.

    1996-12-31

    The total {gamma}-ray and charged-particle energies emitted in fusion-evaporation reactions leading to N=Z compound systems in the A = 50-70 mass region have been measured with the 8{pi} {gamma}-ray spectrometer and the miniball charged-particle detector array. A new method of channel selection has been developed which combines particle identification with these total energy measurements and greatly improves upon the selectivity possible with particle detection alone. In addition, the event by event measurement of total {gamma}-ray energies using the BGO ball of the 8{pi} spectrometer has allowed a determination of excitation energies following particle evaporation for a large number of channels in several different reactions. The new channel selection procedure and excitation energy systematics are illustrated with data from the reaction of {sup 24}Mg on {sup 40}Ca at E{sub lab} = 80MeV.

  1. Autocrine-Based Selection of Drugs That Target Ion Channels from Combinatorial Venom Peptide Libraries.

    PubMed

    Zhang, Hongkai; Du, Mingjuan; Xie, Jia; Liu, Xiao; Sun, Jingying; Wang, Wei; Xin, Xiu; Possani, Lourival D; Yea, Kyungmoo; Lerner, Richard A

    2016-08-01

    Animal venoms represent a rich source of pharmacologically active peptides that interact with ion channels. However, a challenge to discovering drugs remains because of the slow pace at which venom peptides are discovered and refined. An efficient autocrine-based high-throughput selection system was developed to discover and refine venom peptides that target ion channels. The utility of this system was demonstrated by the discovery of novel Kv1.3 channel blockers from a natural venom peptide library that was formatted for autocrine-based selection. We also engineered a Kv1.3 blocker peptide (ShK) derived from sea anemone to generate a subtype-selective Kv1.3 blocker with a long half-life in vivo.

  2. Reconstitution and regulation of cation-selective channels from cardiac sarcoplasmic reticulum.

    PubMed

    Rousseau, E; Chabot, H; Beaudry, C; Muller, B

    1992-09-08

    In order to study the conductances of the Sarcoplasmic Reticulum (SR) membrane, microsomal fractions from cardiac SR were isolated by differential and sucrose gradient centrifugations and fused into planar lipid bilayers (PLB) made of phospholipids. Using either KCl or K-gluconate solutions, a large conducting K+ selective channel was characterized by its ohmic conductance (152 pS in 150 mM K+), and the presence of short and long lasting subconducting states. Its open probability Po increased with depolarizing voltages, thus supporting the idea that this channel might allow counter-charge movements of monovalent cations during rapid SR Ca2+ release. An heterogeneity in the kinetic behavior of this channel would suggest that the cardiac SR K+ channels might be regulated by cytoplasmic, luminal, or intra SR membrane biochemical mechanisms. Since the behavior was not modified by variations of [Ca2+] nor by the addition of soluble metabolites such as ATP, GTP, cAMP, cGMP, nor by phosphorylation conditions on both sides of the PLB, a specific interaction with a SR membrane component is postulated. Another cation selective channel was studied in asymmetric Ca2+, Ba2+ or Mg(2+)-HEPES buffers. This channel displayed large conductance values for the above divalent cations 90, 100, and 40 pS, respectively. This channel was activated by microM Ca2+ while its Ca2+ sensitivity was potentiated by millimolar ATP. However Mg2+ and calmodulin modulated its gating behavior. Ca2+ releasing drugs such as caffeine and ryanodine increased its Po. All these features are characteristics of the SR Ca2+ release channel. The ryanodine receptor which has been purified and reconstituted into PLB, may form a cation selective pathway.(ABSTRACT TRUNCATED AT 250 WORDS)

  3. Comparison of the single channel and multichannel (multivariate) concepts of selectivity in analytical chemistry.

    PubMed

    Dorkó, Zsanett; Verbić, Tatjana; Horvai, George

    2015-07-01

    Different measures of selectivity are in use for single channel and multichannel linear analytical measurements, respectively. It is important to understand that these two measures express related but still distinctly different features of the respective measurements. These relationships are clarified by introducing new arguments. The most widely used selectivity measure of multichannel linear methods (which is based on the net analyte signal, NAS, concept) expresses the sensitivity to random errors of a determination where all bias from interferents is computationally eliminated using pure component spectra. The conventional selectivity measure of single channel linear measurements, on the other hand, helps to estimate the bias caused by an interferent in a biased measurement. In single channel methods expert knowledge about the samples is used to limit the possible range of interferent concentrations. The same kind of expert knowledge allows improved (lower mean squared error, MSE) analyte determinations also in "classical" multichannel measurements if those are intractable due to perfect collinearity or to high noise inflation. To achieve this goal bias variance tradeoff is employed, hence there remains some bias in the results and therefore the concept of single channel selectivity can be extended in a natural way to multichannel measurements. This extended definition and the resulting selectivity measure can also be applied to the so-called inverse multivariate methods like partial least squares regression (PLSR), principal component regression (PCR) and ridge regression (RR).

  4. Aluminium and hydrogen ions inhibit a mechanosensory calcium-selective cation channel

    NASA Technical Reports Server (NTRS)

    Ding, J. P.; Pickard, B. G.

    1993-01-01

    The tension-dependent activity of mechanosensory calcium-selective cation channels in excised plasmalemmal patches from onion bulb scale epidermis is modulated by pH in the physiologically meaningful range between 4.5 and 7.2. It is rapidly lowered by lowering pH and rapidly raised by raising pH. Channel activity is effectively inhibited by low levels of aluminium ions and activity can be partially restored by washing for a few minutes. We suggest that under normal conditions the sensitivity of the mechanosensory channels to pH of the wall free space plays important roles in regulation of plant activities such as growth. We further suggest that, when levels of acid and aluminium ions in the soil solution are high, they might inhibit similar sensory channels in cells of the root tip, thus contributing critically to the acid soil syndrome.

  5. The Doubly Exceptional Child: A Principal's Dilemma.

    ERIC Educational Resources Information Center

    Kesner, Rebecca J., Ed.

    2002-01-01

    This document contains two articles concerned with doubly exceptional children and gifted education. In "The Doubly Exceptional Child: A Principal's Dilemma," (Carol J. Mills and Linda E. Brody), such children do not fit into the usual categories for sorting children because their gifts and disabilities often mask each other. Suggestions are…

  6. Structural plasticity and dynamic selectivity of acid-sensing ion channel-spider toxin complexes

    SciTech Connect

    Baconguis, Isabelle; Gouaux, Eric

    2012-07-29

    Acid-sensing ion channels (ASICs) are voltage-independent, amiloride-sensitive channels involved in diverse physiological processes ranging from nociception to taste. Despite the importance of ASICs in physiology, we know little about the mechanism of channel activation. Here we show that psalmotoxin activates non-selective and Na+-selective currents in chicken ASIC1a at pH7.25 and 5.5, respectively. Crystal structures of ASIC1a–psalmotoxin complexes map the toxin binding site to the extracellular domain and show how toxin binding triggers an expansion of the extracellular vestibule and stabilization of the open channel pore. At pH7.25 the pore is approximately 10Å in diameter, whereas at pH5.5 the pore is largely hydrophobic and elliptical in cross-section with dimensions of approximately 5 by 7Å, consistent with a barrier mechanism for ion selectivity. These studies define mechanisms for activation of ASICs, illuminate the basis for dynamic ion selectivity and provide the blueprints for new therapeutic agents.

  7. Structural plasticity and dynamic selectivity of acid-sensing ion channel-spider toxin complexes.

    PubMed

    Baconguis, Isabelle; Gouaux, Eric

    2012-09-20

    Acid-sensing ion channels (ASICs) are voltage-independent, amiloride-sensitive channels involved in diverse physiological processes ranging from nociception to taste. Despite the importance of ASICs in physiology, we know little about the mechanism of channel activation. Here we show that psalmotoxin activates non-selective and Na(+)-selective currents in chicken ASIC1a at pH 7.25 and 5.5, respectively. Crystal structures of ASIC1a-psalmotoxin complexes map the toxin binding site to the extracellular domain and show how toxin binding triggers an expansion of the extracellular vestibule and stabilization of the open channel pore. At pH 7.25 the pore is approximately 10 Å in diameter, whereas at pH 5.5 the pore is largely hydrophobic and elliptical in cross-section with dimensions of approximately 5 by 7 Å, consistent with a barrier mechanism for ion selectivity. These studies define mechanisms for activation of ASICs, illuminate the basis for dynamic ion selectivity and provide the blueprints for new therapeutic agents.

  8. Energetics of discrete selectivity bands and mutation-induced transitions in the calcium-sodium ion channels family.

    PubMed

    Kaufman, I; Luchinsky, D G; Tindjong, R; McClintock, P V E; Eisenberg, R S

    2013-11-01

    We use Brownian dynamics (BD) simulations to study the ionic conduction and valence selectivity of a generic electrostatic model of a biological ion channel as functions of the fixed charge Q(f) at its selectivity filter. We are thus able to reconcile the discrete calcium conduction bands recently revealed in our BD simulations, M0 (Q(f)=1e), M1 (3e), M2 (5e), with a set of sodium conduction bands L0 (0.5e), L1 (1.5e), thereby obtaining a completed pattern of conduction and selectivity bands vs Q(f) for the sodium-calcium channels family. An increase of Q(f) leads to an increase of calcium selectivity: L0 (sodium-selective, nonblocking channel) → M0 (nonselective channel) → L1 (sodium-selective channel with divalent block) → M1 (calcium-selective channel exhibiting the anomalous mole fraction effect). We create a consistent identification scheme where the L0 band is putatively identified with the eukaryotic sodium channel The scheme created is able to account for the experimentally observed mutation-induced transformations between nonselective channels, sodium-selective channels, and calcium-selective channels, which we interpret as transitions between different rows of the identification table. By considering the potential energy changes during permeation, we show explicitly that the multi-ion conduction bands of calcium and sodium channels arise as the result of resonant barrierless conduction. The pattern of periodic conduction bands is explained on the basis of sequential neutralization taking account of self-energy, as Q(f)(z,i)=ze(1/2+i), where i is the order of the band and z is the valence of the ion. Our results confirm the crucial influence of electrostatic interactions on conduction and on the Ca(2+)/Na(+) valence selectivity of calcium and sodium ion channels. The model and results could be also applicable to biomimetic nanopores with charged walls.

  9. Theoretical analysis of selectivity mechanisms in molecular transport through channels and nanopores

    SciTech Connect

    Agah, Shaghayegh; Pasquali, Matteo; Kolomeisky, Anatoly B.

    2015-01-28

    Selectivity is one of the most fundamental concepts in natural sciences, and it is also critically important in various technological, industrial, and medical applications. Although there are many experimental methods that allow to separate molecules, frequently they are expensive and not efficient. Recently, a new method of separation of chemical mixtures based on utilization of channels and nanopores has been proposed and successfully tested in several systems. However, mechanisms of selectivity in the molecular transport during the translocation are still not well understood. Here, we develop a simple theoretical approach to explain the origin of selectivity in molecular fluxes through channels. Our method utilizes discrete-state stochastic models that take into account all relevant chemical transitions and can be solved analytically. More specifically, we analyze channels with one and two binding sites employed for separating mixtures of two types of molecules. The effects of the symmetry and the strength of the molecular-pore interactions are examined. It is found that for one-site binding channels, the differences in the strength of interactions for two species drive the separation. At the same time, in more realistic two-site systems, the symmetry of interaction potential becomes also important. The most efficient separation is predicted when the specific binding site is located near the entrance to the nanopore. In addition, the selectivity is higher for large entrance rates into the channel. It is also found that the molecular transport is more selective for repulsive interactions than for attractive interactions. The physical-chemical origin of the observed phenomena is discussed.

  10. Unraveling the mechanism of selective ion transport in hydrophobic subnanometer channels.

    PubMed

    Li, Hui; Francisco, Joseph S; Zeng, Xiao Cheng

    2015-09-01

    Recently reported synthetic organic nanopore (SONP) can mimic a key feature of natural ion channels, i.e., selective ion transport. However, the physical mechanism underlying the K(+)/Na(+) selectivity for the SONPs is dramatically different from that of natural ion channels. To achieve a better understanding of the selective ion transport in hydrophobic subnanometer channels in general and SONPs in particular, we perform a series of ab initio molecular dynamics simulations to investigate the diffusivity of aqua Na(+) and K(+) ions in two prototype hydrophobic nanochannels: (i) an SONP with radius of 3.2 Å, and (ii) single-walled carbon nanotubes (CNTs) with radii of 3-5 Å (these radii are comparable to those of the biological potassium K(+) channels). We find that the hydration shell of aqua Na(+) ion is smaller than that of aqua K(+) ion but notably more structured and less yielding. The aqua ions do not lower the diffusivity of water molecules in CNTs, but in SONP the diffusivity of aqua ions (Na(+) in particular) is strongly suppressed due to the rugged inner surface. Moreover, the aqua Na(+) ion requires higher formation energy than aqua K(+) ion in the hydrophobic nanochannels. As such, we find that the ion (K(+) vs. Na(+)) selectivity of the (8, 8) CNT is ∼20× higher than that of SONP. Hence, the (8, 8) CNT is likely the most efficient artificial K(+) channel due in part to its special interior environment in which Na(+) can be fully solvated, whereas K(+) cannot. This work provides deeper insights into the physical chemistry behind selective ion transport in nanochannels.

  11. Event-related brain potentials to irrelevant auditory stimuli during selective listening: effects of channel probability.

    PubMed

    Akai, Toshiyuki

    2004-03-01

    The purpose of this study was to identify the cognitive process reflected by a positive deflection to irrelevant auditory stimuli (Pdi) during selective listening. Event-related brain potentials were recorded from 9 participants in a two-channel (left/right ears) selective listening task. Relative event probabilities of the relevant/irrelevant channels were 25%/75%, 50%/50%, and 75%/25%. With increasing probability of the relevant channel, behavioral performances (the reaction time and hit rate) for the targets within the relevant channel improved, reflecting development of a more robust attentional trace. At the same time, the amplitude of the early Pdi (200-300 ms after stimulus onset) elicited by the stimuli in the irrelevant channel with a decreased probability was enhanced in the central region. This positive relation between the strength of the attentional trace and the amplitude of the early Pdi suggests that the early Pdi is elicited by a mismatching between an incoming irrelevant stimulus and an attentional trace.

  12. Channelrhodopsin-2, a directly light-gated cation-selective membrane channel

    PubMed Central

    Nagel, Georg; Szellas, Tanjef; Huhn, Wolfram; Kateriya, Suneel; Adeishvili, Nona; Berthold, Peter; Ollig, Doris; Hegemann, Peter; Bamberg, Ernst

    2003-01-01

    Microbial-type rhodopsins are found in archaea, prokaryotes, and eukaryotes. Some of them represent membrane ion transport proteins such as bacteriorhodopsin, a light-driven proton pump, or channelrhodopsin-1 (ChR1), a recently identified light-gated proton channel from the green alga Chlamydomonas reinhardtii. ChR1 and ChR2, a related microbial-type rhodopsin from C. reinhardtii, were shown to be involved in generation of photocurrents of this green alga. We demonstrate by functional expression, both in oocytes of Xenopus laevis and mammalian cells, that ChR2 is a directly light-switched cation-selective ion channel. This channel opens rapidly after absorption of a photon to generate a large permeability for monovalent and divalent cations. ChR2 desensitizes in continuous light to a smaller steady-state conductance. Recovery from desensitization is accelerated by extracellular H+ and negative membrane potential, whereas closing of the ChR2 ion channel is decelerated by intracellular H+. ChR2 is expressed mainly in C. reinhardtii under low-light conditions, suggesting involvement in photoreception in dark-adapted cells. The predicted seven-transmembrane α helices of ChR2 are characteristic for G protein-coupled receptors but reflect a different motif for a cation-selective ion channel. Finally, we demonstrate that ChR2 may be used to depolarize small or large cells, simply by illumination. PMID:14615590

  13. The omega-atracotoxins: selective blockers of insect M-LVA and HVA calcium channels.

    PubMed

    Chong, Youmie; Hayes, Jessica L; Sollod, Brianna; Wen, Suping; Wilson, David T; Hains, Peter G; Hodgson, Wayne C; Broady, Kevin W; King, Glenn F; Nicholson, Graham M

    2007-08-15

    The omega-atracotoxins (omega-ACTX) are a family of arthropod-selective peptide neurotoxins from Australian funnel-web spider venoms (Hexathelidae: Atracinae) that are candidates for development as biopesticides. We isolated a 37-residue insect-selective neurotoxin, omega-ACTX-Ar1a, from the venom of the Sydney funnel-web spider Atrax robustus, with high homology to several previously characterized members of the omega-ACTX-1 family. The peptide induced potent excitatory symptoms, followed by flaccid paralysis leading to death, in acute toxicity tests in house crickets. Using isolated smooth and skeletal nerve-muscle preparations, the toxin was shown to lack overt vertebrate toxicity at concentrations up to 1 microM. To further characterize the target of the omega-ACTXs, voltage-clamp analysis using the whole-cell patch-clamp technique was undertaken using cockroach dorsal unpaired median neurons. It is shown here for the first time that omega-ACTX-Ar1a, and its homolog omega-ACTX-Hv1a from Hadronyche versuta, reversibly block both mid-low- (M-LVA) and high-voltage-activated (HVA) insect calcium channel (Ca(v)) currents. This block occurred in the absence of alterations in the voltage-dependence of Ca(v) channel activation, and was voltage-independent, suggesting that omega-ACTX-1 family toxins are pore blockers rather than gating modifiers. At a concentration of 1 microM omega-ACTX-Ar1a failed to significantly affect global K(v) channel currents. However, 1 microM omega-ACTX-Ar1a caused a modest 18% block of insect Na(v) channel currents, similar to the minor block of Na(v) channels reported for other insect Ca(v) channel blockers such as omega-agatoxin IVA. These findings validate both M-LVA and HVA Ca(v) channels as potential targets for insecticides.

  14. Selectivity Mechanism of the Voltage-gated Proton Channel, HV1

    NASA Astrophysics Data System (ADS)

    Dudev, Todor; Musset, Boris; Morgan, Deri; Cherny, Vladimir V.; Smith, Susan M. E.; Mazmanian, Karine; Decoursey, Thomas E.; Lim, Carmay

    2015-05-01

    Voltage-gated proton channels, HV1, trigger bioluminescence in dinoflagellates, enable calcification in coccolithophores, and play multifarious roles in human health. Because the proton concentration is minuscule, exquisite selectivity for protons over other ions is critical to HV1 function. The selectivity of the open HV1 channel requires an aspartate near an arginine in the selectivity filter (SF), a narrow region that dictates proton selectivity, but the mechanism of proton selectivity is unknown. Here we use a reduced quantum model to elucidate how the Asp-Arg SF selects protons but excludes other ions. Attached to a ring scaffold, the Asp and Arg side chains formed bidentate hydrogen bonds that occlude the pore. Introducing H3O+ protonated the SF, breaking the Asp-Arg linkage and opening the conduction pathway, whereas Na+ or Cl- was trapped by the SF residue of opposite charge, leaving the linkage intact, thus preventing permeation. An Asp-Lys SF behaved like the Asp-Arg one and was experimentally verified to be proton-selective, as predicted. Hence, interacting acidic and basic residues form favorable AspH0-H2O0-Arg+ interactions with hydronium but unfavorable Asp--X-/X+-Arg+ interactions with anions/cations. This proposed mechanism may apply to other proton-selective molecules engaged in bioenergetics, homeostasis, and signaling.

  15. Ion Selectivity Mechanism in a Bacterial Pentameric Ligand-Gated Ion Channel

    SciTech Connect

    Fritsch, Sebastian; Ivanov, Ivaylo; Wang, Hailong; Cheng, Xiaolin

    2010-01-01

    The proton-gated ion channel from Gloeobacter violaceus (GLIC) is a prokaryotic homolog of the eukaryotic nicotinic acetylcholine receptor that responds to the binding of neurotransmitter acetylcholine and mediates fast signal transmission. Recent emergence of a high-resolution crystal structure of GLIC captured in a potentially open state allowed detailed, atomic-level insight into ion conduction and selectivity mechanisms in these channels. Herein, we have examined the barriers to ion conduction and origins of ion selectivity in the GLIC channel by the construction of potential-of-mean-force profiles for sodium and chloride ions inside the transmembrane region. Our calculations reveal that the GLIC channel is open for a sodium ion to transport, but presents a 11 kcal/mol free energy barrier for a chloride ion. Our collective findings identify three distinct contributions to the observed preference for the permeant ions. First, there is a substantial contribution due to a ring of negatively charged glutamate residues (E-2 ) at the narrow intracellular end of the channel. The negative electrostatics of this region and the ability of the glutamate side chains to directly bind cations would strongly favor the passage of sodium ions while hindering translocation of chloride ions. Second, our results imply a significant hydrophobic contribution to selectivity linked to differences in the desolvation penalty for the sodium versus chloride ions in the central hydrophobic region of the pore. This hydrophobic contribution is evidenced by the large free energy barriers experienced by Cl in the middle of the pore for both GLIC and the E-2 A mutant. Finally, there is a distinct contribution arising from the overall negative electrostatics of the channel.

  16. Poorly selective cation channels in the apical membrane of A6 cells.

    PubMed

    Van Driessche, W; De Smet, P; de Smedt, H

    1994-03-01

    This paper describes a Ca(2+)-blockable, poorly selective cation pathway in the apical membrane of A6 epithelia. This pathway has properties that resemble the cation-selective channels in the toad urinary bladder and frog skin. Transepithelial short circuit currents (Isc) and power density spectra (PDS) of the fluctuations in current were recorded. The basolateral surface of the tissues was exposed to Cl- or SO4(2-) solutions with Na+ as the major cation. Ca(2+)-blockable inward oriented currents and Lorentzian noise were recorded with isotonic (215 mosmol/kg) mucosal Cl- and hypotonic (144 mos-mol/kg serosal SO4(2-) solution with Na+, K+, Rb+ or Cs+ as the major mucosal cation. Experiments with mucosal K+ demonstrated that the cation-selective channel was markedly activated by serosal hypotonicity. Effects of an increased electrical driving force were excluded on the basis of the results obtained with microelectrode experiments and transepithelial voltage clamping. Cell volume expansion induced by isotonic replacements of serosal sucrose by glycerol or urea also activated the cation-selective pathway. Furthermore, the presence of Cl- in the mucosal solution was a prerequisite for a sustained response to hypotonicity or replacements of the organic compounds. Moreover, we found that the cation-selective channels are mainly expressed in the cells during the early period of epithelial growth.

  17. Channel-morphology data for the Tongue River and selected tributaries, southeastern Montana, 2001-02

    USGS Publications Warehouse

    Chase, Katherine J.

    2004-01-01

    Coal-bed methane exploration and production have begun within the Tongue River watershed in southeastern Montana. The development of coal-bed methane requires production of large volumes of ground water, some of which may be discharged to streams, potentially increasing stream discharge and sediment load. Changes in stream discharge or sediment load may result in changes to channel morphology through changes in erosion and vegetation. These changes might be subtle and difficult to detect without baseline data that indicate stream-channel conditions before extensive coal-bed methane development began. In order to provide this baseline channel-morphology data, the U.S. Geological Survey, in cooperation with the Bureau of Land Management, collected channel-morphology data in 2001-02 to document baseline conditions for several reaches along the Tongue River and selected tributaries. This report presents channel-morphology data for five sites on the mainstem Tongue River and four sites on its tributaries. Bankfull, water-surface, and thalweg elevations, channel sections, and streambed-particle sizes were measured along reaches near streamflow-gaging stations. At each site, the channel was classified using methods described by Rosgen. For six sites, bankfull discharge was determined from the stage- discharge relation at the gage for the stage corresponding to the bankfull elevation. For three sites, the step-backwater computer model HEC-RAS was used to estimate bankfull discharge. Recurrence intervals for the bankfull discharge also were estimated for eight of the nine sites. Channel-morphology data for each site are presented in maps, tables, graphs, and photographs.

  18. Controls on the distribution of channel reach morphology in selectively glaciated catchments

    NASA Astrophysics Data System (ADS)

    Addy, S.; Soulsby, C.; Hartley, A. J.

    2014-04-01

    To assess the controls on the distribution of channel reach morphology in a selectively glaciated landscape, we used field mapping and a geographical information system (GIS) in the River Dee catchment, northeast Scotland. Controls on channel morphology were investigated using (1) continuous longitudinal assessment of channel morphology distribution in relation to geology, glacial history, topography, and total stream power (Ω) in two subcatchments, and (2) slope (S), Ω, and a slope-drainage area (S-A) framework to understand the occurrence of 173 widely distributed bedrock, mixed bedrock-alluvial, and alluvial (three different types) reaches. The S-A framework used indicators of transport capacity (Qc) and sediment supply (Qs) to differentiate channel types. The study highlights the disjointed nature of channel reach distribution at the river scale that reflects variable lithology and glacial modification. Because of the subdued topography in contrast to other regions, colluvial forcing of channel morphology in the headwaters was lacking. However, in common with other glaciated landscapes, repeated sequences of channel reach type progression determined by valley steps were evident. The S-A analysis successfully discriminated 87.2% of alluvial and 91.4% of bedrock reaches despite the variable land use and glacial modification. Discrimination of the full range of channel types using S, Ω, or the S-A framework was poor however. Notably, a third of the transport alluvial reaches were located in the bedrock S-A domain, and the majority of mixed reaches were widely distributed mostly within the bedrock domain and not close to the critical slope (Sc). In comparison to other regions, the Sc above which Qc > Qs and bedrock reaches dominate, was notably higher. We hypothesise that a drier climate and the higher entrainment threshold of coarse, granite-dominated bed materials create a higher Sc.

  19. EMG feature assessment for myoelectric pattern recognition and channel selection: a study with incomplete spinal cord injury.

    PubMed

    Liu, Jie; Li, Xiaoyan; Li, Guanglin; Zhou, Ping

    2014-07-01

    Myoelectric pattern recognition with a large number of electromyogram (EMG) channels provides an approach to assessing motor control information available from the recorded muscles. In order to develop a practical myoelectric control system, a feature dependent channel reduction method was developed in this study to determine a small number of EMG channels for myoelectric pattern recognition analysis. The method selects appropriate raw EMG features for classification of different movements, using the minimum Redundancy Maximum Relevance (mRMR) and the Markov random field (MRF) methods to rank a large number of EMG features, respectively. A k-nearest neighbor (KNN) classifier was used to evaluate the performance of the selected features in terms of classification accuracy. The method was tested using 57 channels' surface EMG signals recorded from forearm and hand muscles of individuals with incomplete spinal cord injury (SCI). Our results demonstrate that appropriate selection of a small number of raw EMG features from different recording channels resulted in similar high classification accuracies as achieved by using all the EMG channels or features. Compared with the conventional sequential forward selection (SFS) method, the feature dependent method does not require repeated classifier implementation. It can effectively reduce redundant information not only cross different channels, but also cross different features in the same channel. Such hybrid feature-channel selection from a large number of EMG recording channels can reduce computational cost for implementation of a myoelectric pattern recognition based control system.

  20. Sequence-function analysis of the K+-selective family of ion channels using a comprehensive alignment and the KcsA channel structure.

    PubMed

    Shealy, Robin T; Murphy, Anuradha D; Ramarathnam, Rampriya; Jakobsson, Eric; Subramaniam, Shankar

    2003-05-01

    Sequence-function analysis of K(+)-selective channels was carried out in the context of the 3.2 A crystal structure of a K(+) channel (KcsA) from Streptomyces lividans (Doyle et al., 1998). The first step was the construction of an alignment of a comprehensive set of K(+)-selective channel sequences forming the putative permeation path. This pathway consists of two transmembrane segments plus an extracellular linker. Included in the alignment are channels from the eight major classes of K(+)-selective channels from a wide variety of species, displaying varied rectification, gating, and activation properties. Segments of the alignment were assigned to structural motifs based on the KcsA structure. The alignment's accuracy was verified by two observations on these motifs: 1), the most variability is shown in the turret region, which functionally is strongly implicated in susceptibility to toxin binding; and 2), the selectivity filter and pore helix are the most highly conserved regions. This alignment combined with the KcsA structure was used to assess whether clusters of contiguous residues linked by hydrophobic or electrostatic interactions in KcsA are conserved in the K(+)-selective channel family. Analysis of sequence conservation patterns in the alignment suggests that a cluster of conserved residues is critical for determining the degree of K(+) selectivity. The alignment also supports the near-universality of the "glycine hinge" mechanism at the center of the inner helix for opening K channels. This mechanism has been suggested by the recent crystallization of a K channel in the open state. Further, the alignment reveals a second highly conserved glycine near the extracellular end of the inner helix, which may be important in minimizing deformation of the extracellular vestibule as the channel opens. These and other sequence-function relationships found in this analysis suggest that much of the permeation path architecture in KcsA is present in most K(+)-selective

  1. EEG Channel Selection Using Particle Swarm Optimization for the Classification of Auditory Event-Related Potentials

    PubMed Central

    Hokari, Haruhide

    2014-01-01

    Brain-machine interfaces (BMI) rely on the accurate classification of event-related potentials (ERPs) and their performance greatly depends on the appropriate selection of classifier parameters and features from dense-array electroencephalography (EEG) signals. Moreover, in order to achieve a portable and more compact BMI for practical applications, it is also desirable to use a system capable of accurate classification using information from as few EEG channels as possible. In the present work, we propose a method for classifying P300 ERPs using a combination of Fisher Discriminant Analysis (FDA) and a multiobjective hybrid real-binary Particle Swarm Optimization (MHPSO) algorithm. Specifically, the algorithm searches for the set of EEG channels and classifier parameters that simultaneously maximize the classification accuracy and minimize the number of used channels. The performance of the method is assessed through offline analyses on datasets of auditory ERPs from sound discrimination experiments. The proposed method achieved a higher classification accuracy than that achieved by traditional methods while also using fewer channels. It was also found that the number of channels used for classification can be significantly reduced without greatly compromising the classification accuracy. PMID:24982944

  2. Non-Selective Cation Channels Mediate Chloroquine-Induced Relaxation in Precontracted Mouse Airway Smooth Muscle

    PubMed Central

    Li, Wen-Er; Ma, Yun-Fei; Chen, Weiwei; Zhai, Kui; Qin, Gangjian; Guo, Donglin; Zheng, Yun-Min; Wang, Yong-Xiao; Shen, Jin-Hua; Ji, Guangju; Liu, Qing-Hua

    2014-01-01

    Bitter tastants can induce relaxation in precontracted airway smooth muscle by activating big-conductance potassium channels (BKs) or by inactivating voltage-dependent L-type Ca2+ channels (VDLCCs). In this study, a new pathway for bitter tastant-induced relaxation was defined and investigated. We found nifedipine-insensitive and bitter tastant chloroquine-sensitive relaxation in epithelium-denuded mouse tracheal rings (TRs) precontracted with acetylcholine (ACH). In the presence of nifedipine (10 µM), ACH induced cytosolic Ca2+ elevation and cell shortening in single airway smooth muscle cells (ASMCs), and these changes were inhibited by chloroquine. In TRs, ACH triggered a transient contraction under Ca2+-free conditions, and, following a restoration of Ca2+, a strong contraction occurred, which was inhibited by chloroquine. Moreover, the ACH-activated whole-cell and single channel currents of non-selective cation channels (NSCCs) were blocked by chloroquine. Pyrazole 3 (Pyr3), an inhibitor of transient receptor potential C3 (TRPC3) channels, partially inhibited ACH-induced contraction, intracellular Ca2+ elevation, and NSCC currents. These results demonstrate that NSCCs play a role in bitter tastant-induced relaxation in precontracted airway smooth muscle. PMID:24992312

  3. Different ionic selectivities for connexins 26 and 32 produce rectifying gap junction channels.

    PubMed Central

    Suchyna, T M; Nitsche, J M; Chilton, M; Harris, A L; Veenstra, R D; Nicholson, B J

    1999-01-01

    The functional diversity of gap junction intercellular channels arising from the large number of connexin isoforms is significantly increased by heterotypic interactions between members of this family. This is particularly evident in the rectifying behavior of Cx26/Cx32 heterotypic channels (. Proc. Natl. Acad. Sci. USA. 88:8410-8414). The channel properties responsible for producing the rectifying current observed for Cx26/Cx32 heterotypic gap junction channels were determined in transfected mouse neuroblastoma 2A (N2A) cells. Transfectants revealed maximum unitary conductances (gamma(j)) of 135 pS for Cx26 and 53 pS for Cx32 homotypic channels in 120 mM KCl. Anionic substitution of glutamate for Cl indicated that Cx26 channels favored cations by 2.6:1, whereas Cx32 channels were relatively nonselective with respect to charge. In Cx26/Cx32 heterotypic cell pairs, the macroscopic fast rectification of the current-voltage relationship was fully explained at the single-channel level by a rectifying gamma(j) that increased by a factor of 2.9 as the transjunctional voltage (V(j)) changed from -100 to +100 mV with the Cx26 cell as the positive pole. A model of electrodiffusion of ions through the gap junction pore based on Nernst-Planck equations for ion concentrations and the Poisson equation for the electrical potential within the junction is developed. Selectivity characteristics are ascribed to each hemichannel based on either pore features (treated as uniform along the length of the hemichannel) or entrance effects unique to each connexin. Both analytical GHK approximations and full numerical solutions predict rectifying characteristics for Cx32/Cx26 heterotypic channels, although not to the full extent seen empirically. The model predicts that asymmetries in the conductance/permeability properties of the hemichannels (also cast as Donnan potentials) will produce either an accumulation or a depletion of ions within the channel, depending on voltage polarity, that

  4. Barium ions selectively activate BK channels via the Ca2+-bowl site.

    PubMed

    Zhou, Yu; Zeng, Xu-Hui; Lingle, Christopher J

    2012-07-10

    Activation of Ca(2+)-dependent BK channels is increased via binding of micromolar Ca(2+) to two distinct high-affinity sites per BK α-subunit. One site, termed the Ca(2+) bowl, is embedded within the second RCK domain (RCK2; regulator of conductance for potassium) of each α-subunit, while oxygen-containing residues in the first RCK domain (RCK1) have been linked to a separate Ca(2+) ligation site. Although both sites are activated by Ca(2+) and Sr(2+), Cd(2+) selectively favors activation via the RCK1 site. Divalent cations of larger ionic radius than Sr(2+) are thought to be ineffective at activating BK channels. Here we show that Ba(2+), better known as a blocker of K(+) channels, activates BK channels and that this effect arises exclusively from binding at the Ca(2+)-bowl site. Compared with previous estimates for Ca(2+) bowl-mediated activation by Ca(2+), the affinity of Ba(2+) to the Ca(2+) bowl is reduced about fivefold, and coupling of binding to activation is reduced from ∼3.6 for Ca(2+) to about ∼2.8 for Ba(2+). These results support the idea that ionic radius is an important determinant of selectivity differences among different divalent cations observed for each Ca(2+)-binding site.

  5. A general method for selecting quantum channel for bidirectional controlled state teleportation and other schemes of controlled quantum communication

    NASA Astrophysics Data System (ADS)

    Thapliyal, Kishore; Verma, Amit; Pathak, Anirban

    2015-12-01

    Recently, a large number of protocols for bidirectional controlled state teleportation (BCST) have been proposed using n-qubit entangled states (nin {5,6,7}) as quantum channel. Here, we propose a general method of selecting multiqubit (n>4) quantum channels suitable for BCST and show that all the channels used in the existing protocols of BCST can be obtained using the proposed method. Further, it is shown that the quantum channels used in the existing protocols of BCST form only a negligibly small subset of the set of all the quantum channels that can be constructed using the proposed method to implement BCST. It is also noted that all these quantum channels are also suitable for controlled bidirectional remote state preparation. Following the same logic, methods for selecting quantum channels for other controlled quantum communication tasks, such as controlled bidirectional joint remote state preparation and controlled quantum dialogue, are also provided.

  6. An Efficient P300-based BCI Using Wavelet Features and IBPSO-based Channel Selection

    PubMed Central

    Perseh, Bahram; Sharafat, Ahmad R.

    2012-01-01

    We present a novel and efficient scheme that selects a minimal set of effective features and channels for detecting the P300 component of the event-related potential in the brain–computer interface (BCI) paradigm. For obtaining a minimal set of effective features, we take the truncated coefficients of discrete Daubechies 4 wavelet, and for selecting the effective electroencephalogram channels, we utilize an improved binary particle swarm optimization algorithm together with the Bhattacharyya criterion. We tested our proposed scheme on dataset IIb of BCI competition 2005 and achieved 97.5% and 74.5% accuracy in 15 and 5 trials, respectively, using a simple classification algorithm based on Bayesian linear discriminant analysis. We also tested our proposed scheme on Hoffmann's dataset for eight subjects, and achieved similar results. PMID:23717804

  7. The selectivity filter of the tandem pore potassium channel TASK-1 and its pH-sensitivity and ionic selectivity.

    PubMed

    Yuill, K; Ashmole, I; Stanfield, P R

    2004-04-01

    We have studied pH sensitivity and ionic selectivity of the tandem pore K(+) channel TASK-1 heterologously expressed in Xenopus oocytes. We fit pH sensitivity assuming that only one of the two residues H98 need be protonated for channels to be shut. The effect of protons was weakly voltage dependent with a p K(a) of 6.02 at +40 mV. Replacement of His (H98D, H98N) reduced pH sensitivity but did not abolish it. Use of a concatameric channel permitted replacement of one His residue only; this concatamer was fully pH-sensitive. Increasing the number of His residues to 4 (mutant D204H) abolished pH sensitivity over the physiological range. The implication that D204 plays a role in pH-sensitivity was confirmed by the finding that pH sensitivity over the physiological range was also abolished in the mutant D204N. Ionic selectivity was also altered in D204H, D204N and H98D mutants. P(Rb)/ P(K) was increased from 0.80+/-0.04 (n=19) in wild type to 1.06+/-0.04 (n=19) in D204H. H98D, D204H and D204N were permeable to Na(+) with P(Na)/ P(K)=0.39+/-0.03 (n=14) in H98D, 0.64+/-0.04 (n=18) in D204H and 0.33+/-0.07 (n=3) in D204N. Thus, the arrangement of ring of residues HDHD appears to optimise both pH sensitivity and ionic selectivity.

  8. EMG Feature Assessment for Myoelectric Pattern Recognition and Channel Selection: A Study with Incomplete Spinal Cord Injury

    PubMed Central

    Liu, Jie; Li, Xiaoyan; Li, Guanglin; Zhou, Ping

    2014-01-01

    Myoelectric pattern recognition with a large number of electromyogram (EMG) channels provides an approach to assessing motor control information available from the recorded muscles. In order to develop a practical myoelectric control system, a feature dependent channel reduction method was developed in this study to determine a small number of EMG channels for myoelectric pattern recognition analysis. The method selects appropriate raw EMG features for classification of different movements, using the minimum Redundancy Maximum Relevance (mRMR) and the Markov random field (MRF) methods to rank a large number of EMG features, respectively. A k-nearest neighbor (KNN) classifier was used to evaluate the performance of the selected features in terms of classification accuracy. The method was tested using 57 channels’ surface EMG signals recorded from forearm and hand muscles of individuals with incomplete spinal cord injury (SCI). Our results demonstrate that appropriate selection of a small number of raw EMG features from different recording channels resulted in similar high classification accuracies as achieved by using all the EMG channels or features. Compared with the conventional sequential forward selection (SFS) method, the feature dependent method does not require repeated classifier implementation. It can effectively reduce redundant information not only cross different channels, but also cross different features in the same channel. Such hybrid feature-channel selection from a large number of EMG recording channels can reduce computational cost for implementation of a myoelectric pattern recognition based control system. PMID:24844608

  9. On the structural basis for ionic selectivity among Na+, K+, and Ca2+ in the voltage-gated sodium channel.

    PubMed Central

    Favre, I; Moczydlowski, E; Schild, L

    1996-01-01

    Voltage-sensitive sodium channels and calcium channels are homologous proteins with distinctly different selectivity for permeation of inorganic cations. This difference in function is specified by amino acid residues located within P-region segments that link presumed transmembrane elements S5 and S6 in each of four repetitive Domains I, II, III, and IV. By analyzing the selective permeability of Na+, K+, and Ca2+ in various mutants of the mu 1 rat muscle sodium channel, the results in this paper support the concept that a conserved motif of four residues contributed by each of the Domains I-IV, termed the DEKA locus in sodium channels and the EEEE locus in calcium channels, determines the ionic selectivity of these channels. Furthermore, the results indicate that the Lys residue in Domain III of the sodium channel is the critical determinant that specifies both the impermeability of Ca2+ and the selective permeability of Na+ over K+. We propose that the alkylammonium ion of the Lys(III) residue acts as an endogenous cation within the ion binding site/selectivity filter of the sodium channel to tune the kinetics and affinity of inorganic cation binding within the pore in a manner analogous to ion-ion interactions that occur in the process of multi-ion channel conduction. PMID:8968582

  10. Distributed Channel Selection in CRAHNs with Heterogeneous Spectrum Opportunities: A Local Congestion Game Approach

    NASA Astrophysics Data System (ADS)

    Xu, Yuhua; Wu, Qihui; Wang, Jinlong; Min, Neng; Anpalagan, Alagan

    This letter investigates the problem of distributed channel selection in cognitive radio ad hoc networks (CRAHNs) with heterogeneous spectrum opportunities. Firstly, we formulate this problem as a local congestion game, which is proved to be an exact potential game. Then, we propose a spatial best response dynamic (SBRD) to rapidly achieve Nash equilibrium via local information exchange. Moreover, the potential function of the game reflects the network collision level and can be used to achieve higher throughput.

  11. Mechanisms Underlying Atrial-Selective Block of Sodium Channels by Wenxin Keli: Experimental and Theoretical Analysis

    PubMed Central

    Hu, Dan; Barajas-Martínez, Hector; Burashnikov, Alexander; Panama, Brian K.; Cordeiro, Jonathan M.; Antzelevitch, Charles

    2016-01-01

    Introduction Atrial-selective inhibition of cardiac sodium channel current (INa) and INa-dependent parameters has been shown to contribute to the safe and effective management of atrial fibrillation. The present study was designed to examine the basis for the atrial-selective actions of Wenxin Keli. Methods Whole cell INa was recorded at rroom temperature in canine atrial and ventricular myocytes. Trains of 40 pulses were elicited over a range of pulse durations and interpulse intervals to determine tonic and use-dependent block. A Markovian model for INa that incorporates interaction of Wenxin Keli with different states of the channel was developed to examine the basis for atrial selectivity of the drug. Results Our data indicate that Wenxin Keli does not bind significantly to either closed or open states of the sodium channel, but binds very rapidly to the inactivated state of the channel and dissociates rapidly from the closed state. Action potentials recorded from atrial and ventricular preparations in the presence of 5g/L Wenxin Keli were introduced into the computer model in current clamp mode to simulate the effects on maximum upstroke velocity (Vmax). The model predicted much greater inhibition of Vmax in atrial vs. ventricular cells at rapid stimulation rates. Conclusion Our findings suggest that atrial selectivity of Wenxin Keli to block INa is due to more negative steady-state inactivation, less negative resting membrane potential, and shorter diastolic intervals in atrial vs. ventricular cells at rapid activation rates. These actions of Wenxin Keli account for its relatively safe and effective suppression of atrial fibrillation. PMID:26820362

  12. Ion Selectivity Mechanism in a Bacterial Pentameric Ligand-Gated Ion Channel

    SciTech Connect

    Fritsch, Sebastian M; Ivanov, Ivaylo N; Wang, Hailong; Cheng, Xiaolin

    2011-01-01

    The proton-gated ion channel from Gloeobacter violaceus (GLIC) is a prokaryotic homolog of the eukaryotic nicotinic acetylcholine receptor (nAChR) that responds to the binding of neurotransmitter acetylcholine and mediates fast signal transmission. Recent emergence of a high resolution crystal structure of GLIC captured in a potentially open state allowed detailed, atomic-level insight into ion conduction and selectivity mechanisms in these channels. Herein, we have examined the barriers to ion conduction and origins of ion selectivity in the GLIC channel by the construction of potential of mean force (PMF) profiles for sodium and chloride ions inside the transmembrane region. Our calculations reveal that the GLIC channel is open for a sodium ion to transport, but presents a ~10 kcal/mol free energy barrier for a chloride ion, which arises primarily from the unfavorable interactions with a ring of negatively charged glutamate residues (E-2 ) at the intracellular end and a ring of hydrophobic residues (I9 ) in the middle of the transmembrane domain. Our collective findings further suggest that the charge selection mechanism can, to a large extent, be attributed to the narrow intracellular end and a ring of glutamate residues in this position their strong negative electrostatics and ability to bind cations. By contrast, E19 at the extracellular entrance only plays a minor role in ion selectivity of GLIC. In addition to electrostatics, both ion hydration and protein dynamics are found to be crucial for ion conduction as well, which explains why a chloride ion experiences a much greater barrier than a sodium ion in the hydrophobic region of the pore.

  13. Doubly special relativity and Finsler geometry

    SciTech Connect

    Mignemi, S.

    2007-08-15

    We discuss the recent proposal of implementing doubly special relativity in configuration space by means of Finsler geometry. Although this formalism leads to a consistent description of the dynamics of a particle, it does not seem to give a complete description of the physics. In particular, the Finsler line element is not invariant under the deformed Lorentz transformations of doubly special relativity. We study in detail some simple applications of the formalism.

  14. Further analysis of counterion permeation through anion-selective glycine receptor channels.

    PubMed

    Barry, Peter H; Sugiharto, Silas; Lewis, Trevor M; Moorhouse, Andrew J

    2010-01-01

    The functional role of ion channels, which allow counterion permeation, depends critically on their relative anion-cation relative selectivity. From whole-cell patch clamp reversal potential measurements under dilution potential conditions, we have already shown that anion-cation permeabilities of anion-selective wild-type (WT) and mutant (with larger pore diameter) glycine receptor (GlyR) channels in the presence of Li(+), Na(+) and Cs(+) counterions, were inversely correlated with the equivalent hydration diameter of the counterion, with chloride-cation permeability increasing as counterion equivalent hydration diameter increased with respect to the channel minimum pore diameter. Corrected for liquid junction potentials (LJPs; using ion activities), the previous chloride-cation permeabilities for the alkali cations were 23.4 (Li(+)), 10.9 (Na(+)) and 5.0 (Cs(+)) for the smaller WT channel. Further analysis to incorporate an initial offset potential correction, to fully allow for slight differences between internal cell composition and external control salt solution, changed the above permeability ratios to 30.6 (Li(+)), 11.8 (Na(+)) and 5.0 (Cs(+)), adding enhanced support for the inverse correlation between anion-to-counterion permeability ratio and equivalent hydrated counterion diameter relative to channel pore diameter (erroneously ignoring LJPs reduces each permeability ratio to about 4). Also, new direct measurements of LJPs (for NaCl and LiCl salt dilutions) using a 3M KCl-agar reference salt bridge (with freshly-cut end for each solution composition change) have shown excellent agreement with calculated LJPs (using ion activities), validating calculated LJP values. We continue to suggest that counterion cations permeate with chloride ions as neutral pairs.

  15. Cation selectivity by the CorA Mg2+ channel requires a fully hydrated cation.

    PubMed

    Moomaw, Andrea S; Maguire, Michael E

    2010-07-27

    The CorA Mg(2+) channel is the primary uptake system in about half of all bacteria and archaea. However, the basis for its Mg(2+) selectivity is unknown. Previous data suggested that CorA binds a fully hydrated Mg(2+) ion, unlike other ion channels. The crystal structure of Thermotoga maritima CorA shows a homopentamer with two transmembrane segments per monomer connected by a short periplasmic loop. This highly conserved loop, (281)EFMPELKWS(289) in Salmonella enterica serovar Typhimurium CorA, is the only portion of the channel outside of the cell, suggesting a role in cation selectivity. Mutation of charged residues in the loop, E281 and K287, to any of several amino acids had little effect, demonstrating that despite conservation electrostatic interactions with these residues are not essential. While mutation of the universally conserved E285 gave a minimally functional channel, E285A and E285K mutants were the most functional, again indicating that the negative charge at this position is not a determining factor. Several mutations at K287 and W288 behaved anomalously in a transport assay. Analysis indicated that mutation of K287 and W288 disrupts cooperative interactions between distinct Mg(2+) binding sites. Overall, these results are not compatible with electrostatic interaction of the Mg(2+) ion with the periplasmic loop. Instead, the loop appears to form an initial binding site for hydrated Mg(2+), not for the dehydrated cation. The loop residues may function to accelerate dehydration of the before entry of Mg(2+) into the pore of the channel.

  16. Ion permeation through a Cl[superscript -]-selective channel designed from a CLC Cl[superscript -]/H[superscript +] exchanger

    SciTech Connect

    Jayaram, Hariharan; Accardi, Alessio; Wu, Fang; Williams, Carole; Miller, Christopher

    2008-09-03

    The CLC family of Cl{sup -}-transporting proteins includes both Cl{sup -} channels and Cl{sup -}/H{sup +} exchange transporters. CLC-ec1, a structurally known bacterial homolog of the transporter subclass, exchanges two Cl{sup -} ions per proton with strict, obligatory stoichiometry. Point mutations at two residues, Glu{sup 148} and Tyr{sup 445}, are known to impair H{sup +} movement while preserving Cl{sup -} transport. In the x-ray crystal structure of CLC-ec1, these residues form putative 'gates' flanking an ion-binding region. In mutants with both of the gate-forming side chains reduced in size, H{sup +} transport is abolished, and unitary Cl{sup -} transport rates are greatly increased, well above values expected for transporter mechanisms. Cl{sup -} transport rates increase as side-chain volume at these positions is decreased. The crystal structure of a doubly ungated mutant shows a narrow conduit traversing the entire protein transmembrane width. These characteristics suggest that Cl{sup -} flux through uncoupled, ungated CLC-ec1 occurs via a channel-like electrodiffusion mechanism rather than an alternating-exposure conformational cycle that has been rendered proton-independent by the gate mutations.

  17. Selective alteration of sodium channel gating by Australian funnel-web spider toxins.

    PubMed

    Nicholson, G M; Little, M J; Tyler, M; Narahashi, T

    1996-01-01

    The actions of potent mammalian neurotoxins isolated from the venom of two Australian funnel-web spiders were investigated using both electrophysiological and neurochemical techniques. Whole-cell patch clamp recording of sodium currents in rat dorsal root ganglion neurons revealed that versutoxin (VTX), isolated from the venom of Hadronyche versuta, produced a concentration-dependent slowing or removal of tetrodotoxin-sensitive (TTX-S) sodium current inactivation and a reduction in peak TTX-S sodium current. In contrast, VTX had no effect on tetrodotoxin-resistant (TTX-R) sodium currents or potassium currents. VTX also shifted the voltage dependence of sodium channel activation in the hyperpolarizing direction and increased the rate of recovery from inactivation. Ion flux studies performed in rat brain synaptosomes also revealed that robustoxin (RTX), from the venom of Atrax robustus, and VTX both produced a partial activation of 22Na+ flux and an inhibition of batrachotoxin-activated 22Na+ flux. This inhibition of flux through batrachotoxin-activated channels was not due to an interaction with neurotoxin receptor site 1 since [3H]saxitoxin binding was unaffected. In addition, the partial activation of 22Na+ flux was not enhanced in the presence of alpha-scorpion toxin and further experiments suggest that VTX also enhances [3H]batrachotoxin binding. These selective actions of funnel-web spider toxins on sodium channel function are comparable to those of alpha-scorpion and sea anemone toxins which bind to neurotoxin receptor site 3 on the channel to slow channel inactivation profoundly. Also, these modifications of sodium channel gating and kinetics are consistent with actions of the spider toxins to produce repetitive firing of action potentials.

  18. Regulatory evolution and voltage-gated ion channel expression in squid axon: selection-mutation balance and fitness cliffs.

    PubMed

    Kim, Min; McKinnon, Don; MacCarthy, Thomas; Rosati, Barbara; McKinnon, David

    2015-01-01

    It has been suggested that optimization of either axonal conduction velocity or the energy efficiency of action potential conduction predominates in the selection of voltage-gated sodium conductance levels in the squid axon. A population genetics model of channel gene regulatory function was used to examine the role of these and other evolutionary forces on the selection of both sodium and potassium channel expression levels. In this model, the accumulating effects of mutations result in degradation of gene regulatory function, causing channel gene expression to fall to near-zero in the absence of positive selection. In the presence of positive selection, channel expression levels fall to the lowest values consistent with the selection criteria, thereby establishing a selection-mutation balance. Within the parameter space of sodium and potassium conductance values, the physiological performance of the squid axon model showed marked discontinuities associated with conduction failure and excitability. These discontinuities in physiological function may produce fitness cliffs. A fitness cliff associated with conduction failure, combined with the effects of phenotypic noise, can account for the selection of sodium conductance levels, without considering either conduction velocity or metabolic cost. A fitness cliff associated with a transition in axonal excitability, combined with phenotypic noise, can explain the selection of potassium channel expression levels. The results suggest that voltage-gated ion channel expression will fall to low levels, consistent with key functional constraints, even in the absence of positive selection for energy efficiency. Channel expression levels and individual variation in channel expression within the population can be explained by regulatory evolution in combination with genetic variation in regulatory function and phenotypic noise, without resorting to more complex mechanisms, such as activity-dependent homeostasis. Only a

  19. Regulatory Evolution and Voltage-Gated Ion Channel Expression in Squid Axon: Selection-Mutation Balance and Fitness Cliffs

    PubMed Central

    MacCarthy, Thomas; Rosati, Barbara; McKinnon, David

    2015-01-01

    It has been suggested that optimization of either axonal conduction velocity or the energy efficiency of action potential conduction predominates in the selection of voltage-gated sodium conductance levels in the squid axon. A population genetics model of channel gene regulatory function was used to examine the role of these and other evolutionary forces on the selection of both sodium and potassium channel expression levels. In this model, the accumulating effects of mutations result in degradation of gene regulatory function, causing channel gene expression to fall to near-zero in the absence of positive selection. In the presence of positive selection, channel expression levels fall to the lowest values consistent with the selection criteria, thereby establishing a selection-mutation balance. Within the parameter space of sodium and potassium conductance values, the physiological performance of the squid axon model showed marked discontinuities associated with conduction failure and excitability. These discontinuities in physiological function may produce fitness cliffs. A fitness cliff associated with conduction failure, combined with the effects of phenotypic noise, can account for the selection of sodium conductance levels, without considering either conduction velocity or metabolic cost. A fitness cliff associated with a transition in axonal excitability, combined with phenotypic noise, can explain the selection of potassium channel expression levels. The results suggest that voltage-gated ion channel expression will fall to low levels, consistent with key functional constraints, even in the absence of positive selection for energy efficiency. Channel expression levels and individual variation in channel expression within the population can be explained by regulatory evolution in combination with genetic variation in regulatory function and phenotypic noise, without resorting to more complex mechanisms, such as activity-dependent homeostasis. Only a

  20. Engineering Highly Potent and Selective Microproteins against Nav1.7 Sodium Channel for Treatment of Pain.

    PubMed

    Shcherbatko, Anatoly; Rossi, Andrea; Foletti, Davide; Zhu, Guoyun; Bogin, Oren; Galindo Casas, Meritxell; Rickert, Mathias; Hasa-Moreno, Adela; Bartsevich, Victor; Crameri, Andreas; Steiner, Alexander R; Henningsen, Robert; Gill, Avinash; Pons, Jaume; Shelton, David L; Rajpal, Arvind; Strop, Pavel

    2016-07-01

    The prominent role of voltage-gated sodium channel 1.7 (Nav1.7) in nociception was revealed by remarkable human clinical and genetic evidence. Development of potent and subtype-selective inhibitors of this ion channel is crucial for obtaining therapeutically useful analgesic compounds. Microproteins isolated from animal venoms have been identified as promising therapeutic leads for ion channels, because they naturally evolved to be potent ion channel blockers. Here, we report the engineering of highly potent and selective inhibitors of the Nav1.7 channel based on tarantula ceratotoxin-1 (CcoTx1). We utilized a combination of directed evolution, saturation mutagenesis, chemical modification, and rational drug design to obtain higher potency and selectivity to the Nav1.7 channel. The resulting microproteins are highly potent (IC50 to Nav1.7 of 2.5 nm) and selective. We achieved 80- and 20-fold selectivity over the closely related Nav1.2 and Nav1.6 channels, respectively, and the IC50 on skeletal (Nav1.4) and cardiac (Nav1.5) sodium channels is above 3000 nm The lead molecules have the potential for future clinical development as novel therapeutics in the treatment of pain.

  1. Recent (circa 1998 to 2011) channel-migration rates of selected streams in Indiana

    USGS Publications Warehouse

    Robinson, Bret A.

    2013-01-01

    An investigation was completed to document recent (circa 1998 to 2011) channel-migration rates at 970 meander bends along 38 of the largest streams in Indiana. Data collection was completed by using the Google Earth™ platform and, for each selected site, identifying two images with capture dates separated by multiple years. Within each image, the position of the meander-bend cutbank was measured relative to a fixed local landscape feature visible in both images, and an average channel-migration rate was calculated at the point of maximum cutbank displacement. From these data it was determined that 65 percent of the measured sites have recently been migrating at a rate less than 1 ft/yr, 75 percent of the sites have been migrating at a rate less than 10 ft/yr, and while some sites are migrating in excess of 20 ft/yr, these occurrences are rare. In addition, it is shown that recent channel-migration activity is not evenly distributed across Indiana. For the stream reaches studied, far northern and much of far southern Indiana are drained by streams that recently have been relatively stationary. At the same time, this study shows that most of the largest streams in west-central Indiana and many of the largest streams in east-central Indiana have shown significant channel-migration activity during the recent past. It is anticipated that these results will support several fluvial-erosion-hazard mitigation activities currently being undertaken in Indiana.

  2. Dimethyl sulfoxide at high concentrations inhibits non-selective cation channels in human erythrocytes.

    PubMed

    Nardid, Oleg A; Schetinskey, Miroslav I; Kucherenko, Yuliya V

    2013-03-01

    Dimethyl sulfoxide (DMSO), a by-product of the pulping industry, is widely used in biological research, cryobiology and medicine. On cellular level DMSO was shown to suppress NMDA-AMPA channels activation, blocks Na+ channel activation and attenuates Ca2+ influx (Lu and Mattson 2001). In the present study we explored the whole-cell patch-clamp to examine the acute effect of high concentrations of DMSO (0.1-2 mol/l) on cation channels activity in human erythrocytes. Acute application of DMSO (0.1-2 mol/l) dissolved in Cl--containing saline buffer solution significantly inhibited cation conductance in human erythrocytes. Inhibition was concentration-dependent and had an exponential decay profile. DMSO (2 mol/l) induced cation inhibition in Cl-- containing saline solutions of: 40.3 ± 3.9% for K+, 35.4 ± 3.1% for Ca2+ and 47.4 ± 1.9% for NMDG+. Substitution of Cl- with gluconate- increased the inhibitory effect of DMSO on the Na+ current. Inhibitory effect of DMSO was neither due to high permeability of erythrocytes to DMSO nor to an increased tonicity of the bath media since no effect was observed in 2 mol/l glycerol solution. In conclusion, we have shown that high concentrations of DMSO inhibit the non-selective cation channels in human erythrocytes and thus protect the cells against Na+ and Ca2+ overload. Possible mechanisms of DMSO effect on cation conductance are discussed.

  3. Protein interactions central to stabilizing the K[superscript +] channel selectivity filter in a four-sited configuration for selective K[superscript +] permeation

    SciTech Connect

    Sauer, David B.; Zeng, Weizhong; Raghunathan, Srinivasan; Jiang, Youxing

    2011-11-18

    The structural and functional conversion of the nonselective NaK channel to a K{sup +} selective channel (NaK2K) allows us to identify two key residues, Tyr and Asp in the filter sequence of TVGYGD, that participate in interactions central to stabilizing the K{sup +} channel selectivity filter. By using protein crystallography and channel electrophysiology, we demonstrate that the K{sup +} channel filter exists as an energetically strained structure and requires these key protein interactions working in concert to hold the filter in the precisely defined four-sited configuration that is essential for selective K{sup +} permeation. Disruption of either interaction, as tested on both the NaK2K and eukaryotic K{sub v}1.6 channels, can reduce or completely abolish K{sup +} selectivity and in some cases may also lead to channel inactivation due to conformational changes at the filter. Additionally, on the scaffold of NaK we recapitulate the protein interactions found in the filter of the Kir channel family, which uses a distinct interaction network to achieve similar stabilization of the filter.

  4. Ion selectivity of porcine skeletal muscle Ca2+ release channels is unaffected by the Arg615 to Cys615 mutation.

    PubMed Central

    Shomer, N H; Mickelson, J R; Louis, C F

    1994-01-01

    The Arg615 to Cys615 mutation of the sarcoplasmic reticulum (SR) Ca2+ release channel of malignant hyperthermia susceptible (MHS) pigs results in a decreased sensitivity of the channel to inhibitory Ca2+ concentrations. To investigate whether this mutation also affects the ion selectivity filter of the channel, the monovalent cation conductances and ion permeability ratios of single Ca2+ release channels incorporated into planar lipid bilayers were compared. Monovalent cation conductances in symmetrical solutions were: Li+, 183 pS +/- 3 (n = 21); Na+, 474 pS +/- 6 (n = 29); K+, 771 pS +/- 7 (n = 29); Rb+, 502 pS +/- 10 (n = 22); and Cs+, 527 pS +/- 5 (n = 16). The single-channel conductances of MHS and normal Ca2+ release channel were not significantly different for any of the monovalent cations tested. Permeability ratios measured under biionic conditions had the permeability sequence Ca2+ >> Li+ > Na+ > K+ > or Rb+ > Cs+, with no significant difference noted between MHS and normal channels. This systematic examination of the conduction properties of the pig skeletal muscle Ca2+ release channel indicated a higher Ca2+ selectivity (PCa2+:Pk+ approximately 15.5) than the sixfold Ca2+ selectivity previously reported for rabbit skeletal (Smith et al., 1988) or sheep cardiac muscle (Tinker et al., 1992) Ca2+ release channels. These results also indicate that although Ca2+ regulation of Ca2+ release channel activity is altered, the Arg615 to Cys615 mutation of the porcine Ca2+ release channel does not affect the conductance or ion selectivity properties of the channel. PMID:7948678

  5. Evolutionary insights into T-type Ca(2+) channel structure, function, and ion selectivity from the Trichoplax adhaerens homologue.

    PubMed

    Smith, Carolyn L; Abdallah, Salsabil; Wong, Yuen Yan; Le, Phuong; Harracksingh, Alicia N; Artinian, Liana; Tamvacakis, Arianna N; Rehder, Vincent; Reese, Thomas S; Senatore, Adriano

    2017-04-03

    Four-domain voltage-gated Ca(2+) (Cav) channels play fundamental roles in the nervous system, but little is known about when or how their unique properties and cellular roles evolved. Of the three types of metazoan Cav channels, Cav1 (L-type), Cav2 (P/Q-, N- and R-type) and Cav3 (T-type), Cav3 channels are optimized for regulating cellular excitability because of their fast kinetics and low activation voltages. These same properties permit Cav3 channels to drive low-threshold exocytosis in select neurons and neurosecretory cells. Here, we characterize the single T-type calcium channel from Trichoplax adhaerens (TCav3), an early diverging animal that lacks muscle, neurons, and synapses. Co-immunolocalization using antibodies against TCav3 and neurosecretory cell marker complexin labeled gland cells, which are hypothesized to play roles in paracrine signaling. Cloning and in vitro expression of TCav3 reveals that, despite roughly 600 million years of divergence from other T-type channels, it bears the defining structural and biophysical features of the Cav3 family. We also characterize the channel's cation permeation properties and find that its pore is less selective for Ca(2+) over Na(+) compared with the human homologue Cav3.1, yet it exhibits a similar potent block of inward Na(+) current by low external Ca(2+) concentrations (i.e., the Ca(2+) block effect). A comparison of the permeability features of TCav3 with other cloned channels suggests that Ca(2+) block is a locus of evolutionary change in T-type channel cation permeation properties and that mammalian channels distinguish themselves from invertebrate ones by bearing both stronger Ca(2+) block and higher Ca(2+) selectivity. TCav3 is the most divergent metazoan T-type calcium channel and thus provides an evolutionary perspective on Cav3 channel structure-function properties, ion selectivity, and cellular physiology.

  6. Differential binding of monovalent cations to KcsA: Deciphering the mechanisms of potassium channel selectivity.

    PubMed

    Montoya, Estefanía; Lourdes Renart, M; Marcela Giudici, A; Poveda, José A; Fernández, Asia M; Morales, Andrés; González-Ros, José M

    2017-05-01

    This work explores whether the ion selectivity and permeation properties of a model potassium channel, KcsA, could be explained based on ion binding features. Non-permeant Na(+) or Li(+) bind with low affinity (millimolar KD's) to a single set of sites contributed by the S1 and S4 sites seen at the selectivity filter in the KcsA crystal structure. Conversely, permeant K(+), Rb(+), Tl(+) and even Cs(+) bind to two different sets of sites as their concentration increases, consistent with crystallographic evidence on the ability of permeant species to induce concentration-dependent transitions between conformational states (non-conductive and conductive) of the channel's selectivity filter. The first set of such sites, assigned also to the crystallographic S1 and S4 sites, shows similarly high affinities for all permeant species (micromolar KD's), thus, securing displacement of potentially competing non-permeant cations. The second set of sites, available only to permeant cations upon the transition to the conductive filter conformation, shows low affinity (millimolar KD's), thus, favoring cation dissociation and permeation and results from the contribution of all S1 through S4 crystallographic sites. The differences in affinities between permeant and non-permeant cations and the similarities in binding behavior within each of these two groups, correlate fully with their permeabilities relative to K(+), suggesting that binding is an important determinant of the channel's ion selectivity. Conversely, the complexity observed in permeation features cannot be explained just in terms of binding and likely relates to reported differences in the occupancy of the S2 and S3 sites by the permeant cations.

  7. Nonlinear and asymmetric open channel characteristics of an ion-selective porin in planar membranes.

    PubMed Central

    Mathes, A; Engelhardt, H

    1998-01-01

    The open channel characteristics of the bacterial porin Omp32 from Comamonas acidovorans were investigated by means of conductance measurements in planar lipid bilayers of the Montal-Mueller type. Particularly at low salt conditions (< or = 30 mM KCl) Omp32 exhibited some unusual asymmetric and nonlinear functional properties. Current-voltage relationship measurements showed that conductance depends on the orientation of porin molecules and is a nonlinear function of the applied membrane potential. Conductance also depends on the salt concentration in a manner not common to porins and the salt concentration modulates the nonlinearity of conductance-voltage relationships. Omp32 is strongly anion-selective. The nonlinear and asymmetric conductance of the open channel is a new observation in porins. PMID:9726928

  8. Discrimination of correlated and entangling quantum channels with selective process tomography

    NASA Astrophysics Data System (ADS)

    Dumitrescu, Eugene; Humble, Travis S.

    2016-10-01

    The accurate and reliable characterization of quantum dynamical processes underlies efforts to validate quantum technologies, where discrimination between competing models of observed behaviors inform efforts to fabricate and operate qubit devices. We present a protocol for quantum channel discrimination that leverages advances in direct characterization of quantum dynamics (DCQD) codes. We demonstrate that DCQD codes enable selective process tomography to improve discrimination between entangling and correlated quantum dynamics. Numerical simulations show selective process tomography requires only a few measurement configurations to achieve a low false alarm rate and that the DCQD encoding improves the resilience of the protocol to hidden sources of noise. Our results show that selective process tomography with DCQD codes is useful for efficiently distinguishing sources of correlated crosstalk from uncorrelated noise in current and future experimental platforms.

  9. Discrimination of correlated and entangling quantum channels with selective process tomography

    DOE PAGES

    Dumitrescu, Eugene; Humble, Travis S.

    2016-10-10

    The accurate and reliable characterization of quantum dynamical processes underlies efforts to validate quantum technologies, where discrimination between competing models of observed behaviors inform efforts to fabricate and operate qubit devices. We present a protocol for quantum channel discrimination that leverages advances in direct characterization of quantum dynamics (DCQD) codes. We demonstrate that DCQD codes enable selective process tomography to improve discrimination between entangling and correlated quantum dynamics. Numerical simulations show selective process tomography requires only a few measurement configurations to achieve a low false alarm rate and that the DCQD encoding improves the resilience of the protocol to hiddenmore » sources of noise. Lastly, our results show that selective process tomography with DCQD codes is useful for efficiently distinguishing sources of correlated crosstalk from uncorrelated noise in current and future experimental platforms.« less

  10. Discrimination of correlated and entangling quantum channels with selective process tomography

    SciTech Connect

    Dumitrescu, Eugene; Humble, Travis S.

    2016-10-10

    The accurate and reliable characterization of quantum dynamical processes underlies efforts to validate quantum technologies, where discrimination between competing models of observed behaviors inform efforts to fabricate and operate qubit devices. We present a protocol for quantum channel discrimination that leverages advances in direct characterization of quantum dynamics (DCQD) codes. We demonstrate that DCQD codes enable selective process tomography to improve discrimination between entangling and correlated quantum dynamics. Numerical simulations show selective process tomography requires only a few measurement configurations to achieve a low false alarm rate and that the DCQD encoding improves the resilience of the protocol to hidden sources of noise. Lastly, our results show that selective process tomography with DCQD codes is useful for efficiently distinguishing sources of correlated crosstalk from uncorrelated noise in current and future experimental platforms.

  11. Enhancement of the NMSU Channel Error Simulator to Provide User-Selectable Link Delays

    NASA Technical Reports Server (NTRS)

    Horan, Stephen; Wang, Ru-Hai

    2000-01-01

    This is the third in a continuing series of reports describing the development of the Space-to-Ground Link Simulator (SGLS) to be used for testing data transfers under simulated space channel conditions. The SGLS is based upon Virtual Instrument (VI) software techniques for managing the error generation, link data rate configuration, and, now, selection of the link delay value. In this report we detail the changes that needed to be made to the SGLS VI configuration to permit link delays to be added to the basic error generation and link data rate control capabilities. This was accomplished by modifying the rate-splitting VIs to include a buffer the hold the incoming data for the duration selected by the user to emulate the channel link delay. In sample tests of this configuration, the TCP/IP(sub ftp) service and the SCPS(sub fp) service were used to transmit 10-KB data files using both symmetric (both forward and return links set to 115200 bps) and unsymmetric (forward link set at 2400 bps and a return link set at 115200 bps) link configurations. Transmission times were recorded at bit error rates of 0 through 10(exp -5) to give an indication of the link performance. In these tests. we noted separate timings for the protocol setup time to initiate the file transfer and the variation in the actual file transfer time caused by channel errors. Both protocols showed similar performance to that seen earlier for the symmetric and unsymmetric channels. This time, the delays in establishing the file protocol also showed that these delays could double the transmission time and need to be accounted for in mission planning. Both protocols also showed a difficulty in transmitting large data files over large link delays. In these tests, there was no clear favorite between the TCP/IP(sub ftp) and the SCPS(sub fp). Based upon these tests, further testing is recommended to extend the results to different file transfer configurations.

  12. New Positive Ca2+-Activated K+ Channel Gating Modulators with Selectivity for KCa3.1

    PubMed Central

    Coleman, Nichole; Brown, Brandon M.; Oliván-Viguera, Aida; Singh, Vikrant; Olmstead, Marilyn M.; Valero, Marta Sofia; Köhler, Ralf

    2014-01-01

    Small-conductance (KCa2) and intermediate-conductance (KCa3.1) calcium-activated K+ channels are voltage-independent and share a common calcium/calmodulin-mediated gating mechanism. Existing positive gating modulators like EBIO, NS309, or SKA-31 activate both KCa2 and KCa3.1 channels with similar potency or, as in the case of CyPPA and NS13001, selectively activate KCa2.2 and KCa2.3 channels. We performed a structure-activity relationship (SAR) study with the aim of optimizing the benzothiazole pharmacophore of SKA-31 toward KCa3.1 selectivity. We identified SKA-111 (5-methylnaphtho[1,2-d]thiazol-2-amine), which displays 123-fold selectivity for KCa3.1 (EC50 111 ± 27 nM) over KCa2.3 (EC50 13.7 ± 6.9 μM), and SKA-121 (5-methylnaphtho[2,1-d]oxazol-2-amine), which displays 41-fold selectivity for KCa3.1 (EC50 109 nM ± 14 nM) over KCa2.3 (EC50 4.4 ± 1.6 μM). Both compounds are 200- to 400-fold selective over representative KV (KV1.3, KV2.1, KV3.1, and KV11.1), NaV (NaV1.2, NaV1.4, NaV1.5, and NaV1.7), as well as CaV1.2 channels. SKA-121 is a typical positive-gating modulator and shifts the calcium-concentration response curve of KCa3.1 to the left. In blood pressure telemetry experiments, SKA-121 (100 mg/kg i.p.) significantly lowered mean arterial blood pressure in normotensive and hypertensive wild-type but not in KCa3.1−/− mice. SKA-111, which was found in pharmacokinetic experiments to have a much longer half-life and to be much more brain penetrant than SKA-121, not only lowered blood pressure but also drastically reduced heart rate, presumably through cardiac and neuronal KCa2 activation when dosed at 100 mg/kg. In conclusion, with SKA-121, we generated a KCa3.1-specific positive gating modulator suitable for further exploring the therapeutical potential of KCa3.1 activation. PMID:24958817

  13. Wavelet Packet Feature Assessment for High-Density Myoelectric Pattern Recognition and Channel Selection toward Stroke Rehabilitation

    PubMed Central

    Wang, Dongqing; Zhang, Xu; Gao, Xiaoping; Chen, Xiang; Zhou, Ping

    2016-01-01

    This study presents wavelet packet feature assessment of neural control information in paretic upper limb muscles of stroke survivors for myoelectric pattern recognition, taking advantage of high-resolution time–frequency representations of surface electromyogram (EMG) signals. On this basis, a novel channel selection method was developed by combining the Fisher’s class separability index and the sequential feedforward selection analyses, in order to determine a small number of appropriate EMG channels from original high-density EMG electrode array. The advantages of the wavelet packet features and the channel selection analyses were further illustrated by comparing with previous conventional approaches, in terms of classification performance when identifying 20 functional arm/hand movements implemented by 12 stroke survivors. This study offers a practical approach including paretic EMG feature extraction and channel selection that enables active myoelectric control of multiple degrees of freedom with paretic muscles. All these efforts will facilitate upper limb dexterity restoration and improved stroke rehabilitation. PMID:27917149

  14. Putative resolution of the EEEE selectivity paradox in L-type Ca2+ and bacterial Na+ biological ion channels

    NASA Astrophysics Data System (ADS)

    Kaufman, I. Kh; Luchinsky, D. G.; Gibby, W. A. T.; McClintock, P. V. E.; Eisenberg, R. S.

    2016-05-01

    The highly selective permeation of ions through biological ion channels can be described and explained in terms of fluctuational dynamics under the influence of powerful electrostatic forces. Hence valence selectivity, e.g. between Ca2+ and Na+ in calcium and sodium channels, can be described in terms of ionic Coulomb blockade, which gives rise to distinct conduction bands and stop-bands as the fixed negative charge Q f at the selectivity filter of the channel is varied. This picture accounts successfully for a wide range of conduction phenomena in a diversity of ion channels. A disturbing anomaly, however, is that what appears to be the same electrostatic charge and structure (the so-called EEEE motif) seems to select Na+ conduction in bacterial channels but Ca2+ conduction in mammalian channels. As a possible resolution of this paradox it is hypothesised that an additional charged protein residue on the permeation path of the mammalian channel increases |{{Q}f}| by e, thereby altering the selectivity from Na+ to Ca2+. Experiments are proposed that will enable the hypothesis to be tested.

  15. Isospin Splittings of Doubly Heavy Baryons

    SciTech Connect

    Brodsky, Stanley J.; Guo, Feng-Kun; Hanhart, Christoph; Meissner, Ulf-G.; /Julich, Forschungszentrum /JCHP, Julich /IAS, Julich /Bonn U., HISKP /Bonn U.

    2011-08-18

    The SELEX Collaboration has reported a very large isospin splitting of doubly charmed baryons. We show that this effect would imply that the doubly charmed baryons are very compact. One intriguing possibility is that such baryons have a linear geometry Q-q-Q where the light quark q oscillates between the two heavy quarks Q, analogous to a linear molecule such as carbon dioxide. However, using conventional arguments, the size of a heavy-light hadron is expected to be around 0.5 fm, much larger than the size needed to explain the observed large isospin splitting. Assuming the distance between two heavy quarks is much smaller than that between the light quark and a heavy one, the doubly heavy baryons are related to the heavy mesons via heavy quark-diquark symmetry. Based on this symmetry, we predict the isospin splittings for doubly heavy baryons including {Xi}{sub cc}, {Xi}{sub bb} and {Xi}{sub bc}. The prediction for the {Xi}{sub cc} is much smaller than the SELEX value. On the other hand, the {Xi}{sub bb} baryons are predicted to have an isospin splitting as large as (6.3 {+-} 1.7) MeV. An experimental study of doubly bottomed baryons is therefore very important to better understand the structure of baryons with heavy quarks.

  16. Selectivity filters and cysteine-rich extracellular loops in voltage-gated sodium, calcium, and NALCN channels

    PubMed Central

    Stephens, Robert F.; Guan, W.; Zhorov, Boris S.; Spafford, J. David

    2015-01-01

    How nature discriminates sodium from calcium ions in eukaryotic channels has been difficult to resolve because they contain four homologous, but markedly different repeat domains. We glean clues from analyzing the changing pore region in sodium, calcium and NALCN channels, from single-cell eukaryotes to mammals. Alternative splicing in invertebrate homologs provides insights into different structural features underlying calcium and sodium selectivity. NALCN generates alternative ion selectivity with splicing that changes the high field strength (HFS) site at the narrowest level of the hourglass shaped pore where the selectivity filter is located. Alternative splicing creates NALCN isoforms, in which the HFS site has a ring of glutamates contributed by all four repeat domains (EEEE), or three glutamates and a lysine residue in the third (EEKE) or second (EKEE) position. Alternative splicing provides sodium and/or calcium selectivity in T-type channels with extracellular loops between S5 and P-helices (S5P) of different lengths that contain three or five cysteines. All eukaryotic channels have a set of eight core cysteines in extracellular regions, but the T-type channels have an infusion of 4–12 extra cysteines in extracellular regions. The pattern of conservation suggests a possible pairing of long loops in Domains I and III, which are bridged with core cysteines in NALCN, Cav, and Nav channels, and pairing of shorter loops in Domains II and IV in T-type channel through disulfide bonds involving T-type specific cysteines. Extracellular turrets of increasing lengths in potassium channels (Kir2.2, hERG, and K2P1) contribute to a changing landscape above the pore selectivity filter that can limit drug access and serve as an ion pre-filter before ions reach the pore selectivity filter below. Pairing of extended loops likely contributes to the large extracellular appendage as seen in single particle electron cryo-microscopy images of the eel Nav1 channel. PMID

  17. GATING OF HCN CHANNELS BY CYCLIC NUCLEOTIDES: RESIDUE CONTACTS THAT UNDERLIE LIGAND BINDING, SELECTIVITY AND EFFICACY

    PubMed Central

    Zhou, Lei; Siegelbaum, Steven A.

    2007-01-01

    SUMMARY Cyclic nucleotides regulate the activity of various proteins by interacting with a conserved cyclic nucleotide-binding domain (CNBD). Although X-ray crystallographic studies have revealed the structures of several CNBDs, the residues responsible for generating the high efficacy with which ligand binding leads to protein activation remain unknown. Here we combine molecular dynamics simulations with mutagenesis to identify ligand contacts important for the regulation of the hyperpolarization-activated HCN2 channel by cyclic nucleotides. Surprisingly, out of seven residues that make strong contacts with ligand, only R632 in the C-helix of the CNBD is essential for high ligand efficacy, due to its selective stabilization of cNMP binding to the open state of the channel. Principle component analysis suggests that a local movement of the C-helix upon ligand binding propagates through the CNBD of one subunit to the C-linker of a neighboring subunit to apply force to the gate of the channel. PMID:17562313

  18. Dynamics of the EAG1 K(+) channel selectivity filter assessed by molecular dynamics simulations.

    PubMed

    Bernsteiner, Harald; Bründl, Michael; Stary-Weinzinger, Anna

    2017-02-26

    EAG1 channels belong to the KCNH family of voltage gated potassium channels. They are expressed in several brain regions and increased expression is linked to certain cancer types. Recent cryo-EM structure determination finally revealed the structure of these channels in atomic detail, allowing computational investigations. In this study, we performed molecular dynamics simulations to investigate the ion binding sites and the dynamical behavior of the selectivity filter. Our simulations suggest that sites S2 and S4 form stable ion binding sites, while ions placed at sites S1 and S3 rapidly switched to sites S2 and S4. Further, ions tended to dissociate away from S0 within less than 20 ns, due to increased filter flexibility. This was followed by water influx from the extracellular side, leading to a widening of the filter in this region, and likely non-conductive filter configurations. Simulations with the inactivation-enhancing mutant Y464A or Na(+) ions lead to trapped water molecules behind the SF, suggesting that these simulations captured early conformational changes linked to C-type inactivation.

  19. A Single-Pore Residue Renders the Arabidopsis Root Anion Channel SLAH2 Highly Nitrate Selective[C][W

    PubMed Central

    Maierhofer, Tobias; Lind, Christof; Hüttl, Stefanie; Scherzer, Sönke; Papenfuß, Melanie; Simon, Judy; Al-Rasheid, Khaled A.S.; Ache, Peter; Rennenberg, Heinz; Hedrich, Rainer; Müller, Thomas D.; Geiger, Dietmar

    2014-01-01

    In contrast to animal cells, plants use nitrate as a major source of nitrogen. Following the uptake of nitrate, this major macronutrient is fed into the vasculature for long-distance transport. The Arabidopsis thaliana shoot expresses the anion channel SLOW ANION CHANNEL1 (SLAC1) and its homolog SLAC1 HOMOLOGOUS3 (SLAH3), which prefer nitrate as substrate but cannot exclude chloride ions. By contrast, we identified SLAH2 as a nitrate-specific channel that is impermeable for chloride. To understand the molecular basis for nitrate selection in the SLAH2 channel, SLAC1 and SLAH2 were modeled to the structure of HiTehA, a distantly related bacterial member. Structure-guided site-directed mutations converted SLAC1 into a SLAH2-like nitrate-specific anion channel and vice versa. Our findings indicate that two pore-occluding phenylalanines constrict the pore. The selectivity filter of SLAC/SLAH anion channels is determined by the polarity of pore-lining residues located on alpha helix 3. Changing the polar character of a single amino acid side chain (Ser-228) to a nonpolar residue turned the nitrate-selective SLAH2 into a chloride/nitrate-permeable anion channel. Thus, the molecular basis of the anion specificity of SLAC/SLAH anion channels seems to be determined by the presence and constellation of polar side chains that act in concert with the two pore-occluding phenylalanines. PMID:24938289

  20. Modification of the conductance, selectivity and concentration-dependent saturation of Pseudomonas aeruginosa protein P channels by chemical acetylation.

    PubMed

    Hancock, R E; Poole, K; Gimple, M; Benz, R

    1983-10-26

    Protein P, an anion-specific channel-forming protein from the outer membrane of Pseudomonas aeruginosa was chemically modified by acetylation and syccinylation of its accessible amino groups. The chemically modified protein retained its ability to form oligomers on sodium dodecyl sulfate polyacrylamide gels, whereas only the acetylated protein formed channels in reconstitution experiments with lipid bilayers. Acetylated protein P demonstrated a substantially reduced mean single channel conductance (25 pS at 1 M KCl) compared to the native protein P channels (250 pS at 1 M KCl) when reconstituted into black lipid bilayer membranes. The homogeneous size distribution of single-channel conductances suggested that all of the protein P molecules had been acetylated. Zero-current potential measurements demonstrated that the acetylated protein P channel was only weakly selective for anions and allowed the permeation of cations, in contrast to the native protein P channels, which were more than 100-fold selective for anions over cations. The dependence of conductance on salt concentration was changed upon acetylation, in that acetylated protein P demonstrated a linear concentration-conductance relationship, whereas native protein P channels became saturated at high salt concentrations. These data strongly suggested that the basis of anion selectivity for native protein P channels is fixed amino groups. In agreement with this, we could demonstrate a 2.5-fold decrease in single-channel conductance between pH 7 and pH 9, between which pH values the epsilon-amino groups of amino acids would start to become deprotonated. Two alternative schemes for the topography of the protein P channel and localization of the fixed amino groups are presented and discussed.

  1. Doubly fed machine review: agenda. Conference report, Washington, DC

    SciTech Connect

    Not Available

    1982-09-01

    The visual aids presented at the doubly fed machine review are presented. The doubly fed machine is a generating system either for wind turbines or hydro systems. Conceptual design and trade-offs are included, as well as testing. (LEW)

  2. An embryo of protocells: The capsule of graphene with selective ion channels

    SciTech Connect

    Li, Zhan; Wang, Chunmei; Tian, Longlong; Bai, Jing; Yao, Huijun; Zhao, Yang; Zhang, Xin; Cao, Shiwei; Qi, Wei; Wang, Suomin; Shi, Keliang; Xu, Youwen; Mingliang, Zhang; Liu, Bo; Qiu, Hongdeng; Liu, Jie; Wu, Wangsuo; Wang, Xiaoli; Wenzhen, An

    2015-05-19

    In this study, the synthesis of artificial cell is a route for searching the origin of protocell. Here, we create a novel cell model of graphene capsules with selective ion channels, indicating that graphene might be an embryo of protocell membrane. Firstly, we found that the highly oxidized graphene and phospholipid-graphene oxide composite would curl into capsules under a strongly acidic saturated solution of heavy metallic salt solution at low temperature. Secondly, L-amino acids exhibited higher reactivity than D-amino acids on graphene oxides to form peptides, and the formed peptides in the influence of graphene would be transformed into a secondary structure, promoting the formation of left-handed proteins. Lastly, monolayer nanoporous graphene, prepared by unfocused 84Kr25+, has a high selectivity for permeation of the monovalent metal ions ( Rb+ > K+ > Cs+ > Na+ > Li+, based on permeation concentration), but does not allow Cl- go through. It is similar to K+ channels, which would cause an influx of K+ into capsule of graphene with the increase of pH in the primitive ocean, creating a suitable inner condition for the origin of life. Therefore, we built a model cell of graphene, which would provide a route for reproducing the origin of life.

  3. An embryo of protocells: The capsule of graphene with selective ion channels

    PubMed Central

    Li, Zhan; Wang, Chunmei; Tian, Longlong; Bai, Jing; Yao, Huijun; Zhao, Yang; Zhang, Xin; Cao, Shiwei; Qi, Wei; Wang, Suomin; Shi, Keliang; Xu, Youwen; Mingliang, Zhang; Liu, Bo; Qiu, Hongdeng; Liu, Jie; Wu, Wangsuo; Wang, Xiaoli; Wenzhen, An

    2015-01-01

    The synthesis of artificial cell is a route for searching the origin of protocell. Here, we create a novel cell model of graphene capsules with selective ion channels, indicating that graphene might be an embryo of protocell membrane. Firstly, we found that the highly oxidized graphene and phospholipid-graphene oxide composite would curl into capsules under a strongly acidic saturated solution of heavy metallic salt solution at low temperature. Secondly, L-amino acids exhibited higher reactivity than D-amino acids on graphene oxides to form peptides, and the formed peptides in the influence of graphene would be transformed into a secondary structure, promoting the formation of left-handed proteins. Lastly, monolayer nanoporous graphene, prepared by unfocused 84Kr25+, has a high selectivity for permeation of the monovalent metal ions ( Rb+ > K+ > Cs+ > Na+ > Li+, based on permeation concentration), but does not allow Cl- go through. It is similar to K+ channels, which would cause an influx of K+ into capsule of graphene with the increase of pH in the primitive ocean, creating a suitable inner condition for the origin of life. Therefore, we built a model cell of graphene, which would provide a route for reproducing the origin of life. PMID:25989440

  4. An embryo of protocells: The capsule of graphene with selective ion channels

    NASA Astrophysics Data System (ADS)

    Li, Zhan; Wang, Chunmei; Tian, Longlong; Bai, Jing; Yao, Huijun; Zhao, Yang; Zhang, Xin; Cao, Shiwei; Qi, Wei; Wang, Suomin; Shi, Keliang; Xu, Youwen; Mingliang, Zhang; Liu, Bo; Qiu, Hongdeng; Liu, Jie; Wu, Wangsuo; Wang, Xiaoli; Wenzhen, An

    2015-05-01

    The synthesis of artificial cell is a route for searching the origin of protocell. Here, we create a novel cell model of graphene capsules with selective ion channels, indicating that graphene might be an embryo of protocell membrane. Firstly, we found that the highly oxidized graphene and phospholipid-graphene oxide composite would curl into capsules under a strongly acidic saturated solution of heavy metallic salt solution at low temperature. Secondly, L-amino acids exhibited higher reactivity than D-amino acids on graphene oxides to form peptides, and the formed peptides in the influence of graphene would be transformed into a secondary structure, promoting the formation of left-handed proteins. Lastly, monolayer nanoporous graphene, prepared by unfocused 84Kr25+, has a high selectivity for permeation of the monovalent metal ions ( Rb+ > K+ > Cs+ > Na+ > Li+, based on permeation concentration), but does not allow Cl- go through. It is similar to K+ channels, which would cause an influx of K+ into capsule of graphene with the increase of pH in the primitive ocean, creating a suitable inner condition for the origin of life. Therefore, we built a model cell of graphene, which would provide a route for reproducing the origin of life.

  5. Kinetic approach with ab initio MO method on ionic selectivity and size in sodium channel.

    PubMed

    Tani, S; Imamura, A; Kanda, K

    1989-10-23

    Three kinds of models for ionic selectivity and size of the filter in sodium channel have been treated by using ab initio molecular orbital (MO) calculations with MINI-3 and MIDI-3* basis sets. A three-components system, HCO2M-H2O (M = Li+, Na+ or K+), is acceptable for describing experimental facts well. Thermochemical parameters obtained from harmonic vibrational analysis with MINI-3 basis sets, for the translocation of the permeant metal cations in the HCO2M-H2O system, are that the activation enthalpies for Li+, Na+ and K+ are 7.0, 6.4 and 23.4 kJ/mol, and also the free energies of activation are 10.6, 1.5 and 19.0 kJ/mol, respectively. These results are qualitatively in good correspondence with experimental facts of the ion selectivity of the channel. One of water molecule was found to have a key role in the translocation of the permeant cations.

  6. Channel selection in the modulation domain for improved speech intelligibility in noise

    PubMed Central

    Wójcicki, Kamil K.; Loizou, Philipos C.

    2012-01-01

    Background noise reduces the depth of the low-frequency envelope modulations known to be important for speech intelligibility. The relative strength of the target and masker envelope modulations can be quantified using a modulation signal-to-noise ratio, (S/N)mod, measure. Such a measure can be used in noise-suppression algorithms to extract target-relevant modulations from the corrupted (target + masker) envelopes for potential improvement in speech intelligibility. In the present study, envelopes are decomposed in the modulation spectral domain into a number of channels spanning the range of 0–30 Hz. Target-dominant modulations are identified and retained in each channel based on the (S/N)mod selection criterion, while modulations which potentially interfere with perception of the target (i.e., those dominated by the masker) are discarded. The impact of modulation-selective processing on the speech-reception threshold for sentences in noise is assessed with normal-hearing listeners. Results indicate that the intelligibility of noise-masked speech can be improved by as much as 13 dB when preserving target-dominant modulations, present up to a modulation frequency of 18 Hz, while discarding masker-dominant modulations from the mixture envelopes. PMID:22501068

  7. An embryo of protocells: The capsule of graphene with selective ion channels

    DOE PAGES

    Li, Zhan; Wang, Chunmei; Tian, Longlong; ...

    2015-05-19

    In this study, the synthesis of artificial cell is a route for searching the origin of protocell. Here, we create a novel cell model of graphene capsules with selective ion channels, indicating that graphene might be an embryo of protocell membrane. Firstly, we found that the highly oxidized graphene and phospholipid-graphene oxide composite would curl into capsules under a strongly acidic saturated solution of heavy metallic salt solution at low temperature. Secondly, L-amino acids exhibited higher reactivity than D-amino acids on graphene oxides to form peptides, and the formed peptides in the influence of graphene would be transformed into amore » secondary structure, promoting the formation of left-handed proteins. Lastly, monolayer nanoporous graphene, prepared by unfocused 84Kr25+, has a high selectivity for permeation of the monovalent metal ions ( Rb+ > K+ > Cs+ > Na+ > Li+, based on permeation concentration), but does not allow Cl- go through. It is similar to K+ channels, which would cause an influx of K+ into capsule of graphene with the increase of pH in the primitive ocean, creating a suitable inner condition for the origin of life. Therefore, we built a model cell of graphene, which would provide a route for reproducing the origin of life.« less

  8. Selective spider toxins reveal a role for Nav1.1 channel in mechanical pain

    PubMed Central

    Osteen, Jeremiah D.; Herzig, Volker; Gilchrist, John; Emrick, Joshua J.; Zhang, Chuchu; Wang, Xidao; Castro, Joel; Garcia-Caraballo, Sonia; Grundy, Luke; Rychkov, Grigori Y.; Weyer, Andy D.; Dekan, Zoltan; Undheim, Eivind A. B.; Alewood, Paul; Stucky, Cheryl L.; Brierley, Stuart M.; Basbaum, Allan I.; Bosmans, Frank; King, Glenn F.; Julius, David

    2016-01-01

    Voltage-gated sodium (Nav) channels initiate action potentials in most neurons, including primary afferent nerve fibers of the pain pathway. Local anesthetics block pain through non-specific actions at all Nav channels, but the discovery of selective modulators would facilitate the analysis of individual subtypes and their contributions to chemical, mechanical, or thermal pain. Here, we identify and characterize spider toxins that selectively activate the Nav1.1 subtype, whose role in nociception and pain has not been explored. We exploit these probes to demonstrate that Nav1.1-expressing fibers are modality-specific nociceptors: their activation elicits robust pain behaviors without neurogenic inflammation and produces profound hypersensitivity to mechanical, but not thermal, stimuli. In the gut, high-threshold mechanosensitive fibers also express Nav1.1 and show enhanced toxin sensitivity in a model of irritable bowel syndrome. Altogether, these findings establish an unexpected role for Nav1.1 in regulating the excitability of sensory nerve fibers that underlie mechanical pain. PMID:27281198

  9. Masses of doubly and triply charmed baryons

    NASA Astrophysics Data System (ADS)

    Wei, Ke-Wei; Chen, Bing; Guo, Xin-Heng

    2015-10-01

    Until now, the first reported doubly charmed baryon Ξcc +(3520 ) is still a puzzle. It was discovered and confirmed by SELEX collaboration, but not confirmed by LHCb, BABAR, BELLE, FOCUS, or any other collaboration. In the present paper, by employing Regge phenomenology, we first express the mass of the ground state (L =0 ) doubly charmed baryon Ωcc *+ as a function of masses of the well established light baryons and singly charmed baryons. Inserting the recent experimental data, the mass of Ωcc *+ is given to be 3809 ±36 MeV , which is independent of any unobservable parameters. Then, with the quadratic mass relations, we calculate the masses of the ground state triply charmed baryon Ωcc c ++ and doubly charmed baryons Ξcc (*)++, Ξcc (*)+ , and Ωcc + [the mass of Ξcc + is determined as 3520-40+41 MeV , which agrees with the mass of Ξcc +(3520 ) ]. The isospin splitting MΞcc ++-MΞcc +=0.4 ±0.3 MeV . After that, masses of the orbitally excited (L =1 , 2, 3) doubly and triply charmed baryons are estimated. The results are reasonable comparing with those extracted in many other approaches. We suggest more efforts to study doubly and triply charmed baryons both theoretically and experimentally, not only for the abundance of baryon spectra, but also for numerically examining whether the linear mass relations or the quadratic mass relations are realized in nature. Our predictions are useful for the discovery of unobserved doubly and triply charmed baryon states and the JP assignment of these states.

  10. A structural, functional, and computational analysis suggests pore flexibility as the base for the poor selectivity of CNG channels

    PubMed Central

    Napolitano, Luisa Maria Rosaria; Bisha, Ina; De March, Matteo; Marchesi, Arin; Arcangeletti, Manuel; Demitri, Nicola; Mazzolini, Monica; Rodriguez, Alex; Magistrato, Alessandra; Onesti, Silvia; Laio, Alessandro; Torre, Vincent

    2015-01-01

    Cyclic nucleotide-gated (CNG) ion channels, despite a significant homology with the highly selective K+ channels, do not discriminate among monovalent alkali cations and are permeable also to several organic cations. We combined electrophysiology, molecular dynamics (MD) simulations, and X-ray crystallography to demonstrate that the pore of CNG channels is highly flexible. When a CNG mimic is crystallized in the presence of a variety of monovalent cations, including Na+, Cs+, and dimethylammonium (DMA+), the side chain of Glu66 in the selectivity filter shows multiple conformations and the diameter of the pore changes significantly. MD simulations indicate that Glu66 and the prolines in the outer vestibule undergo large fluctuations, which are modulated by the ionic species and the voltage. This flexibility underlies the coupling between gating and permeation and the poor ionic selectivity of CNG channels. PMID:26100907

  11. The voltage-dependent gate in MthK potassium channels is located at the selectivity filter.

    PubMed

    Posson, David J; McCoy, Jason G; Nimigean, Crina M

    2013-02-01

    Understanding how ion channels open and close their pores is crucial for comprehending their physiological roles. We used intracellular quaternary ammonium blockers, electrophysiology and X-ray crystallography to locate the voltage-dependent gate in MthK potassium channels from Methanobacterium thermoautotrophicum. Blockers bind in an aqueous cavity between two putative gates: an intracellular gate and the selectivity filter. Thus, these blockers directly probe gate location--an intracellular gate will prevent binding when closed, whereas a selectivity filter gate will always allow binding. Kinetic analysis of tetrabutylammonium block of single MthK channels combined with X-ray crystallographic analysis of the pore with tetrabutyl antimony unequivocally determined that the voltage-dependent gate, like the C-type inactivation gate in eukaryotic channels, is located at the selectivity filter. State-dependent binding kinetics suggest that MthK inactivation leads to conformational changes within the cavity and intracellular pore entrance.

  12. The depressant scorpion neurotoxin LqqIT2 selectively modulates the insect voltage-gated sodium channel.

    PubMed

    Bosmans, Frank; Martin-Eauclaire, Marie-France; Tytgat, Jan

    2005-03-15

    LqqIT2 is a depressant neurotoxin present in the venom of the Leiurus quinquestriatus quinquestriatus scorpion, one of the world's most dangerous scorpions endemic to dry habitats in Africa and Asia. In order to determine its efficacy, potency and selectivity, LqqIT2 was subjected for the first time to an electrophysiological and pharmacological comparison between two different cloned sodium channels expressed in Xenopus laevis oocytes. Aside from typical beta-toxin effects, LqqIT2 also affected the inactivation process and ion selectivity of the insect voltage-gated sodium channel. The most interesting feature of LqqIT2 is its total insect-selectivity. At a concentration of 1 microM, the insect-voltage-gated sodium channel, para, was profoundly modulated while its mammalian counterpart, the rat brain Na(v)1.2 channel, was not affected. This trait offers excellent prospects for the development of novel insecticides.

  13. A structural, functional, and computational analysis suggests pore flexibility as the base for the poor selectivity of CNG channels.

    PubMed

    Napolitano, Luisa Maria Rosaria; Bisha, Ina; De March, Matteo; Marchesi, Arin; Arcangeletti, Manuel; Demitri, Nicola; Mazzolini, Monica; Rodriguez, Alex; Magistrato, Alessandra; Onesti, Silvia; Laio, Alessandro; Torre, Vincent

    2015-07-07

    Cyclic nucleotide-gated (CNG) ion channels, despite a significant homology with the highly selective K(+) channels, do not discriminate among monovalent alkali cations and are permeable also to several organic cations. We combined electrophysiology, molecular dynamics (MD) simulations, and X-ray crystallography to demonstrate that the pore of CNG channels is highly flexible. When a CNG mimic is crystallized in the presence of a variety of monovalent cations, including Na(+), Cs(+), and dimethylammonium (DMA(+)), the side chain of Glu66 in the selectivity filter shows multiple conformations and the diameter of the pore changes significantly. MD simulations indicate that Glu66 and the prolines in the outer vestibule undergo large fluctuations, which are modulated by the ionic species and the voltage. This flexibility underlies the coupling between gating and permeation and the poor ionic selectivity of CNG channels.

  14. Molecular Determinant for Specific Ca/Ba Selectivity Profiles of Low and High Threshold Ca2+ Channels

    PubMed Central

    Cens, Thierry; Rousset, Matthieu; Kajava, Andrey; Charnet, Pierre

    2007-01-01

    Voltage-gated Ca2+ channels (VGCC) play a key role in many physiological functions by their high selectivity for Ca2+ over other divalent and monovalent cations in physiological situations. Divalent/monovalent selection is shared by all VGCC and is satisfactorily explained by the existence, within the pore, of a set of four conserved glutamate/aspartate residues (EEEE locus) coordinating Ca2+ ions. This locus however does not explain either the choice of Ca2+ among other divalent cations or the specific conductances encountered in the different VGCC. Our systematic analysis of high- and low-threshold VGCC currents in the presence of Ca2+ and Ba2+ reveals highly specific selectivity profiles. Sequence analysis, molecular modeling, and mutational studies identify a set of nonconserved charged residues responsible for these profiles. In HVA (high voltage activated) channels, mutations of this set modify divalent cation selectivity and channel conductance without change in divalent/monovalent selection, activation, inactivation, and kinetics properties. The CaV2.1 selectivity profile is transferred to CaV2.3 when exchanging their residues at this location. Numerical simulations suggest modification in an external Ca2+ binding site in the channel pore directly involved in the choice of Ca2+, among other divalent physiological cations, as the main permeant cation for VGCC. In LVA (low voltage activated) channels, this locus (called DCS for divalent cation selectivity) also influences divalent cation selection, but our results suggest the existence of additional determinants to fully recapitulate all the differences encountered among LVA channels. These data therefore attribute to the DCS a unique role in the specific shaping of the Ca2+ influx between the different HVA channels. PMID:17893194

  15. Binding and selectivity in L-type calcium channels: a mean spherical approximation.

    PubMed Central

    Nonner, W; Catacuzzeno, L; Eisenberg, B

    2000-01-01

    L-type calcium channels are Ca(2+) binding proteins of great biological importance. They generate an essential intracellular signal of living cells by allowing Ca(2+) ions to move across the lipid membrane into the cell, thereby selecting an ion that is in low extracellular abundance. Their mechanism of selection involves four carboxylate groups, containing eight oxygen ions, that belong to the side chains of the "EEEE" locus of the channel protein, a setting similar to that found in many Ca(2+)-chelating molecules. This study examines the hypothesis that selectivity in this locus is determined by mutual electrostatic screening and volume exclusion between ions and carboxylate oxygens of finite diameters. In this model, the eight half-charged oxygens of the tethered carboxylate groups of the protein are confined to a subvolume of the pore (the "filter"), but interact spontaneously with their mobile counterions as ions interact in concentrated bulk solutions. The mean spherical approximation (MSA) is used to predict ion-specific excess chemical potentials in the filter and baths. The theory is calibrated using a single experimental observation, concerning the apparent dissociation constant of Ca(2+) in the presence of a physiological concentration of NaCl. When ions are assigned their independently known crystal diameters and the carboxylate oxygens are constrained, e.g., to a volume of 0.375 nm(3) in an environment with an effective dielectric coefficient of 63.5, the hypothesized selectivity filter produces the shape of the calcium binding curves observed in experiment, and it predicts Ba(2+)/Ca(2+) and Na(+)/Li(+) competition, and Cl(-) exclusion as observed. The selectivities for Na(+), Ca(2+), Ba(2+), other alkali metal ions, and Cl(-) thus can be predicted by volume exclusion and electrostatic screening alone. Spontaneous coordination of ions and carboxylates can produce a wide range of Ca(2+) selectivities, depending on the volume density of carboxylate

  16. Molecular dynamics - potential of mean force calculations as a tool for understanding ion permeation and selectivity in narrow channels.

    PubMed

    Allen, Toby W; Andersen, Olaf S; Roux, Benoit

    2006-12-01

    Ion channels catalyze the permeation of charged molecules across cell membranes and are essential for many vital physiological functions, including nerve and muscle activity. To understand better the mechanisms underlying ion conduction and valence selectivity of narrow ion channels, we have employed free energy techniques to calculate the potential of mean force (PMF) for ion movement through the prototypical gramicidin A channel. Employing modern all-atom molecular dynamics (MD) force fields with umbrella sampling methods that incorporate one hundred 1-2 ns trajectories, we find that it is possible to achieve semi-quantitative agreement with experimental binding and conductance measurements. We also examine the sensitivity of the MD-PMF results to the choice of MD force field and compare PMFs for potassium, calcium and chloride ions to explore the basis for the valence selectivity of this narrow and uncharged ion channel. A large central barrier is observed for both anions and divalent ions, consistent with lack of experimental conductance. Neither anion or divalent cation is seen to be stabilized inside the channel relative to the bulk electrolyte and each leads to large disruptions to the protein and membrane structure when held deep inside the channel. Weak binding of calcium ions outside the channel corresponds to a free energy well that is too shallow to demonstrate channel blocking. Our findings emphasize the success of the MD-PMF approach and the sensitivity of ion energetics to the choice of biomolecular force field.

  17. Applied-field molecular dynamics study of a model calcium channel selectivity filter

    NASA Astrophysics Data System (ADS)

    Yang, Yan; Henderson, Douglas; Busath, David

    2003-03-01

    The calcium channel is thought to have a short selectivity filter containing charged glutamate side chains. This filter was modeled using an atomistic cylinder of length 10 Å in which were confined eight half-charged oxygen anions representing glutamate carboxylate oxygens. Current flow through the filter was computed using applied field nonequilibrium molecular dynamics simulations at various mole fractions of Na+ and Ca2+ in 2 M chloride solutions with simple point charge/extended model water. The filter was cation selective and had conductances in the range of those extrapolated from experimental results. For this model, unlike implicit solvent models at lower voltages and concentrations, the mole fraction behavior was not anomalous and cation binding was nonselective at 2.2 V. Perturbations of filter diameter and confined charge resulted in similar behaviors. At physiological voltages, mole fraction conductance behavior could not be reliably simulated in 100 ns runs, but nonselective cation binding persisted. Nevertheless, it is of interest that ion entry into the confinement region was limited by an energy barrier and at least, in the case of Ca2+, led to an increase in the energy of the other Ca2+ ion in the confinement region and prompt exit of one of them. The filter was most commonly occupied by 2 or 3 Na+ ions in pure Na+ solutions or 1 or 2 Ca2+ ions in pure Ca2+ solutions. For CaCl2 solution, the additional ion, if present, was most commonly stalled behind the entry barrier, i.e., within the channel filter but not yet having entered the confinement region. Thus, the simulations demonstrate the concept that entry of a new mobile Ca2+ ion into the selectivity filter serves to release the prior occupant that was tightly bound.

  18. α-SNAP regulates dynamic, on-site assembly and calcium selectivity of Orai1 channels

    PubMed Central

    Li, Peiyao; Miao, Yong; Dani, Adish; Vig, Monika

    2016-01-01

    Orai1 forms a highly calcium-selective pore of the calcium release activated channel, and α-SNAP is necessary for its function. Here we show that α-SNAP regulates on-site assembly of Orai1 dimers into calcium-selective multimers. We find that Orai1 is a dimer in resting primary mouse embryonic fibroblasts but displays variable stoichiometry in the plasma membrane of store-depleted cells. Remarkably, α-SNAP depletion induces formation of higher-order Orai1 oligomers, which permeate significant levels of sodium via Orai1 channels. Sodium permeation in α-SNAP–deficient cells cannot be corrected by tethering multiple Stim1 domains to Orai1 C-terminal tail, demonstrating that α-SNAP regulates functional assembly and calcium selectivity of Orai1 multimers independently of Stim1 levels. Fluorescence nanoscopy reveals sustained coassociation of α-SNAP with Stim1 and Orai1, and α-SNAP–depleted cells show faster and less constrained mobility of Orai1 within ER-PM junctions, suggesting Orai1 and Stim1 coentrapment without stable contacts. Furthermore, α-SNAP depletion significantly reduces fluorescence resonance energy transfer between Stim1 and Orai1 N-terminus but not C-terminus. Taken together, these data reveal a unique role of α-SNAP in the on-site functional assembly of Orai1 subunits and suggest that this process may, in part, involve enabling crucial low-affinity interactions between Orai1 N-terminus and Stim1. PMID:27335124

  19. Ca(2+)-dependent non-selective cation and potassium channels activated by bradykinin in pig coronary artery endothelial cells.

    PubMed Central

    Baron, A; Frieden, M; Chabaud, F; Bény, J L

    1996-01-01

    1. Using the cell-attached and inside-out modes of the patch-clamp technique, we studied the Ca(2+)-dependent ionic channels activated by bradykinin in cultured pig coronary artery endothelial cells to further understand electrophysiological events underlying cellular activation. 2. In the cell-attached mode, bradykinin (94 nM) activated two types of Ca(2+)-dependent channels: a high conductance K+ channel (285 pS in high symmetrical K+), whose open state probability was increased by depolarization, and a lower conductance inwardly rectifying non-selective cation channel (44 pS in high symmetrical K+). 3. The 285 pS K+ channel was half-maximally activated by cytosolic Ca2+ levels of 1.6 and 4.5 microM at +10 and -30 mV, respectively. Such local concentrations should be reached in the presence of bradykinin, which induces a mean maximal cytosolic Ca2+ rise of 1.3 microM. 4. The 285 pS K+ channel was inhibited by d-tubocurarine, which acted by reducing the mean open time duration (flickering pattern), finally reducing the channel conductance. 5. Divalent cations such as Ca2+ could flow through the 44 pS non-selective cation channel, with nearly the same permeability (P) as monovalent cations (PK: PNa: PCa = 1:1:0.7). 6. The cation channel appeared to be more sensitive to Ca2+ than the K+ channel, with a half-maximal open probability induced by 0.7 microM Ca2+ on the intracellular side of the membrane. 7. In contrast to the K+ channel, the cation channel mean open time was clearly increased by bradykinin. This effect was delayed compared with the increase in the channel open state probability and was rapidly lost in the inside-out configuration. Caffeine also activated the cation channel but more transiently than bradykinin and without any effect on the open duration. 8. In the absence of extracellular Ca2+, the bradykinin-induced increase in cytosolic free Ca2+ was shortened temporally by 52% and reduced in amplitude by 88%, whereas the bradykinin

  20. Observation of the doubly strange b baryon Omegab-.

    PubMed

    Abazov, V M; Abbott, B; Abolins, M; Acharya, B S; Adams, M; Adams, T; Aguilo, E; Ahsan, M; Alexeev, G D; Alkhazov, G; Alton, A; Alverson, G; Alves, G A; Anastasoaie, M; Ancu, L S; Andeen, T; Andrieu, B; Anzelc, M S; Aoki, M; Arnoud, Y; Arov, M; Arthaud, M; Askew, A; Asman, B; Assis Jesus, A C S; Atramentov, O; Avila, C; Badaud, F; Bagby, L; Baldin, B; Bandurin, D V; Banerjee, P; Banerjee, S; Barberis, E; Barfuss, A-F; Bargassa, P; Baringer, P; Barreto, J; Bartlett, J F; Bassler, U; Bauer, D; Beale, S; Bean, A; Begalli, M; Begel, M; Belanger-Champagne, C; Bellantoni, L; Bellavance, A; Benitez, J A; Beri, S B; Bernardi, G; Bernhard, R; Bertram, I; Besançon, M; Beuselinck, R; Bezzubov, V A; Bhat, P C; Bhatnagar, V; Biscarat, C; Blazey, G; Blekman, F; Blessing, S; Bloom, K; Boehnlein, A; Boline, D; Bolton, T A; Boos, E E; Borissov, G; Bose, T; Brandt, A; Brock, R; Brooijmans, G; Bross, A; Brown, D; Bu, X B; Buchanan, N J; Buchholz, D; Buehler, M; Buescher, V; Bunichev, V; Burdin, S; Burnett, T H; Buszello, C P; Butler, J M; Calfayan, P; Calvet, S; Cammin, J; Carrera, E; Carvalho, W; Casey, B C K; Castilla-Valdez, H; Chakrabarti, S; Chakraborty, D; Chan, K M; Chandra, A; Cheu, E; Chevallier, F; Cho, D K; Choi, S; Choudhary, B; Christofek, L; Christoudias, T; Cihangir, S; Claes, D; Clutter, J; Cooke, M; Cooper, W E; Corcoran, M; Couderc, F; Cousinou, M-C; Crépé-Renaudin, S; Cuplov, V; Cutts, D; Cwiok, M; da Motta, H; Das, A; Davies, G; De, K; de Jong, S J; De La Cruz-Burelo, E; De Oliveira Martins, C; DeVaughan, K; Degenhardt, J D; Déliot, F; Demarteau, M; Demina, R; Denisov, D; Denisov, S P; Desai, S; Diehl, H T; Diesburg, M; Dominguez, A; Dong, H; Dorland, T; Dubey, A; Dudko, L V; Duflot, L; Dugad, S R; Duggan, D; Duperrin, A; Dyer, J; Dyshkant, A; Eads, M; Edmunds, D; Ellison, J; Elvira, V D; Enari, Y; Eno, S; Ermolov, P; Evans, H; Evdokimov, A; Evdokimov, V N; Ferapontov, A V; Ferbel, T; Fiedler, F; Filthaut, F; Fisher, W; Fisk, H E; Fortner, M; Fox, H; Fu, S; Fuess, S; Gadfort, T; Galea, C F; Garcia, C; Garcia-Bellido, A; Gavrilov, V; Gay, P; Geist, W; Geng, W; Gerber, C E; Gershtein, Y; Gillberg, D; Ginther, G; Gollub, N; Gómez, B; Goussiou, A; Grannis, P D; Greenlee, H; Greenwood, Z D; Gregores, E M; Grenier, G; Gris, Ph; Grivaz, J-F; Grohsjean, A; Grünendahl, S; Grünewald, M W; Guo, F; Guo, J; Gutierrez, G; Gutierrez, P; Haas, A; Hadley, N J; Haefner, P; Hagopian, S; Haley, J; Hall, I; Hall, R E; Han, L; Harder, K; Harel, A; Hauptman, J M; Hays, J; Hebbeker, T; Hedin, D; Hegeman, J G; Heinson, A P; Heintz, U; Hensel, C; Herner, K; Hesketh, G; Hildreth, M D; Hirosky, R; Hobbs, J D; Hoeneisen, B; Hoeth, H; Hohlfeld, M; Hossain, S; Houben, P; Hu, Y; Hubacek, Z; Hynek, V; Iashvili, I; Illingworth, R; Ito, A S; Jabeen, S; Jaffré, M; Jain, S; Jakobs, K; Jarvis, C; Jesik, R; Johns, K; Johnson, C; Johnson, M; Johnston, D; Jonckheere, A; Jonsson, P; Juste, A; Kajfasz, E; Kalk, J M; Karmanov, D; Kasper, P A; Katsanos, I; Kau, D; Kaushik, V; Kehoe, R; Kermiche, S; Khalatyan, N; Khanov, A; Kharchilava, A; Kharzheev, Y M; Khatidze, D; Kim, T J; Kirby, M H; Kirsch, M; Klima, B; Kohli, J M; Komissarov, E V; Konrath, J-P; Kozelov, A V; Kraus, J; Kuhl, T; Kumar, A; Kupco, A; Kurca, T; Kuzmin, V A; Kvita, J; Lacroix, F; Lam, D; Lammers, S; Landsberg, G; Lebrun, P; Lee, W M; Leflat, A; Lellouch, J; Li, J; Li, L; Li, Q Z; Lietti, S M; Lim, J K; Lima, J G R; Lincoln, D; Linnemann, J; Lipaev, V V; Lipton, R; Liu, Y; Liu, Z; Lobodenko, A; Lokajicek, M; Love, P; Lubatti, H J; Luna, R; Lyon, A L; Maciel, A K A; Mackin, D; Madaras, R J; Mättig, P; Magass, C; Magerkurth, A; Mal, P K; Malbouisson, H B; Malik, S; Malyshev, V L; Maravin, Y; Martin, B; McCarthy, R; Melnitchouk, A; Mendoza, L; Mercadante, P G; Merekov, Y P; Merkin, M; Merritt, K W; Meyer, A; Meyer, J; Mitrevski, J; Mommsen, R K; Mondal, N K; Moore, R W; Moulik, T; Muanza, G S; Mulhearn, M; Mundal, O; Mundim, L; Nagy, E; Naimuddin, M; Narain, M; Naumann, N A; Neal, H A; Negret, J P; Neustroev, P; Nilsen, H; Nogima, H; Novaes, S F; Nunnemann, T; O'Dell, V; O'Neil, D C; Obrant, G; Ochando, C; Onoprienko, D; Orduna, J; Oshima, N; Osman, N; Osta, J; Otec, R; Otero y Garzón, G J; Owen, M; Padley, P; Pangilinan, M; Parashar, N; Park, S-J; Park, S K; Parsons, J; Partridge, R; Parua, N; Patwa, A; Pawloski, G; Penning, B; Perfilov, M; Peters, K; Peters, Y; Pétroff, P; Petteni, M; Piegaia, R; Piper, J; Pleier, M-A; Podesta-Lerma, P L M; Podstavkov, V M; Pogorelov, Y; Pol, M-E; Polozov, P; Pope, B G; Popov, A V; Potter, C; Prado da Silva, W L; Prosper, H B; Protopopescu, S; Qian, J; Quadt, A; Quinn, B; Rakitine, A; Rangel, M S; Ranjan, K; Ratoff, P N; Renkel, P; Rich, P; Rieger, J; Rijssenbeek, M; Ripp-Baudot, I; Rizatdinova, F; Robinson, S; Rodrigues, R F; Rominsky, M; Royon, C; Rozhdestvenski, A; Rubinov, P; Ruchti, R; Safronov, G; Sajot, G; Sánchez-Hernández, A; Sanders, M P; Sanghi, B; Savage, G; Sawyer, L; Scanlon, T; Schaile, D; Schamberger, R D; Scheglov, Y; Schellman, H; Schliephake, T; Schlobohm, S; Schwanenberger, C; Schwartzman, A; Schwienhorst, R; Sekaric, J; Severini, H; Shabalina, E; Shamim, M; Shary, V; Shchukin, A A; Shivpuri, R K; Siccardi, V; Simak, V; Sirotenko, V; Skubic, P; Slattery, P; Smirnov, D; Snow, G R; Snow, J; Snyder, S; Söldner-Rembold, S; Sonnenschein, L; Sopczak, A; Sosebee, M; Soustruznik, K; Spurlock, B; Stark, J; Steele, J; Stolin, V; Stoyanova, D A; Strandberg, J; Strandberg, S; Strang, M A; Strauss, E; Strauss, M; Ströhmer, R; Strom, D; Stutte, L; Sumowidagdo, S; Svoisky, P; Sznajder, A; Tamburello, P; Tanasijczuk, A; Taylor, W; Tiller, B; Tissandier, F; Titov, M; Tokmenin, V V; Torchiani, I; Tsybychev, D; Tuchming, B; Tully, C; Tuts, P M; Unalan, R; Uvarov, L; Uvarov, S; Uzunyan, S; Vachon, B; van den Berg, P J; Van Kooten, R; van Leeuwen, W M; Varelas, N; Varnes, E W; Vasilyev, I A; Verdier, P; Vertogradov, L S; Vertogradova, Y; Verzocchi, M; Vilanova, D; Villeneuve-Seguier, F; Vint, P; Vokac, P; Voutilainen, M; Wagner, R; Wahl, H D; Wang, M H L S; Warchol, J; Watts, G; Wayne, M; Weber, G; Weber, M; Welty-Rieger, L; Wenger, A; Wermes, N; Wetstein, M; White, A; Wicke, D; Williams, M; Wilson, G W; Wimpenny, S J; Wobisch, M; Wood, D R; Wyatt, T R; Xie, Y; Yacoob, S; Yamada, R; Yang, W-C; Yasuda, T; Yatsunenko, Y A; Yin, H; Yip, K; Yoo, H D; Youn, S W; Yu, J; Zeitnitz, C; Zelitch, S; Zhao, T; Zhou, B; Zhu, J; Zielinski, M; Zieminska, D; Zieminski, A; Zivkovic, L; Zutshi, V; Zverev, E G

    2008-12-05

    We report the observation of the doubly strange b baryon Omegab- in the decay channel Omegab(-)-->J/psiOmega-, with J/psi-->mu+mu(-) and Omega(-)-->LambdaK(-)-->(ppi-)K-, in pp collisions at sqrt[s]=1.96 TeV. Using approximately 1.3 fb(-1) of data collected with the D0 detector at the Fermilab Tevatron Collider, we observe 17.8+/-4.9(stat)+/-0.8(syst) Omegab- signal events at a mass of 6.165+/-0.010(stat)+/-0.013(syst) GeV. The significance of the observed signal is 5.4sigma, corresponding to a probability of 6.7 x 10(-8) of it arising from a background fluctuation.

  1. Selectivity of Ca2+ channel blockers in inhibiting muscular and nerve activities in isolated colon.

    PubMed Central

    Lecchini, S.; Marcoli, M.; De Ponti, F.; Castelletti, C. A.; Frigo, G. M.

    1991-01-01

    1. Potency and efficacy of nifedipine, verapamil and diltiazem and of Bay K 8644 in modifying propulsion and nerve or smooth muscle activities have been compared in the guinea-pig isolated distal colon. Both the neuronal and muscular effects of Ca2+ channel blockers seem to develop at concentrations that are devoid of any significant effect apart from that on Ca2+ channels. 2. Nifedipine, verapamil and diltiazem were all able to impair propulsion, resting and stimulated acetylcholine (ACh) release and smooth muscle contractility in a concentration-dependent way. However, some degree of selectivity for neuronal and muscular effects could be observed. Nifedipine was more than 500 fold more potent than verapamil in relaxing musculature but less than twice as potent in reducing ACh release. On the other hand, verapamil was the most efficacious Ca2+ channel blocker tested in inhibiting ACh release, its effects being inversely correlated to the external Ca2+ concentration, and completely abolished by Bay K 8644. 3. By comparing the potencies exhibited by each drug against peristaltic reflex, smooth muscle contractility and ACh release, verapamil proved to be almost as potent in slowing the peristaltic reflex as in reducing ACh release, while nifedipine was about 100 fold more potent against the peristaltic reflex than against ACh release, but nearly equal against the peristaltic reflex and smooth muscle tone. Therefore, interference with cholinergic neurotransmission is likely to play a major role in the antipropulsive effect of verapamil, while peristaltic reflex impairment by nifedipine is likely to be dependent on inhibition of smooth muscle.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1285398

  2. Tackling the combined effects of reverberation and masking noise using ideal channel selection

    PubMed Central

    Hazrati, Oldooz

    2012-01-01

    Purpose A new signal processing algorithm is proposed and evaluated in this study for the suppression of the combined effects of reverberation and noise. Method The proposed algorithm decomposes, on a short-term basis (every 20 ms), the reverberant stimuli into a number of channels and retains only a subset of the channels satisfying a signal-to-reverberant ratio (SRR) criterion. The construction of this criterion assumes access to a priori knowledge of the target (anechoic) signal and the aim of the present study is to assess the full potential of the proposed channel-selection algorithm assuming that this criterion can be estimated accurately. Listening tests were conducted with normal-hearing listeners to assess the performance of the proposed algorithm in highly reverberant conditions (T60 = 1.0 s) which included additive noise at 0 and 5 dB SNR. Results A substantial gain in intelligibility was obtained in both reverberant and combined reverberant and noise conditions. The mean intelligibility scores improved by 44 and 33 percentage points at 0 and 5 dB SNR reverberant+noise conditions. Feature analysis of the consonant confusion matrices revealed that the transmission of voicing information was most negatively affected, followed by manner and place of articulation. Conclusions The proposed algorithm was found to produce substantial gains in intelligibility, and this benefit was attributed to the ability of the proposed SRR criterion to accurately detect voiced/unvoiced boundaries. Detection of those boundaries is postulated to be critical for better perception of voicing information and manner of articulation. PMID:22232411

  3. Temperature tuned doubly resonant OPO: Peculiarities

    NASA Astrophysics Data System (ADS)

    Jarutis, Vygandas; Jurkus, Karolis; Smilgevičius, Valerijus

    2017-01-01

    We show experimentally and theoretically that under some circumstances the doubly resonant OPO's output energy and spectrum periodically depend on the nonlinear crystal temperature. We explain these phenomena using a simple matrix formalism, and interpret them as oscillations between two states of light in the DRO cavity.

  4. Doubly perturbed neutral stochastic functional equations

    NASA Astrophysics Data System (ADS)

    Hu, Lanying; Ren, Yong

    2009-09-01

    In this paper, we prove the existence and uniqueness of the solution to a class of doubly perturbed neutral stochastic functional equations (DPNSFEs in short) under some non-Lipschitz conditions. The solution is constructed by successive approximation. Furthermore, we give the continuous dependence of the solution on the initial value by means of the corollary of Bihari inequality.

  5. Osteoinduction of porous Ti implants with a channel structure fabricated by selective laser melting.

    PubMed

    Fukuda, A; Takemoto, M; Saito, T; Fujibayashi, S; Neo, M; Pattanayak, Deepak K; Matsushita, T; Sasaki, K; Nishida, N; Kokubo, T; Nakamura, T

    2011-05-01

    Many studies have shown that certain biomaterials with specific porous structures can induce bone formation in non-osseous sites without the need for osteoinductive biomolecules, however, the mechanisms responsible for this phenomenon (intrinsic osteoinduction of biomaterials) remain unclear. In particular, to our knowledge the type of pore structure suitable for osteoinduction has not been reported in detail. In the present study we investigated the effects of interconnective pore size on osteoinductivity and the bone formation processes during osteoinduction. Selective laser melting was employed to fabricate porous Ti implants (diameter 3.3mm, length 15 mm) with a channel structure comprising four longitudinal square channels, representing pores, of different diagonal widths, 500, 600, 900, and 1200 μm (termed p500, p600, p900, and p1200, respectively). These were then subjected to chemical and heat treatments to induce bioactivity. Significant osteoinduction was observed in p500 and p600, with the highest observed osteoinduction occurring at 5mm from the end of the implants. A distance of 5mm probably provides a favorable balance between blood circulation and fluid movement. Thus, the simple architecture of the implants allowed effective investigation of the influence of the interconnective pore size on osteoinduction, as well as the relationship between bone quantity and its location for different pore sizes.

  6. Serum factor induces selective increase in Na-channel expression in cultured skeletal muscle

    SciTech Connect

    Brodie, C.; Sampson, S.R. )

    1991-07-01

    The authors have examined effects of horse serum (HS) and various fractions (1 million-1M, 300K, 100K, and 30K nominal molecular weight limit) obtained by ultrafiltration on expression of TTX-sensitive Na-channels and on activities of the Na-K pump and glucose transport systems in cultured myotubes obtained from 1-2-day-old neonatal rat pups. Five-day-old cells were transferred to serum-free medium with no hormone or growth factor supplements (DMEM) for 24 hr and then treated with the various serum fractions for 48 hr. Measurements were made of specific (3H)-saxitoxin (STX) binding, action potential properties, 86Rb-uptake and 2-deoxyglucose (2-DG) uptake. HS significantly increased all parameters compared to DMEM (increases in STX-binding, 69%; Rb-uptake, 65%; 2-DG uptake, 93%). Results of treatment with the separate fractions showed that the 300K fraction caused a significantly greater increase in STX-binding than either HS or the other fractions. In contrast, the increases in Rb and 2-DG uptakes induced by the different fractions were not different from that obtained with HS. They conclude that serum contains a factor that selectively increases expression of TTX-sensitive Na-channels in skeletal muscle.

  7. Selective trapping and concentration of nanoparticles and viruses in dual-height nanofluidic channels.

    PubMed

    Hamblin, Mark N; Xuan, Jie; Maynes, Daniel; Tolley, H Dennis; Belnap, David M; Woolley, Adam T; Lee, Milton L; Hawkins, Aaron R

    2010-01-21

    Nanofluidic systems offer advantages for chemical analysis, including small sample volumes, size-selective particle trapping, sample concentration and the ability to separate and detect single molecules. Such systems can be fabricated using planar nanochannels, which rely on standard photolithographic techniques. Nanochannel fluid flow can be driven by capillary action, which benefits from simple injection and reasonably high flow rates. We demonstrate an analysis chip fabricated with planar nanochannels that consist of two adjoining segments of different heights. When nano-analytes elute through the channel, they become physically trapped when the channel dimensions shrink below the size of the particles. We demonstrate the capability of these devices to trap and concentrate by using the following: 120-nm polymer beads, 30-nm polymer beads, Herpes simplex virus 1 capsids, and hepatitis B virus capsids. Each species was fluorescently labeled and its resulting fluorescent signal was detected using a cooled CCD camera. We show how the signal-to-noise ratio of trapped analyte intensity varies linearly with analyte concentration. The goal of this work is to eventually perform size-based fractionation of a variety of nanoparticles, including biomolecules such as proteins.

  8. Single-Tap Precoders and Decoders for Multiuser MIMO FBMC-OQAM Under Strong Channel Frequency Selectivity

    NASA Astrophysics Data System (ADS)

    Rottenberg, Francois; Mestre, Xavier; Horlin, Francois; Louveaux, Jerome

    2017-02-01

    The design of linear precoders or decoders for multiuser (MU) multiple-input multiple-output (MIMO) filterbank multicarrier (FBMC) modulations in the case of strong channel frequency selectivity is presented. The users and the base station (BS) communicate using space division multiple access (SDMA). The low complexity proposed solution is based on a single tap per-subcarrier precoding/decoding matrix at the base station (BS) in the downlink/uplink. As opposed to classical approaches that assume flat channel frequency selectivity at the subcarrier level, the BS does not make this assumption and takes into account the distortion caused by channel frequency selectivity. The expression of the FBMC asymptotic mean squared error (MSE) in the case of strong channel selectivity derived in earlier works is developed and extended. The linear precoders and decoders are found by optimizing the MSE formula under two design criteria, namely zero forcing (ZF) or minimum mean squared error (MMSE). Finally, simulation results demonstrate the performance of the optimized design. As long as the number of BS antennas is larger than the number of users, it is shown that those extra degrees of freedom can be used to compensate for the channel frequency selectivity.

  9. Attentional selection of superimposed surfaces cannot be explained by modulation of the gain of color channels.

    PubMed

    Mitchell, Jude F; Stoner, Gene R; Fallah, Mazyar; Reynolds, John H

    2003-06-01

    When two differently colored, superimposed patterns of dots rotate in opposite directions, this yields the percept of two superimposed transparent surfaces. If observers are cued to attend to one set of dots, they are impaired in making judgments about the other set. Since the two sets of dots are overlapping, the cueing effect cannot be explained by spatial attention. This has led to the interpretation that the impairment reflects surface-based attentional selection. However, recent single-unit recording studies in monkeys have found that attention can modulate the gain of neurons tuned for features such as color. Thus, rather than reflecting the selection of a surface, the behavioral effects might simply reflect a reduction in the gain of color channels selective for the color of the uncued set of dots (feature-based attention), as if viewing the surfaces through a colored filter. If so, then the impairment should be eliminated when the two surfaces are made the same color. Instead, we find that the impairment persists with no reduction in strength. Our findings thus rule out the color gain explanation.

  10. Contribution of a leucine residue in the first transmembrane segment to the selectivity filter region in the CFTR chloride channel.

    PubMed

    Negoda, Alexander; El Hiani, Yassine; Cowley, Elizabeth A; Linsdell, Paul

    2017-05-01

    The anion selectivity and conductance of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel are determined predominantly by interactions between permeant anions and the narrow region of the channel pore. This narrow region has therefore been described as functioning as the "selectivity filter" of the channel. Multiple pore-lining transmembrane segments (TMs) have previously been shown to contribute to the selectivity filter region. However, little is known about the three-dimensional organization of this region, or how multiple TMs combine to determine its functional properties. In the present study we have used patch clamp recording to identify changes in channel function associated with the formation of disulfide cross-links between cysteine residues introduced into different TMs within the selectivity filter. Cysteine introduced at position L102 in TM1 was able to form disulfide bonds with F337C and T338C in TM6, two positions that are known to play key roles in determining anion permeation properties. Consistent with this proximal arrangement of L102, F337 and T338, different mutations at L102 altered anion selectivity and conductance properties in a way that suggests that this residue plays an important role in determining selectivity filter function, albeit a much lesser role than that of F337. These results suggest an asymmetric three-dimensional arrangement of the key selectivity filter region of the pore, as well as having important implications regarding the molecular mechanism of anion permeation.

  11. X-ray structure of acid-sensing ion channel 1-snake toxin complex reveals open state of a Na(+)-selective channel.

    PubMed

    Baconguis, Isabelle; Bohlen, Christopher J; Goehring, April; Julius, David; Gouaux, Eric

    2014-02-13

    Acid-sensing ion channels (ASICs) detect extracellular protons produced during inflammation or ischemic injury and belong to the superfamily of degenerin/epithelial sodium channels. Here, we determine the cocrystal structure of chicken ASIC1a with MitTx, a pain-inducing toxin from the Texas coral snake, to define the structure of the open state of ASIC1a. In the MitTx-bound open state and in the previously determined low-pH desensitized state, TM2 is a discontinuous α helix in which the Gly-Ala-Ser selectivity filter adopts an extended, belt-like conformation, swapping the cytoplasmic one-third of TM2 with an adjacent subunit. Gly 443 residues of the selectivity filter provide a ring of three carbonyl oxygen atoms with a radius of ∼3.6 Å, presenting an energetic barrier for hydrated ions. The ASIC1a-MitTx complex illuminates the mechanism of MitTx action, defines the structure of the selectivity filter of voltage-independent, sodium-selective ion channels, and captures the open state of an ASIC.

  12. X-ray structure of acid-sensing ion channel 1–snake toxin complex reveals open state of a Na+-selective channel

    PubMed Central

    Baconguis, Isabelle; Bohlen, Christopher J.; Goehring, April; Julius, David; Gouaux, Eric

    2014-01-01

    Summary Acid sensing ion channels (ASICs) detect extracellular protons produced during inflammation or ischemic injury and belong to the super family of degenerin/epithelial sodium channels. Here, we determine the cocrystal structure of chicken ASIC1a with MitTx, a pain-inducing toxin from the Texas coral snake, to define the structure of the open state of ASIC1a. In the MitTx-bound open state and in the previously determined low pH desensitized state, TM2 is a discontinuous α-helix in which the Gly-Ala-Ser selectivity filter adopts an extended, belt-like conformation, swapping the cytoplasmic one-third of TM2 with an adjacent subunit. Gly 443 residues of the selectivity filter provide a ring of 3 carbonyl oxygen atoms with a radius of ~3.6 Å, presenting an energetic barrier for hydrated ions. The ASIC1a-MitTx complex illuminates the mechanism of MitTx action, defines the structure of the selectivity filter of voltage-independent, sodium-selective ion channels and captures the open state of an ASIC. PMID:24507937

  13. A novel selective and orally bioavailable Nav1.8 channel blocker, PF-01247324, attenuates nociception and sensory neuron excitability

    PubMed Central

    Payne, Claire Elizabeth; Brown, Adam R; Theile, Jonathon W; Loucif, Alexandre J C; Alexandrou, Aristos J; Fuller, Mathew D; Mahoney, John H; Antonio, Brett M; Gerlach, Aaron C; Printzenhoff, David M; Prime, Rebecca L; Stockbridge, Gillian; Kirkup, Anthony J; Bannon, Anthony W; England, Steve; Chapman, Mark L; Bagal, Sharan; Roeloffs, Rosemarie; Anand, Uma; Anand, Praveen; Bungay, Peter J; Kemp, Mark; Butt, Richard P; Stevens, Edward B

    2015-01-01

    Background and Purpose NaV1.8 ion channels have been highlighted as important molecular targets for the design of low MW blockers for the treatment of chronic pain. Here, we describe the effects of PF-01247324, a new generation, selective, orally bioavailable Nav1.8 channel blocker of novel chemotype. Experimental Approach The inhibition of Nav1.8 channels by PF-01247324 was studied using in vitro patch-clamp electrophysiology and the oral bioavailability and antinociceptive effects demonstrated using in vivo rodent models of inflammatory and neuropathic pain. Key Results PF-01247324 inhibited native tetrodotoxin-resistant (TTX-R) currents in human dorsal root ganglion (DRG) neurons (IC50: 331 nM) and in recombinantly expressed h Nav1.8 channels (IC50: 196 nM), with 50-fold selectivity over recombinantly expressed TTX-R hNav1.5 channels (IC50: ∼10 μM) and 65–100-fold selectivity over TTX-sensitive (TTX-S) channels (IC50: ∼10–18 μM). Native TTX-R currents in small-diameter rodent DRG neurons were inhibited with an IC50 448 nM, and the block of both human recombinant Nav1.8 channels and TTX-R from rat DRG neurons was both frequency and state dependent. In vitro current clamp showed that PF-01247324 reduced excitability in both rat and human DRG neurons and also altered the waveform of the action potential. In vivo experiments n rodents demonstrated efficacy in both inflammatory and neuropathic pain models. Conclusions and Implications Using PF-01247324, we have confirmed a role for Nav1.8 channels in both inflammatory and neuropathic pain. We have also demonstrated a key role for Nav1.8 channels in action potential upstroke and repetitive firing of rat and human DRG neurons. PMID:25625641

  14. Multilevel Concatenated Block Modulation Codes for the Frequency Non-selective Rayleigh Fading Channel

    NASA Technical Reports Server (NTRS)

    Lin, Shu; Rhee, Dojun

    1996-01-01

    This paper is concerned with construction of multilevel concatenated block modulation codes using a multi-level concatenation scheme for the frequency non-selective Rayleigh fading channel. In the construction of multilevel concatenated modulation code, block modulation codes are used as the inner codes. Various types of codes (block or convolutional, binary or nonbinary) are being considered as the outer codes. In particular, we focus on the special case for which Reed-Solomon (RS) codes are used as the outer codes. For this special case, a systematic algebraic technique for constructing q-level concatenated block modulation codes is proposed. Codes have been constructed for certain specific values of q and compared with the single-level concatenated block modulation codes using the same inner codes. A multilevel closest coset decoding scheme for these codes is proposed.

  15. Spatial filter and feature selection optimization based on EA for multi-channel EEG.

    PubMed

    Wang, Yubo; Mohanarangam, Krithikaa; Mallipeddi, Rammohan; Veluvolu, K C

    2015-01-01

    The EEG signals employed for BCI systems are generally band-limited. The band-limited multiple Fourier linear combiner (BMFLC) with Kalman filter was developed to obtain amplitude estimates of the EEG signal in a pre-fixed frequency band in real-time. However, the high-dimensionality of the feature vector caused by the application of BMFLC to multi-channel EEG based BCI deteriorates the performance of the classifier. In this work, we apply evolutionary algorithm (EA) to tackle this problem. The real-valued EA encodes both the spatial filter and the feature selection into its solution and optimizes it with respect to the classification error. Three BMFLC based BCI configurations are proposed. Our results show that the BMFLC-KF with covariance matrix adaptation evolution strategy (CMAES) has the best overall performance.

  16. Channel selection and feature projection for cognitive load estimation using ambulatory EEG.

    PubMed

    Lan, Tian; Erdogmus, Deniz; Adami, Andre; Mathan, Santosh; Pavel, Misha

    2007-01-01

    We present an ambulatory cognitive state classification system to assess the subject's mental load based on EEG measurements. The ambulatory cognitive state estimator is utilized in the context of a real-time augmented cognition (AugCog) system that aims to enhance the cognitive performance of a human user through computer-mediated assistance based on assessments of cognitive states using physiological signals including, but not limited to, EEG. This paper focuses particularly on the offline channel selection and feature projection phases of the design and aims to present mutual-information-based techniques that use a simple sample estimator for this quantity. Analyses conducted on data collected from 3 subjects performing 2 tasks (n-back/Larson) at 2 difficulty levels (low/high) demonstrate that the proposed mutual-information-based dimensionality reduction scheme can achieve up to 94% cognitive load estimation accuracy.

  17. Enterobacter aerogenes OmpX, a cation-selective channel mar- and osmo-regulated.

    PubMed

    Dupont, Myrielle; Dé, Emmanuelle; Chollet, Renaud; Chevalier, Jacqueline; Pagès, Jean-Marie

    2004-07-02

    The ompX gene of Enterobacter aerogenes was cloned. Its overexpression induced a decrease in the major porin Omp36 production and consequently a beta-lactam resistance was noted. Purified outer membrane protein X (OmpX) was reconstituted into artificial membranes and formed ion channels with a conductance of 20 pS in 1 M NaCl and a cationic selectivity. Both MarA expression and high osmolarity induced a noticeable increase of the OmpX synthesis in the E. aerogenes ATCC 13048 strain. In addition, OmpX synthesis increased under conditions in which the expression of the E. aerogenes major non-specific porins, Omp36 and Omp35, decreased.

  18. Charged residues distribution modulates selectivity of the open state of human isoforms of the voltage dependent anion-selective channel.

    PubMed

    Amodeo, Giuseppe Federico; Scorciapino, Mariano Andrea; Messina, Angela; De Pinto, Vito; Ceccarelli, Matteo

    2014-01-01

    Voltage Dependent Anion-selective Channels (VDACs) are pore-forming proteins located in the outer mitochondrial membrane. They are responsible for the access of ions and energetic metabolites into the inner membrane transport systems. Three VDAC isoforms exist in mammalian, but their specific role is unknown. In this work we have performed extensive (overall ∼5 µs) Molecular Dynamics (MD) simulations of the human VDAC isoforms to detect structural and conformational variations among them, possibly related to specific functional roles of these proteins. Secondary structure analysis of the N-terminal domain shows a high similarity among the three human isoforms of VDAC but with a different plasticity. In particular, the N-terminal domain of the hVDAC1 is characterized by a higher plasticity, with a ∼20% occurrence for the 'unstructured' conformation throughout the folded segment, while hVDAC2, containing a peculiar extension of 11 amino acids at the N-terminal end, presents an additional 310-helical folded portion comprising residues 10' to 3, adhering to the barrel wall. The N-terminal sequences of hVDAC isoforms are predicted to have a low flexibility, with possible consequences in the dynamics of the human VDACs. Clear differences were found between hVDAC1 and hVDAC3 against hVDAC2: a significantly modified dynamics with possible important consequence on the voltage-gating mechanism. Charge distribution inside and at the mouth of the pore is responsible for a different preferential localization of ions with opposite charge and provide a valuable rationale for hVDAC1 and hVDAC3 having a Cl-/K+ selectivity ratio of 1.8, whereas hVDAC2 of 1.4. Our conclusion is that hVDAC isoforms, despite sharing a similar scaffold, have modified working features and a biological work is now requested to give evidence to the described dissimilarities.

  19. Bias-Exchange Metadynamics Simulations: An Efficient Strategy for the Analysis of Conduction and Selectivity in Ion Channels.

    PubMed

    Domene, Carmen; Barbini, Paolo; Furini, Simone

    2015-04-14

    Conduction through ion channels possesses two interesting features: (i) different ionic species are selected with high-selectivity and (ii) ions travel across the channel with rates approaching free-diffusion. Molecular dynamics simulations have the potential to reveal how these processes take place at the atomic level. However, analysis of conduction and selectivity at atomistic detail is still hampered by the short time scales accessible by computer simulations. Several algorithms have been developed to "accelerate" sampling along the slow degrees of freedom of the process under study and thus to probe longer time scales. In these algorithms, the slow degrees of freedom need to be defined in advance, which is a well-known shortcoming. In the particular case of ion conduction, preliminary assumptions about the number and type of ions participating in the permeation process need to be made. In this study, a novel approach for the analysis of conduction and selectivity based on bias-exchange metadynamics simulations was tested. This approach was compared with umbrella sampling simulations, using a model of a Na(+)-selective channel. Analogous conclusions resulted from both techniques, but the computational cost of bias-exchange simulations was lower. In addition, with bias-exchange metadynamics it was possible to calculate free energy profiles in the presence of a variable number and type of permeating ions. This approach might facilitate the definition of the set of collective variables required to analyze conduction and selectivity in ion channels.

  20. Agonist activation of arachidonate-regulated Ca2+-selective (ARC) channels in murine parotid and pancreatic acinar cells.

    PubMed

    Mignen, Olivier; Thompson, Jill L; Yule, David I; Shuttleworth, Trevor J

    2005-05-01

    ARC channels (arachidonate-regulated Ca(2+)-selective channels) are a novel type of highly Ca(2+)-selective channel that are specifically activated by low concentrations of agonist-induced arachidonic acid. This activation occurs in the absence of any depletion of internal Ca(2+) stores (i.e. they are 'non-capacitative'). Previous studies in HEK293 cells have shown that these channels provide the predominant pathway for the entry of Ca(2+) seen at low agonist concentrations where oscillatory [Ca(2+)](i) signals are typically produced. In contrast, activation of the more widely studied store-operated Ca(2+) channels (e.g. CRAC channels) is only seen at higher agonist concentrations where sustained 'plateau-type'[Ca(2+)](i) responses are observed. We have now demonstrated the presence of ARC channels in both parotid and pancreatic acinar cells and shown that, again, they are specifically activated by the low concentrations of appropriate agonists (carbachol in the parotid, and both carbachol and cholecystokinin in the pancreas) that are associated with oscillatory [Ca(2+)](i) signals in these cells. Uncoupling the receptor-mediated activation of cytosolic phospholipase A(2) (cPLA(2)) with isotetrandrine reduces the activation of the ARC channels by carbachol and, correspondingly, markedly inhibits the [Ca(2+)](i) signals induced by low carbachol concentrations, whilst those signals seen at high agonist concentrations are essentially unaffected. Interestingly, in the pancreatic acinar cells, activation by cholecystokinin induces a current through the ARC channels that is only approximately 60% of that seen with carbachol. This is consistent with previous reports indicating that carbachol-induced [Ca(2+)](i) signals in these cells are much more dependent on Ca(2+) entry than are the cholecystokinin-induced responses.

  1. Ozone activates airway nerves via the selective stimulation of TRPA1 ion channels.

    PubMed

    Taylor-Clark, Thomas E; Undem, Bradley J

    2010-02-01

    Inhalation of ozone is a major health risk in industrialized nations. Ozone can impair lung function and induce respiratory symptoms through sensory neural-mediated pathways, yet the specific interaction of ozone with airway sensory nerves has yet to be elucidated. Here we demonstrate, using a vagally innervated ex vivo tracheal-lung mouse preparation, that ozone selectively and directly evokes action potential discharge in a subset of nociceptive bronchopulmonary nerves, namely slow conducting C-fibres. Sensitivity to ozone correlated with the transient receptor potential (TRP) A1 agonist, cinnamaldehyde, with ozone having no effect on cinnamaldehyde-insensitive fibres. C-fibre responses to ozone were abolished by ruthenium red (TRP inhibitor). Ozone also stimulated a subset of nociceptive sensory neurones isolated from vagal ganglia of wild-type mice, but failed to activate neurones isolated from transient receptor potential ankyrin 1 (TRPA1) knockout mice. Ozone activated HEK293 cells transfected with TRPA1, but failed to activate non-transfected HEK293 or HEK293 transfected with the capsaicin-sensitive transient receptor potential vanilloid 1 (TRPV1) channel. Thus, ozone is not an indiscriminate neuronal activator, but rather it potently and selectively activates a subset of airway C-fibres by directly stimulating TRPA1.

  2. The food dye FD&C Blue No. 1 is a selective inhibitor of the ATP release channel Panx1.

    PubMed

    Wang, Junjie; Jackson, David George; Dahl, Gerhard

    2013-05-01

    The food dye FD&C Blue No. 1 (Brilliant Blue FCF [BB FCF]) is structurally similar to the purinergic receptor antagonist Brilliant Blue G (BBG), which is a well-known inhibitor of the ionotropic P2X7 receptor (P2X7R). The P2X7R functionally interacts with the membrane channel protein pannexin 1 (Panx1) in inflammasome signaling. Intriguingly, ligands to the P2X7R, regardless of whether they are acting as agonists or antagonists at the receptor, inhibit Panx1 channels. Thus, because both P2X7R and Panx1 are inhibited by BBG, the diagnostic value of the drug is limited. Here, we show that the food dye BB FCF is a selective inhibitor of Panx1 channels, with an IC50 of 0.27 µM. No significant effect was observed with concentrations as high as 100 µM of BB FCF on P2X7R. Differing by just one hydroxyl group from BB FCF, the food dye FD&C Green No. 3 exhibited similar selective inhibition of Panx1 channels. A reverse selectivity was observed for the P2X7R antagonist, oxidized ATP, which in contrast to other P2X7R antagonists had no significant inhibitory effect on Panx1 channels. Based on its selective action, BB FCF can be added to the repertoire of drugs to study the physiology of Panx1 channels. Furthermore, because Panx1 channels appear to be involved directly or indirectly through P2X7Rs in several disorders, BB FCF and derivatives of this "safe" food dye should be given serious consideration for pharmacological intervention of conditions such as acute Crohn's disease, stroke, and injuries to the central nervous system.

  3. Ion Trapping with Fast-Response Ion-Selective Microelectrodes Enhances Detection of Extracellular Ion Channel Gradients

    PubMed Central

    Messerli, Mark A.; Collis, Leon P.; Smith, Peter J.S.

    2009-01-01

    Previously, functional mapping of channels has been achieved by measuring the passage of net charge and of specific ions with electrophysiological and intracellular fluorescence imaging techniques. However, functional mapping of ion channels using extracellular ion-selective microelectrodes has distinct advantages over the former methods. We have developed this method through measurement of extracellular K+ gradients caused by efflux through Ca2+-activated K+ channels expressed in Chinese hamster ovary cells. We report that electrodes constructed with short columns of a mechanically stable K+-selective liquid membrane respond quickly and measure changes in local [K+] consistent with a diffusion model. When used in close proximity to the plasma membrane (<4 μm), the ISMs pose a barrier to simple diffusion, creating an ion trap. The ion trap amplifies the local change in [K+] without dramatically changing the rise or fall time of the [K+] profile. Measurement of extracellular K+ gradients from activated rSlo channels shows that rapid events, 10–55 ms, can be characterized. This method provides a noninvasive means for functional mapping of channel location and density as well as for characterizing the properties of ion channels in the plasma membrane. PMID:19217875

  4. Mechanisms for production of doubly excited states in low energies Iq+-He collisions

    NASA Astrophysics Data System (ADS)

    Harel, C.; Jouin, H.; Pons, B.

    1993-06-01

    We present a theoretical study of the mechanisms leading to the formation of doubly excited states of the series 3l3l' (or 4l') and 2lnl' in N7+, O8+ and C6+-He low energy collisions. The importance of both direct transitions from the entry channel (involving electron-electron interaction couplings) and transitions through a single electron capture channel has been analyzed for a range of impact velocities between 0.2 and 0.6 a.u.

  5. K⁺-dependent selectivity and external Ca²⁺ block of Shab K⁺ channels.

    PubMed

    Carrillo, Elisa; Pacheco, Lucero; Balleza, Daniel; Gomez-Lagunas, Froylan

    2015-01-01

    Potassium channels allow the selective flux of K⁺ excluding the smaller, and more abundant in the extracellular solution, Na⁺ ions. Here we show that Shab is a typical K⁺ channel that excludes Na⁺ under bi-ionic, Na(o)/K(i) or Na(o)/Rb(i), conditions. However, when internal K⁺ is replaced by Cs⁺ (Na(o)/Cs(i)), stable inward Na⁺ and outward Cs⁺ currents are observed. These currents show that Shab selectivity is not accounted for by protein structural elements alone, as implicit in the snug-fit model of selectivity. Additionally, here we report the block of Shab channels by external Ca²⁺ ions, and compare the effect that internal K⁺ replacement exerts on both Ca²⁺ and TEA block. Our observations indicate that Ca²⁺ blocks the channels at a site located near the external TEA binding site, and that this pore region changes conformation under conditions that allow Na⁺ permeation. In contrast, the latter ion conditions do not significantly affect the binding of quinidine to the pore central cavity. Based on our observations and the structural information derived from the NaK bacterial channel, we hypothesize that Ca²⁺ is probably coordinated by main chain carbonyls of the pore's first K⁺-binding site.

  6. Receiver Optimization for Detection in Doubly Spread Communication Channels.

    DTIC Science & Technology

    1984-12-10

    h1T- dt RS T9) -00 aoCHN x [ 0x(t’-T) g*(t’) e j 2 ir ( t ’ - T/ 2 ) dt’ dTd¢ x [ x(t’-T/2) g*(t’+T/2) ej2rot dJ drd4 . (3.2-36) The bracketed terms in...4.3-11) Applying (4.3-11) to (4.3-10) gives IP p . ...................- 66 ff Xx,2+cn(T, RS(T,) dTdO =-f I xgt(T,1)2 RS (T,) drd4 + 2 e ff Re{JXxg...3.2.2 to be given by [0€ EIZ CHNI 2 I f IXx,g(T, ) 2 RSCHN(T,4) drd4 . (3.2-38) If R1 is defined to be the region of the (T,4) plane where the cross

  7. Nitric oxide selectively suppresses IH currents mediated by HCN1-containing channels

    PubMed Central

    Kopp-Scheinpflug, Cornelia; Pigott, Beatrice M; Forsythe, Ian D

    2015-01-01

    Key points The superior olivary complex (SOC) exhibits a spectrum of HCN1 and HCN2 subunit expression, which generate IH currents with fast and slow kinetics, respectively. Neuronal nitric oxide synthase (nNOS) was broadly distributed across the SOC. NO hyperpolarizes the half-activation voltage of HCN1-mediated currents and caused a slowing of the IH current kinetics in the respective nuclei (medial and lateral superior olives and superior paraolivary nucleus). This signalling was independent of cGMP. NO also caused a depolarizing shift in the half-activation voltage of HCN2-mediated IH currents, increasing activation at resting potentials; this was cGMP-dependent. Thus, NO signalling suppressed fast HCN1-mediated currents and potentiated slow HCN2-mediated currents, modulating the overall kinetics and magnitude of the endogenous IH. Abstract Hyperpolarization-activated non-specific cation-permeable channels (HCN) mediate IH currents, which are modulated by cGMP and cAMP and by nitric oxide (NO) signalling. Channel properties depend upon subunit composition (HCN1–4 and accessory subunits) as demonstrated in expression systems, but physiological relevance requires investigation in native neurons with intact intracellular signalling. Here we use the superior olivary complex (SOC), which exhibits a distinctive pattern of HCN1 and HCN2 expression, to investigate NO modulation of the respective IH currents, and compare properties in wild-type and HCN1 knockout mice. The medial nucleus of the trapezoid body (MNTB) expresses HCN2 subunits exclusively, and sends inhibitory projections to the medial and lateral superior olives (MSO, LSO) and the superior paraolivary nucleus (SPN). In contrast to the MNTB, these target nuclei possess an IH with fast kinetics, and they express HCN1 subunits. NO is generated in the SOC following synaptic activity and here we show that NO selectively suppresses HCN1, while enhancing IH mediated by HCN2 subunits. NO hyperpolarizes the half

  8. Potent and selective inhibitors of the TASK-1 potassium channel through chemical optimization of a bis-amide scaffold

    PubMed Central

    Flaherty, Daniel P.; Simpson, Denise S.; Miller, Melissa; Maki, Brooks E.; Zou, Beiyan; Shi, Jie; Wu, Meng; McManus, Owen B.; Aubé, Jeffrey; Li, Min; Golden, Jennifer E.

    2014-01-01

    TASK-1 is a two-pore domain potassium channel that is important to modulating cell excitability, most notably in the context of neuronal pathways. In order to leverage TASK-1 for therapeutic benefit, its physiological role needs better characterization; however, designing selective inhibitors that avoid the closely related TASK-3 channel has been challenging. In this study, a series of bis-amide derived compounds were found to demonstrate improved TASK-1 selectivity over TASK-3 compared to reported inhibitors. Optimization of a marginally selective hit led to analog 35 which displays a TASK-1 IC50 = 16 nM with 62-fold selectivity over TASK-3 in an orthogonal electrophysiology assay. PMID:25017033

  9. Selective blockade of TRPA1 channel attenuates pathological pain without altering noxious cold sensation or body temperature regulation.

    PubMed

    Chen, Jun; Joshi, Shailen K; DiDomenico, Stanley; Perner, Richard J; Mikusa, Joe P; Gauvin, Donna M; Segreti, Jason A; Han, Ping; Zhang, Xu-Feng; Niforatos, Wende; Bianchi, Bruce R; Baker, Scott J; Zhong, Chengmin; Simler, Gricelda H; McDonald, Heath A; Schmidt, Robert G; McGaraughty, Steve P; Chu, Katharine L; Faltynek, Connie R; Kort, Michael E; Reilly, Regina M; Kym, Philip R

    2011-05-01

    Despite the increasing interest in TRPA1 channel as a pain target, its role in cold sensation and body temperature regulation is not clear; the efficacy and particularly side effects resulting from channel blockade remain poorly understood. Here we use a potent, selective, and bioavailable antagonist to address these issues. A-967079 potently blocks human (IC(50): 51 nmol/L, electrophysiology, 67 nmol/L, Ca(2+) assay) and rat TRPA1 (IC(50): 101 nmol/L, electrophysiology, 289 nmol/L, Ca(2+) assay). It is >1000-fold selective over other TRP channels, and is >150-fold selective over 75 other ion channels, enzymes, and G-protein-coupled receptors. Oral dosing of A-967079 produces robust drug exposure in rodents, and exhibits analgesic efficacy in allyl isothiocyanate-induced nocifensive response and osteoarthritic pain in rats (ED(50): 23.2 mg/kg, p.o.). A-967079 attenuates cold allodynia produced by nerve injury but does not alter noxious cold sensation in naive animals, suggesting distinct roles of TRPA1 in physiological and pathological states. Unlike TRPV1 antagonists, A-967079 does not alter body temperature. It also does not produce locomotor or cardiovascular side effects. Collectively, these data provide novel insights into TRPA1 function and suggest that the selective TRPA1 blockade may present a viable strategy for alleviating pain without untoward side effects.

  10. A model of the L-type Ca2+ channel in rat ventricular myocytes: ion selectivity and inactivation mechanisms

    PubMed Central

    Sun, Liang; Fan, Jing-Song; Clark, John W; Palade, Philip T

    2000-01-01

    We have developed a mathematical model of the L-type Ca2+ current, which is based on data from whole-cell voltage clamp experiments on rat ventricular myocytes. Ion substitution methods were employed to investigate the ionic selectivity of the channel. Experiments were configured with Na+, Ca2+ or Ba2+ as the majority current carrier. The amplitude of current through the channel is attenuated in the presence of extracellular Ca2+ or Ba2+. Our model accounts for channel selectivity by using a modified Goldman-Hodgkin-Katz (GHK) configuration that employs voltage-dependent channel binding functions for external divalent ions. Stronger binding functions were used for Ca2+ than for Ba2+. Decay of the ionic current during maintained depolarization was characterized by means of voltage- and Ca2+-dependent inactivation pathways embedded in a five-state dynamic channel model. Particularly, Ca2+ first binds to calmodulin and the Ca2+-calmodulin complex is the mediator of Ca2+ inactivation. Ba2+-dependent inactivation was characterized using the same scheme, but with a decreased binding to calmodulin. A reduced amount of steady-state inactivation, as evidenced by a U-shaped curve at higher depolarization levels (>40 mV) in the presence of [Ca2+]o, was observed in double-pulse protocols used to study channel inactivation. To characterize this phenomenon, a mechanism was incorporated into the model whereby Ca2+ or Ba2+ also inhibits the voltage-dependent inactivation pathway. The five-state dynamic channel model was also used to simulate single channel activity. Calculations of the open probability of the channel model are generally consistent with experimental data. A sixth state can be used to simulate modal activity by way of introducing long silent intervals. Our model has been tested extensively using experimental data from a wide variety of voltage clamp protocols and bathing solution manipulations. It provides: (a) biophysically based explanations of putative mechanisms

  11. An inactivation gate in the selectivity filter of KCNQ1 potassium channels.

    PubMed

    Gibor, Gilad; Yakubovich, Daniel; Rosenhouse-Dantsker, Avia; Peretz, Asher; Schottelndreier, Hella; Seebohm, Guiscard; Dascal, Nathan; Logothetis, Diomedes E; Paas, Yoav; Attali, Bernard

    2007-12-15

    Inactivation is an inherent property of most voltage-gated K(+) channels. While fast N-type inactivation has been analyzed in biophysical and structural details, the mechanisms underlying slow inactivation are yet poorly understood. Here, we characterized a slow inactivation mechanism in various KCNQ1 pore mutants, including L273F, which hinders entry of external Ba(2+) to its deep site in the pore and traps it by slowing its egress. Kinetic studies, molecular modeling, and dynamics simulations suggest that this slow inactivation involves conformational changes that converge to the outer carbonyl ring of the selectivity filter, where the backbone becomes less flexible. This mechanism involves acceleration of inactivation kinetics and enhancement of Ba(2+) trapping at elevated external K(+) concentrations. Hence, KCNQ1 slow inactivation considerably differs from C-type inactivation where vacation of K(+) from the filter was invoked. We suggest that trapping of K(+) at s(1) due to filter rigidity and hindrance of the dehydration-resolvation transition underlie the slow inactivation of KCNQ1 pore mutants.

  12. Selective disruption of high sensitivity heat activation but not capsaicin activation of TRPV1 channels by pore turret mutations.

    PubMed

    Cui, Yuanyuan; Yang, Fan; Cao, Xu; Yarov-Yarovoy, Vladimir; Wang, KeWei; Zheng, Jie

    2012-04-01

    The capsaicin receptor transient receptor potential vanilloid (TRPV)1 is a highly heat-sensitive ion channel. Although chemical activation and heat activation of TRPV1 elicit similar pungent, painful sensation, the molecular mechanism underlying synergistic activation remains mysterious. In particular, where the temperature sensor is located and whether heat and capsaicin share a common activation pathway are debated. To address these fundamental issues, we searched for channel mutations that selectively affected one form of activation. We found that deletion of the first 10 amino acids of the pore turret significantly reduced the heat response amplitude and shifted the heat activation threshold, whereas capsaicin activation remained unchanged. Removing larger portions of the turret disrupted channel function. Introducing an artificial sequence to replace the deleted region restored sensitive capsaicin activation in these nonfunctional channels. The heat activation, however, remained significantly impaired, with the current exhibiting diminishing heat sensitivity to a level indistinguishable from that of a voltage-gated potassium channel, Kv7.4. Our results demonstrate that heat and capsaicin activation of TRPV1 are structurally and mechanistically distinct processes, and the pore turret is an indispensible channel structure involved in the heat activation process but is not part of the capsaicin activation pathway. Synergistic effect of heat and capsaicin on TRPV1 activation may originate from convergence of the two pathways on a common activation gate.

  13. Purification, sequence, and model structure of charybdotoxin, a potent selective inhibitor of calcium-activated potassium channels.

    PubMed Central

    Gimenez-Gallego, G; Navia, M A; Reuben, J P; Katz, G M; Kaczorowski, G J; Garcia, M L

    1988-01-01

    Charybdotoxin (ChTX), a protein present in the venom of the scorpion Leiurus quinquestriatus var. hebraeus, has been purified to homogeneity by a combination of ion-exchange and reversed-phase chromatography. Polyacrylamide gel electrophoresis, amino acid analysis, and complete amino acid sequence determination of the pure protein reveal that it consists of a single polypeptide chain of 4.3 kDa. Purified ChTX is a potent and selective inhibitor of the approximately 220-pS Ca2+-activated K+ channel present in GH3 anterior pituitary cells and primary bovine aortic smooth muscle cells. The toxin reversibly blocks channel activity by interacting at the external pore of the channel protein with an apparent Kd of 2.1 nM. The primary structure of ChTX is similar to a number of neurotoxins of diverse origin, which suggests that ChTX is a member of a superfamily of proteins that modify ion-channel activities. On the basis of this similarity, the three-dimensional structure of ChTX has been modeled from the known crystal structure of alpha-bungarotoxin. These studies indicate that ChTX is useful as a probe of Ca2+-activated K+-channel function and suggest that the proposed tertiary structure of ChTX may provide insight into the mechanism of channel block. Images PMID:2453055

  14. Outage Performance of Cooperative Relay Selection with Multiple Source and Destination Antennas over Dissimilar Nakagami-m Fading Channels

    NASA Astrophysics Data System (ADS)

    Lee, Wooju; Yoon, Dongweon

    Cooperative relay selection, in which one of multiple relays is selected to retransmit the source signal to the destination, has received considerable attention in recent years, because it is a simple way to obtain cooperative diversity in wireless networks. The exact expression of outage probability for a decode-and-forward cooperative relay selection with multiple source and destination antennas over Rayleigh fading channels was recently derived in [9]. In this letter, we derive the exact expressions of outage probability and diversity-multiplexing tradeoff over independent and non-identically distributed Nakagami-m fading channels as an extension of [9]. We then analyze the effects of various parameters such as fading conditions, number of relays, and number of source and destination antennas on the outage probability.

  15. Fragmentation of doubly charged HDO, H{sub 2}O, and D{sub 2}O molecules induced by proton and monocharged fluorine beam impact at 3 keV

    SciTech Connect

    Martin, S.; Chen, L.; Brédy, R.; Bernard, J.; Cassimi, A.

    2015-03-07

    Doubly charged ions HDO{sup 2+}, H{sub 2}O{sup 2+}, and D{sub 2}O{sup 2+} were prepared selectively to triplet or singlet excited states in collisions with F{sup +} or H{sup +} projectiles at 3 keV. Excitation energies of dications following two-body or three-body dissociation channels were measured and compared with recent calculations using ab initio multi-reference configuration interaction method [Gervais et al., J. Chem. Phys. 131, 024302 (2009)]. For HDO{sup 2+}, preferential cleavage of O–H rather than O–D bond has been observed and the ratio between the populations of the fragmentation channels OD{sup +}-H{sup +} and OH{sup +}-D{sup +} were measured. The kinetic energy release has been measured and compared with previous experiments.

  16. Structural and Functional Consequences of an Amide-to-Ester Substitution in the Selectivity Filter of a Potassium Channel

    PubMed Central

    Valiyaveetil, Francis I.; Sekedat, Matthew; MacKinnon, Roderick; Muir, W.

    2008-01-01

    The selectivity filter of K+ channels comprises four contiguous ion binding sites, S1 through S4. Structural and functional data indicate that the filter contains on average two K+ ions at any given time and that these ions reside primarily in two configurations, namely to sites S1 and S3 or to sites S2 and S4. Maximum ion flux through the channel is expected to occur when the energy difference between these two binding configurations is zero. In this study, we have used protein semisynthesis to selectively perturb site 1 within the filter of the KcsA channel through use of an amide-to-ester substitution. The modification alters K+ conduction properties. The structure of the selectivity filter is largely unperturbed by the modification, despite the loss of an ordered water molecule normally located just behind the filter. Introduction of the ester moiety was found to alter the distribution of K+, Rb+ and Cs+ within the filter, with the most dramatic change found for Rb+. The redistribution of ions is associated with the appearance of a partially hydrated ion just external to the filter, at a position where no ion is observed in the wild type channel. The appearance of this new ion-binding site creates a change in the distance between a pair of K+ ions some fraction of the time, apparently leading to a reduction in the ion conduction rate. Importantly, this finding suggests that the selectivity filter of a potassium channel is optimized both in terms of absolute ion occupancy and in terms of the separation in distance between the conducting ions. PMID:16939283

  17. Tackling the Combined Effects of Reverberation and Masking Noise Using Ideal Channel Selection

    ERIC Educational Resources Information Center

    Hazrati, Oldooz; Loizou, Philipos C.

    2012-01-01

    Purpose: In this article, a new signal-processing algorithm is proposed and evaluated for the suppression of the combined effects of reverberation and noise. Method: The proposed algorithm decomposes, on a short-term basis (every 20 ms), the reverberant stimuli into a number of channels and retains only a subset of the channels satisfying a…

  18. T-type channels become highly permeable to sodium ions using an alternative extracellular turret region (S5-P) outside the selectivity filter.

    PubMed

    Senatore, Adriano; Guan, Wendy; Boone, Adrienne N; Spafford, J David

    2014-04-25

    T-type (Cav3) channels are categorized as calcium channels, but invertebrate ones can be highly sodium-selective channels. We illustrate that the snail LCav3 T-type channel becomes highly sodium-permeable through exon splicing of an extracellular turret and descending helix in domain II of the four-domain Cav3 channel. Highly sodium-permeable T-type channels are generated without altering the invariant ring of charged residues in the selectivity filter that governs calcium selectivity in calcium channels. The highly sodium-permeant T-type channel expresses in the brain and is the only splice isoform expressed in the snail heart. This unique splicing of turret residues offers T-type channels a capacity to serve as a pacemaking sodium current in the primitive heart and brain in lieu of Nav1-type sodium channels and to substitute for voltage-gated sodium channels lacking in many invertebrates. T-type channels would also contribute substantially to sodium leak conductances at rest in invertebrates because of their large window currents.

  19. Vm24, a Natural Immunosuppressive Peptide, Potently and Selectively Blocks Kv1.3 Potassium Channels of Human T Cells

    PubMed Central

    Varga, Zoltan; Gurrola-Briones, Georgina; Papp, Ferenc; Rodríguez de la Vega, Ricardo C.; Pedraza-Alva, Gustavo; Tajhya, Rajeev B.; Gaspar, Rezso; Cardenas, Luis; Rosenstein, Yvonne; Beeton, Christine; Possani, Lourival D.

    2012-01-01

    Blockade of Kv1.3 K+ channels in T cells is a promising therapeutic approach for the treatment of autoimmune diseases such as multiple sclerosis and type 1 diabetes mellitus. Vm24 (α-KTx 23.1) is a novel 36-residue Kv1.3-specific peptide isolated from the venom of the scorpion Vaejovis mexicanus smithi. Vm24 inhibits Kv1.3 channels of human lymphocytes with high affinity (Kd = 2.9 pM) and exhibits >1500-fold selectivity over other ion channels assayed. It inhibits the proliferation and Ca2+ signaling of human T cells in vitro and reduces delayed-type hypersensitivity reactions in rats in vivo. Our results indicate that Vm24 has exceptional pharmacological properties that make it an excellent candidate for treatment of certain autoimmune diseases. PMID:22622363

  20. An iterative detection method of MIMO over spatial correlated frequency selective channel: using list sphere decoding for simplification

    NASA Astrophysics Data System (ADS)

    Shi, Zhiping; Yan, Bing

    2010-08-01

    In multiple-input multiple-output(MIMO) wireless systems, combining good channel codes(e.g., Non-binary Repeat Accumulate codes) with adaptive turbo equalization is a good option to get better performance and lower complexity under Spatial Correlated Frequency Selective(SCFS) Channel. The key of this method is after joint antennas MMSE detection (JAD/MMSE) based on interruption cancelling using soft information, considering the detection result as an output of a Gaussian equivalent flat fading channel, and performing maximum likelihood detection(ML) to get more correct estimated result. But the using of ML brings great complexity increase, which is not allowed. In this paper, a low complexity method called list sphere decoding is introduced and applied to replace the ML in order to simplify the adaptive iterative turbo equalization system.

  1. Examining the Relationship Between Flexible Resources and Health Information Channel Selection.

    PubMed

    Manierre, Matthew

    2016-01-01

    This study examines how variations in flexible resources influence where individuals begin their search for health information. Access to flexible resources such as money, power, and knowledge can alter the accessibility of channels for health information, such as doctors, the Internet, and print media. Using the HINTS 3 sample, whether information channel utilization is predicted by the same factors in two groups with distinct levels of access to flexible resources, as approximated by high and low levels of education, is investigated. Differences in access to flexible resources are hypothesized to produce variations in channel utilization in bivariate analyses, as well as changes in coefficient strength and statistical significance in multivariate models. Multinomial logit models were used to assess how a number of variables influence the probability of using a specific information channel first in either flexible resource group. Results suggest that individuals with higher levels of education, a proxy for flexible resources, are more likely to report seeking information from the Internet first, which is consistent with research on the digital divide. It appears that diminished access to flexible resources is also associated with heightened utilization of offline channels, including doctors. A handful of differences in predictors were found between the low and high flexible resource groups when multivariate models were compared. Future research should take into account the distinctions between different offline channels while also seeking to further understand how social inequality relates to the utilization of different channels and corresponding health outcomes.

  2. Methods for Scaling to Doubly Stochastic Form,

    DTIC Science & Technology

    1981-06-26

    BIRKHOFF, G.: Tres observaciones sobre le algebra lineal , Rev. univ. nec. Tucuman, ser A, . 147-151, [1948] BRUALDI, R.A., S.V. PARTER, and H. SCHNEIDER...scaling square, nonnegative matrices to dou- bly stochastic form are described. A generalized version of the convergence theorem in SINKI-ORN and KNOPP... matrices D and E for a given square nonnegative matrix, A, such that DAE is doubly stochastic--or determine that such :.p h" du:es 7’. -,.xist. A

  3. Riparian vegetation patterns in relation to fluvial landforms and channel evolution along selected rivers of Tuscany (Central Italy)

    USGS Publications Warehouse

    Hupp, C.R.; Rinaldi, M.

    2007-01-01

    Riparian vegetation distribution patterns and diversity relative to various fluvial geomorphic channel patterns, landforms, and processes are described and interpreted for selected rivers of Tuscany, Central Italy; with emphasis on channel evolution following human impacts. Field surveys were conducted along thirteen gauged reaches for species presence, fluvial landforms, and the type and amount of channel/riparian zone change. Inundation frequency of different geomorphic surfaces was determined, and vegetation data were analyzed using BDA (binary discriminate analysis) and DCA (detrended correspondence analysis) and related to hydrogeomorphology. Multivariate analyses revealed distinct quantitative vegetation patterns relative to six major fluvial geomorphic surfaces. DCA of the vegetation data also showed distinct associations of plants to processes of adjustment that are related to stage of channel evolution, and clearly separated plants along disturbance/landform/soil moisture gradients. Species richness increases from the channel bed to the terrace and on heterogeneous riparian areas, whereas species richness decreases from moderate to intense incision and from low to intense narrowing. ?? 2007 by Association of American Geographers.

  4. Reversal of Ion Charge Selectivity Renders the Pentameric Ligand-Gated Ion Channel GLIC Insensitive to Anesthetics

    PubMed Central

    Tillman, Tommy; Cheng, Mary H.; Chen, Qiang; Tang, Pei; Xu, Yan

    2014-01-01

    Pentameric ligand gated ion channels (pLGICs) are a family of structurally homologous cationic and anionic channels involved in neurotransmission. Cationic members of the pLGIC family are typically inhibited by general anesthetics, while anionic members are potentiated. GLIC is a prokaryotic cationic pLGIC and can be inhibited by clinical concentrations of general anesthetics. The introduction of three mutations, Y221A (Y–3′A), E222P (E–2′P) and N224R (N0′R), at the selectivity filter and one, A237T (A13′T), at the hydrophobic gate, converted GLIC to an anion channel. The mutated GLIC (GLIC4) became insensitive to the anesthetics propofol and etomidate as well as the channel blocker picrotoxin. Molecular dynamics (MD) simulations revealed changes in the structure and dynamics of GLIC4 in comparison to GLIC, particularly in the tilting angles of the pore-lining helix (TM2) that consequently resulted in different pore radius and hydration profiles. Propofol binding to an intra-subunit site of GLIC shifted the tilting angles of TM2 towards closure at the hydrophobic gate region, consistent with propofol inhibition of GLIC. In contrast, the pore of GLIC4 was much more resilient to perturbation from propofol binding. This study underscores the importance of pore dynamics and conformation to anesthetic effects on channel functions. PMID:22978431

  5. The selective serotonin reuptake inhibitor dapoxetine inhibits voltage-dependent K(+) channels in rabbit coronary arterial smooth muscle cells.

    PubMed

    Kim, Han Sol; Li, Hongliang; Kim, Hye Won; Shin, Sung Eun; Jung, Won-Kyo; Ha, Kwon-Soo; Han, Eun-Taek; Hong, Seok-Ho; Firth, Amy L; Choi, Il-Whan; Park, Won Sun

    2017-04-01

    We investigated the inhibitory effect of dapoxetine, a selective serotonin reuptake inhibitor (SSRI), on voltage-dependent K(+) (Kv) channels using native smooth muscle cells from rabbit coronary arteries. Dapoxetine inhibited Kv channel currents in a concentration-dependent manner, with an IC50 value of 2.68±0.94 μmol/L and a slope value (Hill coefficient) of 0.63±0.11. Application of 10 μmol/L dapoxetine accelerated the rate of inactivation of Kv currents. Although dapoxetine did not modify current activation kinetics, it caused a significant negative shift in the inactivation curves. Application of train step (1 or 2 Hz) progressively increased the inhibitory effect of dapoxetine on Kv channels. In addition, the recovery time constant was extended in its presence, suggesting that the longer recovery time constant from inactivation underlies a use-dependent inhibition of the channel. From these results, we conclude that dapoxetine inhibits Kv channels in a dose-, time-, use-, and state (open)-dependent manner, independent of serotonin reuptake inhibition.

  6. Cation-selective channels in the vacuolar membrane of Saccharomyces: Dependence on calcium, redox state, and voltage

    SciTech Connect

    Bertl, A.; Slayman, C.L. )

    1990-10-01

    The vacuolar membrane of the yeast Saccharomyces cerevisiae, which is proposed as a system for functional expression of membrane proteins, was examined by patch-clamp techniques. Its most conspicuous feature, in the absence of energizing substrates, is a cation channel /with a characteristic conductance of {approx}120 pS for symmetric 100 mM KCl solutions and with little selectivity between K{sup {plus}} and Na{sup {plus}} but strong selectivity for cations over anions. Channel gating is voltage-dependent. The time-averaged current-voltage curve shows strong rectification, with negative currents much larger than positive currents. The open probability also depends strongly on cytoplasmic Ca{sup 2{plus}} concentration but, for ordinary recording conditions, is high only at unphysiologically high Ca{sup 2{plus}}. However, reducing agents such as dithiothreitol and 2-mercaptoethanol poise the channels so that they can be activated by micromolar cytoplasmic Ca{sup 2{plus}}. The channels are blocked irreversibly by chloramine T, which is known to oxidize exposed methionine and cysteine residues specifically.

  7. Reduction of the pectoral spine and girdle in domesticated Channel catfish is likely caused by changes in selection pressure.

    PubMed

    Fine, Michael L; Lahiri, Shweta; Sullivan, Amanda D H; Mayo, Mark; Newton, Scott H; Sismour, Edward N

    2014-07-01

    Locked pectoral spines of the Channel Catfish Ictalurus punctatus more than double the fish's width and complicate ingestion by gape-limited predators. The spine mates with the pectoral girdle, a robust structure that anchors the spine. This study demonstrates that both spine and girdle exhibit negative allometric growth and that pectoral spines and girdles are lighter in domesticated than in wild Channel Catfish. This finding could be explained by changes in selection pressure for spine growth during domestication or by an epigenetic effect in which exposure to predators in wild fish stimulates pectoral growth. We tested the epigenetic hypothesis by exposing domesticated Channel Catfish fingerlings to Largemouth Bass Micropterus salmoides predators for 13 weeks. Spines and girdles grow isometrically in the fingerlings, and regression analysis indicates no difference in proportional pectoral growth between control and predator-exposed fish. Therefore a change in selection pressure likely accounts for smaller pectoral growth in domesticated Channel Catfish. Decreasing spine growth in older fish suggests anti-predator functions are most important in smaller fish. Additionally, growth of the appendicular and axial skeleton is controlled differentially, and mechanical properties of the spine and not just its length are an important component of this defensive adaptation.

  8. Subunit-selective role of the M3 transmembrane domain of the nicotinic acetylcholine receptor in channel gating.

    PubMed

    De Rosa, María José; Corradi, Jeremías; Bouzat, Cecilia

    2008-02-01

    The nicotinic acetylcholine receptor (AChR) can be either hetero-pentameric, composed of alpha and non-alpha subunits, or homo-pentameric, composed of alpha7 subunits. To explore the subunit-selective contributions of transmembrane domains to channel gating we analyzed single-channel activity of chimeric muscle AChRs. We exchanged M3 between alpha1 and epsilon or alpha7 subunits. The replacement of M3 in alpha1 by epsilonM3 significantly alters activation properties. Channel activity appears as bursts of openings whose durations are 20-fold longer than those of wild-type AChRs. In contrast, 7-fold briefer openings are observed in AChRs containing the reverse epsilon chimeric subunit. The duration of the open state decreases with the increase in the number of alpha1M3 segments, indicating additive contributions of M3 of all subunits to channel closing. Each alpha1M3 segment decreases the energy barrier of the closing process by approximately 0.8 kcal/mol. Partial chimeric subunits show that small stretches of the M3 segment contribute additively to the open duration. The replacement of alpha1 sequence by alpha7 in M3 leads to 3-fold briefer openings whereas in M1 it leads to 10-fold prolonged openings, revealing that the subunit-selective role is unique to each transmembrane segment.

  9. (-)-Englerin A is a potent and selective activator of TRPC4 and TRPC5 calcium channels.

    PubMed

    Akbulut, Yasemin; Gaunt, Hannah J; Muraki, Katsuhiko; Ludlow, Melanie J; Amer, Mohamed S; Bruns, Alexander; Vasudev, Naveen S; Radtke, Lea; Willot, Matthieu; Hahn, Sven; Seitz, Tobias; Ziegler, Slava; Christmann, Mathias; Beech, David J; Waldmann, Herbert

    2015-03-16

    Current therapies for common types of cancer such as renal cell cancer are often ineffective and unspecific, and novel pharmacological targets and approaches are in high demand. Here we show the unexpected possibility for the rapid and selective killing of renal cancer cells through activation of calcium-permeable nonselective transient receptor potential canonical (TRPC) calcium channels by the sesquiterpene (-)-englerin A. This compound was found to be a highly efficient, fast-acting, potent, selective, and direct stimulator of TRPC4 and TRPC5 channels. TRPC4/5 activation through a high-affinity extracellular (-)-englerin A binding site may open up novel opportunities for drug discovery aimed at renal cancer.

  10. Selective phosphorylation modulates the PIP2 sensitivity of the CaM-SK channel complex

    PubMed Central

    Zhang, Miao; Meng, Xuan-Yu; Cui, Meng; Pascal, John M.; Logothetis, Diomedes E.; Zhang, Ji-Fang

    2015-01-01

    Phosphatidylinositol bisphosphate (PIP2) regulates the activities of many membrane proteins including ion channels through direct interactions. However, the affinity of PIP2 is so high for some channel proteins that its physiological role as a modulator has been questioned. Here we show that PIP2 is an important cofactor for activation of small conductance Ca2+-activated potassium channels (SK) by Ca2+-bound calmodulin (CaM). Removal of the endogenous PIP2 inhibits SK channels. The PIP2-binding site resides at the interface of CaM and the SK C-terminus. We further demonstrate that the affinity of PIP2 for its target proteins can be regulated by cellular signaling. Phosphorylation of CaM T79, located adjacent to the PIP2-binding site, by Casein Kinase 2 reduces the affinity of PIP2 for the CaM-SK channel complex by altering the dynamic interactions among amino acid residues surrounding the PIP2-binding site. This effect of CaM phosphorylation promotes greater channel inhibition by G-protein-mediated hydrolysis of PIP2. PMID:25108821

  11. Double photoionization of doubly-excited lithium

    NASA Astrophysics Data System (ADS)

    Armstrong, G.; Pindzola, M. S.; Kheifets, A.; Schuricke, M.; Veeravalli, G.; Dornes, Ch.; Zhu, G.; Joachimsmeyer, K.; Treusch, R.; Dorn, A.; Colgan, J.

    2012-06-01

    We present triple differential cross sections and recoil ion momentum distributions for double photoionization of the 1s2s2p state of lithium. Double ionization of lithium may be treated as a two-active-electron process, where the ``active'' 2s and 2p electrons move in the field of the ``frozen-core'' Li^2+ 1s state.The time-dependent close-coupling (TDCC) method is used to solve the two-electron time-dependent Schr"odinger equation in full dimensionality. This work is motivated by recent FLASH experiments, which have obtained recoil-ion momentum distributions at a photon energy of 59 eV, where the 1s2s2p state is first reached via a 1s-2p photoexcitation from the initial ground state, and may then be doubly-ionized after the absorption of a second photon. The TDCC calculations in this work treat the subsequent photoionization of this doubly-excited state. The results are compared to those obtained by the convergent close-coupling method and to measurement, and provide a first comparison between theory and experiment in this fundamental few-photon few-body problem.

  12. Selective positive modulation of the SK3 and SK2 subtypes of small conductance Ca2+-activated K+ channels

    PubMed Central

    Hougaard, C; Eriksen, B L; Jørgensen, S; Johansen, T H; Dyhring, T; Madsen, L S; Strøbæk, D; Christophersen, P

    2007-01-01

    Background and purpose: Positive modulators of small conductance Ca2+-activated K+ channels (SK1, SK2, and SK3) exert hyperpolarizing effects that influence the activity of excitable and non-excitable cells. The prototype compound 1-EBIO or the more potent compound NS309, do not distinguish between the SK subtypes and they also activate the related intermediate conductance Ca2+-activated K+ channel (IK). This paper demonstrates, for the first time, subtype-selective positive modulation of SK channels. Experimental approach: Using patch clamp and fluorescence techniques we studied the effect of the compound cyclohexyl-[2-(3,5-dimethyl-pyrazol-1-yl)-6-methyl-pyrimidin-4-yl]-amine (CyPPA) on recombinant hSK1-3 and hIK channels expressed in HEK293 cells. CyPPA was also tested on SK3 and IK channels endogenously expressed in TE671 and HeLa cells. Key results: CyPPA was found to be a positive modulator of hSK3 (EC50 = 5.6 ± 1.6 μM, efficacy 90 ± 1.8 %) and hSK2 (EC50 = 14 ± 4 μM, efficacy 71 ± 1.8 %) when measured in inside-out patch clamp experiments. CyPPA was inactive on both hSK1 and hIK channels. At hSK3 channels, CyPPA induced a concentration-dependent increase in the apparent Ca2+-sensitivity of channel activation, changing the EC50(Ca2+) from 429 nM to 59 nM. Conclusions and implications: As a pharmacological tool, CyPPA may be used in parallel with the IK/SK openers 1-EBIO and NS309 to distinguish SK3/SK2- from SK1/IK-mediated pharmacological responses. This is important for the SK2 and SK1 subtypes, since they have overlapping expression patterns in the neocortical and hippocampal regions, and for SK3 and IK channels, since they co-express in certain peripheral tissues. PMID:17486140

  13. In pursuit of small molecule chemistry for calcium-permeable non-selective TRPC channels -- mirage or pot of gold?

    PubMed

    Bon, Robin S; Beech, David J

    2013-10-01

    The primary purpose of this review is to address the progress towards small molecule modulators of human Transient Receptor Potential Canonical proteins (TRPC1, TRPC3, TRPC4, TRPC5, TRPC6 and TRPC7). These proteins generate channels for calcium and sodium ion entry. They are relevant to many mammalian cell types including acinar gland cells, adipocytes, astrocytes, cardiac myocytes, cochlea hair cells, endothelial cells, epithelial cells, fibroblasts, hepatocytes, keratinocytes, leukocytes, mast cells, mesangial cells, neurones, osteoblasts, osteoclasts, platelets, podocytes, smooth muscle cells, skeletal muscle and tumour cells. There are broad-ranging positive roles of the channels in cell adhesion, migration, proliferation, survival and turning, vascular permeability, hypertrophy, wound-healing, hypo-adiponectinaemia, angiogenesis, neointimal hyperplasia, oedema, thrombosis, muscle endurance, lung hyper-responsiveness, glomerular filtration, gastrointestinal motility, pancreatitis, seizure, innate fear, motor coordination, saliva secretion, mast cell degranulation, cancer cell drug resistance, survival after myocardial infarction, efferocytosis, hypo-matrix metalloproteinase, vasoconstriction and vasodilatation. Known small molecule stimulators of the channels include hyperforin, genistein and rosiglitazone, but there is more progress with inhibitors, some of which have promising potency and selectivity. The inhibitors include 2-aminoethoxydiphenyl borate, 2-aminoquinolines, 2-aminothiazoles, fatty acids, isothiourea derivatives, naphthalene sulfonamides, N-phenylanthranilic acids, phenylethylimidazoles, piperazine/piperidine analogues, polyphenols, pyrazoles and steroids. A few of these agents are starting to be useful as tools for determining the physiological and pathophysiological functions of TRPC channels. We suggest that the pursuit of small molecule modulators for TRPC channels is important but that it requires substantial additional effort and

  14. Receptor model for the molecular basis of tissue selectivity of 1,4-dihydropyridine calcium channel drugs

    NASA Astrophysics Data System (ADS)

    Langs, David A.; Strong, Phyllis D.; Triggle, David J.

    1990-09-01

    Our analysis of the solid state conformations of nifedipine [dimethyl 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinecarboxylate] and its 1,4-dihydropyridine (1,4-DHP) analogues produced a cartoon description of the important interactions between these drugs and their voltage-dependent calcium channel receptor. In the present study a molecular-level detailed model of the 1,4-DHP receptor binding site has been built from the published amino acid sequence of the 215-1 subunit of the voltage-dependent calcium channel isolated from rabbit skeletal muscle transverse tubule membranes. The voltage-sensing component of the channel described in this work differs from others reported for the homologous sodium channel in that it incorporates a water structure and a staggered, rather than eclipsed, hydrogen bonded S4 helix conformation. The major recognition surfaces of the receptor lie in helical grooves on the S4 or voltagesensing α-helix that is positioned in the center of the bundle of transmembrane helices that define each of the four calcium channel domains. Multiple binding clefts defined by Arg-X-X-Arg-P-X-X-S `reading frames' exist on the S4 strand. The tissue selectivity of nifedipine and its analogues may arise, in part, from conservative changes in the amino acid residues at the P and S positions of the reading frame that define the ester-binding regions of receptors from different tissues. The crystal structures of two tissue-selective nifedipine analogues, nimodipine [isopropyl (2-methoxyethyl) 1,4-dihydro-2,6- dimethyl-4-(3-nitrophenyl)-3,5-pyridinecarboxylate] and nitrendipine [ethyl methyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinecarboxylate] are reported. Nimodipine was observed to have an unusual ester side chain conformation that enhances the fit to the proposed ester-sensing region of the receptor.

  15. Selective potentiation of 2-APB-induced activation of TRPV1–3 channels by acid

    PubMed Central

    Gao, Luna; Yang, Pu; Qin, Peizhong; Lu, Yungang; Li, Xinxin; Tian, Quan; Li, Yang; Xie, Chang; Tian, Jin-bin; Zhang, Chengwei; Tian, Changlin; Zhu, Michael X.; Yao, Jing

    2016-01-01

    Temperature-sensitive TRP channels are important for responses to pain and inflammation, to both of which tissue acidosis is a major contributing factor. However, except for TRPV1, acid-sensing by other ThermoTRP channels remains mysterious. We show here that unique among TRPV1–3 channels, TRPV3 is directly activated by protons from cytoplasmic side. This effect is very weak and involves key cytoplasmic residues L508, D512, S518, or A520. However, mutations of these residues did not affect a strong proton induced potentiation of TRPV3 currents elicited by the TRPV1–3 common agonist, 2-aminoethoxydiphenyl borate (2-APB), no matter if the ligand was applied from extracellular or cytoplasmic side. The acid potentiation was common among TRPV1–3 and only seen with 2-APB-related ligands. Using 1H-nuclear magnetic resonance to examine the solution structures of 2-APB and its analogs, we observed striking structural differences of the boron-containing compounds at neutral/basic as compared to acidic pH, suggesting that a pH-dependent configuration switch of 2-APB-based drugs may underlie their functionality. Supporting this notion, protons also enhanced the inhibitory action of 2-APB on TRPM8. Collectively, our findings reveal novel insights into 2-APB action on TRP channels, which should facilitate the design of new drugs for these channels. PMID:26876731

  16. Evaluation of habitat quality for selected wildlife species associated with back channels.

    USGS Publications Warehouse

    Anderson, James T.; Zadnik, Andrew K.; Wood, Petra Bohall; Bledsoe, Kerry

    2013-01-01

    The islands and associated back channels on the Ohio River, USA, are believed to provide critical habitat features for several wildlife species. However, few studies have quantitatively evaluated habitat quality in these areas. Our main objective was to evaluate the habitat quality of back and main channel areas for several species using habitat suitability index (HSI) models. To test the effectiveness of these models, we attempted to relate HSI scores and the variables measured for each model with measures of relative abundance for the model species. The mean belted kingfisher (Ceryle alcyon) HSI was greater on the main than back channel. However, the model failed to predict kingfisher abundance. The mean reproduction component of the great blue heron (Ardea herodias) HSI, total common muskrat (Ondatra zibethicus) HSI, winter cover component of the snapping turtle (Chelydra serpentina) HSI, and brood-rearing component of the wood duck (Aix sponsa) HSI were all greater on the back than main channel, and were positively related with the relative abundance of each species. We found that island back channels provide characteristics not found elsewhere on the Ohio River and warrant conservation as important riparian wildlife habitat. The effectiveness of using HSI models to predict species abundance on the river was mixed. Modifications to several of the models are needed to improve their use on the Ohio River and, likely, other large rivers.

  17. Signal of doubly charged Higgs at e+e- colliders

    NASA Astrophysics Data System (ADS)

    Hue, L. T.; Huong, D. T.; Long, H. N.; Hung, H. T.; Thao, N. H.

    2015-11-01

    The masses and signals of the production of doubly charged Higgses (DCH) in the framework of the supersymmetric reduced minimal 3-3-1 model are investigated. In the DCH sector, we prove that there always exists a region of the parameter space where the mass of the lightest DCH is of the order of O(100) GeV even when all other new particles are very heavy. The lightest DCH mainly decays to two same-sign leptons while the dominant decay channels of the heavy DCHs are those decaying to heavy particles. We analyze each production cross section for e^+e^- ⇒ H^{++} H^{-} as a function of a few kinematic variables, which are useful to discuss the creation of DCHs in e^+e^- colliders as an indicator of new physics beyond the Standard Model. A numerical study shows that the cross sections for creating the lightest DCH can reach values of a few pb. The other two DCHs are too heavy, beyond the observable range of experiments. The lightest DCH may be detected by the International Linear Collider or the Compact Linear Collider by searching for its decay to a same-sign charged lepton pair.

  18. Gas-phase reactions of doubly charged actinide cations with alkanes and alkenes--probing the chemical activity of 5f electrons from Th to Cm.

    PubMed

    Marçalo, Joaquim; Santos, Marta; Gibson, John K

    2011-11-07

    Small alkanes (methane, ethane, propane, n-butane) and alkenes (ethene, propene, 1-butene) were used to probe the gas-phase reactivity of doubly charged actinide cations, An(2+) (An = Th, Pa, U, Np, Pu, Am, Cm), by means of Fourier transform ion cyclotron resonance mass spectrometry. Different combinations of doubly and singly charged ions were observed as reaction products, comprising species formed via metal-ion induced eliminations of small molecules, simple adducts and ions resulting from electron, hydride or methide transfer channels. Th(2+), Pa(2+), U(2+) and Np(2+) preferentially yielded doubly charged products of hydrocarbon activation, while Pu(2+), Am(2+) and Cm(2+) reacted mainly through transfer channels. Cm(2+) was also capable of forming doubly charged products with some of the hydrocarbons whereas Pu(2+) and Am(2+) were not, these latter two ions conversely being the only for which adduct formation was observed. The product distributions and the reaction efficiencies are discussed in relation to the electronic configurations of the metal ions, the energetics of the reactions and similar studies previously performed with doubly charged lanthanide and transition metal cations. The conditions for hydrocarbon activation to occur as related to the accessibility of electronic configurations with one or two 5f and/or 6d unpaired electrons are examined and the possible chemical activity of the 5f electrons in these early actinide ions, particularly Pa(2+), is considered.

  19. ML418: The first selective, sub-micromolar pore blocker of Kir7.1 potassium channels

    PubMed Central

    Swale, Daniel R.; Kurata, Haruto; Kharade, Sujay V.; Sheehan, Jonathan; Raphemot, Rene R.; Voigtritter, Karl R.; Figueroa, Eric; Meiler, Jens; Blobaum, Anna L.; Lindsley, Craig W.; Hopkins, Corey R.; Denton, Jerod S.

    2016-01-01

    The inward rectifier potassium (Kir) channel Kir7.1 (KCNJ13) has recently emerged as a key regulator of melanocortin signaling in the brain, electrolyte homeostasis in the eye, and uterine muscle contractility during pregnancy. The pharmacological tools available for exploring the physiology and therapeutic potential of Kir7.1 have been limited to relatively weak and non-selective small-molecule inhibitors. Here, we report the discovery in a fluorescence-based high-throughput screen of a novel Kir7.1 channel inhibitor, VU714. Site-directed mutagenesis of pore-lining amino acid residues identified Glutamate 149 and Alanine 150 as essential determinants of VU714 activity. Lead optimization with medicinal chemistry generated ML418, which exhibits sub-micromolar activity (IC50 = 310 nM) and superior selectivity over other Kir channels (at least 17-fold selective over Kir1.1, Kir2.1, Kir2.2, Kir2.3, Kir3.1/3.2, and Kir4.1) except for Kir6.2/SUR1 (equally potent). Evaluation in the EuroFins Lead Profiling panel of 64 GPCRs, ion-channels and transporters for off-target activity of ML418 revealed a relatively clean ancillary pharmacology. While ML418 exhibited low CLHEP in human microsomes which could be modulated with lipophilicity adjustments, it showed high CLHEP in rat microsomes regardless of lipophilicity. A subsequent in vivo PK study of ML418 by intraperitoneal (IP) administration (30 mg/kg dosage) revealed a suitable PK profile (Cmax = 0.20 µM and Tmax = 3 hours) and favorable CNS distribution (mouse brain:plasma Kp of 10.9 to support in vivo studies for in vivo studies. ML418, which represents the current state-of-the-art in Kir7.1 inhibitors, should be useful for exploring the physiology of Kir7.1 in vitro and in vivo. PMID:27184474

  20. Baseline Channel Geometry and Aquatic Habitat Data for Selected Streams in the Matanuska-Susitna Valley, Alaska

    USGS Publications Warehouse

    Curran, Janet H.; Rice, William J.

    2009-01-01

    Small streams in the rapidly developing Matanuska-Susitna Valley in south-central Alaska are known to support anadromous and resident fish but little is known about their hydrologic and riparian conditions, or their sensitivity to the rapid development of the area or climate variability. To help address this need, channel geometry and aquatic habitat data were collected in 2005 as a baseline of stream conditions for selected streams. Three streams were selected as representative of various stream types, and one drainage network, the Big Lake drainage basin, was selected for a systematic assessment. Streams in the Big Lake basin were drawn in a Geographic Information System (GIS), and 55 reaches along 16 miles of Meadow Creek and its primary tributary Little Meadow Creek were identified from orthoimagery and field observations on the basis of distinctive physical and habitat parameters, most commonly gradient, substrate, and vegetation. Data-collection methods for sites at the three representative reaches and the 55 systematically studied reaches consisted of a field survey of channel and flood-plain geometry and collection of 14 habitat attributes using published protocols or slight modifications. Width/depth and entrenchment ratios along the Meadow-Little Meadow Creek corridor were large and highly variable upstream of Parks Highway and lower and more consistent downstream of Parks Highway. Channel width was strongly correlated with distance, increasing downstream in a log-linear relation. Runs formed the most common habitat type, and instream vegetation dominated the habitat cover types, which collectively covered 53 percent of the channel. Gravel suitable for spawning covered isolated areas along Meadow Creek and about 29 percent of Little Meadow Creek. Broad wetlands were common along both streams. For a comprehensive assessment of small streams in the Mat-Su Valley, critical additional data needs include hydrologic, geologic and geomorphic, and biologic data

  1. Structural basis for the selective permeability of channels made of communicating junction proteins

    PubMed Central

    Ek-Vitorin, Jose F.; Burt, Janis M.

    2012-01-01

    The open state(s) of gap junction channels is evident from their permeation by small ions in response to an applied intercellular (transjunctional/transchannel) voltage gradient. That an open channel allows variable amounts of current to transit from cell-to-cell in the face of a constant intercellular voltage difference indicates channel open/closing can be complete or partial. The physiological significance of such open state options is, arguably, the main concern of junctional regulation. Because gap junctions are permeable to many substances, it is sensible to inquire whether and how each open state influences the intercellular diffusion of molecules as valuable as, but less readily detected than current-carrying ions. Presumably, structural changes perceived as shifts in channel conductivity would significantly alter the transjunctional diffusion of molecules whose limiting diameter approximates the pore’s limiting diameter. Moreover, changes in junctional permeability to some molecules might occur without evident changes in conductivity, either at macroscopic or single channel level. Open gap junction channels allow the exchange of cytoplasmic permeants between contacting cells by simple diffusion. The identity of such permeants, and the functional circumstances and consequences of their junctional exchange presently constitute the most urgent (and demanding) themes of the field. Here, we consider the necessity for regulating this exchange, the possible mechanism(s) and structural elements likely involved in such regulation, and how regulatory phenomena could be perceived as changes in chemical vs. electrical coupling; an overall reflection on our collective knowledge of junctional communication is then applied to suggest new avenues of research. PMID:22342665

  2. Guide for selecting Manning's roughness coefficients for natural channels and flood plains

    USGS Publications Warehouse

    Arcement, George J.; Schneider, Verne R.

    1989-01-01

    Although much research has been done on Manning's roughness coefficient, n, for stream channels, very little has been done concerning the roughness values for densely vegetated flood plains. The n value is determined from the values of the factors that affect the roughness of channels and flood plains. In densely vegetated flood plains, the major roughness is caused by trees, vines, and brush. The n value for this type of flood plain can be determined by measuring the vegetation density of the flood plain. Photographs of flood-plain segments where n values have been verified can be used as a comparison standard to aid in assigning n values to similar flood plains.

  3. Harnessing mode-selective nonlinear optics for on-chip multi-channel all-optical signal processing

    NASA Astrophysics Data System (ADS)

    Ma, Ming; Chen, Lawrence R.

    2016-11-01

    All-optical signal processing based on nonlinear optical effects allows for the realization of important functions in telecommunications including wavelength conversion, optical multiplexing/demultiplexing, Fourier transformation, and regeneration, amongst others, on ultrafast time scales to support high data rate transmission. In integrated photonic subsystems, the majority of all-optical signal processing systems demonstrated to date typically process only a single channel at a time or perform a single processing function, which imposes a serious limitation on the functionality of integrated solutions. Here, we demonstrate how nonlinear optical effects can be harnessed in a mode-selective manner to perform simultaneous multi-channel (two) and multi-functional optical signal processing (i.e., regenerative wavelength conversion) in an integrated silicon photonic device. This approach, which can be scaled to a higher number of channels, opens up a new degree of freedom for performing a broad range of multi-channel nonlinear optical signal processing functions using a single integrated photonic device.

  4. Molecular origin of the cation selectivity in OmpF porin: single channel conductances vs. free energy calculation.

    PubMed

    Danelon, Christophe; Suenaga, Atsushi; Winterhalter, Mathias; Yamato, Ichiro

    2003-07-01

    Ion current through single outer membrane protein F (OmpF) trimers was recorded and compared to molecular dynamics simulation. Unidirectional insertion was revealed from the asymmetry in channel conductance. Single trimer conductance showed particularly high values at low symmetrical salt solution. The conductance values of various alkali metal ion solutions were proportional to the monovalent cation mobility values in the bulk phase, LiClSelectivity measurements at low concentration showed that OmpF channels favored permeation of alkali metal ions over chloride and suggested size preference for smaller cations. These results suggest that there are specific interactions between the permeating cation and charged residues lining the channel walls. This hypothesis was supported by computational study which predicted that monovalent cations bind to Asp113 at low concentration. Here, free energy calculations revealed that the affinity of the alkali metal ions to its binding site increased with their atomic radii, Li(+) approximately Na(+)channel increases the translocation rate of cations under applied voltage by increasing their local concentration relative to the bulk solution.

  5. Specific binding of aluminium and iron ions to a cation-selective cell wall channel of Microthrix parvicella.

    PubMed

    Knaf, Tobias; Schade, Margit; Lemmer, Hilde; Benz, Roland

    2013-10-01

    Heavy metal salts containing aluminium or iron are used in wastewater treatment to control excessive growth of the Gram-positive bacterium Microthrix parvicella, frequently observed in wastewater plants suffering from bulking, foaming and scum. Microthrix parvicella belongs to the class Actinobacteria but not to mycolata, although its taxonomic position in this class is not identified. Investigations using the microspheres adhesion to cells method (MAC) suggested that M. parvicella is as strongly hydrophobic as the mycolic acid containing actinomycetes. The cell wall of M. parvicella was investigated for the presence of water-filled channels using the lipid bilayer assay. An ion-permeable channel called MppA with a conductance of 600 pS in 1 M KCl was identified in cell wall extracts and purified to homogeneity. The cation-selective channel showed no voltage-dependent closure at higher voltages. Interestingly, MPPA could be blocked by heavy metal ions. Binding of polyvalent cations such as iron and aluminium was studied in titration experiments and revealed stability constants for their binding to MppA up to 700 M(-1). The cell wall channel of M. parvicella contains a binding site for polyvalent cations which may play a crucial role for the effect of heavy metals salts on M. parvicella-dominated activated sludge.

  6. A distinct sodium channel voltage-sensor locus determines insect selectivity of the spider toxin Dc1a

    PubMed Central

    Bende, Niraj S; Dziemborowicz, Slawomir; Mobli, Mehdi; Herzig, Volker; Gilchrist, John; Wagner, Jordan; Nicholson, Graham M; King, Glenn F; Bosmans, Frank

    2014-01-01

    β-Diguetoxin-Dc1a (Dc1a) is a toxin from the desert bush spider Diguetia canities that incapacitates insects at concentrations that are non-toxic to mammals. Dc1a promotes opening of German cockroach voltage-gated sodium (Nav) channels (BgNav1), whereas human Nav channels are insensitive. Here, by transplanting commonly targeted S3b-S4 paddle motifs within BgNav1 voltage sensors into Kv2.1, we find that Dc1a interacts with the domain II voltage sensor. In contrast, Dc1a has little effect on sodium currents mediated by PaNav1 channels from the American cockroach even though their domain II paddle motifs are identical. When exploring regions responsible for PaNav1 resistance to Dc1a, we identified two residues within the BgNav1 domain II S1–S2 loop that when mutated to their PaNav1 counterparts drastically reduce toxin susceptibility. Overall, our results reveal a distinct region within insect Nav channels that helps determine Dc1a sensitivity, aconcept that will be valuable for the design of insect-selective insecticides. PMID:25014760

  7. A distinct sodium channel voltage-sensor locus determines insect selectivity of the spider toxin Dc1a

    NASA Astrophysics Data System (ADS)

    Bende, Niraj S.; Dziemborowicz, Sławomir; Mobli, Mehdi; Herzig, Volker; Gilchrist, John; Wagner, Jordan; Nicholson, Graham M.; King, Glenn F.; Bosmans, Frank

    2014-07-01

    β-Diguetoxin-Dc1a (Dc1a) is a toxin from the desert bush spider Diguetia canities that incapacitates insects at concentrations that are non-toxic to mammals. Dc1a promotes opening of German cockroach voltage-gated sodium (Nav) channels (BgNav1), whereas human Nav channels are insensitive. Here, by transplanting commonly targeted S3b-S4 paddle motifs within BgNav1 voltage sensors into Kv2.1, we find that Dc1a interacts with the domain II voltage sensor. In contrast, Dc1a has little effect on sodium currents mediated by PaNav1 channels from the American cockroach even though their domain II paddle motifs are identical. When exploring regions responsible for PaNav1 resistance to Dc1a, we identified two residues within the BgNav1 domain II S1-S2 loop that when mutated to their PaNav1 counterparts drastically reduce toxin susceptibility. Overall, our results reveal a distinct region within insect Nav channels that helps determine Dc1a sensitivity, a concept that will be valuable for the design of insect-selective insecticides.

  8. Differential inhibition of cardiac and neuronal Na(+) channels by the selective serotonin-norepinephrine reuptake inhibitors duloxetine and venlafaxine.

    PubMed

    Stoetzer, Carsten; Papenberg, Bastian; Doll, Thorben; Völker, Marc; Heineke, Joerg; Stoetzer, Marcus; Wegner, Florian; Leffler, Andreas

    2016-07-15

    Duloxetine and venlafaxine are selective serotonin-norepinephrine-reuptake-inhibitors used as antidepressants and co-analgesics. While venlafaxine rather than duloxetine induce cardiovascular side-effects, neither of the substances are regarded cardiotoxic. Inhibition of cardiac Na(+)-channels can be associated with cardiotoxicity, and duloxetine was demonstrated to block neuronal Na(+)-channels. The aim of this study was to investigate if the non-life threatening cardiotoxicities of duloxetine and venlafaxine correlate with a weak inhibition of cardiac Na(+)-channels. Effects of duloxetine, venlafaxine and amitriptyline were examined on endogenous Na(+)-channels in neuroblastoma ND7/23 cells and on the α-subunits Nav1.5, Nav1.7 and Nav1.8 with whole-cell patch clamp recordings. Tonic block of the cardiac Na(+)-channel Nav1.5 and rat-cardiomyocytes (CM) revealed a higher potency for duloxetine (Nav 1.5 IC50 14±1µM, CM IC50 27±3µM) as compared to venlafaxine (Nav 1.5 IC50 671±26µM, CM IC50 452±34µM). Duloxetine was as potent as the cardiotoxic antidepressant amitriptyline (IC50 13±1µM). While venlafaxine almost failed to induce use-dependent block on Nav1.5 and cardiomyocytes, low concentrations of duloxetine (1, 10µM) induced prominent use-dependent block similar to amitriptyline. Duloxetine, but not venlafaxine stabilized fast and slow inactivation and delayed recovery from inactivation. Duloxetine induced an unselective inhibition of neuronal Na(+)-channels (IC50 ND7/23 23±1µM, Nav1.7 19±2µM, Nav1.8 29±2). Duloxetine, but not venlafaxine inhibits cardiac Na(+)-channels with a potency similar to amitriptyline. These data indicate that an inhibition of Na(+)-channels does not predict a clinically relevant cardiotoxicity.

  9. Structural basis for ion selectivity revealed by high-resolution crystal structure of Mg2+ channel MgtE.

    PubMed

    Takeda, Hironori; Hattori, Motoyuki; Nishizawa, Tomohiro; Yamashita, Keitaro; Shah, Syed T A; Caffrey, Martin; Maturana, Andrés D; Ishitani, Ryuichiro; Nureki, Osamu

    2014-11-04

    Magnesium is the most abundant divalent cation in living cells and is crucial to several biological processes. MgtE is a Mg(2+) channel distributed in all domains of life that contributes to the maintenance of cellular Mg(2+) homeostasis. Here we report the high-resolution crystal structures of the transmembrane domain of MgtE, bound to Mg(2+), Mn(2+) and Ca(2+). The high-resolution Mg(2+)-bound crystal structure clearly visualized the hydrated Mg(2+) ion within its selectivity filter. Based on those structures and biochemical analyses, we propose a cation selectivity mechanism for MgtE in which the geometry of the hydration shell of the fully hydrated Mg(2+) ion is recognized by the side-chain carboxylate groups in the selectivity filter. This is in contrast to the K(+)-selective filter of KcsA, which recognizes a dehydrated K(+) ion. Our results further revealed a cation-binding site on the periplasmic side, which regulate channel opening and prevents conduction of near-cognate cations.

  10. Optimized Energy Harvesting, Cluster-Head Selection and Channel Allocation for IoTs in Smart Cities

    PubMed Central

    Aslam, Saleem; Hasan, Najam Ul; Jang, Ju Wook; Lee, Kyung-Geun

    2016-01-01

    This paper highlights three critical aspects of the internet of things (IoTs), namely (1) energy efficiency, (2) energy balancing and (3) quality of service (QoS) and presents three novel schemes for addressing these aspects. For energy efficiency, a novel radio frequency (RF) energy-harvesting scheme is presented in which each IoT device is associated with the best possible RF source in order to maximize the overall energy that the IoT devices harvest. For energy balancing, the IoT devices in close proximity are clustered together and then an IoT device with the highest residual energy is selected as a cluster head (CH) on a rotational basis. Once the CH is selected, it assigns channels to the IoT devices to report their data using a novel integer linear program (ILP)-based channel allocation scheme by satisfying their desired QoS. To evaluate the presented schemes, exhaustive simulations are carried out by varying different parameters, including the number of IoT devices, the number of harvesting sources, the distance between RF sources and IoT devices and the primary user (PU) activity of different channels. The simulation results demonstrate that our proposed schemes perform better than the existing ones. PMID:27918424

  11. Optimized Energy Harvesting, Cluster-Head Selection and Channel Allocation for IoTs in Smart Cities.

    PubMed

    Aslam, Saleem; Hasan, Najam Ul; Jang, Ju Wook; Lee, Kyung-Geun

    2016-12-02

    This paper highlights three critical aspects of the internet of things (IoTs), namely (1) energy efficiency, (2) energy balancing and (3) quality of service (QoS) and presents three novel schemes for addressing these aspects. For energy efficiency, a novel radio frequency (RF) energy-harvesting scheme is presented in which each IoT device is associated with the best possible RF source in order to maximize the overall energy that the IoT devices harvest. For energy balancing, the IoT devices in close proximity are clustered together and then an IoT device with the highest residual energy is selected as a cluster head (CH) on a rotational basis. Once the CH is selected, it assigns channels to the IoT devices to report their data using a novel integer linear program (ILP)-based channel allocation scheme by satisfying their desired QoS. To evaluate the presented schemes, exhaustive simulations are carried out by varying different parameters, including the number of IoT devices, the number of harvesting sources, the distance between RF sources and IoT devices and the primary user (PU) activity of different channels. The simulation results demonstrate that our proposed schemes perform better than the existing ones.

  12. Inhibition of collagen synthesis by select calcium and sodium channel blockers can be mitigated by ascorbic acid and ascorbyl palmitate.

    PubMed

    Ivanov, Vadim; Ivanova, Svetlana; Kalinovsky, Tatiana; Niedzwiecki, Aleksandra; Rath, Matthias

    2016-01-01

    Calcium, sodium and potassium channel blockers are widely prescribed medications for a variety of health problems, most frequently for cardiac arrhythmias, hypertension, angina pectoris and other disorders. However, chronic application of channel blockers is associated with numerous side effects, including worsening cardiac pathology. For example, nifedipine, a calcium-channel blocker was found to be associated with increased mortality and increased risk for myocardial infarction. In addition to the side effects mentioned above by different channel blockers, these drugs can cause arterial wall damage, thereby contributing to vascular wall structure destabilization and promoting events facilitating rupture of plaques. Collagen synthesis is regulated by ascorbic acid, which is also essential for its optimum structure as a cofactor in lysine and proline hydroxylation, a precondition for optimum crosslinking of collagen and elastin. Therefore, the main objective in this study was to evaluate effects of various types of channel blockers on intracellular accumulation and cellular functions of ascorbate, specifically in relation to formation and extracellular deposition of major collagen types relevant for vascular function. Effects of select Na- and Ca- channel blockers on collagen synthesis and deposition were evaluated in cultured human dermal fibroblasts and aortic smooth muscle cells by immunoassay. All channel blockers tested demonstrated inhibitory effects on collagen type I deposition to the ECM by fibroblasts, each to a different degree. Ascorbic acid significantly increased collagen I ECM deposition. Nifedipine (50 µM), a representative of channel blockers tested, significantly reduced ascorbic acid and ascorbyl palmitate-dependent ECM deposition of collagen type l and collagen type lV by cultured aortic smooth muscle cells. In addition, nifedipine (50 µM) significantly reduced ascorbate-dependent collagen type l and type lV synthesis by cultured aortic smooth

  13. Inhibition of collagen synthesis by select calcium and sodium channel blockers can be mitigated by ascorbic acid and ascorbyl palmitate

    PubMed Central

    Ivanov, Vadim; Ivanova, Svetlana; Kalinovsky, Tatiana; Niedzwiecki, Aleksandra; Rath, Matthias

    2016-01-01

    Calcium, sodium and potassium channel blockers are widely prescribed medications for a variety of health problems, most frequently for cardiac arrhythmias, hypertension, angina pectoris and other disorders. However, chronic application of channel blockers is associated with numerous side effects, including worsening cardiac pathology. For example, nifedipine, a calcium-channel blocker was found to be associated with increased mortality and increased risk for myocardial infarction. In addition to the side effects mentioned above by different channel blockers, these drugs can cause arterial wall damage, thereby contributing to vascular wall structure destabilization and promoting events facilitating rupture of plaques. Collagen synthesis is regulated by ascorbic acid, which is also essential for its optimum structure as a cofactor in lysine and proline hydroxylation, a precondition for optimum crosslinking of collagen and elastin. Therefore, the main objective in this study was to evaluate effects of various types of channel blockers on intracellular accumulation and cellular functions of ascorbate, specifically in relation to formation and extracellular deposition of major collagen types relevant for vascular function. Effects of select Na- and Ca- channel blockers on collagen synthesis and deposition were evaluated in cultured human dermal fibroblasts and aortic smooth muscle cells by immunoassay. All channel blockers tested demonstrated inhibitory effects on collagen type I deposition to the ECM by fibroblasts, each to a different degree. Ascorbic acid significantly increased collagen I ECM deposition. Nifedipine (50 µM), a representative of channel blockers tested, significantly reduced ascorbic acid and ascorbyl palmitate-dependent ECM deposition of collagen type l and collagen type lV by cultured aortic smooth muscle cells. In addition, nifedipine (50 µM) significantly reduced ascorbate-dependent collagen type l and type lV synthesis by cultured aortic smooth

  14. Verification of roughness coefficients for selected natural and constructed stream channels in Arizona

    USGS Publications Warehouse

    Phillips, Jeff V.; Ingersoll, Todd L.

    1998-01-01

    Physical and hydraulic characteristics are presented for 14 river and canal reaches in Arizona for which 37 roughness coefficients have been determined. The verified roughness coefficients which ranged from 0.017 to 0.067, were computed from discharges, channel geometry, and water-surface profiles measured at each of the sites. The information given for each stream segment includes bed and bank descriptions, data tables showing hydraulic components, a plan view, cross-section plots, and color photographs that can be used as a comparison aid in determining roughness coefficients for similarly channeled streams. Relations derived from the data presented relate Manning's roughness coefficient (n) to various hydraulic components. For gravel-bed streams, verified roughness coefficients are related to median grain size of the bed material and hydraulic radius resulting in an equation that can be used to transfer results to similar dry-land channels. The equation developed for base values of n for gravel-bed channels in Arizona is significantly different from similarly derived equations for other regions of the United States and the world.

  15. Drifting localized structures in doubly diffusive convection

    NASA Astrophysics Data System (ADS)

    Knobloch, Edgar; Lo Jacono, David; Bergeon, Alain

    2016-11-01

    We use numerical continuation to compute a multiplicity of spatially localized states in doubly diffusive convection in a vertical slot driven by imposed horizontal temperature and concentration differences. The calculations focus on the so-called opposing case, in which the resulting gradients are in balance. No-slip boundary conditions are used at the sides and periodic boundary conditions with large spatial period are used in the vertical direction. This system exhibits homoclinic snaking of stationary spatially localized structures with point symmetry. In this talk we demonstrate the existence, near threshold, of drifting pulses of spatially localized convection that appear when mixed concentration boundary conditions are used, and use homotopic continuation to identify similar states in the case of fixed concentration boundary conditions. We show that these states persist to large values of the Grasshof number and provide a detailed study of their properties.

  16. Levels in doubly odd 138Pr

    NASA Astrophysics Data System (ADS)

    Gangopadhyay, G.; Bhowal, Samit; Bhowmik, R. K.; Datta Pramanik, U.; Ghosh, P.; Goswami, A.; Petrache, C.; Mukherjee, A.; Muralithar, S.; Raut, Rajarshi; Saha Sarkar, M.; Singh, A. K.; Singh, R. P.; Bhattacharya, S.

    2005-05-01

    The band structures of the doubly odd 138Pr nucleus have been investigated using the 128Te(14N, 4n)138Pr reaction at a beam energy of 55-65 MeV. Altogether six distinct structures have been established, of which the lower part of the yrast band and two side bands were known from earlier works. The observed level properties of the members of the yrast band have been compared with theoretical calculations performed within the Particle Rotor Model (PRM) with axially symmetric core. The experimental branching ratios and B(M1)/B(E2) values when compared with the theoretical results of the PRM, suggest an oblate core.

  17. A voltage-gated sodium channel is essential for the positive selection of CD4(+) T cells.

    PubMed

    Lo, Wan-Lin; Donermeyer, David L; Allen, Paul M

    2012-09-01

    The sustained entry of Ca(2+) into CD4(+)CD8(+) double-positive thymocytes is required for positive selection. Here we identified a voltage-gated Na(+) channel (VGSC) that was essential for positive selection of CD4(+) T cells. Pharmacological inhibition of VGSC activity inhibited the sustained Ca(2+) influx induced by positively selecting ligands and the in vitro positive selection of CD4(+) but not CD8(+) T cells. In vivo short hairpin RNA (shRNA)-mediated knockdown of the gene encoding a regulatory β-subunit of a VGSC specifically inhibited the positive selection of CD4(+) T cells. Ectopic expression of VGSC in peripheral AND CD4(+) T cells bestowed the ability to respond to a positively selecting ligand, which directly demonstrated that VGSC expression was responsible for the enhanced sensitivity. Thus, active VGSCs in thymocytes provide a mechanism by which a weak positive selection signal can induce the sustained Ca(2+) signals required for CD4(+) T cell development.

  18. Recent characterizations of MscS and its homologs provide insight into the basis of ion selectivity in mechanosensitive channels.

    PubMed

    Maksaev, Grigory; Haswell, Elizabeth S

    2013-01-01

    The bacterial mechanosensitive channel MscS provides an excellent model system for the study of mechanosensitivity and for investigations into the cellular response to hypoosmotic shock. Numerous studies have elucidated the structure, function and gating mechanism of Escherichia coli MscS, providing a wealth of information for the comparative analysis of MscS family members in bacteria, archaea, fungi and plants. We recently reported the electrophysiological characterization of MscS-Like (MSL)10, a MscS homolog from the model flowering plant Arabidopsis thaliana. Here we summarize our results and briefly compare MSL10 to previously described members of the MscS family. Finally, we comment on how this and other recently published studies illuminate the possible mechanisms by which ion selectivity is accomplished in this fascinating family of channels.

  19. Selective serotonin reuptake inhibitor sertraline inhibits voltage-dependent K+ channels in rabbit coronary arterial smooth muscle cells.

    PubMed

    Kim, Han Sol; Li, Hongliang; Kim, Hye Won; Shin, Sung Eun; Choi, Il-Whan; Firth, Amy L; Bang, Hyoweon; Bae, Young Min; Park, Won Sun

    2016-12-01

    We examined the effects of the selective serotonin reuptake inhibitor (SSRI) sertraline on voltage-dependent K+ (Kv) channels in freshly isolated rabbit coronary arterial smooth muscle cells using the voltage-clamp technique. Sertraline decreased the Kv channel current in a dose-dependent manner, with an IC50 value of 0.18 mu M and a slope value (Hill coefficient) of 0.61. Although the application of 1 mu M sertraline did not affect the steady-state activation curves, sertraline caused a significant, negative shift in the inactivation curves. Pretreatment with another SSRI, paroxetine, had no significant effect on Kv currents and did not alter the inhibitory effects of sertraline on Kv currents. From these results, we concluded that sertraline dose-dependently inhibited Kv currents independently of serotonin reuptake inhibition by shifting inactivation curves to a more negative potential.

  20. Doubly Magic Optical Trapping for Cs Atom Hyperfine Clock Transitions

    NASA Astrophysics Data System (ADS)

    Carr, A. W.; Saffman, M.

    2016-10-01

    We analyze doubly magic trapping of Cs hyperfine transitions including previously neglected contributions from the ground state hyperpolarizability and the interaction of the laser light and a static magnetic field. Extensive numerical searches do not reveal any doubly magic trapping conditions for any pair of hyperfine states. However, including the hyperpolarizability reveals light intensity insensitive traps for a wide range of wavelengths at specific intensities. We then investigate the use of bichromatic trapping light fields. Deploying a bichromatic scheme, we demonstrate doubly magic red and blue detuned traps for pairs of states separated by one or two single photon transitions.

  1. A Single P-loop Glutamate Point Mutation to either Lysine or Arginine Switches the Cation–Anion Selectivity of the CNGA2 Channel

    PubMed Central

    Qu, Wei; Moorhouse, Andrew J.; Chandra, Meenak; Pierce, Kerrie D.; Lewis, Trevor M.; Barry, Peter H.

    2006-01-01

    Cyclic nucleotide-gated (CNG) channels play a critical role in olfactory and visual transduction. Site-directed mutagenesis and inside-out patch-clamp recordings were used to investigate ion permeation and selectivity in two mutant homomeric rat olfactory CNGA2 channels expressed in HEK293 cells. A single point mutation of the negatively charged pore loop (P-loop) glutamate (E342) to either a positively charged lysine or arginine resulted in functional channels, which consistently responded to cGMP, although the currents were generally extremely small. The concentration–response curve of the lysine mutant channel was very similar to that of wild-type (WT) channels, suggesting no major structural alteration to the mutant channels. Reversal potential measurements, during cytoplasmic NaCl dilutions, showed that the lysine and the arginine mutations switched the selectivity of the channel from cations (PCl/PNa = 0.07 [WT]) to anions (PCl/PNa = 14 [Lys] or 10 [Arg]). Relative anion permeability sequences for the two mutant channels, measured with bi-ionic substitutions, were NO3− > I− > Br− > Cl− > F− > acetate−, the same as those obtained for anion-selective GABA and glycine channels. The mutant channels also seem to have an extremely small single-channel conductance, measured using noise analysis of about 1–2 pS, compared to a WT value of about 29 pS. The results showed that it is predominantly the charge of the E342 residue in the P-loop, rather than the pore helix dipoles, which controls the cation–anion selectivity of this channel. However, the outward rectification displayed by both mutant channels in symmetrical NaCl solutions suggests that the negative ends of the pore helix dipoles may play a role in reducing the outward movement of Cl− ions through these anion-selective channels. These results have potential implications for the determinants of anion–cation selectivity in the large family of P-loop–containing channels. PMID:16533895

  2. On Frequency Offset Estimation Using the iNET Preamble in Frequency Selective Fading Channels

    DTIC Science & Technology

    2014-03-01

    ASM fields; (bottom) the relationship between the indexes of the received samples r(n), the signal samples s(n), the preamble samples p (n) and the short...frequency offset estimators for SOQPSK-TG equipped with the iNET preamble and operating in ISI channels. Four of the five estimators exam - ined here are...sync marker ( ASM ), and data bits (an LDPC codeword). The availability of a preamble introduces the possibility of data-aided synchro- nization in

  3. Inelastic scattering from glyoxal: collision kinematics rather than the interaction potential dominates rotational channel selection.

    PubMed

    Clegg, Samuel M; Parmenter, Charles S

    2006-10-07

    Relative cross sections have been obtained for the rotationally and rovibrationally inelastic scattering of S1 trans-glyoxal (CHO-CHO) in its zero point level with K' = 0 from the target gases H2, D2, and He. Emphasis is placed on using crossed molecular beam conditions that provide several choices of collision kinematics (center-of-mass collision energy, relative velocity, center-of-mass collision momentum) for each collision pair. The cross sections define the state-to-state competition among numerous rotational channels involving destination states with DeltaK' ranging from 1 to >15 for collisions with each target gas and under every kinematic condition. They also resolve a similar rotational competition among rovibrational channels where the torsion nu7' is collisionally excited. The cross section sets also allow the relative overall magnitudes of the two types of scattering to be compared. The primary motivation of these experiments concerns the rotationally inelastic scattering. Earlier studies with rare gases and fixed kinematics demonstrated that the distribution of rotational cross sections is remarkably similar from one collision pair to another. The new data show that the competition among rotational channels actually has a small but distinct dependence on kinematic conditions. Data analysis shows that the dependence is a systematic function of the available collision momentum and entirely unrelated to the identity of the target gases, including the heavier rare gases used in earlier studies. The competition among the rotational energy transfer channels and its kinematic heritage is discussed in the context of a classical hard ellipse model of linear momentum to angular momentum conversion much used with room temperature systems. When adapted to our beam conditions, the resulting account of the rotational scattering is accurate and provides insight into the collisional details.

  4. A K(+)-selective CNG channel orchestrates Ca(2+) signalling in zebrafish sperm.

    PubMed

    Fechner, Sylvia; Alvarez, Luis; Bönigk, Wolfgang; Müller, Astrid; Berger, Thomas K; Pascal, Rene; Trötschel, Christian; Poetsch, Ansgar; Stölting, Gabriel; Siegfried, Kellee R; Kremmer, Elisabeth; Seifert, Reinhard; Kaupp, U Benjamin

    2015-12-09

    Calcium in the flagellum controls sperm navigation. In sperm of marine invertebrates and mammals, Ca(2+) signalling has been intensely studied, whereas for fish little is known. In sea urchin sperm, a cyclic nucleotide-gated K(+) channel (CNGK) mediates a cGMP-induced hyperpolarization that evokes Ca(2+) influx. Here, we identify in sperm of the freshwater fish Danio rerio a novel CNGK family member featuring non-canonical properties. It is located in the sperm head rather than the flagellum and is controlled by intracellular pH, but not cyclic nucleotides. Alkalization hyperpolarizes sperm and produces Ca(2+) entry. Ca(2+) induces spinning-like swimming, different from swimming of sperm from other species. The "spinning" mode probably guides sperm into the micropyle, a narrow entrance on the surface of fish eggs. A picture is emerging of sperm channel orthologues that employ different activation mechanisms and serve different functions. The channel inventories probably reflect adaptations to species-specific challenges during fertilization.

  5. A K+-selective CNG channel orchestrates Ca2+ signalling in zebrafish sperm

    PubMed Central

    Fechner, Sylvia; Alvarez, Luis; Bönigk, Wolfgang; Müller, Astrid; Berger, Thomas K; Pascal, Rene; Trötschel, Christian; Poetsch, Ansgar; Stölting, Gabriel; Siegfried, Kellee R; Kremmer, Elisabeth; Seifert, Reinhard; Kaupp, U Benjamin

    2015-01-01

    Calcium in the flagellum controls sperm navigation. In sperm of marine invertebrates and mammals, Ca2+ signalling has been intensely studied, whereas for fish little is known. In sea urchin sperm, a cyclic nucleotide-gated K+ channel (CNGK) mediates a cGMP-induced hyperpolarization that evokes Ca2+ influx. Here, we identify in sperm of the freshwater fish Danio rerio a novel CNGK family member featuring non-canonical properties. It is located in the sperm head rather than the flagellum and is controlled by intracellular pH, but not cyclic nucleotides. Alkalization hyperpolarizes sperm and produces Ca2+ entry. Ca2+ induces spinning-like swimming, different from swimming of sperm from other species. The “spinning” mode probably guides sperm into the micropyle, a narrow entrance on the surface of fish eggs. A picture is emerging of sperm channel orthologues that employ different activation mechanisms and serve different functions. The channel inventories probably reflect adaptations to species-specific challenges during fertilization. DOI: http://dx.doi.org/10.7554/eLife.07624.001 PMID:26650356

  6. Data selection criteria in star-based monitoring of GOES imager visible-channel responsivities

    NASA Astrophysics Data System (ADS)

    Chang, I.-Lok; Crosby, David; Dean, Charles; Weinreb, Michael; Baltimore, Perry; Baucom, Jeanette; Han, Dejiang

    2004-10-01

    Monitoring the responsivities of the visible channels of the operational Geostationary Operational Environmental Satellites (GOES) is an on-going effort at NOAA. Various techniques are being used. In this paper we describe the technique based on the analysis of star signals that are used in the GOES Orbit and Attitude Tracking System (OATS) for satellite attitude and orbit determination. Time series of OATS star observations give information on the degradation of the detectors of a visible channel. Investigations of star data from the past three years have led to several modifications of the method we initially used to calculate the exponential degradation coefficient of a star-signal time series. First we observed that different patterns of detector output versus time result when star images drift across the detector array along different trajectories. We found that certain trajectories should be rejected in the data analysis. We found also that some detector-dependent weighting coefficients used in the OATS analysis tend to scatter the star signals measured by different detectors. We present a set of modifications to our star monitoring algorithms for resolving such problems. Other simple enhancements on the algorithms will also be described. With these modifications, the time series of the star signals show less scatter. This allows for more confidence in the estimated degradation rates and a more realistic statistical analysis on the extent of uncertainty in those rates. The resulting time series and estimated degradation rates for the visible channels of GOES-8 and GOES-10 Imagers will be presented.

  7. Developing a comparative docking protocol for the prediction of peptide selectivity profiles: investigation of potassium channel toxins.

    PubMed

    Chen, Po-Chia; Kuyucak, Serdar

    2012-02-01

    During the development of selective peptides against highly homologous targets, a reliable tool is sought that can predict information on both mechanisms of binding and relative affinities. These tools must first be tested on known profiles before application on novel therapeutic candidates. We therefore present a comparative docking protocol in HADDOCK using critical motifs, and use it to "predict" the various selectivity profiles of several major αKTX scorpion toxin families versus K(v)1.1, K(v)1.2 and K(v)1.3. By correlating results across toxins of similar profiles, a comprehensive set of functional residues can be identified. Reasonable models of channel-toxin interactions can be then drawn that are consistent with known affinity and mutagenesis. Without biological information on the interaction, HADDOCK reproduces mechanisms underlying the universal binding of αKTX-2 toxins, and K(v)1.3 selectivity of αKTX-3 toxins. The addition of constraints encouraging the critical lysine insertion confirms these findings, and gives analogous explanations for other families, including models of partial pore-block in αKTX-6. While qualitatively informative, the HADDOCK scoring function is not yet sufficient for accurate affinity-ranking. False minima in low-affinity complexes often resemble true binding in high-affinity complexes, despite steric/conformational penalties apparent from visual inspection. This contamination significantly complicates energetic analysis, although it is usually possible to obtain correct ranking via careful interpretation of binding-well characteristics and elimination of false positives. Aside from adaptations to the broader potassium channel family, we suggest that this strategy of comparative docking can be extended to other channels of interest with known structure, especially in cases where a critical motif exists to improve docking effectiveness.

  8. Developing a Comparative Docking Protocol for the Prediction of Peptide Selectivity Profiles: Investigation of Potassium Channel Toxins

    PubMed Central

    Chen, Po-Chia; Kuyucak, Serdar

    2012-01-01

    During the development of selective peptides against highly homologous targets, a reliable tool is sought that can predict information on both mechanisms of binding and relative affinities. These tools must first be tested on known profiles before application on novel therapeutic candidates. We therefore present a comparative docking protocol in HADDOCK using critical motifs, and use it to “predict” the various selectivity profiles of several major αKTX scorpion toxin families versus Kv1.1, Kv1.2 and Kv1.3. By correlating results across toxins of similar profiles, a comprehensive set of functional residues can be identified. Reasonable models of channel-toxin interactions can be then drawn that are consistent with known affinity and mutagenesis. Without biological information on the interaction, HADDOCK reproduces mechanisms underlying the universal binding of αKTX-2 toxins, and Kv1.3 selectivity of αKTX-3 toxins. The addition of constraints encouraging the critical lysine insertion confirms these findings, and gives analogous explanations for other families, including models of partial pore-block in αKTX-6. While qualitatively informative, the HADDOCK scoring function is not yet sufficient for accurate affinity-ranking. False minima in low-affinity complexes often resemble true binding in high-affinity complexes, despite steric/conformational penalties apparent from visual inspection. This contamination significantly complicates energetic analysis, although it is usually possible to obtain correct ranking via careful interpretation of binding-well characteristics and elimination of false positives. Aside from adaptations to the broader potassium channel family, we suggest that this strategy of comparative docking can be extended to other channels of interest with known structure, especially in cases where a critical motif exists to improve docking effectiveness. PMID:22474570

  9. Analyzing the components of the free-energy landscape in a calcium selective ion channel by Widom's particle insertion method.

    PubMed

    Boda, Dezso; Giri, Janhavi; Henderson, Douglas; Eisenberg, Bob; Gillespie, Dirk

    2011-02-07

    The selectivity filter of the L-type calcium channel works as a Ca(2+) binding site with a very large affinity for Ca(2+) versus Na(+). Ca(2+) replaces half of the Na(+) ions in the filter even when these ions are present in 1 μM and 30 mM concentrations in the bath, respectively. The energetics of this strong selectivity is analyzed in this paper. We use Widom's particle insertion method to compute the space-dependent profiles of excess chemical potential in our grand canonical Monte Carlo simulations. These profiles define the free-energy landscape for the various ions. Following Gillespie [Biophys. J. 94, 1169 (2008)], the difference of the excess chemical potentials for the two competing ions defines the advantage that one of the ions has over the other in the competition for space in the crowded selectivity filter. These advantages depend on ionic bath concentrations: the ion that is present in the bath in larger quantity (Na(+)) has the "number" advantage which is balanced by the free-energy advantage of the other ion (Ca(2+)). The excess chemical potentials are decomposed into hard sphere exclusion and electrostatic components. The electrostatic terms correspond to interactions with the mean electric field produced by ions and induced charges as well to ionic correlations beyond the mean field description. Dielectrics are needed to produce micromolar Ca(2+) versus Na(+) selectivity in the L-type channel. We study the behavior of these terms with changes in bath concentrations of ions, charges, and diameters of ions, as well as geometrical parameters such as radius of the pore and the dielectric constant of the protein. Ion selectivity in calcium binding proteins probably has a similar mechanism.

  10. Masses and axial currents of the doubly charmed baryons

    NASA Astrophysics Data System (ADS)

    Sun, Zhi-Feng; Liu, Zhan-Wei; Liu, Xiang; Zhu, Shi-Lin

    2015-05-01

    The chiral dynamics of the doubly heavy baryons is solely governed by the light quark. In this paper, we have derived the chiral corrections to the mass of the doubly heavy baryons up to N3LO . The mass splitting of Ξc c and Ωc c at the N2LO depends on one unknown low energy constant c7. By fitting the lattice masses of Ξc c(3520 ), we estimate the mass of Ωc c to be around 3.726 GeV. Moreover, we have also performed a systematical analysis of the chiral corrections to the axial currents and axial charges of the doubly heavy baryons. The chiral structure and analytical expressions will be very useful to the chiral extrapolations of the future lattice QCD simulations of the doubly heavy baryons.

  11. Color fluxes in the production of doubly heavy baryons

    SciTech Connect

    Baranov, S. P.

    2007-04-15

    The production of doubly heavy baryons in hadron-hadron collisions is considered. A method is proposed for decomposing the respective differential cross section into parts associated with contributions of various color-flux configurations.

  12. Doubly slanted layer structures in holographic gelatin emulsions: solar concentrators

    NASA Astrophysics Data System (ADS)

    Hung, Jenny; Chan, Po Shan; Sun, Caiming; Wing Ho, Choi; Tam, Wing Yim

    2010-04-01

    We have fabricated doubly slanted layer structures in holographic gelatin emulsions using a double-exposure two-beam interference from two light sources with different wavelengths. The doubly slanted layers, with different spacings and overlapping with each other, are fabricated such that they are slanted in opposite directions making a 30° angle with the holographic plate. The doubly slanted layer structures exhibit photonic stop bands corresponding to the two layered structures. More importantly, diffracted light beams from the slanted layers travel in different directions and emerge, through internal reflections, at the opposite edges of the gelatin plate. The doubly slanted layer structures could be used as solar concentrators such that sunlight is separated into different components and steered directly to photovoltaics with the corresponding wavelength sensitivities to enhance energy conversion efficiency.

  13. External Ba2+ block of the two-pore domain potassium channel TREK-1 defines conformational transition in its selectivity filter.

    PubMed

    Ma, Xiao-Yun; Yu, Jin-Mei; Zhang, Shu-Zhuo; Liu, Xiao-Yan; Wu, Bao-Hong; Wei, Xiao-Li; Yan, Jia-Qing; Sun, Hong-Liang; Yan, Hai-Tao; Zheng, Jian-Quan

    2011-11-18

    TREK-1 is a member of the two-pore domain potassium channel family that is known as a leak channel and plays a key role in many physiological and pathological processes. The conformational transition of the selectivity filter is considered as an effective strategy for potassium channels to control the course of potassium efflux. It is well known that TREK-1 is regulated by a large volume of extracellular and intracellular signals. However, until now, little was known about the selectivity filter gating mechanism of the channel. In this research, it was found that Ba(2+) blocked the TREK-1 channel in a concentration- and time-dependent manner. A mutagenesis analysis showed that overlapped binding of Ba(2+) at the assumed K(+) binding site 4 (S4) within the selectivity filter was responsible for the inhibitory effects on TREK-1. Then, Ba(2+) was used as a probe to explore the conformational transition in the selectivity filter of the channel. It was confirmed that collapsed conformations were induced by extracellular K(+)-free and acidification at the selectivity filters, leading to nonconductive to permeable ions. Further detailed characterization demonstrated that the two conformations presented different properties. Additionally, the N-terminal truncated isoform (ΔN41), a product derived from alternative translation initiation, was identified as a constitutively nonconductive variant. Together, these results illustrate the important role of selectivity filter gating in the regulation of TREK-1 by the extracellular K(+) and proton.

  14. Affinity purification of the voltage-sensitive sodium channel from electroplax with resins selective for sialic acid

    SciTech Connect

    James, W.M.; Emerick, M.C.; Agnew, W.S. )

    1989-07-11

    The voltage-sensitive sodium channel present in the eel (Electrophorus electricus) has an unusually high content of sialic acid, including {alpha}-(2{yields}8)-linked polysialic acid, not found in other electroplax membrane glycopeptides. Lectins from Limax flavus (LFA) and wheat germ (WGA) proved the most effective of 11 lectin resins tried. The most selective resin was prepared from IgM antibodies against Neisseria meningitidis {alpha}-(2{yields}8)-polysialic acid which were affinity purified and coupled to Sepharose 4B. The sodium channel was found to bind to WGA, LFA, and IgM resins and was readily eluted with the appropriate soluble carbohydrates. Experiments with LFA and IgM resins demonstrated binding and unbinding rates and displacement kinetics, which suggest highly specific binding at multiple sites on the sodium channel protein. In preparative-scale purification of protein previously fractionated by anion-exchange chromatography, without stabilizing TTX, high yields were reproducibly obtained. Further, when detergent extracts were prepared from electroplax membranes fractionated by low-speed sedimentation, a single step over the IgM resin provided a 70-fold purification, yielding specific activities of 3,200 pmol of ({sup 3}H)TTX-binding sites/mg of protein and a single polypeptide of {approximately}285,000 Da on SDS-acrylamide gels. No small peptides were observed after this 5-h isolation. The authors describe a cation-dependent stabilization with millimolar levels of monovalent and micromolar levels of divalent species.

  15. Affinity purification of the voltage-sensitive sodium channel from electroplax with resins selective for sialic acid.

    PubMed

    James, W M; Emerick, M C; Agnew, W S

    1989-07-11

    The voltage-sensitive sodium channel present in the eel (Electrophorus electricus) has an unusually high content of sialic acid, including alpha-(2----8)-linked polysialic acid, not found in other electroplax membrane glycopeptides. Lectins from Limax flavus (LFA) and wheat germ (WGA) proved the most effective of 11 lectin resins tried. The most selective resin was prepared from IgM antibodies against Neisseria meningitidis alpha-(2----8)-polysialic acid which were affinity purified and coupled to Sepharose 4B. The sodium channel was found to bind to WGA, LFA, and IgM resins and was readily eluted with the appropriate soluble carbohydrates. Experiments with LFA and IgM resins demonstrated binding and unbinding rates and displacement kinetics, which suggest highly specific binding at multiple sites on the sodium channel protein. In preparative-scale purification of protein previously fractionated by anion-exchange chromatography, without stabilizing TTX, high yields were reproducibly obtained. Further, when detergent extracts were prepared from electroplax membranes fractionated by low-speed sedimentation, a single step over the IgM resin provided a 70-fold purification, yielding specific activities of 3200 pmol of [3H]TTX-binding sites/mg of protein and a single polypeptide of approximately 285,000 Da on SDS-acrylamide gels. No small peptides were observed after this 5-h isolation. We further describe a cation-dependent stabilization with millimolar levels of monovalent and micromolar levels of divalent species.

  16. Doubly Fed Induction Machine Control For Wind Energy Conversion System

    DTIC Science & Technology

    2009-06-01

    Induction Generator (DFIG), Voltage Source Inverter (VSI), Space Vector Modulation (SVM), Wind Turbine, Field Programmable Gate Array ( FPGA ), Wind...basics of using a doubly-fed induction generator (DFIG) to convert the mechanical energy of the wind into useful electrical power that can be used to...thesis covers the basics of using a doubly-fed induction generator (DFIG) to convert the mechanical energy of the wind into useful electrical power

  17. Discovery and evaluation of selective N-type calcium channel blockers: 6-unsubstituted-1,4-dihydropyridine-5-carboxylic acid derivatives.

    PubMed

    Yamamoto, Takashi; Niwa, Seiji; Tokumasu, Munetaka; Onishi, Tomoyuki; Ohno, Seiji; Hagihara, Masako; Koganei, Hajime; Fujita, Shin-ichi; Takeda, Tomoko; Saitou, Yuki; Iwayama, Satoshi; Takahara, Akira; Iwata, Seinosuke; Shoji, Masataka

    2012-06-01

    A structure-activity relationship study of 6-unsubstituted-1,4-dihydropyridine and 2,6-unsubstituted-1,4-dihydropyridine derivatives was conducted in an attempt to discover N-type calcium channel blockers that were highly selective over L-type calcium channel blockers. Among the tested compounds, (+)-4-(3,5-dichloro-4-methoxy-phenyl)-1,4-dihydro-pyridine-3,5-dicarboxylic acid 3-cinnamyl ester was found to be an effective and selective N-type calcium channel blocker with oral analgesic potential.

  18. Alpha-helical hydrophobic polypeptides form proton-selective channels in lipid bilayers

    NASA Technical Reports Server (NTRS)

    Oliver, A. E.; Deamer, D. W.

    1994-01-01

    Proton translocation is important in membrane-mediated processes such as ATP-dependent proton pumps, ATP synthesis, bacteriorhodopsin, and cytochrome oxidase function. The fundamental mechanism, however, is poorly understood. To test the theoretical possibility that bundles of hydrophobic alpha-helices could provide a low energy pathway for ion translocation through the lipid bilayer, polyamino acids were incorporated into extruded liposomes and planar lipid membranes, and proton translocation was measured. Liposomes with incorporated long-chain poly-L-alanine or poly-L-leucine were found to have proton permeability coefficients 5 to 7 times greater than control liposomes, whereas short-chain polyamino acids had relatively little effect. Potassium permeability was not increased markedly by any of the polyamino acids tested. Analytical thin layer chromatography measurements of lipid content and a fluorescamine assay for amino acids showed that there were approximately 135 polyleucine or 65 polyalanine molecules associated with each liposome. Fourier transform infrared spectroscopy indicated that a major fraction of the long-chain hydrophobic peptides existed in an alpha-helical conformation. Single-channel recording in both 0.1 N HCl and 0.1 M KCl was also used to determine whether proton-conducting channels formed in planar lipid membranes (phosphatidylcholine/phosphatidylethanolamine, 1:1). Poly-L-leucine and poly-L-alanine in HCl caused a 10- to 30-fold increase in frequency of conductive events compared to that seen in KCl or by the other polyamino acids in either solution. This finding correlates well with the liposome observations in which these two polyamino acids caused the largest increase in membrane proton permeability but had little effect on potassium permeability. Poly-L-leucine was considerably more conductive than poly-L-alanine due primarily to larger event amplitudes and, to a lesser extent, a higher event frequency. Poly-L-leucine caused two

  19. Nonlinear Electroosmosis and Biomolecule Electrokinetic Trapping Induced by Ion Selective Nanofluidic Channels

    NASA Astrophysics Data System (ADS)

    Wang, Ying-Chih; Han, Jongyoon

    2006-03-01

    This paper describes a nanofluidic device that can concentrate dilute biomolecule by electrokinetic trapping mechanism. This device has nanofluidic channels with a depth down to 40 nm, therefore, having significant Debye layer overlap. Depending on the strength of the applied potential across the nanochannel, one can observe phenomena such as concentration polarization; charge depletion and nonlinear electrokinetic flow in the adjacent microfluidic channel using fluorescent microscopy. By manipulating the electric field, the device can generate an extended space charge region, maintained for several hours, within a microchannel as a mean to collect and trap biomolecules. Our studies demonstrate such device can achieve up to 10 million fold sample preconcentration within 30 minutes. Besides, if applied a higher potential, a much faster chaotic flow can be seen in the microchannel adjacent to nanochannels. This kind of nonlinear electrokinetic flow is often called the electroosmosis of the second kind or induced-charge electroosmosis in electrode and ion exchange membrane studies. The presented device can be used as either a preconcentrator or an injector to other separation and detection systems preferred its performance and integrabilty. Also, it is an ideal experimental platform for studying such nonlinear electrokinetic effects, by directly tracking molecules in situ.

  20. Selective expression of ligand-gated ion channels in L5 pyramidal cell axons

    PubMed Central

    Christie, Jason M.; Jahr, Craig E.

    2009-01-01

    NMDA receptor (NMDAR)-dependent strengthening of neurotransmitter release has been widely observed, including in layer 5 (L5) pyramidal cells of the visual cortex, and is attributed to the axonal expression of NMDARs. However, we failed to detect NMDAR-mediated depolarizations or Ca2+ entry in L5 pyramidal cell axons when focally stimulated with NMDAR agonists. This suggests that NMDARs are excluded from the axon. In contrast, local GABAAR activation alters axonal excitability indicating that exclusion of ligand-gated ion channels from the axon is not absolute. Because NMDARs are restricted to the dendrite, NMDARs must signal to the axon by an indirect mechanism to alter release. Although subthreshold somatic depolarizations were found to spread electrotonically hundreds of micrometers through the axon, the resulting axonal potential was insufficient to open voltage-sensitive Ca2+ channels (VSCCs). Therefore, if NMDAR-mediated facilitation of release is cell-autonomous, it may depend on voltage signaling but apparently is independent of changes in basal Ca2+. Alternatively, this facilitation may be even less direct, requiring a cascade of events that are merely triggered by NMDAR activation. PMID:19759293

  1. A plasma membrane-targeted cytosolic domain of STIM1 selectively activates ARC channels, an arachidonate-regulated store-independent Orai channel.

    PubMed

    Thompson, Jill L; Shuttleworth, Trevor J

    2012-01-01

    The Orai family of calcium channels includes the store-operated CRAC channels and store-independent, arachidonic acid (AA)-regulated ARC channels. Both depend on STIM1 for their activation but, whereas CRAC channel activation involves sensing the depletion of intracellular calcium stores via a luminal N terminal EF-hand of STIM1 in the endoplasmic reticulum (ER) membrane, ARC channels are exclusively activated by the pool of STIM1 that constitutively resides in the plasma membrane (PM). Here, the EF-hand is extracellular and unlikely to ever lose its bound calcium, suggesting that STIM1-dependent activation of ARC channels is very different from that of CRAC channels. We now show that attachment of the cytosolic portion of STIM1 to the inner face of the PM via an N terminal Lck-domain sequence is sufficient to enable normal AA-dependent activation of ARC channels, while failing to allow activation of store-operated CRAC channels. Introduction of a point mutation within the Lck-domain resulted in the loss of both PM localization and ARC channel activation. Reversing the orientation of the PM-anchored STIM1 C terminus via a C-terminal CAAX-box fails to support either CRAC or ARC channel activation. Finally, the Lck-anchored STIM1 C-terminal domain also enabled the exclusive activation of the ARC channels following physiological agonist addition. These data demonstrate that simple tethering of the cytosolic C-terminal domain of STIM1 to the inner face of the PM is sufficient to allow the full, normal and exclusive activation of ARC channels, and that the N-terminal regions of STIM1 (including the EF-hand domain) play no significant role in this activation.

  2. Effect of a selective chloride channel activator, lubiprostone, on gastrointestinal transit, gastric sensory, and motor functions in healthy volunteers.

    PubMed

    Camilleri, Michael; Bharucha, Adil E; Ueno, Ryuji; Burton, Duane; Thomforde, George M; Baxter, Kari; McKinzie, Sanna; Zinsmeister, Alan R

    2006-05-01

    Chloride channels modulate gastrointestinal neuromuscular functions in vitro. Lubiprostone, a selective type 2 chloride channel (ClC-2) activator, induces intestinal secretion and has been shown to relieve constipation in clinical trials; however, the effects of lubiprostone on gastric function and whole gut transit in humans are unclear. Our aim was to compare the effects of the selective ClC-2 activator lubiprostone on maximum tolerated volume (MTV) of a meal, postprandial symptoms, gastric volumes, and gastrointestinal and colonic transit in humans. We performed a randomized, parallel-group, double-blind, placebo-controlled study evaluating the effects of lubiprostone (24 microg bid) in 30 healthy volunteers. Validated methods were used: scintigraphic gastrointestinal and colonic transit, SPECT to measure gastric volumes, and the nutrient drink ("satiation") test to measure MTV and postprandial symptoms. Lubiprostone accelerated small bowel and colonic transit, increased fasting gastric volume, and retarded gastric emptying. MTV values were reduced compared with placebo; however, the MTV was within the normal range for healthy adults in 13 of 14 participants, and there was no significant change compared with baseline measurements. Lubiprostone had no significant effect on postprandial gastric volume or aggregate symptoms but did decrease fullness 30 min after the fully satiating meal. Thus the ClC-2 activator lubiprostone accelerates small intestinal and colonic transit, which confers potential in the treatment of constipation.

  3. Gas-Phase Reactions of Doubly Charged Lanthanide Cations with Alkanes and Alkenes. Trends in Metal(2+) Reactivity

    SciTech Connect

    Gibson, John K.; Marcalo, Joaquim; Santos, Marta; Pires de Matos, Antonio; Haire, Richard G.

    2008-12-08

    The gas-phase reactivity of doubly-charged lanthanide cations, Ln2+ (Ln = La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu), with alkanes (methane, ethane, propane, n-butane) and alkenes (ethene, propene, 1-butene) was studied by Fourier transform ion cyclotron resonance mass spectrometry. The reaction products consisted of different combinations of doubly-charged organometallic ions?adducts or species formed via metal-ion-induced hydrogen, dihydrogen, alkyl, or alkane eliminations from the hydrocarbons?and singly-charged ions that resulted from electron, hydride, or methide transfers from the hydrocarbons to the metal ions. The only lanthanide cations capable of activating the hydrocarbons to form doubly-charged organometallic ions were La2+, Ce2+, Gd2+, and Tb2+, which have ground-state or low-lying d1 electronic configurations. Lu2+, with an accessible d1 electronic configuration but a rather high electron affinity, reacted only through transfer channels. The remaining Ln2+ reacted via transfer channels or adduct formation. The different accessibilities of d1 electronic configurations and the range of electron affinities of the Ln2+ cations allowed for a detailed analysis of the trends for metal(2+) reactivity and the conditions for occurrence of bond activation, adduct formation, and electron, hydride, and methide transfers.

  4. Learning doubly sparse transforms for images.

    PubMed

    Ravishankar, Saiprasad; Bresler, Yoram

    2013-12-01

    The sparsity of images in a transform domain or dictionary has been exploited in many applications in image processing. For example, analytical sparsifying transforms, such as wavelets and discrete cosine transform (DCT), have been extensively used in compression standards. Recently, synthesis sparsifying dictionaries that are directly adapted to the data have become popular especially in applications such as image denoising. Following up on our recent research, where we introduced the idea of learning square sparsifying transforms, we propose here novel problem formulations for learning doubly sparse transforms for signals or image patches. These transforms are a product of a fixed, fast analytic transform such as the DCT, and an adaptive matrix constrained to be sparse. Such transforms can be learnt, stored, and implemented efficiently. We show the superior promise of our learnt transforms as compared with analytical sparsifying transforms such as the DCT for image representation. We also show promising performance in image denoising that compares favorably with approaches involving learnt synthesis dictionaries such as the K-SVD algorithm. The proposed approach is also much faster than K-SVD denoising.

  5. Mechanical Properties of Doubly Stabilized Microtubule Filaments

    PubMed Central

    Hawkins, Taviare L.; Sept, David; Mogessie, Binyam; Straube, Anne; Ross, Jennifer L.

    2013-01-01

    Microtubules are cytoskeletal filaments responsible for cell morphology and intracellular organization. Their dynamical and mechanical properties are regulated through the nucleotide state of the tubulin dimers and the binding of drugs and/or microtubule-associated proteins. Interestingly, microtubule-stabilizing factors have differential effects on microtubule mechanics, but whether stabilizers have cumulative effects on mechanics or whether one effect dominates another is not clear. This is especially important for the chemotherapeutic drug Taxol, an important anticancer agent and the only known stabilizer that reduces the rigidity of microtubules. First, we ask whether Taxol will combine additively with another stabilizer or whether one stabilizer will dominate another. We call microtubules in the presence of Taxol and another stabilizer, doubly stabilized. Second, since Taxol is often added to a number of cell types for therapeutic purposes, it is important from a biomedical perspective to understand how Taxol added to these systems affects the mechanical properties in treated cells. To address these questions, we use the method of freely fluctuating filaments with our recently developed analysis technique of bootstrapping to determine the distribution of persistence lengths of a large population of microtubules treated with different stabilizers, including Taxol, guanosine-5′ [(α, β)-methyleno] triphosphate, guanosine-5′-O-(3-thiotriphosphate), tau, and MAP4. We find that combinations of these stabilizers have novel effects on the mechanical properties of microtubules. PMID:23561528

  6. Mechanical properties of doubly stabilized microtubule filaments.

    PubMed

    Hawkins, Taviare L; Sept, David; Mogessie, Binyam; Straube, Anne; Ross, Jennifer L

    2013-04-02

    Microtubules are cytoskeletal filaments responsible for cell morphology and intracellular organization. Their dynamical and mechanical properties are regulated through the nucleotide state of the tubulin dimers and the binding of drugs and/or microtubule-associated proteins. Interestingly, microtubule-stabilizing factors have differential effects on microtubule mechanics, but whether stabilizers have cumulative effects on mechanics or whether one effect dominates another is not clear. This is especially important for the chemotherapeutic drug Taxol, an important anticancer agent and the only known stabilizer that reduces the rigidity of microtubules. First, we ask whether Taxol will combine additively with another stabilizer or whether one stabilizer will dominate another. We call microtubules in the presence of Taxol and another stabilizer, doubly stabilized. Second, since Taxol is often added to a number of cell types for therapeutic purposes, it is important from a biomedical perspective to understand how Taxol added to these systems affects the mechanical properties in treated cells. To address these questions, we use the method of freely fluctuating filaments with our recently developed analysis technique of bootstrapping to determine the distribution of persistence lengths of a large population of microtubules treated with different stabilizers, including Taxol, guanosine-5' [(α, β)-methyleno] triphosphate, guanosine-5'-O-(3-thiotriphosphate), tau, and MAP4. We find that combinations of these stabilizers have novel effects on the mechanical properties of microtubules.

  7. The selectivity of different external binding sites for quaternary ammonium ions in cloned potassium channels.

    PubMed

    Jarolimek, W; Soman, K V; Brown, A M; Alam, M

    1995-09-01

    Tetraethylammonium (TEA) is thought to be the most effective quaternary ammonium (QA) ion blocker at the external site of K+ channels, and small changes to the TEA ion reduce its potency. To examine the properties of the external QA receptor, we applied a variety of QA ions to excised patches from human embryonic kidney cells or Xenopus oocytes transfected with the delayed rectifying K+ channels Kv 2.1 and Kv 3.1. In outside-out patches of Kv 3.1, the relative potencies were TEA > tetrapropylammonium (TPA) > tetrabutylammonium (TBA). In contrast to Kv 3.1, the relative potencies in Kv 2.1 were TBA > TEA > TPA. In Kv 3.1 and Kv 2.1, external tetrapentylammonium (TPeA) blocked K+ currents in a fast, reversible and, in contrast to TEA, time-dependent manner. The external binding of TPeA appeared to be voltage independent, unlike the effects of TPeA applied to inside-out patches. External n-alkyl-triethylammonium compounds (C8, C10 chain length) had a lower affinity than TEA in Kv 3.1, but a higher affinity than TEA in Kv 2.1. In Kv 3.1, the decrease in QA affinity was large when one or two methyl groups were substituted for ethyl groups in TEA, but minor when propyl groups replaced ethyl groups. Changes in the free energy of binding could be correlated to changes in the free energy of hydration of TEA derivatives calculated by continuum methodology. These results reveal a substantial hydrophobic component of external QA ion binding to Kv 2.1, and to a lesser degree to Kv 3.1, in addition to the generally accepted electrostatic interactions. The chain length of hydrophobic TEA derivatives affects the affinity for the hydrophobic binding site, whereas the hydropathy of QA ions determines the electrostatic interaction energy.

  8. Outage Performance Analysis of Relay Selection Schemes in Wireless Energy Harvesting Cooperative Networks over Non-Identical Rayleigh Fading Channels.

    PubMed

    Do, Nhu Tri; Bao, Vo Nguyen Quoc; An, Beongku

    2016-02-26

    In this paper, we study relay selection in decode-and-forward wireless energy harvesting cooperative networks. In contrast to conventional cooperative networks, the relays harvest energy from the source's radio-frequency radiation and then use that energy to forward the source information. Considering power splitting receiver architecture used at relays to harvest energy, we are concerned with the performance of two popular relay selection schemes, namely, partial relay selection (PRS) scheme and optimal relay selection (ORS) scheme. In particular, we analyze the system performance in terms of outage probability (OP) over independent and non-identical (i.n.i.d.) Rayleigh fading channels. We derive the closed-form approximations for the system outage probabilities of both schemes and validate the analysis by the Monte-Carlo simulation. The numerical results provide comprehensive performance comparison between the PRS and ORS schemes and reveal the effect of wireless energy harvesting on the outage performances of both schemes. Additionally, we also show the advantages and drawbacks of the wireless energy harvesting cooperative networks and compare to the conventional cooperative networks.

  9. The Scorpion Toxin Analogue BmKTX-D33H as a Potential Kv1.3 Channel-Selective Immunomodulator for Autoimmune Diseases.

    PubMed

    Ye, Fang; Hu, Youtian; Yu, Weiwei; Xie, Zili; Hu, Jun; Cao, Zhijian; Li, Wenxin; Wu, Yingliang

    2016-04-19

    The Kv1.3 channel-acting scorpion toxins usually adopt the conserved anti-parallel β-sheet domain as the binding interface, but it remains challenging to discover some highly selective Kv1.3 channel-acting toxins. In this work, we investigated the pharmacological profile of the Kv1.3 channel-acting BmKTX-D33H, a structural analogue of the BmKTX scorpion toxin. Interestingly, BmKTX-D33H, with its conserved anti-parallel β-sheet domain as a Kv1.3 channel-interacting interface, exhibited more than 1000-fold selectivity towards the Kv1.3 channel as compared to other K⁺ channels (including Kv1.1, Kv1.2, Kv1.7, Kv11.1, KCa2.2, KCa2.3, and KCa3.1). As expected, BmKTX-D33H was found to inhibit the cytokine production and proliferation of both Jurkat cells and human T cells in vitro. It also significantly improved the delayed-type hypersensitivity (DTH) responses, an autoreactive T cell-mediated inflammation in rats. Amino acid sequence alignment and structural analysis strongly suggest that the "evolutionary" Gly11 residue of BmKTX-D33H interacts with the turret domain of Kv1 channels; it appears to be a pivotal amino acid residue with regard to the selectivity of BmKTX-D33H towards the Kv1.3 channel (in comparison with the highly homologous scorpion toxins). Together, our data indicate that BmKTX-D33H is a Kv1.3 channel-specific blocker. Finally, the remarkable selectivity of BmKTX-D33H highlights the great potential of evolutionary-guided peptide drug design in future studies.

  10. Selective regulation of spontaneous activity of neurons of the deep cerebellar nuclei by N-type calcium channels in juvenile rats.

    PubMed

    Alviña, Karina; Khodakhah, Kamran

    2008-05-15

    The cerebellum coordinates movement and maintains body posture. The main output of the cerebellum is formed by three deep nuclei, which receive direct inhibitory inputs from cerebellar Purkinje cells, and excitatory collaterals from mossy and climbing fibres. Neurons of deep cerebellar nuclei (DCN) are spontaneously active, and disrupting their activity results in severe cerebellar ataxia. It is suggested that voltage-gated calcium channels make a significant contribution to the spontaneous activity of DCN neurons, although the exact identity of these channels is not known. We sought to delineate the functional role and identity of calcium channels that contribute to pacemaking in DCN neurons of juvenile rats. We found that in the majority of cells blockade of calcium currents results in avid high-frequency bursting, consistent with the notion that the net calcium-dependent current in DCN neurons is outward. We showed that the bursting seen in these neurons after block of calcium channels is the consequence of reduced activation of small-conductance calcium-activated (SK) potassium channels. With the use of selective pharmacological blockers we showed that L-, P/Q-, R- and T-type calcium channels do not contribute to the spontaneous activity of DCN neurons. In contrast, blockade of high-threshold N-type calcium channels increased the firing rate and caused the cells to burst. Our results thus suggest a selective coupling of N-type voltage-gated calcium channels with calcium-activated potassium channels in DCN neurons. In addition, we demonstrate the presence of a cadmium-sensitive calcium conductance coupled with SK channels, that is pharmacologically distinct from L-, N-, P/Q-, R- and T-type calcium channels.

  11. Acid-sensitive TWIK and TASK Two-pore Domain Potassium Channels Change Ion Selectivity and Become Permeable to Sodium in Extracellular Acidification*

    PubMed Central

    Ma, Liqun; Zhang, Xuexin; Zhou, Min; Chen, Haijun

    2012-01-01

    Two-pore domain K+ channels (K2P) mediate background K+ conductance and play a key role in a variety of cellular functions. Among the 15 mammalian K2P isoforms, TWIK-1, TASK-1, and TASK-3 K+ channels are sensitive to extracellular acidification. Lowered or acidic extracellular pH (pHo) strongly inhibits outward currents through these K2P channels. However, the mechanism of how low pHo affects these acid-sensitive K2P channels is not well understood. Here we show that in Na+-based bath solutions with physiological K+ gradients, lowered pHo largely shifts the reversal potential of TWIK-1, TASK-1, and TASK-3 K+ channels, which are heterologously expressed in Chinese hamster ovary cells, into the depolarizing direction and significantly increases their Na+ to K+ relative permeability. Low pHo-induced inhibitions in these acid-sensitive K2P channels are more profound in Na+-based bath solutions than in channel-impermeable N-methyl-d-glucamine-based bath solutions, consistent with increases in the Na+ to K+ relative permeability and decreases in electrochemical driving forces of outward K+ currents of the channels. These findings indicate that TWIK-1, TASK-1, and TASK-3 K+ channels change ion selectivity in response to lowered pHo, provide insights on the understanding of how extracellular acidification modulates acid-sensitive K2P channels, and imply that these acid-sensitive K2P channels may regulate cellular function with dynamic changes in their ion selectivity. PMID:22948150

  12. Enhancement of Hippocampal Pyramidal Cell Excitability by the Novel Selective Slow-Afterhyperpolarization Channel Blocker 3-(Triphenylmethylaminomethyl)pyridine (UCL2077)

    PubMed Central

    Shah, Mala M.; Javadzadeh-Tabatabaie, Mazyar; Benton, David C. H.; Ganellin, C. Robin; Haylett, Dennis G.

    2008-01-01

    The slow afterhyperpolarization (sAHP) in hippocampal neurons has been implicated in learning and memory. However, its precise role in cell excitability and central nervous system function has not been explicitly tested for 2 reasons: 1) there are, at present, no selective inhibitors that effectively reduce the underlying current in vivo or in intact in vitro tissue preparations, and 2) although it is known that a small conductance K+ channel that activates after a rise in [Ca2+]i underlies the sAHP, the exact molecular identity remains unknown. We show that 3-(triphenylmethylaminomethyl)pyridine (UCL2077), a novel compound, suppressed the sAHP present in hippocampal neurons in culture (IC50 = 0.5 μM) and in the slice preparation (IC50 ≈ 10 μM). UCL2077 was selective, having minimal effects on Ca2+ channels, action potentials, input resistance and the medium afterhyperpolarization. UCL2077 also had little effect on heterologously expressed small conductance Ca2+-activated K+ (SK) channels. Moreover, UCL2077 and apamin, a selective SK channel blocker, affected spike firing in hippocampal neurons in different ways. These results provide further evidence that SK channels are unlikely to underlie the sAHP. This study also demonstrates that UCL2077, the most potent, selective sAHP blocker described so far, is a useful pharmacological tool for exploring the role of sAHP channels in the regulation of cell excitability in intact tissue preparations and, potentially, in vivo. PMID:16877678

  13. Conformational changes in the selectivity filter of the open-state KcsA channel: an energy minimization study.

    PubMed

    Miloshevsky, Gennady V; Jordan, Peter C

    2008-10-01

    Potassium channels switch between closed and open conformations and selectively conduct K(+) ions. There are at least two gates. The TM2 bundle at the intracellular site is the primary gate of KcsA, and rearrangements at the selectivity filter (SF) act as the second gate. The SF blocks ion flow via an inactivation process similar to C-type inactivation of voltage-gated K(+) channels. We recently generated the open-state conformation of the KcsA channel. We found no major, possibly inactivating, structural changes in the SF associated with this massive inner-pore rearrangement, which suggests that the gates might act independently. Here we energy-minimize the open state of wild-type and mutant KcsA, validating in silico structures of energy-minimized SFs by comparison with crystallographic structures, and use these data to gain insight into how mutation, ion depletion, and K(+) to Na(+) substitution influence SF conformation. Both E71 or D80 protonations/mutations and the presence/absence of protein-buried water molecule(s) modify the H-bonding network stabilizing the P-loops, spawning numerous SF conformations. We find that the inactivated state corresponds to conformations with a partially unoccupied or an entirely empty SF. These structures, involving modifications in all four P-loops, are stabilized by H-bonds between amide H and carbonyl O atoms from adjacent P-loops, which block ion passage. The inner portions of the P-loops are more rigid than the outer parts. Changes are localized to the outer binding sites, with innermost site S4 persisting in the inactivated state. Strong binding by Na(+) locally contracts the SF around Na(+), releasing ligands that do not participate in Na(+) coordination, and occluding the permeation pathway. K(+) selectivity primarily appears to arise from the inability of the SF to completely dehydrate Na(+) ions due to basic structural differences between liquid water and the "quasi-liquid" SF matrix.

  14. TRP Channels

    PubMed Central

    Venkatachalam, Kartik; Montell, Craig

    2011-01-01

    The TRP (Transient Receptor Potential) superfamily of cation channels is remarkable in that it displays greater diversity in activation mechanisms and selectivities than any other group of ion channels. The domain organizations of some TRP proteins are also unusual, as they consist of linked channel and enzyme domains. A unifying theme in this group is that TRP proteins play critical roles in sensory physiology, which include contributions to vision, taste, olfaction, hearing, touch, and thermo- and osmosensation. In addition, TRP channels enable individual cells to sense changes in their local environment. Many TRP channels are activated by a variety of different stimuli and function as signal integrators. The TRP superfamily is divided into seven subfamilies: the five group 1 TRPs (TRPC, TRPV, TRPM, TRPN, and TRPA) and two group 2 subfamilies (TRPP and TRPML). TRP channels are important for human health as mutations in at least four TRP channels underlie disease. PMID:17579562

  15. Nerve compression activates selective nociceptive pathways and upregulates peripheral sodium channel expression in Schwann cells.

    PubMed

    Frieboes, Laura Rummler; Palispis, Winnie Anne; Gupta, Ranjan

    2010-06-01

    Chronic nerve compression (CNC) injuries, such as carpal tunnel syndrome, are common musculoskeletal conditions that affect patients with debilitating loss of sensory function and pain. Although early detection and treatment are important, our understanding of pain-related molecular mechanisms remains largely unclear. Here we investigate these mechanisms using an animal model for CNC injury. To confirm that CNC injury induces pain, we assessed expression of c-fos, a gene that is rapidly expressed in spinal sensory afferents in response to painful peripheral stimuli, and TNF-alpha and IL-6, two proinflammatory cytokines that are crucial to development of inflammatory-mediated pain. Results show c-fos upregulation 1-2 weeks postinjury in the absence of TNF-alpha or IL-6 expression, indicating increased neural sensitivity without an inflammatory response. This is consistent with previous studies that showed no morphologic evidence of inflammation in the CNC model. Surprisingly, we also found de novo expression of Na(V)1.8, a sodium channel linked to the development of neuropathic pain, in endoneurial Schwann cells following injury. Until now, Na(V)1.8 expression was thought to be restricted to sensory neurons. CNC injury appears to be a unique model of noninflammatory neuropathic pain. Further investigation of the underlying molecular basis could yield promising targets for early diagnosis and treatment.

  16. Norharmane: old yet highly selective dual channel ratiometric fluoride and hydrogen sulfate ion sensor.

    PubMed

    Mallick, Arabinda; Katayama, Tetsuro; Ishibasi, Yukihide; Yasuda, Masakazu; Miyasaka, Hiroshi

    2011-01-21

    Norharmane provides a simple unexplored class of anion receptor, that allows for the ratiometric selective detection of F(-) and HSO(4)(-) ions. The presence of a strong base can easily form hydrogen bonds with the acidic hydrogen bond donor moiety and the relatively strong acid can easily protonate the basic hydrogen bond acceptor moiety, which can modulate the optical response and can detect the anions efficiently with high selectivity. In view of that, it is promising to conceive the use of these systems in various sensing applications as well as in other situations, such as anion transport and purification, where the availability of cheap and easy-to-make anion receptors, would be advantageous.

  17. The Sodium Channel β4 Auxiliary Subunit Selectively Controls Long-Term Depression in Core Nucleus Accumbens Medium Spiny Neurons

    PubMed Central

    Ji, Xincai; Saha, Sucharita; Gao, Guangping; Lasek, Amy W.; Homanics, Gregg E.; Guildford, Melissa; Tapper, Andrew R.; Martin, Gilles E.

    2017-01-01

    Voltage-gated sodium channels are essential for generating the initial rapid depolarization of neuronal membrane potential during action potentials (APs) that enable cell-to-cell communication, the propagation of signals throughout the brain, and the induction of synaptic plasticity. Although all brain neurons express one or several variants coding for the core pore-forming sodium channel α subunit, the expression of the β (β1–4) auxiliary subunits varies greatly. Of particular interest is the β4 subunit, encoded by the Scn4b gene, that is highly expressed in dorsal and ventral (i.e., nucleus accumbens – NAc) striata compared to other brain regions, and that endows sodium channels with unique gating properties. However, its role on neuronal activity, synaptic plasticity, and behaviors related to drugs of abuse remains poorly understood. Combining whole-cell patch-clamp recordings with two-photon calcium imaging in Scn4b knockout (KO) and knockdown mice, we found that Scn4b altered the properties of APs in core accumbens medium spiny neurons (MSNs). These alterations are associated with a reduction of the probability of MSNs to evoke spike-timing-dependent long-term depression (tLTD) and a reduced ability of backpropagating APs to evoke dendritic calcium transients. In contrast, long-term potentiation (tLTP) remained unaffected. Interestingly, we also showed that amphetamine-induced locomotor activity was significantly reduced in male Scn4b KO mice compared to wild-type controls. Taken together, these data indicate that the Scn4b subunit selectively controls tLTD by modulating dendritic calcium transients evoked by backpropagating APs. PMID:28243192

  18. Neurons and β-Cells of the Pancreas Express Connexin36, Forming Gap Junction Channels that Exhibit Strong Cationic Selectivity

    PubMed Central

    2013-01-01

    We examined the permeability of connexin36 (Cx36) homotypic gap junction (GJ) channels, expressed in neurons and β-cells of the pancreas, to dyes differing in molecular mass and net charge. Experiments were performed in HeLa cells stably expressing Cx36 tagged with EGFP by combining a dual whole-cell voltage clamp and fluorescence imaging. To assess the permeability of the single GJ channel (Pγ), we used a dual-mode excitation of fluorescent dyes that allowed us to measure cell-to-cell dye transfer at levels not resolvable using whole-field excitation solely. We demonstrate that Pγ of Cx36 for cationic dyes (EAM-1+ and EAM-2+) is ∼10-fold higher than that for an anionic dye of the same net charge and similar molecular mass, Alexa fluor-350 (AFl-350−). In addition, Pγ for Lucifer yellow (LY2−) is approximately fourfold smaller than that for AFl-350−, which suggests that the higher negativity of LY2− significantly reduces permeability. The Pγ of Cx36 for AFl-350 is approximately 358, 138, 23 and four times smaller than the Pγs of Cx43, Cx40, Cx45, and Cx57, respectively. In contrast, it is 6.5-fold higher than the Pγ of mCx30.2, which exhibits a smaller single-channel conductance. Thus, Cx36 GJs are highly cation-selective and should exhibit relatively low permeability to numerous vital negatively charged metabolites and high permeability to K+, a major charge carrier in cell– cell communication. PMID:22752717

  19. Selective positive modulator of calcium-activated potassium channels exerts beneficial effects in a mouse model of spinocerebellar ataxia type 2.

    PubMed

    Kasumu, Adebimpe W; Hougaard, Charlotte; Rode, Frederik; Jacobsen, Thomas A; Sabatier, Jean Marc; Eriksen, Birgitte L; Strøbæk, Dorte; Liang, Xia; Egorova, Polina; Vorontsova, Dasha; Christophersen, Palle; Rønn, Lars Christian B; Bezprozvanny, Ilya

    2012-10-26

    Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disorder caused by a polyglutamine expansion within the Ataxin-2 (Atxn2) protein. Purkinje cells (PC) of the cerebellum fire irregularly and eventually die in SCA2. We show here that the type 2 small conductance calcium-activated potassium channel (SK2) play a key role in control of normal PC activity. Using cerebellar slices from transgenic SCA2 mice we demonstrate that SK channel modulators restore regular pacemaker activity of SCA2 PCs. Furthermore, we also show that oral delivery of a more selective positive modulator of SK2/3 channels (NS13001) alleviates behavioral and neuropathological phenotypes of aging SCA2 transgenic mice. We conclude that SK2 channels constitute a therapeutic target for SCA2 treatment and that the developed selective SK2/3 modulator NS13001 holds promise as a potential therapeutic agent for treatment of SCA2 and possibly other cerebellar ataxias.

  20. Photonic crystal fiber-based surface plasmon resonance sensor with selective analyte channels and graphene-silver deposited core.

    PubMed

    Rifat, Ahmmed A; Mahdiraji, G Amouzad; Chow, Desmond M; Shee, Yu Gang; Ahmed, Rajib; Adikan, Faisal Rafiq Mahamd

    2015-05-19

    We propose a surface plasmon resonance (SPR) sensor based on photonic crystal fiber (PCF) with selectively filled analyte channels. Silver is used as the plasmonic material to accurately detect the analytes and is coated with a thin graphene layer to prevent oxidation. The liquid-filled cores are placed near to the metallic channel for easy excitation of free electrons to produce surface plasmon waves (SPWs). Surface plasmons along the metal surface are excited with a leaky Gaussian-like core guided mode. Numerical investigations of the fiber's properties and sensing performance are performed using the finite element method (FEM). The proposed sensor shows maximum amplitude sensitivity of 418 Refractive Index Units (RIU-1) with resolution as high as 2.4 × 10(-5) RIU. Using the wavelength interrogation method, a maximum refractive index (RI) sensitivity of 3000 nm/RIU in the sensing range of 1.46-1.49 is achieved. The proposed sensor is suitable for detecting various high RI chemicals, biochemical and organic chemical analytes. Additionally, the effects of fiber structural parameters on the properties of plasmonic excitation are investigated and optimized for sensing performance as well as reducing the sensor's footprint.

  1. Photonic Crystal Fiber-Based Surface Plasmon Resonance Sensor with Selective Analyte Channels and Graphene-Silver Deposited Core

    PubMed Central

    Rifat, Ahmmed A.; Mahdiraji, G. Amouzad; Chow, Desmond M.; Shee, Yu Gang; Ahmed, Rajib; Adikan, Faisal Rafiq Mahamd

    2015-01-01

    We propose a surface plasmon resonance (SPR) sensor based on photonic crystal fiber (PCF) with selectively filled analyte channels. Silver is used as the plasmonic material to accurately detect the analytes and is coated with a thin graphene layer to prevent oxidation. The liquid-filled cores are placed near to the metallic channel for easy excitation of free electrons to produce surface plasmon waves (SPWs). Surface plasmons along the metal surface are excited with a leaky Gaussian-like core guided mode. Numerical investigations of the fiber’s properties and sensing performance are performed using the finite element method (FEM). The proposed sensor shows maximum amplitude sensitivity of 418 Refractive Index Units (RIU−1) with resolution as high as 2.4 × 10−5 RIU. Using the wavelength interrogation method, a maximum refractive index (RI) sensitivity of 3000 nm/RIU in the sensing range of 1.46–1.49 is achieved. The proposed sensor is suitable for detecting various high RI chemicals, biochemical and organic chemical analytes. Additionally, the effects of fiber structural parameters on the properties of plasmonic excitation are investigated and optimized for sensing performance as well as reducing the sensor’s footprint. PMID:25996510

  2. ZD7288, a selective hyperpolarization-activated cyclic nucleotide-gated channel blocker, inhibits hippocampal synaptic plasticity

    PubMed Central

    Zhang, Xiao-xue; Min, Xiao-chun; Xu, Xu-lin; Zheng, Min; Guo, Lian-jun

    2016-01-01

    The selective hyperpolarization-activated cyclic nucleotide-gated (HCN) channel blocker 4-(N-ethyl-N-phenylamino)-1,2-dimethyl-6-(methylamino) pyrimidinium chloride (ZD7288) blocks the induction of long-term potentiation in the perforant path–CA3 region in rat hippocampus in vivo. To explore the mechanisms underlying the action of ZD7288, we recorded excitatory postsynaptic potentials in perforant path–CA3 synapses in male Sprague-Dawley rats. We measured glutamate content in the hippocampus and in cultured hippocampal neurons using high performance liquid chromatography, and determined intracellular Ca2+ concentration [Ca2+]i) using Fura-2. ZD7288 inhibited the induction and maintenance of long-term potentiation, and these effects were mirrored by the nonspecific HCN channel blocker cesium. ZD7288 also decreased glutamate release in hippocampal tissue and in cultured hippocampal neurons. Furthermore, ZD7288 attenuated glutamate-induced rises in [Ca2+]i in a concentration-dependent manner and reversed 8-Br-cAMP-mediated facilitation of these glutamate-induced [Ca2+]i rises. Our results suggest that ZD7288 inhibits hippocampal synaptic plasticity both glutamate release and resultant [Ca2+]i increases in rat hippocampal neurons. PMID:27335562

  3. An easy prepared dual-channel chemosensor for selective and instant detection of fluoride based on double Schiff-base.

    PubMed

    Leng, Yan-Li; Zhang, Jian-Hui; Li, Qiao; Zhang, You-Ming; Lin, Qi; Yao, Hong; Wei, Tai-Bao

    2016-10-05

    A colorimetric and fluorescent dual-channel fluoride chemosensor N,N'-bis (4-diethylaminosalicylidene) hydrazine (sensor S) bearing two imine groups has been designed and synthesized. This structurally simple probe displays rapid response and high selectivity for fluoride over other common anions (Cl(-), Br(-), I(-), AcO(-), H2PO4(-), HSO4(-), ClO4(-), CN(-) and SCN(-)) in a highly polar aqueous DMSO solution. Mechanism studies suggested that the sensor firstly combined with F(-) through hydrogen bonds and then experienced the deprotonation process at higher concentrations of F(-) anion to the two Ar-OH groups. The detection limit was 5.78×10(-7)M of F(-), which points to the high detection sensitivity. Test strips based on sensor S were fabricated, which could act as a convenient and efficient F(-) test kit to detect F(-) for "in-the-field" measurement.

  4. An easy prepared dual-channel chemosensor for selective and instant detection of fluoride based on double Schiff-base

    NASA Astrophysics Data System (ADS)

    Leng, Yan-Li; Zhang, Jian-Hui; Li, Qiao; Zhang, You-Ming; Lin, Qi; Yao, Hong; Wei, Tai-Bao

    2016-10-01

    A colorimetric and fluorescent dual-channel fluoride chemosensor N,N‧-bis (4-diethylaminosalicylidene) hydrazine (sensor S) bearing two imine groups has been designed and synthesized. This structurally simple probe displays rapid response and high selectivity for fluoride over other common anions (Cl-, Br-, I-, AcO-, H2PO4-, HSO4-, ClO4-, CN- and SCN-) in a highly polar aqueous DMSO solution. Mechanism studies suggested that the sensor firstly combined with F- through hydrogen bonds and then experienced the deprotonation process at higher concentrations of F- anion to the two Ar-OH groups. The detection limit was 5.78 × 10- 7 M of F-, which points to the high detection sensitivity. Test strips based on sensor S were fabricated, which could act as a convenient and efficient F- test kit to detect F- for "in-the-field" measurement.

  5. Performance optimization for doubly fed wind power generation systems

    SciTech Connect

    Bhowmik, S.; Spee, R.; Enslin, J.H.R.

    1999-08-01

    Significant variation of the resource kinetic energy, in the form of wind speed, results in substantially reduced energy capture in a fixed-speed wind turbine. In order to increase the wind energy capture in the turbine, variable-speed generation (VSG) strategies have been proposed and implemented. However, that requires an expensive ac/ac power converter, which increases the capital investment significantly. Consequently, doubly fed systems have been proposed to reduce the size of the power converter and, thereby, the associated cost. Additionally, in doubly fed systems, as a fixed operating point (power and speed), power flow can be regulated between the two winding systems on the machine. This feature can by utilized to essentially minimize losses in the machine associated with the given operating point or achieve other desired performance enhancements. In this paper, a brushless doubly fed machine (BDFM) is utilized to develop a VSG wind power generator. The VSG controller employs a wind-speed-estimation-based maximum power point tracker and a heuristic-model-based maximum efficiency point tracker to optimize the power output of the system. The controller has been verified for efficacy on a 1.5-kW laboratory VSG wind generator. The strategy is applicable to all doubly fed configurations, including conventional wound-rotor induction machines, Scherbius cascades, BDFM's and doubly fed reluctance machines.

  6. The Scorpion Toxin Analogue BmKTX-D33H as a Potential Kv1.3 Channel-Selective Immunomodulator for Autoimmune Diseases

    PubMed Central

    Ye, Fang; Hu, Youtian; Yu, Weiwei; Xie, Zili; Hu, Jun; Cao, Zhijian; Li, Wenxin; Wu, Yingliang

    2016-01-01

    The Kv1.3 channel-acting scorpion toxins usually adopt the conserved anti-parallel β-sheet domain as the binding interface, but it remains challenging to discover some highly selective Kv1.3 channel-acting toxins. In this work, we investigated the pharmacological profile of the Kv1.3 channel-acting BmKTX-D33H, a structural analogue of the BmKTX scorpion toxin. Interestingly, BmKTX-D33H, with its conserved anti-parallel β-sheet domain as a Kv1.3 channel-interacting interface, exhibited more than 1000-fold selectivity towards the Kv1.3 channel as compared to other K+ channels (including Kv1.1, Kv1.2, Kv1.7, Kv11.1, KCa2.2, KCa2.3, and KCa3.1). As expected, BmKTX-D33H was found to inhibit the cytokine production and proliferation of both Jurkat cells and human T cells in vitro. It also significantly improved the delayed-type hypersensitivity (DTH) responses, an autoreactive T cell-mediated inflammation in rats. Amino acid sequence alignment and structural analysis strongly suggest that the “evolutionary” Gly11 residue of BmKTX-D33H interacts with the turret domain of Kv1 channels; it appears to be a pivotal amino acid residue with regard to the selectivity of BmKTX-D33H towards the Kv1.3 channel (in comparison with the highly homologous scorpion toxins). Together, our data indicate that BmKTX-D33H is a Kv1.3 channel–specific blocker. Finally, the remarkable selectivity of BmKTX-D33H highlights the great potential of evolutionary-guided peptide drug design in future studies. PMID:27104568

  7. Non-pore lining amino acid side chains influence anion selectivity of the human CFTR Cl− channel expressed in mammalian cell lines

    PubMed Central

    Linsdell, Paul; Zheng, Shu-Xian; Hanrahan, John W

    1998-01-01

    The effects of individually mutating two adjacent threonine residues in the sixth membrane-spanning region (TM6) of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl− channel on permeation properties were examined using patch clamp recording from mammalian cell lines stably expressing human CFTR.A number of mutations of T338 significantly affected the permeation properties of the channel. Increases and decreases in single channel conductance were observed for different mutants. Anion selectivity was strongly affected, with no two channel variants sharing the same selectivity sequence. Several mutations led to strong inward rectification of the macroscopic current-voltage relationship. The effects of these mutations on permeation properties were correlated with the size of the amino acid side chain substituted, rather than its chemical nature.Most mutations of T339 resulted in a lack of functional channel expression and apparent misprocessing of the protein. One mutant, T339V, was characterized in detail; its permeation properties were significantly altered, although these effects were not as strong as for T338 mutations.These results suggest an important role for T338 in controlling the permeation properties of the CFTR Cl− channel. It is suggested that mutation of this residue alters the interaction between permeating anions and the channel pore via an indirect effect on the orientation of the TM6 helix. PMID:9729613

  8. Structural model of the outer vestibule and selectivity filter of the Shaker voltage-gated K+ channel.

    PubMed

    Durell, S R; Guy, H R

    1996-01-01

    A new generation of structural models were developed of the outer vestibule and ion-selective portion of the voltage-gated Shaker K+ channel. Some features of these models are similar to those that we have developed previously [Durrel S. R. and Guy H. R. (1992) Biophys. J. 62, 238-250; Guy H. R. (1990) In Monovalent Cations in Biological Systems (Pasternak C. A., Ed.), pp. 31-58, CRC Press, Boca Raton, FL; Guy H. R. and Durell S. R. (1994) In Molecular Evolution of Physiological processes (Fambrough D., Ed.), pp. 197-212, The Rockefeller University Press, NY; Guy H. R. and Durell S. R. (1995) In Ion Channels and Genetic Diseases (Dawson D., Ed.), pp. 1-16, The Rockefeller University Press, NY] and other features were modified to make the models more consistent with recent experimental findings. The first part of the P segment is postulated, as always, to form a short alpha helix that spans only the outer portion of the membrane. The helix is tilted so that its C-terminal is nearer the pore than its N-terminal. The latter part of the P segment, P2, is postulated to have a relatively elongated conformation that is positioned approximately parallel to the axis of the pore. Four of the P2 segments assemble to form an ion-selective region that has two narrow regions; one formed by the Y445 side-chains at the outer entrance of the pore and one formed by the backbone of the T442 residues near the innermost part of the P segments. The S6 segment is postulated to form two alpha helices. The first S6 helix packs next to the P segments in our models. The NMR structures of two scorpion toxins, charybdotoxin and agitoxin 2, have been docked into the models of the outer vestibules. The shape of the outer vestibule has been modeled so that specific toxin-channel residue-residue interactions correspond to those that have been identified experimentally.

  9. Increase in cytosolic Ca2+ produced by hypoxia and other depolarizing stimuli activates a non-selective cation channel in chemoreceptor cells of rat carotid body

    PubMed Central

    Kang, Dawon; Wang, Jiaju; Hogan, James O; Vennekens, Rudi; Freichel, Marc; White, Carl; Kim, Donghee

    2014-01-01

    The current model of O2 sensing by carotid body chemoreceptor (glomus) cells is that hypoxia inhibits the outward K+ current and causes cell depolarization, Ca2+ influx via voltage-dependent Ca2+ channels and a rise in intracellular [Ca2+] ([Ca2+]i). Here we show that hypoxia (<5% O2), in addition to inhibiting the two-pore domain K+ channels TASK-1/3 (TASK), indirectly activates an ∼20 pS channel in isolated glomus cells. The 20 pS channel was permeable to K+, Na+ and Cs+ but not to Cl− or Ca2+. The 20 pS channel was not sensitive to voltage. Inhibition of TASK by external acid, depolarization of glomus cells with high external KCl (20 mm) or opening of the Ca2+ channel with FPL64176 activated the 20 pS channel when 1 mm Ca2+ was present in the external solution. Ca2+ (10 μm) applied to the cytosolic side of inside-out patches activated the 20 pS channel. The threshold [Ca2+]i for activation of the 20 pS channel in cell-attached patches was ∼200 nm. The reversal potential of the 20 pS channel was estimated to be −28 mV. Our results reveal a sequential mechanism in which hypoxia (<5% O2) first inhibits the K+ conductance and then activates a Na+-permeable, non-selective cation channel via depolarization-induced rise in [Ca2+]i. Our results suggest that inhibition of K+ efflux and stimulation of Na+ influx both contribute to the depolarization of glomus cells during moderate to severe hypoxia. PMID:24591572

  10. Characterization of edible film fabricated with channel catfish (Ictalurus punctatus) gelatin extract using selected pretreatment methods.

    PubMed

    Zhang, S; Wang, Y; Herring, J L; Oh, J-H

    2007-11-01

    Farm-raised catfish are important to the economy of the southeastern states in the United States, and catfish processing produces about 55% of by-products for inexpensive sale. Therefore, the utilization of catfish by-products is of great interest to the catfish industry. The objectives of this research were to determine the optimum pretreatment method to extract catfish gelatin for edible film application, and to characterize physical, mechanical, and barrier properties of edible films fabricated with catfish skin gelatin. Catfish skins obtained from a local plant were treated with 6 selected pretreatment methods. The main extraction was performed with deionized water at 50 degrees C after pretreatment. The gelatin yield was calculated and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) was performed to characterize molecular weight (MW) profile. Color, tensile strength (TS), elongation, and water barrier property were determined to characterize the fabricated catfish gelatin films. From the results of gelatin yield, color, SDS-PAGE, as well as mechanical and barrier properties of the film, the pretreatment method with 0.25 M NaOH and 0.09 M acetic acid, followed by extraction at 50 degrees C for 3 h, was determined as the optimum extraction method. The catfish gelatin exhibited higher MW fractions than commercial mammalian gelatin. The catfish gelatin extracts possessed film-forming properties determined by TS, elongation, and water vapor permeability (WVP) comparable to those of commercial mammalian gelatin. The selected formula for catfish gelatin film was determined as 1% gelatin and 20% glycerol, resulting in greatest TS and lowest WVP.

  11. Tityus gamma toxin, a high affinity effector of the Na+ channel in muscle, with a selectivity for channels in the surface membrane.

    PubMed

    Barhanin, J; Ildefonse, M; Rougier, O; Sampaio, S V; Giglio, J R; Lazdunski, M

    1984-01-01

    Toxin gamma from the venom of Tityus serrulatus scorpion produces a partial block of the surface Na+ channel in frog muscle. This block occurs with no change in the voltage-dependence or in the kinetics of the remaining surface Na+ current. The partial blockade of Na+ channel activity occurs with no change in tubular Na+ currents nor in twitch tension. The maximum effect of the toxin is attained at concentrations as low as 3 X 10(-10) M. Hyperpolarization to potentials more negative than the resting potential (E = -90 mV) reduces or abolishes the effect of the toxin. Radioiodinated toxin gamma binds to frog muscle membranes with a very high affinity corresponding to a dissociation constant of about 1 X 10(-11) M. Data obtained with both rabbit and frog muscle indicate that toxin gamma is specific for Na+ channels in surface membranes. Toxin gamma does not seem to bind to Na+ channels in T-tubule membranes. The biochemical data are in good agreement with electrophysiological studies and data on contraction. There is one Tityus gamma toxin binding site per tetrodotoxin binding site in surface membranes. Competition experiments have confirmed that Tityus gamma toxin binds to a new toxin receptor site on the Na+ channel structure. This site is the same that the toxin II from Centruroides suffusus binding site, but this toxin has 100 times less affinity for the Na+ channel than Tityus gamma toxin.

  12. Residues beyond the selectivity filter of the K+ channel kir2.1 regulate permeation and block by external Rb+ and Cs+.

    PubMed

    Thompson, G A; Leyland, M L; Ashmole, I; Sutcliffe, M J; Stanfield, P R

    2000-07-15

    1. Kir2.1 channels are blocked by Rb+ and Cs+ in a voltage-dependent manner, characteristic of many inward rectifier K+ channels. Mutation of Ser165 in the transmembrane domain M2 to Leu (S165L) abolished Rb+ blockage and lowered Cs+ blocking affinity. At negative voltages Rb+ carried large inward currents. 2. A model of the Kir2.1 channel, built by homology with the structure of the Streptomyces lividans K+ channel KcsA, suggested the existence of an intersubunit hydrogen bond between Ser165 and Thr141 in the channel pore-forming P-region that helps stabilise the structure of this region. However, mutations of Thr141 and Ser165 did not produce effects consistent with a hydrogen bond between these residues being essential for blockage. 3. An alternative alignment between the M2 regions of Kir2.1 and KcsA suggested that Ser165 is itself a pore-lining residue, more directly affecting blockage. We were able to replace Ser165 with a variety of polar and non-polar residues, consistent with this residue being pore lining. Some of these changes affected channel blockage. 4. We tested the hypothesis that Asp172 - a residue implicated in channel gating by polyamines - formed an additional selectivity filter by using the triple mutant T141A/S165L/D172N. Large Rb+ and Cs+ currents were measured in this mutant. 5. We propose that both Thr141 and Ser165 are likely to provide binding sites for monovalent blocking cations in wild-type channels. These residues lie beyond the carbonyl oxygen tunnel thought to form the channel selectivity filter, which the blocking cations must therefore traverse.

  13. Ultrafast nuclear dynamics in halomethanes studied with time-resolved Coulomb explosion imaging and channel-selective Fourier spectroscopy

    NASA Astrophysics Data System (ADS)

    Malakar, Y.; Kaderiya, B.; Pearson, W. L.; Ziaee, F.; Kanaka Raju, P.; Zohrabi, M.; Jensen, K.; Rajput, J.; Ben-Itzhak, I.; Rolles, D.; Rudenko, A.

    2016-05-01

    Halomethanes have recently attracted considerable attention since they often serve as prototype systems for laser-controlled chemistry (e.g., selective bond breaking or concerted elimination reactions), and are important molecules in atmospheric chemistry. Here we combine a femtosecond laser pump-probe setup with coincident 3D ion momentum imaging apparatus to study strong-field induced nuclear dynamics in methane and several of its halogenated derivatives (CH3 I, CH2 I2, CH2 ICl). We apply a time-resolved Coulomb explosion imaging technique to map the nuclear motion on both, bound and continuum potential surfaces, disentangle different fragmentation pathways and, for halogenated molecules, observe clear signatures of vibrational wave packets in neutral or ionized states. Channel-selective and kinetic-energy resolved Fourier analysis of these data allows for unique identification of different electronic states and vibrational modes responsible for a particular structure. Supported by the Chemical Sciences, Geosciences, and Biosciences Division, Office of Basic Energy Sciences, Office of Science, U. S. DOE. K. R. P. and W. L. P. supported by NSF Award No. IIA-143049. K.J. supported by the NSF-REU Grant No. PHYS-1461251.

  14. A selective Gβγ-linked intracellular mechanism for modulation of a ligand-gated ion channel by ethanol

    PubMed Central

    Yevenes, Gonzalo E.; Moraga-Cid, Gustavo; Peoples, Robert W.; Schmalzing, Günther; Aguayo, Luis G.

    2008-01-01

    The current understanding about ethanol effects on the ligand-gated ion channel (LGIC) superfamily has been restricted to identify potential binding sites within transmembrane (TM) domains in the Cys-loop family. Here, we demonstrate a key role of the TM3–4 intracellular loop and Gβγ signaling for potentiation of glycine receptors (GlyRs) by ethanol. We discovered 2 motifs within the large intracellular loop of the GlyR α1 subunit that are critical for the actions of pharmacological concentrations of ethanol. Significantly, the sites were ethanol-specific because they did not alter the sensitivity to general anesthetics, neurosteroids, or longer n-alcohols. Furthermore, Gβγ scavengers selectively attenuated the ethanol effects on recombinant and native neuronal GlyRs. These results show a selective mechanism for low-ethanol concentration effects on the GlyR and provide a mechanism on ethanol pharmacology, which may be applicable to other LGIC members. Moreover, these data provide an opportunity to develop new genetically modified animal models and novel drugs to treat alcohol-related medical concerns. PMID:19074265

  15. Ferrocene-based heteroditopic receptors displaying high selectivity toward lead and mercury metal cations through different channels.

    PubMed

    Alfonso, María; Tárraga, Alberto; Molina, Pedro

    2011-02-04

    The synthesis and electrochemical, optical, and ion-sensing properties of ferrocene-imidazophenazine dyads are presented. Dyad 4 behaves as a highly selective chemosensor molecule for Pb(2+) cations in CH(3)-CN/H(2)O (9:1). The emission spectrum (λ(exc) = 317 nm) undergoes an important chelation-enhanced fluorescence effect (CHEF = 47) in the presence of Pb(2+) cations, a new low-energy band appeared at 502 nm, in its UV/vis spectrun, and the oxidation redox peak is anodically shifted (ΔE(1/2) = 230 mV). The presence of Hg(2+) cations also induced a perturbation of the redox potencial although in less extension than those found with Pb(2+) cations. Dyad 7, bearing two fused pyridine rings, has shown its ability for sensing Hg(2+) cations selectively through three channels: electrochemical, optical, and fluorescent; the oxidation redox peak is anodically shifted (ΔE(1/2) = 200 mV), a new low-energy band of the absorption spectrum appeared at 485 nm, and the emission spectrum (λ(exc) = 340 nm) is red-shifted by 32 nm accompanied by a remarkable chelation-enhanced fluorescent effect (CHEF = 165). Linear sweep voltammetry revealed that Cu(2+) cations induced oxidation of the ferrocene unit in both dyads. (1)H NMR studies have been carried out to obtain information about the molecular sites which are involved in the binding process.

  16. Selective recognition and discrimination of water-soluble azo dyes by a seven-channel molecularly imprinted polymer sensor array.

    PubMed

    Long, Zerong; Lu, Yi; Zhang, Mingliang; Qiu, Hongdeng

    2014-10-01

    A seven-channel molecularly imprinted polymer sensor array was prepared and characterized by scanning electron microscopy, Fourier transform infrared spectroscopy, UV-Vis spectroscopy, and nitrogen physisorption studies. The results revealed that the imprinted polymers have distinct-binding affinities from those of structurally similar azo dyes. Analysis of the UV-Vis spectral response patterns of the seven dye analytes against the imprinted polymer array suggested that the different selectivity patterns of the array were closely connected to the imprinting process. To evaluate the effectiveness of the array format, the binding of a series of analytes was individually measured for each of the seven polymers, made with different templates (including one control polymer synthesized without the use of a template). The response patterns of the array to the selected azo dyes were processed by canonical discriminant analysis. The results showed that the molecularly imprinted array was able to discriminate each analyte with 100% accuracy. Moreover, the azo dyes in two real samples, spiked chrysoidin in smoked bean curd extract and Fanta lime soda (containing tartrazine), were successfully classified by the array.

  17. Measurement of Doubly Charged Ions in Ion Thruster Plumes

    NASA Technical Reports Server (NTRS)

    Williams, George J., Jr.; Domonkos, Matthew T.; Chavez, Joy M.

    2002-01-01

    The ratio of doubly to singly charged ions was measured in the plumes of a 30 cm and of a 40 cm ion thruster. The measured ratio was correlated with observed erosion rates and thruster operating conditions. The measured and calculated erosion rates paralleled variation in the j(sup ++)/j(sup +) ratio and indicated that the erosion was dominated by Xe III. Simple models of cathode potential surfaces which were developed in support of this work were in agreement with this conclusion and provided a predictive capability of the erosion given the ratio of doubly to singly charged ion currents.

  18. A mathematical model for the doubly fed wound rotor generator

    NASA Technical Reports Server (NTRS)

    Brady, F. J.

    1983-01-01

    A mathematical analysis of a doubly-fed wound rotor machine used as a constant frequency generator is presented. The purpose of this analysis is to derive a consistent set of circuit equations which produce constant stator frequency and constant stator voltage. Starting with instantaneous circuit equations, the necessary rotor voltages and currents are derived. The model, thus obtained, is assumed to be valid, since the resulting relationships between mechanical power and active volt-amperes agrees with the results of others. In addition, the model allows for a new interpretation of the power flow in the doubly-fed generator.

  19. Search for doubly charged Higgs bosons at LEP2

    NASA Astrophysics Data System (ADS)

    DELPHI Collaboration; Abdallah, J.; Abreu, P.; Adam, W.; Adzic, P.; Albrecht, T.; Alderweireld, T.; Alemany-Fernandez, R.; Allmendinger, T.; Allport, P. P.; Amaldi, U.; Amapane, N.; Amato, S.; Anashkin, E.; Andreazza, A.; Andringa, S.; Anjos, N.; Antilogus, P.; Apel, W.-D.; Arnoud, Y.; Ask, S.; Asman, B.; Augustin, J. E.; Augustinus, A.; Baillon, P.; Ballestrero, A.; Bambade, P.; Barbier, R.; Bardin, D.; Barker, G.; Baroncelli, A.; Battaglia, M.; Baubillier, M.; Becks, K.-H.; Begalli, M.; Behrmann, A.; Ben-Haim, E.; Benekos, N.; Benvenuti, A.; Berat, C.; Berggren, M.; Berntzon, L.; Bertrand, D.; Besancon, M.; Besson, N.; Bloch, D.; Blom, M.; Bluj, M.; Bonesini, M.; Boonekamp, M.; Booth, P. S. L.; Borisov, G.; Botner, O.; Bouquet, B.; Bowcock, T. J. V.; Boyko, I.; Bracko, M.; Brenner, R.; Brodet, E.; Bruckman, P.; Brunet, J. M.; Bugge, L.; Buschmann, P.; Calvi, M.; Camporesi, T.; Canale, V.; Carena, F.; Castro, N.; Cavallo, F.; Chapkin, M.; Charpentier, Ph.; Checchia, P.; Chierici, R.; Chliapnikov, P.; Chudoba, J.; Chung, S. U.; Cieslik, K.; Collins, P.; Contri, R.; Cosme, G.; Cossutti, F.; Costa, M. J.; Crawley, B.; Crennell, D.; Cuevas, J.; D'Hondt, J.; Dalmau, J.; da Silva, T.; da Silva, W.; della Ricca, G.; de Angelis, A.; de Boer, W.; de Clercq, C.; de Lotto, B.; de Maria, N.; de Min, A.; de Paula, L.; di Ciaccio, L.; di Simone, A.; Doroba, K.; Drees, J.; Dris, M.; Eigen, G.; Ekelof, T.; Ellert, M.; Elsing, M.; Espirito Santo, M. C.; Fanourakis, G.; Fassouliotis, D.; Feindt, M.; Fernandez, J.; Ferrer, A.; Ferro, F.; Flagmeyer, U.; Foeth, H.; Fokitis, E.; Fulda-Quenzer, F.; Fuster, J.; Gandelman, M.; Garcia, C.; Gavillet, Ph.; Gazis, E.; Geralis, T.; Gokieli, R.; Golob, B.; Gomez-Ceballos, G.; Goncalves, P.; Graziani, E.; Grosdidier, G.; Grzelak, K.; Guy, J.; Haag, C.; Hallgren, A.; Hamacher, K.; Hamilton, K.; Hansen, J.; Haug, S.; Hauler, F.; Hedberg, V.; Hennecke, M.; Herr, H.; Hoffman, J.; Holmgren, S.-O.; Holt, P. J.; Houlden, M. A.; Hultqvist, K.; Jackson, J. N.; Jarlskog, G.; Jarry, P.; Jeans, D.; Johansson, E. K.; Johansson, P. D.; Jonsson, P.; Joram, C.; Jungermann, L.; Kapusta, F.; Katsanevas, S.; Katsoufis, E.; Kernel, G.; Kersevan, B. P.; Kiiskinen, A.; King, B. T.; Kjaer, N. J.; Kluit, P.; Kokkinias, P.; Kourkoumelis, C.; Kouznetsov, O.; Krumstein, Z.; Kucharczyk, M.; Lamsa, J.; Leder, G.; Ledroit, F.; Leinonen, L.; Leitner, R.; Lemonne, J.; Lepeltier, V.; Lesiak, T.; Liebig, W.; Liko, D.; Lipniacka, A.; Lopes, J. H.; Lopez, J. M.; Loukas, D.; Lutz, P.; Lyons, L.; MacNaughton, J.; Malek, A.; Maltezos, S.; Mandl, F.; Marco, J.; Marco, R.; Marechal, B.; Margoni, M.; Marin, J.-C.; Mariotti, C.; Markou, A.; Martinez-Rivero, C.; Masik, J.; Mastroyiannopoulos, N.; Matorras, F.; Matteuzzi, C.; Mazzucato, F.; Mazzucato, M.; Mc Nulty, R.; Meroni, C.; Meyer, W. T.; Migliore, E.; Mitaroff, W.; Mjoernmark, U.; Moa, T.; Moch, M.; Moenig, K.; Monge, R.; Montenegro, J.; Moraes, D.; Moreno, S.; Morettini, P.; Mueller, U.; Muenich, K.; Mulders, M.; Mundim, L.; Murray, W.; Muryn, B.; Myatt, G.; Myklebust, T.; Nassiakou, M.; Navarria, F.; Nawrocki, K.; Nicolaidou, R.; Nikolenko, M.; Oblakowska-Mucha, A.; Obraztsov, V.; Olshevski, A.; Onofre, A.; Orava, R.; Osterberg, K.; Ouraou, A.; Oyanguren, A.; Paganoni, M.; Paiano, S.; Palacios, J. P.; Palka, H.; Papadopoulou, Th. D.; Pape, L.; Parkes, C.; Parodi, F.; Parzefall, U.; Passeri, A.; Passon, O.; Peralta, L.; Perepelitsa, V.; Perrotta, A.; Petrolini, A.; Piedra, J.; Pieri, L.; Pierre, F.; Pimenta, M.; Piotto, E.; Podobnik, T.; Poireau, V.; Pol, M. E.; Polok, G.; Poropat, P.; Pozdniakov, V.; Pukhaeva, N.; Pullia, A.; Rames, J.; Ramler, L.; Read, A.; Rebecchi, P.; Rehn, J.; Reid, D.; Reinhardt, R.; Renton, P.; Richard, F.; Ridky, J.; Rivero, M.; Rodriguez, D.; Romero, A.; Ronchese, P.; Rosenberg, E.; Roudeau, P.; Rovelli, T.; Ruhlmann-Kleider, V.; Ryabtchikov, D.; Sadovsky, A.; Salmi, L.; Salt, J.; Savoy-Navarro, A.; Schwickerath, U.; Segar, A.; Sekulin, R.; Siebel, M.; Sisakian, A.; Smadja, G.; Smirnova, O.; Sokolov, A.; Sopczak, A.; Sosnowski, R.; Spassov, T.; Stanitzki, M.; Stocchi, A.; Strauss, J.; Stugu, B.; Szczekowski, M.; Szeptycka, M.; Szumlak, T.; Tabarelli, T.; Taffard, A. C.; Tegenfeldt, F.; Timmermans, J.; Tkatchev, L.; Tobin, M.; Todorovova, S.; Tomaradze, A.; Tome, B.; Tonazzo, A.; Tortosa, P.; Travnicek, P.; Treille, D.; Tristram, G.; Trochimczuk, M.; Troncon, C.; Turluer, M.-L.; Tyapkin, I. A.; Tyapkin, P.; Tzamarias, S.; Uvarov, V.; Valenti, G.; van Dam, P.; van Eldik, J.; van Lysebetten, A.; van Remortel, N.; van Vulpen, I.; Vegni, G.; Veloso, F.; Venus, W.; Verbeure, F.; Verdier, P.; Verzi, V.; Vilanova, D.; Vitale, L.; Vrba, V.; Wahlen, H.; Washbrook, A. J.; Weiser, C.; Wicke, D.; Wickens, J.; Wilkinson, G.; Winter, M.; Witek, M.; Yushchenko, O.; Zalewska, A.; Zalewski, P.; Zavrtanik, D.; Zimin, N. I.; Zintchenko, A.; Zupan, M.

    2003-01-01

    A search for pair-produced doubly charged Higgs bosons has been performed using the data collected by the DELPHI detector at LEP at centre-of-mass energies between 189 and 209 GeV. No excess is observed in the data with respect to the Standard Model background. A lower limit for the mass of 97.3 GeV/c2 at the 95% confidence level has been set for doubly charged Higgs bosons in left-right symmetric models for any value of the Yukawa coupling between the Higgs bosons and the /τ leptons.

  20. Search for doubly charged Higgs bosons at LEP2

    NASA Astrophysics Data System (ADS)

    Abdallah, J.; Abreu, P.; Adam, W.; Adzic, P.; Albrecht, T.; Alderweireld, T.; Alemany-Fernandez, R.; Allmendinger, T.; Allport, P. P.; Amaldi, U.; Amapane, N.; Amato, S.; Anashkin, E.; Andreazza, A.; Andringa, S.; Anjos, N.; Antilogus, P.; Apel, W.-D.; Arnoud, Y.; Ask, S.; Asman, B.; Augustin, J. E.; Augustinus, A.; Baillon, P.; Ballestrero, A.; Bambade, P.; Barbier, R.; Bardin, D.; Barker, G.; Baroncelli, A.; Battaglia, M.; Baubillier, M.; Becks, K.-H.; Begalli, M.; Behrmann, A.; Ben-Haim, E.; Benekos, N.; Benvenuti, A.; Berat, C.; Berggren, M.; Berntzon, L.; Bertrand, D.; Besancon, M.; Besson, N.; Bloch, D.; Blom, M.; Bluj, M.; Bonesini, M.; Boonekamp, M.; Booth, P. S. L.; Borisov, G.; Botner, O.; Bouquet, B.; Bowcock, T. J. V.; Boyko, I.; Bracko, M.; Brenner, R.; Brodet, E.; Bruckman, P.; Brunet, J. M.; Bugge, L.; Buschmann, P.; Calvi, M.; Camporesi, T.; Canale, V.; Carena, F.; Castro, N.; Cavallo, F.; Chapkin, M.; Charpentier, Ph.; Checchia, P.; Chierici, R.; Chliapnikov, P.; Chudoba, J.; Chung, S. U.; Cieslik, K.; Collins, P.; Contri, R.; Cosme, G.; Cossutti, F.; Costa, M. J.; Crawley, B.; Crennell, D.; Cuevas, J.; D'Hondt, J.; Dalmau, J.; da Silva, T.; da Silva, W.; Della Ricca, G.; de Angelis, A.; de Boer, W.; de Clercq, C.; de Lotto, B.; de Maria, N.; de Min, A.; de Paula, L.; di Ciaccio, L.; di Simone, A.; Doroba, K.; Drees, J.; Dris, M.; Eigen, G.; Ekelof, T.; Ellert, M.; Elsing, M.; Espirito Santo, M. C.; Fanourakis, G.; Fassouliotis, D.; Feindt, M.; Fernandez, J.; Ferrer, A.; Ferro, F.; Flagmeyer, U.; Foeth, H.; Fokitis, E.; Fulda-Quenzer, F.; Fuster, J.; Gandelman, M.; Garcia, C.; Gavillet, Ph.; Gazis, E.; Geralis, T.; Gokieli, R.; Golob, B.; Gomez-Ceballos, G.; Goncalves, P.; Graziani, E.; Grosdidier, G.; Grzelak, K.; Guy, J.; Haag, C.; Hallgren, A.; Hamacher, K.; Hamilton, K.; Hansen, J.; Haug, S.; Hauler, F.; Hedberg, V.; Hennecke, M.; Herr, H.; Hoffman, J.; Holmgren, S.-O.; Holt, P. J.; Houlden, M. A.; Hultqvist, K.; Jackson, J. N.; Jarlskog, G.; Jarry, P.; Jeans, D.; Johansson, E. K.; Johansson, P. D.; Jonsson, P.; Joram, C.; Jungermann, L.; Kapusta, F.; Katsanevas, S.; Katsoufis, E.; Kernel, G.; Kersevan, B. P.; Kiiskinen, A.; King, B. T.; Kjaer, N. J.; Kluit, P.; Kokkinias, P.; Kourkoumelis, C.; Kouznetsov, O.; Krumstein, Z.; Kucharczyk, M.; Lamsa, J.; Leder, G.; Ledroit, F.; Leinonen, L.; Leitner, R.; Lemonne, J.; Lepeltier, V.; Lesiak, T.; Liebig, W.; Liko, D.; Lipniacka, A.; Lopes, J. H.; Lopez, J. M.; Loukas, D.; Lutz, P.; Lyons, L.; MacNaughton, J.; Malek, A.; Maltezos, S.; Mandl, F.; Marco, J.; Marco, R.; Marechal, B.; Margoni, M.; Marin, J.-C.; Mariotti, C.; Markou, A.; Martinez-Rivero, C.; Masik, J.; Mastroyiannopoulos, N.; Matorras, F.; Matteuzzi, C.; Mazzucato, F.; Mazzucato, M.; Mc Nulty, R.; Meroni, C.; Meyer, W. T.; Migliore, E.; Mitaroff, W.; Mjoernmark, U.; Moa, T.; Moch, M.; Moenig, K.; Monge, R.; Montenegro, J.; Moraes, D.; Moreno, S.; Morettini, P.; Mueller, U.; Muenich, K.; Mulders, M.; Mundim, L.; Murray, W.; Muryn, B.; Myatt, G.; Myklebust, T.; Nassiakou, M.; Navarria, F.; Nawrocki, K.; Nicolaidou, R.; Nikolenko, M.; Oblakowska-Mucha, A.; Obraztsov, V.; Olshevski, A.; Onofre, A.; Orava, R.; Osterberg, K.; Ouraou, A.; Oyanguren, A.; Paganoni, M.; Paiano, S.; Palacios, J. P.; Palka, H.; Papadopoulou, Th. D.; Pape, L.; Parkes, C.; Parodi, F.; Parzefall, U.; Passeri, A.; Passon, O.; Peralta, L.; Perepelitsa, V.; Perrotta, A.; Petrolini, A.; Piedra, J.; Pieri, L.; Pierre, F.; Pimenta, M.; Piotto, E.; Podobnik, T.; Poireau, V.; Pol, M. E.; Polok, G.; Poropat, P.; Pozdniakov, V.; Pukhaeva, N.; Pullia, A.; Rames, J.; Ramler, L.; Read, A.; Rebecchi, P.; Rehn, J.; Reid, D.; Reinhardt, R.; Renton, P.; Richard, F.; Ridky, J.; Rivero, M.; Rodriguez, D.; Romero, A.; Ronchese, P.; Rosenberg, E.; Roudeau, P.; Rovelli, T.; Ruhlmann-Kleider, V.; Ryabtchikov, D.; Sadovsky, A.; Salmi, L.; Salt, J.; Savoy-Navarro, A.; Schwickerath, U.; Segar, A.; Sekulin, R.; Siebel, M.; Sisakian, A.; Smadja, G.; Smirnova, O.; Sokolov, A.; Sopczak, A.; Sosnowski, R.; Spassov, T.; Stanitzki, M.; Stocchi, A.; Strauss, J.; Stugu, B.; Szczekowski, M.; Szeptycka, M.; Szumlak, T.; Tabarelli, T.; Taffard, A. C.; Tegenfeldt, F.; Timmermans, J.; Tkatchev, L.; Tobin, M.; Todorovova, S.; Tomaradze, A.; Tome, B.; Tonazzo, A.; Tortosa, P.; Travnicek, P.; Treille, D.; Tristram, G.; Trochimczuk, M.; Troncon, C.; Turluer, M.-L.; Tyapkin, I. A.; Tyapkin, P.; Tzamarias, S.; Uvarov, V.; Valenti, G.; van Dam, P.; van Eldik, J.; van Lysebetten, A.; van Remortel, N.; van Vulpen, I.; Vegni, G.; Veloso, F.; Venus, W.; Verbeure, F.; Verdier, P.; Verzi, V.; Vilanova, D.; Vitale, L.; Vrba, V.; Wahlen, H.; Washbrook, A. J.; Weiser, C.; Wicke, D.; Wickens, J.; Wilkinson, G.; Winter, M.; Witek, M.; Yushchenko, O.; Zalewska, A.; Zalewski, P.; Zavrtanik, D.; Zimin, N. I.; Zintchenko, A.; Zupan, M.; Delphi Collaboration

    2003-01-01

    A search for pair-produced doubly charged Higgs bosons has been performed using the data collected by the DELPHI detector at LEP at centre-of-mass energies between 189 and 209 GeV. No excess is observed in the data with respect to the Standard Model background. A lower limit for the mass of 97.3 GeV/c2 at the 95% confidence level has been set for doubly charged Higgs bosons in left-right symmetric models for any value of the Yukawa coupling between the Higgs bosons and the τ leptons.

  1. Ion channels of N-terminally linked alamethicin dimers: enhancement of cation-selectivity by substitution of Glu for Gln at position 7.

    PubMed

    Okazaki, Takashi; Nagaoka, Yasuo; Asami, Koji

    2007-05-01

    Alamethicin forms voltage-gated ion channels that have moderate cation-selectivity. The enhancement of the cation-selectivity by introducing negatively charged residues at positions 7 and 18 has been studied using the tethered homodimers of alamethicin with Q7 and E18 (di-alm-Q7E18) and its analog with E7 and Q18 (di-alm-E7Q18). In the dimeric peptides, monomer peptides are linked at the N-termini by a disulfide bond. Both the peptides formed long lasting ion channels at cis-positive voltages when added to the cis-side membrane. Their long open duration enabled us to obtain current-voltage (I-V(m)) relations and reversal potentials at the single-channel level by applying a voltage ramp during the channel opening. The reversal potentials measured in asymmetric KCl solutions indicated that ionized E7 provided strong cation-selectivity, whereas ionized E18 little influenced the charge selectivity. This was also the case for the macroscopic charge selectivity determined from the reversal potentials obtained by the macroscopic I-V(m) measurements. The results are accounted for by stronger electrostatic interactions between permeant ions and negatively charged residues at the narrowest part of the pore than at the pore mouth.

  2. Relationship between expression of muscle-specific uncoupling protein 2 messenger RNA and genetic selection toward growth in channel catfish.

    PubMed

    Kobayashi, Y; Peterson, B C; Waldbieser, G C

    2015-04-01

    This study tested the hypothesis that increased growth in channel catfish is associated with expression of the genes that code for uncoupling proteins (UCP) 2 and 3, members of the mitochondrial channel proteins involved in nutrient sensing and metabolism. The specific objective was to contrast the levels of UCP2 messenger RNA (mRNA) in fast vs slow growing catfish as well as in fed vs fasted catfish. Two distinct UCP2 transcripts were identified and named UCP2a and UCP2b, respectively. Nucleotide and amino acid sequence of catfish UCP2s were highly similar to UCP2 and other UCPs from other fish and mammals (>75%). Expression of UCP2a mRNA was detectable at very low levels in various metabolically active tissues, whereas the expression of UCP2b mRNA was readily detectable in the muscle and heart. In a 21-wk feeding study, fish that grew faster had a greater percent body fat at the end of the study (P < 0.01). Expression of UCP2b mRNA tended to be lower (P < 0.10) in fast growing fish in the middle of the study although levels were similar at the beginning and the end of the study. In the fed vs fasted study, expression of UCP2b mRNA in muscle was increased (P < 0.05) in fish assigned to 30 d of fasting. Our results suggest that, based on the nucleotide and amino acid sequence similarities and tissue mRNA distribution, catfish UCP2b may be the analog to UCP3. Moreover, our results suggest selection toward growth and associated fat accumulation appears to be independent of muscle UCP2b mRNA expression and UCP2b-mediated mechanisms.

  3. Positive selection on sperm ion channels in a brooding brittle star: consequence of life-history traits evolution.

    PubMed

    Weber, A A-T; Abi-Rached, L; Galtier, N; Bernard, A; Montoya-Burgos, J I; Chenuil, A

    2017-01-18

    Closely related species are key models to investigate mechanisms leading to reproductive isolation and early stages of diversification, also at the genomic level. The brittle star cryptic species complex Ophioderma longicauda encompasses the sympatric broadcast-spawning species C3 and the internal brooding species C5. Here, we used de novo transcriptome sequencing and assembly in two closely related species displaying contrasting reproductive modes to compare their genetic diversity and to investigate the role of natural selection in reproductive isolation. We reconstructed 20 146 and 22 123 genes for C3 and C5, respectively, and characterized a set of 12 229 orthologs. Genetic diversity was 1.5-2 times higher in C3 compared to C5, confirming that species with low parental investment display higher levels of genetic diversity. Forty-eight genes were the targets of positive diversifying selection during the evolution of the two species. Notably, two genes (NHE and TetraKCNG) are sperm-specific ion channels involved in sperm motility. Ancestral sequence reconstructions show that natural selection targeted the two genes in the brooding species. This may result from an adaptation to the novel environmental conditions surrounding sperm in the brooding species, either directly affecting sperm or via an increase in male/female conflict. This phenomenon could have promoted prezygotic reproductive isolation between C3 and C5. Finally, the sperm receptors to egg chemoattractants differed between C3 and C5 in the ligand-binding region. We propose that mechanisms of species-specific gamete recognition in brittle stars occur during sperm chemotaxis (sperm attraction towards the eggs), contrary to other marine invertebrates where prezygotic barriers to interspecific hybridization typically occur before sperm-egg fusion.

  4. Design, synthesis and pharmacological evaluation of pyrimidobenzothiazole-3-carboxylate derivatives as selective L-type calcium channel blockers.

    PubMed

    Chikhale, Rupesh; Thorat, Sonali; Pant, Amit; Jadhav, Ankush; Thatipamula, Krishna Chary; Bansode, Ratnadeep; Bhargavi, G; Karodia, Nazira; Rajasekharan, M V; Paradkar, Anant; Khedekar, Pramod

    2015-10-15

    L-type voltage gated calcium channels play essential role in contraction of various skeletal and vascular smooth muscles, thereby plays important role in regulating blood pressure. Dihydropyridine receptors have been targeted for development of newer antihypertensive agents, one of the structurally analogs nucleus dihydropyrimidines have been reported earlier by us as a potential agent toward development of calcium channel modulator. A pre-synthetic QSAR was run and on the basis of structure activity relationship a series of twenty three molecules was synthesized and studied by myosin light chain kinase assay (MLCK), Angiotensin Converting Enzyme (ACE) colorimetric assay, non-invasive blood pressure (NIBP) and invasive blood pressure (IBP) methods. Molecules with significant efficacy were studied for their single crystal X-ray diffraction, molecular docking, molecular dynamics and post-synthetic QSAR. The NIBP and IBP methods screened molecules with better percentage inhibition versus time compared to standard drug Nifedipine. The lead compound ethyl 2-methyl-4-(3-nitrophenyl)-4H-pyrimido [2,1-b] [1,3] benzothiazole-3-carboxylate (26) presented a triclinic structure with polymeric chain packing in lattice. 26 exhibited IC50 on MLCK assay of 2.1±1.7 μM with selectivity of L-type calcium channels and comparative to Nifedipine. It offered satisfactory physicochemical properties with partition coefficient of (ClogP) 4.64. Its pharmacokinetic profile is also good with Cmax at 0.40 μg/ml by oral route with Tmax reaching in 0.5 h which means in 30 min. 26 also exhibits superior t1/2 of 5.4 h and oral bioavailability of (F) 56.75% with an AUC0-∞ of 0.84 μg h/ml. Molecular docking studies indicates toward the interaction of lead compound via hydrogen bonds with Lys144, Glu181 and Asp183, it forms the Van der Walls interactions with Ser18, Asp20, Asn187, Pro185, Glu180, Glu181 and Arg10 with Glide score and Glide energy to be -3.602 and -47.098, respectively. Post

  5. Subtype-selective reconstitution of synaptic transmission in sympathetic ganglion neurons by expression of exogenous calcium channels

    PubMed Central

    Mochida, Sumiko; Westenbroek, Ruth E.; Yokoyama, Charles T.; Itoh, Kanako; Catterall, William A.

    2003-01-01

    Fast cholinergic neurotransmission between superior cervical ganglion neurons (SCGNs) in cell culture is initiated by N-type Ca2+ currents through Cav2.2 channels. To test the ability of different Ca2+-channel subtypes to initiate synaptic transmission in these cells, SCGNs were injected with cDNAs encoding Cav1.2 channels, which conduct L-type currents, Cav2.1 channels, which conduct P/Q-type Ca2+ currents, and Cav2.3 channels, which conduct R-type Ca2+ currents. Exogenously expressed Cav2.1 channels were localized in nerve terminals, as assessed by immunocytochemistry with subtype-specific antibodies, and these channels effectively initiated synaptic transmission. Injection with cDNA encoding Cav2.3 channels yielded a lower level of presynaptic labeling and synaptic transmission, whereas injection with cDNA encoding Cav1.2 channels resulted in no presynaptic labeling and no synaptic transmission. Our results show that exogenously expressed Ca2+ channels can mediate synaptic transmission in SCGNs and that the specificity of reconstitution of neurotransmission (Cav2.1 > Cav2.3 ≫ Cav1.2) follows the same order as in neurons in vivo. The specificity of reconstitution of neurotransmission parallels the specificity of trafficking of these Cav channels to nerve terminals. PMID:12601155

  6. The Selective Nav1.7 Inhibitor, PF-05089771, Interacts Equivalently with Fast and Slow Inactivated Nav1.7 Channels.

    PubMed

    Theile, Jonathan W; Fuller, Matthew D; Chapman, Mark L

    2016-11-01

    Voltage-gated sodium (Nav) channel inhibitors are used clinically as analgesics and local anesthetics. However, the absence of Nav channel isoform selectivity of current treatment options can result in adverse cardiac and central nervous system side effects, limiting their therapeutic utility. Human hereditary gain- or loss-of-pain disorders have demonstrated an essential role of Nav1.7 sodium channels in the sensation of pain, thus making this channel an attractive target for new pain therapies. We previously identified a novel, state-dependent human Nav1.7 selective inhibitor (PF-05089771, IC50 = 11 nM) that interacts with the voltage-sensor domain (VSD) of domain IV. We further characterized the state-dependent interaction of PF-05089771 by systematically varying the voltage, frequency, and duration of conditioning prepulses to provide access to closed, open, and fast- or slow-inactivated states. The current study demonstrates that PF-05089771 exhibits a slow onset of block that is depolarization and concentration dependent, with a similarly slow recovery from block. Furthermore, the onset of block by PF-05089771 develops with similar rates using protocols that bias channels into predominantly fast- or slow-inactivated states, suggesting that channel inhibition is less dependent on the availability of a particular inactivated state than the relative time that the channel is depolarized. Taken together, the inhibitory profile of PF-05089771 suggests that a conformational change in the domain IV VSD after depolarization is necessary and sufficient to reveal a high-affinity binding site with which PF-05089771 interacts, stabilizing the channel in a nonconducting conformation from which recovery is slow.

  7. Doubly Lopsided Models From SUSY SU(N)

    SciTech Connect

    Barr, S. M.

    2008-11-23

    It is shown that the doubly lopsided mass matrices, which are known to give realistic patterns of quark and lepton masses and mixings, arise naturally in the context of supersymmetric grand unified models based on SU(N) with N>5. An SU(7) model is presented as an illustration.

  8. Band structure of doubly-odd nuclei around mass 130

    SciTech Connect

    Higashiyama, Koji; Yoshinaga, Naotaka

    2011-05-06

    Nuclear structure of the doublet bands in the doubly-odd nuclei with mass A{approx}130 is studied in terms of a pair-truncated shell model. The model reproduces quite well the energy levels of the doublet bands and the electromagnetic transitions. The analysis of the electromagnetic transitions reveals new band structure of the doublet bands.

  9. Phyla- and Subtype-Selectivity of CgNa, a Na Channel Toxin from the Venom of the Giant Caribbean Sea Anemone Condylactis Gigantea.

    PubMed

    Billen, Bert; Debaveye, Sarah; Béress, Lászlo; Garateix, Anoland; Tytgat, Jan

    2010-01-01

    Because of their prominent role in electro-excitability, voltage-gated sodium (Na(V)) channels have become the foremost important target of animal toxins. These toxins have developed the ability to discriminate between closely related Na(V) subtypes, making them powerful tools to study Na(V) channel function and structure. CgNa is a 47-amino acid residue type I toxin isolated from the venom of the Giant Caribbean Sea Anemone Condylactis gigantea. Previous studies showed that this toxin slows the fast inactivation of tetrodotoxin-sensitive Na(V) currents in rat dorsal root ganglion neurons. To illuminate the underlying Na(V) subtype-selectivity pattern, we have assayed the effects of CgNa on a broad range of mammalian isoforms (Na(V)1.2-Na(V)1.8) expressed in Xenopus oocytes. This study demonstrates that CgNa selectively slows the fast inactivation of rNa(V)1.3/β(1), mNa(V)1.6/β(1) and, to a lesser extent, hNa(V)1.5/β(1), while the other mammalian isoforms remain unaffected. Importantly, CgNa was also examined on the insect sodium channel DmNa(V)1/tipE, revealing a clear phyla-selectivity in the efficacious actions of the toxin. CgNa strongly inhibits the inactivation of the insect Na(V) channel, resulting in a dramatic increase in peak current amplitude and complete removal of fast and steady-state inactivation. Together with the previously determined solution structure, the subtype-selective effects revealed in this study make of CgNa an interesting pharmacological probe to investigate the functional role of specific Na(V) channel subtypes. Moreover, further structural studies could provide important information on the molecular mechanism of Na(V) channel inactivation.

  10. STIM1 regulates Ca2+ entry via arachidonate-regulated Ca2+-selective (ARC) channels without store depletion or translocation to the plasma membrane.

    PubMed

    Mignen, Olivier; Thompson, Jill L; Shuttleworth, Trevor J

    2007-03-15

    Recent studies have indicated a critical role for STIM (stromal interacting molecule) proteins in the regulation of the store-operated mode of receptor-activated Ca2+ entry. Current models emphasize the role of STIM located in the endoplasmic reticulum membrane, where a Ca2+-binding EF-hand domain within the N-terminal of the protein lies within the lumen and is thought to represent the sensor for the depletion of intracellular Ca2+ stores. Dissociation of Ca2+ from this domain induces the aggregation of STIM to regions of the ER immediately adjacent to the plasma membrane where it acts to regulate the activity of store-operated Ca2+ channels. However, the possible effects of STIM on other modes of receptor-activated Ca2+ entry have not been examined. Here we show that STIM1 also regulates the arachidonic-acid-regulated Ca2+-selective (ARC) channels - receptor-activated Ca2+ entry channels whose activation is entirely independent of store depletion. Regulation of the ARC channels by STIM1 does not involve dissociation of Ca2+ from the EF-hand, or any translocation of STIM1. Instead, a critical role of STIM1 resident in the plasma membrane is indicated. Thus, exposure of intact cells to an antibody targeting the extracellular N-terminal domain of STIM1 inhibits ARC channel activity without significantly affecting the store-operated channels. A similar specific inhibition of the ARC channels is seen in cells expressing a STIM1 construct in which the N-linked glycosylation sites essential for the constitutive cell surface expression of STIM1, were mutated. We conclude that, in contrast to store-operated channels, regulation of ARC channels by STIM1 depends exclusively on the pool of STIM1 constitutively residing in the plasma membrane. These data demonstrate that STIM1 is a more universal regulator of Ca2+ entry pathways than previously thought, and appears to have multiple modes of action.

  11. X-ray crystallographic and mass spectrometric structure determination and functional characterization of succinylated porin from Rhodobacter capsulatus: implications for ion selectivity and single-channel conductance.

    PubMed Central

    Przybylski, M.; Glocker, M. O.; Nestel, U.; Schnaible, V.; Blüggel, M.; Diederichs, K.; Weckesser, J.; Schad, M.; Schmid, A.; Welte, W.; Benz, R.

    1996-01-01

    The role of charges near the pore mouth has been discussed in theoretical work about ion channels. To introduce new negative charges in a channel protein, amino groups of porin from Rhodobacter capsulatus 37b4 were succinylated with succinic anhydride, and the precise extent and sites of succinylations and structures of the succinylporins determined by mass spectrometry and X-ray crystallography. Molecular weight and peptide mapping analyses using matrix-assisted laser desorption-ionization mass spectrometry identified selective succinylation of three lysine-epsilon-amino groups (Lys-46, Lys-298, Lys-300) and the N-terminal alpha-amino group. The structure of a tetra-succinylated porin (TS-porin) was determined to 2.4 A and was generally found unchanged in comparison to native porin to form a trimeric complex. All succinylated amino groups found in a mono/di-succinylated porin (MS-porin) and a TS-porin are localized at the inner channel surface and are solvent-accessible: Lys-46 is located at the channel constriction site, whereas Lys-298, Lys-300, and the N-terminus are all near the periplasmic entrance of the channel. The Lys-46 residue at the central constriction loop was modeled as succinyl-lysine from the electron density data and shown to bend toward the periplasmic pore mouth. The electrical properties of the MS-and TS-porins were determined by reconstitution into black lipid membranes, and showed a negative charge effect on ion transport and an increased cation selectivity through the porin channel. The properties of a typical general diffusion porin changed to those of a channel that contains point charges near the pore mouth. The single-channel conductance was no longer a linear function of the bulk aqueous salt concentration. The substantially higher cation selectivity of the succinylated porins compared with the native protein is consistent with the increase of negatively charged groups introduced. These results show tertiary structure-selective

  12. Voltage-gated Na+ channel II immunoreactivity is selectively up-regulated in hippocampal interneurons of seizure sensitive gerbils.

    PubMed

    Kim, Ji-Eun; Kwak, Sung-Eun; Choi, Hui-Chul; Song, Hong-Ki; Kim, Yeong-In; Jo, Seung-Mook; Kang, Tae-Cheon

    2008-06-27

    In the present study, we investigated the distribution of voltage-gated Na(+) channels (VGSCs) in the normal and epileptic hippocampus of gerbils (a genetic epilepsy model) in order to confirm the relationship between VGSC and seizure activity in these animals. There was no difference of VGSC I immunoreactivity in the hippocampus between seizure-resistant (SR) and seizure sensitive (SS) gerbils. VGSC II immunoreactivity was rarely detected in the perikarya of principal neurons and interneurons in the SR gerbil hippocampus. However, in the SS gerbil hippocampus, VGSC II immunoreactivity was densely observed in the somata of interneurons located in the stratum radiatum and stratum lacunosum-moleculare. Double immunofluorescent study showed immunoreactivity for calretinin (approximately 80% in VGSC II-positive neurons) or calbindin D-28k (approximately 20% in VGSC II-positive neurons) in VGSC II-immunoreactive neurons. VGSC II-immunoreactive neurons did not show parvalbumin immunoreactivity. These findings suggest that seizure activity in SS gerbils may be related to the selective hyperactivation of interneurons in stratum lacunosum-moleculare via the up-regulation of VGSC II expression, which leads to the disinhibition of CA1 pyramidal cells.

  13. Adaptive selective relaying in cooperative free-space optical systems over atmospheric turbulence and misalignment fading channels.

    PubMed

    Boluda-Ruiz, Rubén; García-Zambrana, Antonio; Castillo-Vázquez, Carmen; Castillo-Vázquez, Beatriz

    2014-06-30

    In this paper, a novel adaptive cooperative protocol with multiple relays using detect-and-forward (DF) over atmospheric turbulence channels with pointing errors is proposed. The adaptive DF cooperative protocol here analyzed is based on the selection of the optical path, source-destination or different source-relay links, with a greater value of fading gain or irradiance, maintaining a high diversity order. Closed-form asymptotic bit error-rate (BER) expressions are obtained for a cooperative free-space optical (FSO) communication system with Nr relays, when the irradiance of the transmitted optical beam is susceptible to either a wide range of turbulence conditions, following a gamma-gamma distribution of parameters α and β, or pointing errors, following a misalignment fading model where the effect of beam width, detector size and jitter variance is considered. A greater robustness for different link distances and pointing errors is corroborated by the obtained results if compared with similar cooperative schemes or equivalent multiple-input multiple-output (MIMO) systems. Simulation results are further demonstrated to confirm the accuracy and usefulness of the derived results.

  14. Effect of englitazone on KATP and calcium-activated non-selective cation channels in CRI-G1 insulin-secreting cells.

    PubMed

    Rowe, I C; Lee, K; Khan, R N; Ashford, M L

    1997-06-01

    1. The effects of englitazone sodium, an antidiabetic agent, on ion channel activity in the CRI-G1 insulin secreting cell line was examined by use of the patch clamp technique. 2. Application of englitazone to the outside of CRI-G1 cells in the whole-cell recording configuration produced concentration-dependent inhibition of KATP currents with an IC50 value of 8 microM. The inhibition of the K+ current was not affected by the removal of Mg2+ ions from or the addition of trypsin to the solution bathing the intracellular surface of the cell membrane. 3. Englitazone also inhibited KATP channel activity in recordings from inside out excise membrane patches. The concentration-dependence of inhibition was identical to that observed in whole-cell recordings and was voltage-independent. Single channel recordings confirmed that neither the absence or presence of Mg2+ ions nor the addition of trypsin at the intracellular surface of the membrane influenced the inhibition of KATP channels by englitazone. 4. Englitazone also inhibited Ca(2+)-activated non-selective cation (NSCa) channels in inside-out patches in a concentration-dependent and voltage-independent manner with an IC50 value of 10 microM. In comparison, the non-sulphonylurea KATP channel blocker ciclazindol produced a slight voltage-dependent inhibition of the NSCa channel at a concentration of 20 microM. 5. In whole-cell recordings englitazone, at a relatively high concentration (50 microM) in comparison with that required to block KATP and NSCa channels, inhibited voltage-activated Ca2+ currents by 33% but did not inhibit voltage-activated K+ and Na+ currents. 6. It is concluded that englitazone is a novel blocker of NSCa and KATP channels. The inhibition of KATP channels occurs following procedures that dissociate sulphonylurea receptor coupling to the channel. The equipotent and voltage-independent inhibition of NSCa and KATP channels by englitazone may indicate a common mechanism of block.

  15. Selective blocking effects of 4,9-anhydrotetrodotoxin, purified from a crude mixture of tetrodotoxin analogues, on NaV1.6 channels and its chemical aspects.

    PubMed

    Teramoto, Noriyoshi; Yotsu-Yamashita, Mari

    2015-02-12

    Tetrodotoxin (TTX) is a potent neurotoxin found in a number of marine creatures including the pufferfish, where it is synthesized by bacteria and accumulated through the food chain. It is a potent and selective blocker of some types of voltage-gated Na+ channel (NaV channel). 4,9-Anhydrotetrodotoxin (4,9-anhydroTTX) was purified from a crude mixture of TTX analogues (such as TTX, 4-epiTTX, 6-epiTTX, 11-oxoTTX and 11-deoxyTTX) by the use of liquid chromatography-fluorescence detection (LC-FLD) techniques. Recently, it has been reported that 4,9-anhydroTTX selectively blocks the activity of NaV1.6 channels with a blocking efficacy 40-160 times higher than that for other TTX-sensitive NaV1.x channel isoforms. However, little attention has been paid to the molecular properties of the α-subunit in NaV1.6 channels and the characteristics of binding of 4,9-anhydroTTX. From a functional point of view, it is important to determine the relative expression of NaV1.6 channels in a wide variety of tissues. The aim of this review is to discuss briefly current knowledge about the pharmacology of 4,9-anhydroTTX, and provide an analysis of the molecular structure of native NaV1.6 channels. In addition, chemical aspects of 4,9-anhydroTTX are briefly covered.

  16. Selective filling for patterning in microfluidic channels and integration of chromatography in "lab-on-a-chip" devices using sol-gel technology

    NASA Astrophysics Data System (ADS)

    Jindal, Rohit

    The last decade has seen tremendous advancement in the development of miniaturized chemical analysis system also known as "lab-on-a-chip". It is believed that the true potential of these devices will be achieved by integrating various functions such as separation, reaction, sensing, mixing, pumping, injection and detection onto a single chip. The ability to pattern different functionalities is indispensable for the development of highly integrated devices. In this work, a simple method based on the concept of selective filling is described for patterning in the microfluidic channels. It is based on the difference in the free energy of filling between an open and a covered part of the channel. This method was used for the integration of chromatography in the microfluidic devices. A chromatographic column was realized by utilizing sol-gel as an immobilization matrix for entrapping reversed phase chromatographic particles. Localization of the stationary phase was achieved using the selective filling technique. Channels were fabricated in quartz using photolithography and wet etching. Electroosmotic flow was used for manipulating fluid movement in the channels. Cross channel design was used for making a pulse injection of the solutes in the separation channel. An optical fiber setup was developed for carrying out on-chip UV absorbance detection. Stationary phase was created under different sol-gel synthesis conditions. It was established that the sol-gel synthesis carried out under acidic conditions provides the optimum synthesis conditions for creating separation column. Chromatographic performance of the stationary phase material was demonstrated by separating peptides present in a mixture. The sol-gel immobilization method was extended for the integration of micropump in the chip. The micropump enables pumping of the fluid in field free channels. Preliminary results, demonstrating the potential of carbon nanotubes as a support material in the microfluidic channels

  17. Single Residue Substitutions That Confer Voltage-Gated Sodium Ion Channel Subtype Selectivity in the NaV1.7 Inhibitory Peptide GpTx-1.

    PubMed

    Murray, Justin K; Long, Jason; Zou, Anruo; Ligutti, Joseph; Andrews, Kristin L; Poppe, Leszek; Biswas, Kaustav; Moyer, Bryan D; McDonough, Stefan I; Miranda, Les P

    2016-03-24

    There is interest in the identification and optimization of new molecular entities selectively targeting ion channels of therapeutic relevance. Peptide toxins represent a rich source of pharmacology for ion channels, and we recently reported GpTx-1 analogs that inhibit NaV1.7, a voltage-gated sodium ion channel that is a compelling target for improved treatment of pain. Here we utilize multi-attribute positional scan (MAPS) analoging, combining high-throughput synthesis and electrophysiology, to interrogate the interaction of GpTx-1 with NaV1.7 and related NaV subtypes. After one round of MAPS analoging, we found novel substitutions at multiple residue positions not previously identified, specifically glutamic acid at positions 10 or 11 or lysine at position 18, that produce peptides with single digit nanomolar potency on NaV1.7 and 500-fold selectivity against off-target sodium channels. Docking studies with a NaV1.7 homology model and peptide NMR structure generated a model consistent with the key potency and selectivity modifications mapped in this work.

  18. Historical Channel Adjustment and Estimates of Selected Hydraulic Values in the Lower Sabine River and Lower Brazos River Basins, Texas and Louisiana

    USGS Publications Warehouse

    Heitmuller, Franklin T.; Greene, Lauren E.

    2009-01-01

    The U.S. Geological Survey, in cooperation with the Texas Water Development Board, evaluated historical channel adjustment and estimated selected hydraulic values at U.S. Geological Survey streamflow-gaging stations in the lower Sabine River Basin in Texas and Louisiana and lower Brazos River Basin in Texas to support geomorphic assessments of the Texas Instream Flow Program. Channel attributes including cross-section geometry, slope, and planform change were evaluated to learn how each river's morphology changed over the years in response to natural and anthropogenic disturbances. Historical and contemporary cross-sectional channel geometries at several gaging stations on each river were compared, planform changes were assessed, and hydraulic values were estimated including mean flow velocity, bed shear stress, Froude numbers, and hydraulic depth. The primary sources of historical channel morphology information were U.S. Geological Survey hard-copy discharge-measurement field notes. Additional analyses were done using computations of selected flow hydraulics, comparisons of historical and contemporary aerial photographs, comparisons of historical and contemporary ground photographs, evaluations of how frequently stage-discharge rating curves were updated, reviews of stage-discharge relations for field measurements, and considerations of bridge and reservoir construction activities. Based on historical cross sections at three gaging stations downstream from Toledo Bend Reservoir, the lower Sabine River is relatively stable, but is subject to substantial temporary scour-and-fill processes during floods. Exceptions to this characterization of relative stability include an episode of channel aggradation at the Sabine River near Bon Wier, Texas, during the 1930s, and about 2 to 3 feet of channel incision at the Sabine River near Burkeville, Texas, since the late 1950s. The Brazos River, at gaging stations downstream from Waco, Texas, has adjusted to a combination of

  19. Relationship between expression of muscle-specific uncoupling protein 2 messenger RNA and genetic selection toward growth in channel catfish

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Uncoupling protein 2 is a member of the mitochondrial channel proteins that regulate the flow of hydrogen ions and ATP generation. The relationship between UCP2 and nutrient metabolism has been well-defined in humans but unclear in fish. We hypothesized that increased muscle growth in channel catf...

  20. Autodissociation of doubly charged water molecules

    NASA Astrophysics Data System (ADS)

    Scully, S. W. J.; Wyer, J. A.; Senthil, V.; Shah, M. B.; Montenegro, E. C.

    2006-04-01

    The electron impact dissociative double-ionization cross sections for H2O between 45 and 1500eV have been measured using time of flight mass spectrometry. The energy dependence of the H++OH+ and H++O+ ion pair production cross sections indicate that Auger-like autoionization following a vacancy in the 2a1 molecular orbital is the main double ionization channel at high velocities. In contrast to expectation, these findings show that dissociation through the H2O2+ precursor state is a significant process at high collision energies. Knowledge of this process is vital as it has a direct affect on the production of important molecular species, such as H2 , during water radiolysis. Branching ratios of the various fragments produced following both autoionization and double ionization have also been obtained.

  1. TRP Channels

    NASA Astrophysics Data System (ADS)

    Voets, Thomas; Owsianik, Grzegorz; Nilius, Bernd

    The TRP superfamily represents a highly diverse group of cation-permeable ion channels related to the product of the Drosophila trp (transient receptor potential) gene. The cloning and characterization of members of this cation channel family has experienced a remarkable growth during the last decade, uncovering a wealth of information concerning the role of TRP channels in a variety of cell types, tissues, and species. Initially, TRP channels were mainly considered as phospholipase C (PLC)-dependent and/or store-operated Ca2+-permeable cation channels. More recent research has highlighted the sensitivity of TRP channels to a broad array of chemical and physical stimuli, allowing them to function as dedicated biological sensors involved in processes ranging from vision to taste, tactile sensation, and hearing. Moreover, the tailored selectivity of certain TRP channels enables them to play key roles in the cellular uptake and/or transepithelial transport of Ca2+, Mg2+, and trace metal ions. In this chapter we give a brief overview of the TRP channel superfamily followed by a survey of current knowledge concerning their structure and activation mechanisms.

  2. Evidence for a common pharmacological interaction site on K(Ca)2 channels providing both selective activation and selective inhibition of the human K(Ca)2.1 subtype.

    PubMed

    Hougaard, Charlotte; Hammami, Sofia; Eriksen, Birgitte L; Sørensen, Ulrik S; Jensen, Marianne L; Strøbæk, Dorte; Christophersen, Palle

    2012-02-01

    We have previously identified Ser293 in transmembrane segment 5 as a determinant for selective K(Ca)2.1 channel activation by GW542573X (4-(2-methoxyphenylcarbamoyloxymethyl)-piperidine-1-carboxylic acid tert-butyl ester). Now we show that Ser293 mediates both activation and inhibition of K(Ca)2.1: CM-TPMF (N-{7-[1-(4-chloro-2-methylphenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N'-methoxy-formamidine) and B-TPMF (N-{7-[1-(4-tert-butyl-phenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N'-methoxy-formamidine), two newly identified and structurally related [1,2,4]triazolo[1,5-a]pyrimidines, act either as activators or as inhibitors of the human K(Ca)2.1 channel. Whereas (-)-CM-TPMF activates K(Ca)2.1 with an EC(50) value of 24 nM, (-)-B-TPMF inhibits the channel with an IC(50) value of 31 nM. In contrast, their (+)-enantiomers are 40 to 100 times less active. Both (-)-CM-TPMF and (-)-B-TPMF are subtype-selective, with 10- to 20-fold discrimination toward other K(Ca)2 channels and the K(Ca)3 channel. Coapplication experiments reveal competitive-like functional interactions between the effects of (-)-CM-TPMF and (-)-B-TPMF. Despite belonging to a different chemical class than GW542573X, the K(Ca)2.1 selectivity of (-)-CM-TPMF and (-)-B-TPMF depend critically on Ser293 as revealed by loss- and gain-of-function mutations. We conclude that compounds occupying the TPMF site may either positively or negatively influence the gating process depending on their substitution patterns. It is noteworthy that (-)-CM-TPMF is 10 times more potent on K(Ca)2.1 than NS309 (6,7-dichloro-1H-indole-2,3-dione 3-oxime), an unselective but hitherto the most potent K(Ca)3/K(Ca)2 channel activator. (-)-B-TPMF is the first small-molecule inhibitor with significant selectivity among the K(Ca)2 channel subtypes. In contrast to peptide blockers such as apamin and scyllatoxin, which preferentially affect K(Ca)2.2, (-)-B-TPMF exhibits K(Ca)2.1 selectivity. These high-affinity compounds

  3. A measurement of the top pair production cross-section in the dilepton channel using lepton plus track selection

    SciTech Connect

    Mills, Corrinne Elaine

    2007-06-01

    Using 1.1 fb-1 of data collected by the Collider Detector at Fermilab (CDF) from Run II of the Fermilab Tevatron, they measure the t$\\bar{t}$ production cross section in events with two leptons, significant missing transverse energy, and ≥ 2 jets. As the Run II dataset grows, more stringent tests of Standard Model predictions for the top quark sector are becoming possible. The dilepton channel, where both top quarks decay t → Wb → ℓvb, is of particular interest due to its high purity even in the absence of a b jet 'tagging' requirement. Use of an isolated track as the second lepton significant increases the dilepton acceptance, at the price of some increase in background, particular from W + jets events where one of the jets is identified as a lepton. With the amount of data available, it has been possible to improve the estimate of the contribution from that background, reflected in a reduced systematic uncertainty. Assuming a branching ratio of BR(W → ℓv) = 10.8% and a top mass of mt = 175 GeV/c2, the measured cross-section is σ(p$\\bar{p}$ → t$\\bar{t}$) = 8.3 ± 1.3(stat.) ± 0.7(syst.) ± 0.5(lumi.) pb. The result is consistent with the Standard Model prediction of 6.7$+0.7\\atop{-0.9}$ pb and represents a significant improvement in precision over previous results using this selection.

  4. C-Terminal residues in small potassium channel blockers OdK1 and OSK3 from scorpion venom fine-tune the selectivity.

    PubMed

    Kuzmenkov, Alexey I; Peigneur, Steve; Chugunov, Anton O; Tabakmakher, Valentin M; Efremov, Roman G; Tytgat, Jan; Grishin, Eugene V; Vassilevski, Alexander A

    2017-02-04

    We report isolation, sequencing, and electrophysiological characterization of OSK3 (α-KTx 8.8 in Kalium and Uniprot databases), a potassium channel blocker from the scorpion Orthochirus scrobiculosus venom. Using the voltage clamp technique, OSK3 was tested on a wide panel of 11 voltage-gated potassium channels expressed in Xenopus oocytes, and was found to potently inhibit Kv1.2 and Kv1.3 with IC50 values of ~331nM and ~503nM, respectively. OdK1 produced by the scorpion Odontobuthus doriae differs by just two C-terminal residues from OSK3, but shows marked preference to Kv1.2. Based on the charybdotoxin-potassium channel complex crystal structure, a model was built to explain the role of the variable residues in OdK1 and OSK3 selectivity.

  5. Communication: Determining the structure of the N₂Ar van der Waals complex with laser-based channel-selected Coulomb explosion.

    PubMed

    Wu, Chengyin; Wu, Cong; Song, Di; Su, Hongmei; Xie, Xiguo; Li, Min; Deng, Yongkai; Liu, Yunquan; Gong, Qihuang

    2014-04-14

    We experimentally reconstructed the structure of the N2Ar van der Waals complex with the technique of laser-based channel-selected Coulomb explosion imaging. The internuclear distance between the N2 center of mass and the Ar atom, i.e., the length of the van der Waals bond, was determined to be 3.88 Å from the two-body explosion channels. The angle between the van der Waals bond and the N2 principal axis was determined to be 90° from the three-body explosion channels. The reconstructed structure was contrasted with our high level ab initio calculations. The agreement demonstrated the potential application of laser-based Coulomb explosion in imaging transient molecular structure, particularly for floppy van der Waals complexes, whose structures remain difficult to be determined by conventional spectroscopic methods.

  6. The Effects of the Selective Serotonin Reuptake Inhibitor Fluvoxamine on Voltage-Dependent K(+) Channels in Rabbit Coronary Arterial Smooth Muscle Cells.

    PubMed

    Hong, Da Hye; Li, Hongliang; Kim, Han Sol; Kim, Hye Won; Shin, Sung Eun; Jung, Won-Kyo; Na, Sung Hun; Choi, Il-Whan; Firth, Amy Leanne; Park, Won Sun; Kim, Dae-Joong

    2015-01-01

    We demonstrated the inhibitory effect of fluvoxamine, a selective serotonin reuptake inhibitor (SSRI), on voltage-dependent K(+) (Kv) channels in freshly isolated rabbit coronary arterial smooth muscle cells using a whole-cell patch clamp technique. Fluvoxamine reduced the amplitude of Kv currents in a concentration-dependent manner with an IC50 value of 3.71±1.09 µM and a Hill coefficient of 0.62±0.14. Although fluvoxamine did not significantly affect the steady-state activation curve, it shifted the steady-state inactivation curve toward a more negative potential. Pretreatment with another SSRI, paroxetine, did not affect the basal Kv current and did not alter the inhibitory effect of fluvoxamine on Kv channels. We concluded that fluvoxamine inhibits the Kv current in a concentration-dependent manner and in a closed (inactivated) state of the Kv channels independent of serotonin reuptake inhibition.

  7. Vpr Protein of Human Immunodeficiency Virus Type 1 Forms Cation-Selective Channels in Planar Lipid Bilayers

    NASA Astrophysics Data System (ADS)

    Piller, S. C.; Ewart, G. D.; Premkumar, A.; Cox, G. B.; Gage, P. W.

    1996-01-01

    A small (96-aa) protein, virus protein R (Vpr), of human immunodeficiency virus type 1 contains one hydrophobic segment that could form a membrane-spanning helix. Recombinant Vpr, expressed in Escherichia coli and purified by affinity chromatography, formed ion channels in planar lipid bilayers when it was added to the cis chamber and when the trans chamber was held at a negative potential. The channels were more permeable to Na+ than to Cl- ions and were inhibited when the trans potential was made positive. Similar channel activity was caused by Vpr that had a truncated C terminus, but the potential dependence of channel activity was no longer seen. Antibody raised to a peptide mimicking part of the C terminus of Vpr (AbC) inhibited channel activity when added to the trans chamber but had no effect when added to the cis chamber. Antibody to the N terminus of Vpr (AbN) increased channel activity when added to the cis chamber but had no effect when added to the trans chamber. The effects of potential and antibodies on channel activity are consistent with a model in which the positive C-terminal end of dipolar Vpr is induced to traverse the bilayer membrane when the opposite (trans) side of the membrane is at a negative potential. The C terminus of Vpr would then be available for interaction with AbC in the trans chamber, and the N terminus would be available for interaction with AbN in the cis chamber. The ability of Vpr to form ion channels in vitro suggests that channel formation by Vpr in vivo is possible and may be important in the life cycle of human immunodeficiency virus type 1 and/or may cause changes in cells that contribute to AIDS-related pathologies.

  8. Speeding the Recovery from Ultraslow Inactivation of Voltage-Gated Na+ Channels by Metal Ion Binding to the Selectivity Filter: A Foot-on-the-Door?

    PubMed Central

    Szendroedi, Julia; Sandtner, Walter; Zarrabi, Touran; Zebedin, Eva; Hilber, Karlheinz; Dudley, Samuel C.; Fozzard, Harry A.; Todt, Hannes

    2007-01-01

    Slow inactivated states in voltage-gated ion channels can be modulated by binding molecules both to the outside and to the inside of the pore. Thus, external K+ inhibits C-type inactivation in Shaker K+ channels by a “foot-in-the-door” mechanism. Here, we explore the modulation of a very long-lived inactivated state, ultraslow inactivation (IUS), by ligand binding to the outer vestibule in voltage-gated Na+ channels. Blocking the outer vestibule by a mutant μ-conotoxin GIIIA substantially accelerated recovery from IUS. A similar effect was observed if Cd2+ was bound to a cysteine engineered to the selectivity filter (K1237C). In K1237C channels, exposed to 30 μM Cd2+, the time constant of recovery from IUS was decreased from 145.0 ± 10.2 s to 32.5 ± 3.3 s (P < 0.001). Recovery from IUS was only accelerated if Cd2+ was added to the bath solution during recovery (V = −120 mV) from IUS, but not when the channels were selectively exposed to Cd2+ during the development of IUS (−20 mV). These data could be explained by a kinetic model in which Cd2+ binds with high affinity to a slow inactivated state (IS), which is transiently occupied during recovery from IUS. A total of 50 μM Cd2+ produced an ∼8 mV hyperpolarizing shift of the steady-state inactivation curve of IS, supporting this kinetic model. Binding of lidocaine to the internal vestibule significantly reduced the number of channels entering IUS, suggesting that IUS is associated with a conformational change of the internal vestibule of the channel. We propose a molecular model in which slow inactivation (IS) occurs by a closure of the outer vestibule, whereas IUS arises from a constriction of the internal vestibule produced by a widening of the selectivity filter region. Binding of Cd2+ to C1237 promotes the closure of the selectivity filter region, thereby hastening recovery from IUS. Thus, Cd2+ ions may act like a foot-on-the-door, kicking the IS gate to close. PMID:17720727

  9. Excited state mass spectra of doubly heavy Ξ baryons

    NASA Astrophysics Data System (ADS)

    Shah, Zalak; Rai, Ajay Kumar

    2017-02-01

    In this paper, the mass spectra are obtained for doubly heavy Ξ baryons, namely, Ξ _{cc}+, Ξ _{cc}^{++}, Ξ _{bb}-, Ξ _{bb}0, Ξ _{bc}0 and Ξ _{bc}+. These baryons consist of two heavy quarks ( cc, bb, and bc) with a light ( d or u) quark. The ground, radial, and orbital states are calculated in the framework of the hypercentral constituent quark model with Coulomb plus linear potential. Our results are also compared with other predictions, thus, the average possible range of excited states masses of these Ξ baryons can be determined. The study of the Regge trajectories is performed in ( n, M2) and ( J, M2) planes and their slopes and intercepts are also determined. Lastly, the ground state magnetic moments of these doubly heavy baryons are also calculated.

  10. A doubly-localized solution of plane Couette flow

    NASA Astrophysics Data System (ADS)

    Brand, Evan; Gibson, John

    2013-11-01

    We present a new equilibrium solution of plane Couette flow localized in two spatially extended directions. The solution is derived from the EQ7/HVS solution of plane Couette flow discovered independently by Itano and Generalis (PRL 2009) and Gibson et al. (JFM 2009), of which a spanwise localized version has also recently been produced (Gibson, these proceedings). The doubly localized solution displays relatively long length scales in comparison with the spatially periodic and spanwise localized solutions, suggesting the importance of these scales in capturing the spatial complexity of transitional and low-Reynolds number turbulence. The solution is comparable in size and appearance to the doubly-localized, chaotically evolving edge states previously computed in this flow by Duguet et al. (PoF 2009) and Schneider et al. (JFM 2010). Additionally, we address the structure of localized solutions in the ``tails,'' i.e. in the region approaching laminar.

  11. Selective Loss of Presynaptic Potassium Channel Clusters at the Cerebellar Basket Cell Terminal Pinceau in Adam11 Mutants Reveals Their Role in Ephaptic Control of Purkinje Cell Firing

    PubMed Central

    Kole, Matthew J.; Qian, Jing; Waase, Marc P.; Klassen, Tara L.; Chen, Tim T.; Augustine, George J.

    2015-01-01

    A specialized axonal ending, the basket cell “pinceau,” encapsulates the Purkinje cell axon initial segment (AIS), exerting final inhibitory control over the integrated outflow of the cerebellar cortex. This nonconventional axo-axonic contact extends beyond the perisomatic chemical GABAergic synaptic boutons to the distal AIS, lacks both sodium channels and local exocytotic machinery, and yet contains a dense cluster of voltage-gated potassium channels whose functional contribution is unknown. Here, we show that ADAM11, a transmembrane noncatalytic disintegrin, is the first reported Kv1-interacting protein essential for localizing Kv1.1 and Kv1.2 subunit complexes to the distal terminal. Selective absence of these channels at the pinceau due to mutation of ADAM11 spares spontaneous GABA release from basket cells at the perisomatic synapse yet eliminates ultrarapid ephaptic inhibitory synchronization of Purkinje cell firing. Our findings identify a critical role for presynaptic K+ channels at the pinceau in ephaptic control over the speed and stability of spike rate coding at the Purkinje cell AIS in mice. SIGNIFICANCE STATEMENT This study identifies ADAM11 as the first essential molecule for the proper localization of potassium ion channels at presynaptic nerve terminals, where they modulate excitability and the release of neural transmitters. Genetic truncation of the transmembrane disintegrin and metalloproteinase protein ADAM11 resulted in the absence of Kv1 channels that are normally densely clustered at the terminals of basket cell axons in the cerebellar cortex. These specialized terminals are responsible for the release of the neurotransmitter GABA onto Purkinje cells and also display electrical signaling. In the ADAM11 mutant, GABAergic release was not altered, but the ultrarapid electrical signal was absent, demonstrating that the dense presynaptic cluster of Kv1 ion channels at these terminals mediate electrical transmission. Therefore, ADAM11 plays a

  12. Doubly curved nanofiber-reinforced optically transparent composites

    NASA Astrophysics Data System (ADS)

    Shams, Md. Iftekhar; Yano, Hiroyuki

    2015-11-01

    Doubly curved nanofiber-reinforced optically transparent composites with low thermal expansion of 15 ppm/k are prepared by hot pressing vacuum-filtered Pickering emulsions of hydrophobic acrylic resin monomer, hydrophilic chitin nanofibers and water. The coalescence of acrylic monomer droplets in the emulsion is prevented by the chitin nanofibers network. This transparent composite has 3D shape moldability, making it attractive for optical precision parts.

  13. Doubly Excited Resonances in the Positronium Negative Ion

    NASA Technical Reports Server (NTRS)

    Ho, Y.K.

    2007-01-01

    The recent theoretical studies on the doubly excited states of the Ps' ion are described. The results obtained by using the method of complex coordinate rotation show that the three-lepton system behaves very much like an XYX tri-atomic molecule. Furthermore, the recent investigation on the positronium negative ion embedded in Debye plasma environments is discussed. The problem is modeled by the use of a screened Coulomb potential to represent the interaction between the charge particles.

  14. Doubly-charged ions in the planetary ionospheres: a review.

    PubMed

    Thissen, Roland; Witasse, Olivier; Dutuit, Odile; Wedlund, Cyril Simon; Gronoff, Guillaume; Lilensten, Jean

    2011-11-07

    This paper presents a review of the current knowledge on the doubly-charged atomic and molecular positive ions in the planetary atmospheres of the Solar System. It is focused on the terrestrial planets which have a dense atmosphere of N(2) or CO(2), i.e. Venus, the Earth and Mars, but also includes Titan, the largest satellite of Saturn, which has a dense atmosphere composed mainly of N(2) and a few percent of methane. Given the composition of these neutral atmospheres, the following species are considered: C(++), N(++), O(++), CH(4)(++), CO(++), N(2)(++), NO(++), O(2)(++), Ar(++) and CO(2)(++). We first discuss the status of their detection in the atmospheres of planets. Then, we provide a comprehensive review of their complex and original photochemistry, production and loss processes. Synthesis tables are provided for those ions, while a discussion on individual species is also provided. Methods for detecting doubly-charged ions in planetary atmospheres are presented, namely with mass-spectrometry, remote sensing and fine plasma density measurements. A section covers some original applications, like the possible effect of the presence of doubly-charged ions on the escape of an atmosphere, which is a key topic of ongoing planetary exploration, related to the evolution of a planet. The results of models, displayed in a comparative way for Venus, Earth, Mars and Titan, are discussed, as they can predict the presence of doubly-charged ions and will certainly trigger new investigations. Finally we give our view concerning next steps, challenges and needs for future studies, hoping that new scientific results will be achieved in the coming years and feed the necessary interdisciplinary exchanges amongst different scientific communities.

  15. Alternating parity structure in doubly odd /sup 218/Ac

    SciTech Connect

    Debray, M.E.; Davidson, M.; Kreiner, A.J.; Davidson, J.; Falcone, G.; Hojman, D.; Santos, D.

    1989-03-01

    States in doubly odd /sup 218/Ac have been studied using in-beam ..cap alpha..-, ..gamma..-, and e/sup -/-spectroscopy techniques mainly through the /sup 209/Bi(/sup 12/C,3n)= fusion-evaporation reaction. /sup 218/Ac shows a band structure, with interleaved states of alternating parities connected by enhanced B(E1) transitions, which is strikingly similar to the one in its isotone /sup 217/Ra.

  16. Doubly curved nanofiber-reinforced optically transparent composites

    PubMed Central

    Shams, Md. Iftekhar; Yano, Hiroyuki

    2015-01-01

    Doubly curved nanofiber-reinforced optically transparent composites with low thermal expansion of 15 ppm/k are prepared by hot pressing vacuum-filtered Pickering emulsions of hydrophobic acrylic resin monomer, hydrophilic chitin nanofibers and water. The coalescence of acrylic monomer droplets in the emulsion is prevented by the chitin nanofibers network. This transparent composite has 3D shape moldability, making it attractive for optical precision parts. PMID:26552990

  17. Doubly Excited Resonance States of Helium Atom: Complex Entropies

    NASA Astrophysics Data System (ADS)

    Kuroś, Arkadiusz; Kościk, Przemysław; Saha, Jayanta K.

    2016-12-01

    We provide a diagonal form of a reduced density matrix of S-symmetry resonance states of two electron systems determined under the framework of the complex scaling method. We have employed the variational Hylleraas type wavefunction to estimate the complex entropies in doubly excited resonance states of helium atom. Our results are in good agreement with the corresponding ones determined under the framework of the stabilization method (Lin and Ho in Few-Body Syst 56:157, 2015).

  18. Passive synchronization of finite dipoles in a doubly periodic domain

    NASA Astrophysics Data System (ADS)

    Tsang, Alan Cheng Hou; Kanso, Eva

    2012-11-01

    We consider the interaction dynamics of finite dipoles in a doubly periodic domain. A finite dipole is a pair of equal and opposite strength point vortices separated by a finite distance throughout its time evolution. The finite dipole dynamical system has been proposed as a model that captures the far-field hydrodynamics interactions in fish schools or collections of swimming bodies in an inviscid fluid. In this work, we formulate the equations of motion governing the dynamics of finite dipoles in a doubly periodic domain. We show that a single dipole in a doubly-periodic box exhibits either regular or chaotic behavior, depending on the initial angle of orientation of the dipole. In the case of the two dipoles, we identify a variety of interesting interaction modes including collision, switching, and passive synchronization of the dipoles. In the case of three dipoles, we observe the formation of relative equilibrium in finite time when the dipoles move together in a way reminiscent to that of flocking behavior.

  19. On the existence in human auditory pathways of channels selectively tuned to the modulation present in frequency-modulated tones

    PubMed Central

    Kay, R. H.; Matthews, D. R.

    1972-01-01

    amplitude modulation in a tone is conditioned by prior exposure to either amplitude- or frequency-modulated tones, in contrast the detectability of 8/sec frequency-modulated signals is conditioned only by prior exposure to frequency-modulated tones and not by amplitude-modulated conditioning tones. This underlines the special place of frequency modulation in human audition and emphasizes that the operative stimulus cannot be some aspect common to amplitude modulation and frequency modulation, like identical periodicity or coincident positioning of bands in the integrated spectra of the tones, but points to the instantaneous frequency-modulated wave form as the adequate stimulus. 8. These findings strongly suggest that the human auditory pathways contain `channels' in their organization which determine a final response selectively tuned to particular frequency-modulations. Periodicity coding alone cannot adequately explain this effect which may well only be understood in terms of a `place' theory of frequency selectivity. 9. This organization is well suited to subserve the recognition of frequency-modulation patterns in acoustic signals rather independently of the mean audiofrequency that carries the frequency modulation. PMID:5076392

  20. Mutating the Conserved Q-loop Glutamine 1291 Selectively Disrupts Adenylate Kinase-dependent Channel Gating of the ATP-binding Cassette (ABC) Adenylate Kinase Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) and Reduces Channel Function in Primary Human Airway Epithelia.

    PubMed

    Dong, Qian; Ernst, Sarah E; Ostedgaard, Lynda S; Shah, Viral S; Ver Heul, Amanda R; Welsh, Michael J; Randak, Christoph O

    2015-05-29

    The ATP-binding cassette (ABC) transporter cystic fibrosis transmembrane conductance regulator (CFTR) and two other non-membrane-bound ABC proteins, Rad50 and a structural maintenance of chromosome (SMC) protein, exhibit adenylate kinase activity in the presence of physiologic concentrations of ATP and AMP or ADP (ATP + AMP ⇆ 2 ADP). The crystal structure of the nucleotide-binding domain of an SMC protein in complex with the adenylate kinase bisubstrate inhibitor P(1),P(5)-di(adenosine-5') pentaphosphate (Ap5A) suggests that AMP binds to the conserved Q-loop glutamine during the adenylate kinase reaction. Therefore, we hypothesized that mutating the corresponding residue in CFTR, Gln-1291, selectively disrupts adenylate kinase-dependent channel gating at physiologic nucleotide concentrations. We found that substituting Gln-1291 with bulky side-chain amino acids abolished the effects of Ap5A, AMP, and adenosine 5'-monophosphoramidate on CFTR channel function. 8-Azidoadenosine 5'-monophosphate photolabeling of the AMP-binding site and adenylate kinase activity were disrupted in Q1291F CFTR. The Gln-1291 mutations did not alter the potency of ATP at stimulating current or ATP-dependent gating when ATP was the only nucleotide present. However, when physiologic concentrations of ADP and AMP were added, adenylate kinase-deficient Q1291F channels opened significantly less than wild type. Consistent with this result, we found that Q1291F CFTR displayed significantly reduced Cl(-) channel function in well differentiated primary human airway epithelia. These results indicate that a highly conserved residue of an ABC transporter plays an important role in adenylate kinase-dependent CFTR gating. Furthermore, the results suggest that adenylate kinase activity is important for normal CFTR channel function in airway epithelia.

  1. Mutating the Conserved Q-loop Glutamine 1291 Selectively Disrupts Adenylate Kinase-dependent Channel Gating of the ATP-binding Cassette (ABC) Adenylate Kinase Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) and Reduces Channel Function in Primary Human Airway Epithelia*

    PubMed Central

    Dong, Qian; Ernst, Sarah E.; Ostedgaard, Lynda S.; Shah, Viral S.; Ver Heul, Amanda R.; Welsh, Michael J.; Randak, Christoph O.

    2015-01-01

    The ATP-binding cassette (ABC) transporter cystic fibrosis transmembrane conductance regulator (CFTR) and two other non-membrane-bound ABC proteins, Rad50 and a structural maintenance of chromosome (SMC) protein, exhibit adenylate kinase activity in the presence of physiologic concentrations of ATP and AMP or ADP (ATP + AMP ⇆ 2 ADP). The crystal structure of the nucleotide-binding domain of an SMC protein in complex with the adenylate kinase bisubstrate inhibitor P1,P5-di(adenosine-5′) pentaphosphate (Ap5A) suggests that AMP binds to the conserved Q-loop glutamine during the adenylate kinase reaction. Therefore, we hypothesized that mutating the corresponding residue in CFTR, Gln-1291, selectively disrupts adenylate kinase-dependent channel gating at physiologic nucleotide concentrations. We found that substituting Gln-1291 with bulky side-chain amino acids abolished the effects of Ap5A, AMP, and adenosine 5′-monophosphoramidate on CFTR channel function. 8-Azidoadenosine 5′-monophosphate photolabeling of the AMP-binding site and adenylate kinase activity were disrupted in Q1291F CFTR. The Gln-1291 mutations did not alter the potency of ATP at stimulating current or ATP-dependent gating when ATP was the only nucleotide present. However, when physiologic concentrations of ADP and AMP were added, adenylate kinase-deficient Q1291F channels opened significantly less than wild type. Consistent with this result, we found that Q1291F CFTR displayed significantly reduced Cl− channel function in well differentiated primary human airway epithelia. These results indicate that a highly conserved residue of an ABC transporter plays an important role in adenylate kinase-dependent CFTR gating. Furthermore, the results suggest that adenylate kinase activity is important for normal CFTR channel function in airway epithelia. PMID:25887396

  2. Molecular simulations study of novel 1,4-dihydropyridines derivatives with a high selectivity for Cav3.1 calcium channel

    PubMed Central

    Liu, Xiaoguang; Yu, Hui; Zhao, Xi; Huang, Xu-Ri

    2015-01-01

    1,4-Dihydropyridines (DHPs) have been developed to treat hypertension, angina, and nerve system disease. They are thought to mainly target the L-type calcium channels, but low selectivity prompts them to block Cav1.2 and Cav3.1 channels simultaneously. Recently, some novel DHPs with different hydrophobic groups have been synthesized and among them M12 has a higher selectivity for Cav3.1. However, the structural information about Cav3.1-DHPs complexes is not available in the experiment. Thus, we combined homology modeling, molecular docking, molecular dynamics simulations, and binding free energy calculations to quantitatively elucidate the inhibition mechanism of DHPs. The calculated results indicate that our model is in excellent agreement with experimental results. On the basis of conformational analysis, we identify the main interactions between DHPs and calcium channels and further elaborate on the different selectivity of ligands from the micro perspective. In conjunction with energy distribution, we propose that the binding sites of Cav3.1-DHPs is characterized by several interspersed hydrophobic amino acid residues on the IIIS6 and IVS6 segments. We also speculate the favorable function groups on prospective DHPs. Besides, our model provides important information for further mutagenesis experiments. PMID:26256672

  3. Molecular simulations study of novel 1,4-dihydropyridines derivatives with a high selectivity for Cav3.1 calcium channel.

    PubMed

    Liu, Xiaoguang; Yu, Hui; Zhao, Xi; Huang, Xu-Ri

    2015-11-01

    1,4-Dihydropyridines (DHPs) have been developed to treat hypertension, angina, and nerve system disease. They are thought to mainly target the L-type calcium channels, but low selectivity prompts them to block Cav1.2 and Cav3.1 channels simultaneously. Recently, some novel DHPs with different hydrophobic groups have been synthesized and among them M12 has a higher selectivity for Cav3.1. However, the structural information about Cav3.1-DHPs complexes is not available in the experiment. Thus, we combined homology modeling, molecular docking, molecular dynamics simulations, and binding free energy calculations to quantitatively elucidate the inhibition mechanism of DHPs. The calculated results indicate that our model is in excellent agreement with experimental results. On the basis of conformational analysis, we identify the main interactions between DHPs and calcium channels and further elaborate on the different selectivity of ligands from the micro perspective. In conjunction with energy distribution, we propose that the binding sites of Cav3.1-DHPs is characterized by several interspersed hydrophobic amino acid residues on the IIIS6 and IVS6 segments. We also speculate the favorable function groups on prospective DHPs. Besides, our model provides important information for further mutagenesis experiments.

  4. Arene guest selectivity and pore flexibility in a metal–organic framework with semi-fluorinated channel walls

    PubMed Central

    Smith, Rebecca; Vitórica-Yrezábal, Iñigo J.; Hill, Adrian

    2017-01-01

    A metal–organic framework (MOF) with one-dimensional channels of approximately hexagonal cross-section [Ag2(O2CCF2CF2CO2)(TMP)] 1 (TMP =2,3,5,6-tetramethylpyrazine) has been synthesized with MeOH filling the channels in its as-synthesized form as [Ag2(O2CCF2CF2CO2)(TMP)]·n(MeOH) 1-MeOH (n = 1.625 by X-ray crystallography). The two types of ligand connect columns of Ag(I) centres in an alternating manner, both around the channels and along their length, leading to an alternating arrangement of hydrocarbon (C–H) and fluorocarbon (C–F) groups lining the channel walls, with the former groups projecting further into the channel than the latter. MeOH solvent in the channels can be exchanged for a variety of arene guests, ranging from xylenes to tetrafluorobenzene, as confirmed by gas chromatography, 1H nuclear magnetic resonance (NMR) spectroscopy, thermogravimetric analysis and 13C cross-polarization magic angle spinning NMR spectroscopy. Alkane and perfluoroalkane guests, however, do not enter the channels. Although exhibiting some stability under a nitrogen atmosphere, sufficient to enable crystal structure determination, the evacuated MOF 1 is unstable for periods of more than minutes under ambient conditions or upon heating, whereupon it undergoes an irreversible solid-state transformation to a non-porous polymorph 2, which comprises Ag2(O2CCF2CF2CO2) coordination layers that are pillared by TMP ligands. This transformation has been followed in situ by powder X-ray diffraction and shown to proceed via a crystalline intermediate. This article is part of the themed issue ‘Coordination polymers and metal–organic frameworks: materials by design’. PMID:27895259

  5. Arene guest selectivity and pore flexibility in a metal-organic framework with semi-fluorinated channel walls

    NASA Astrophysics Data System (ADS)

    Smith, Rebecca; Vitórica-Yrezábal, Iñigo J.; Hill, Adrian; Brammer, Lee

    2017-01-01

    A metal-organic framework (MOF) with one-dimensional channels of approximately hexagonal cross-section [Ag2(O2CCF2CF2CO2)(TMP)] 1 (TMP =2,3,5,6-tetramethylpyrazine) has been synthesized with MeOH filling the channels in its as-synthesized form as [Ag2(O2CCF2CF2CO2)(TMP)]·n(MeOH) 1-MeOH (n = 1.625 by X-ray crystallography). The two types of ligand connect columns of Ag(I) centres in an alternating manner, both around the channels and along their length, leading to an alternating arrangement of hydrocarbon (C-H) and fluorocarbon (C-F) groups lining the channel walls, with the former groups projecting further into the channel than the latter. MeOH solvent in the channels can be exchanged for a variety of arene guests, ranging from xylenes to tetrafluorobenzene, as confirmed by gas chromatography, 1H nuclear magnetic resonance (NMR) spectroscopy, thermogravimetric analysis and 13C cross-polarization magic angle spinning NMR spectroscopy. Alkane and perfluoroalkane guests, however, do not enter the channels. Although exhibiting some stability under a nitrogen atmosphere, sufficient to enable crystal structure determination, the evacuated MOF 1 is unstable for periods of more than minutes under ambient conditions or upon heating, whereupon it undergoes an irreversible solid-state transformation to a non-porous polymorph 2, which comprises Ag2(O2CCF2CF2CO2) coordination layers that are pillared by TMP ligands. This transformation has been followed in situ by powder X-ray diffraction and shown to proceed via a crystalline intermediate. This article is part of the themed issue 'Coordination polymers and metal-organic frameworks: materials by design'.

  6. A multi-channel device for high-density target-selective stimulation and long-term monitoring of cells and subcellular features in C. elegans.

    PubMed

    Lee, Hyewon; Kim, Shin Ae; Coakley, Sean; Mugno, Paula; Hammarlund, Marc; Hilliard, Massimo A; Lu, Hang

    2014-12-07

    Selective cell ablation can be used to identify neuronal functions in multicellular model organisms such as Caenorhabditis elegans. The optogenetic tool KillerRed facilitates selective ablation by enabling light-activated damage of cell or subcellular components in a temporally and spatially precise manner. However, the use of KillerRed requires stimulating (5 min-1 h), culturing (~24 h) and imaging (often repeatedly) a large number of individual animals. Current manual manipulation methods are limited by their time-consuming, labor-intensive nature, and their usage of anesthetics. To facilitate large-scale selective ablation, culturing, and repetitive imaging, we developed a densely-packed multi-channel device and used it to perform high-throughput neuronal ablation on KillerRed-expressing animals. The ability to load worms in identical locations with high loading efficiency allows us to ablate selected neurons in multiple worms simultaneously. Our device also enables continuous observation of animals for 24 h following KillerRed activation, and allows the animals to be recovered for behavioural assays. We expect this multi-channel device to facilitate a broad range of long-term imaging and selective illumination experiments in neuroscience.

  7. Ion transport in the gramicidin channel: molecular dynamics study of single and double occupancy.

    PubMed Central

    Roux, B; Prod'hom, B; Karplus, M

    1995-01-01

    The structural and thermodynamic factors responsible for the singly and doubly occupied saturation states of the gramicidin channel are investigated with molecular dynamics simulations and free energy perturbation methods. The relative free energy of binding of all of the five common cations Li+, Na+, K+, Rb+, and Cs+ is calculated in the singly and doubly occupied channel and in bulk water. The atomic system, which includes the gramicidin channel, a model membrane made of neutral Lennard-Jones particles and 190 explicit water molecules to form the bulk region, is similar to the one used in previous work to calculate the free energy profile of a Na+ ion along the axis of the channel. In all of the calculations, the ions are positioned in the main binding sites located near the entrances of the channel. The calculations reveal that the doubly occupied state is relatively more favorable for the larger ions. Thermodynamic decomposition is used to show that the origin of the trend observed in the calculations is due to the loss of favorable interactions between the ion and the single file water molecules inside the channel. Small ions are better solvated by the internal water molecules in the singly occupied state than in the doubly occupied state; bigger ions are solvated almost as well in both occupation states. Water-channel interactions play a role in the channel response. The observed trends are related to general thermodynamical properties of electrolyte solutions. Images FIGURE 2 PMID:7538804

  8. Plasma membrane Ca2+ release-activated Ca2+ channels with a high selectivity for Ca2+ identified by patch-clamp recording in rat liver cells.

    PubMed

    Rychkov, G; Brereton, H M; Harland, M L; Barritt, G J

    2001-04-01

    Repetitive waves of increased cytoplasmic Ca2+ concentration play a central role in the process by which hormones regulate liver function. Maintenance of these Ca2+ waves requires Ca2+ inflow through store-operated Ca2+ channels. The properties and mechanism(s) of activation of these channels are not well understood. Store-operated Ca2+ channels (SOCs) in the H4-IIE rat liver cell line were studied by whole-cell patch clamping. Depletion of Ca2+ in intracellular stores by intracellular perfusion with either inositol 1,4,5-trisphosphate (InsP(3)) or thapsigargin in the presence of 10 mmol/L ethylene glycol-bis(beta-aminoethyl ether)-N,N-tetraacetic acid (EGTA), or with 10 mmol/L EGTA alone, activated an inward current that reversed at a membrane potential above +40 mV. In physiologic extracellular medium, this inward current was carried exclusively by Ca2+ and was blocked by a variety of di- and trivalent cations. In the absence of extracellular Ca2+ and Mg2+, the inward current was carried by monovalent cations. This current was 10 to 30 times larger than that observed in the presence of extracellular Ca2+, and permitted the detection of single-channel events that corresponded to a single-channel conductance of about 40 pS. Both the Ca2+ and Na+ inward currents were blocked by the calmodulin antagonist, N-(6-amino hexyl)-5-chloro-1-naphthalenesulphonamide (W7), but not by calmidazolium or calmodulin-dependent protein kinase II fragment 290-309. It is concluded that liver cells possess plasma membrane Ca2+ channels that have a high selectivity for Ca2+, are activated by a decrease in the concentration of Ca2+ in intracellular stores through a mechanism that is unlikely to involve calmodulin, and are involved in re-filling intracellular Ca2+ stores during Ca2+ signaling.

  9. CASEIN KINASE-MEDIATED PHOSPHORYLATION OF SERINE 839 IS NECESSARY FOR BASOLATERAL LOCALIZATION OF THE Ca2+-ACTIVATED NON-SELECTIVE CATION CHANNEL TRPM4

    PubMed Central

    Cerda, Oscar; Cáceres, Mónica; Park, Kang-Sik; Leiva-Salcedo, Elías; Romero, Aníbal; Varela, Diego

    2014-01-01

    TRPM4 is a Ca2+-activated non-selective cation channel expressed in a wide range of human tissues. TRPM4 participates in a variety of physiological processes such as T cell activation, myogenic vasoconstriction and allergic reactions. TRPM4 Ca2+ sensitivity is enhanced by calmodulin (CaM) and phosphathydilinositol 4, 5-biphosphate (PI(4,5)P2) binding, as well as, under certain conditions, PKC activation. However, information as to the mechanisms of modulation of this channel remain unknown, including direct identification of phosphorylation sites on TRPM4 and their role in channel features. Here, we use mass-spectrometric-based proteomic approaches (immunoprecipitation and tandem mass spectrometry), to unambiguously identify S839 as a phosphorylation site present on human TRPM4 expressed in a human cell line. Site-directed mutagenesis employing a serine to alanine mutation to eliminate phosphorylation, and a phospho-mimetic aspartate mutation, as well as biochemical and immunocytochemical experiments, revealed a role for S839 phosphorylation in the basolateral expression of TRPM4 channels in epithelial cells. Moreover, we demonstrated that casein kinase 1 (CK1) phosphorylates S839 and is responsible for the basolateral localization of TRPM4. PMID:25231975

  10. A Novel Toxin from Haplopelma lividum Selectively Inhibits the NaV1.8 Channel and Possesses Potent Analgesic Efficacy

    PubMed Central

    Meng, Ping; Huang, Honggang; Wang, Gan; Yang, Shilong; Lu, Qiuming; Liu, Jingze; Lai, Ren; Rong, Mingqiang

    2016-01-01

    Spider venoms are a complex mixture of peptides with a large number of neurotoxins targeting ion channels. Although thousands of peptide toxins have been identified from venoms of numerous species of spiders, many unknown species urgently need to be investigated. In this study, a novel sodium channel inhibitor, µ-TRTX-Hl1a, was identified from the venom of Haplopelma lividum. It contained eight cysteines and formed a conserved cysteine pattern of ICK motif. µ-TRTX-Hl1a inhibited the TTX-resistant (TTX-r) sodium channel current rather than the TTX-sensitive (TTX-s) sodium channel current. Meanwhile, µ-TRTX-Hl1a selectively inhibited NaV1.8 with an IC50 value of 2.19 μM. Intraperitoneal injection of µ-TRTX-Hl1a dose-dependently reduced inflammatory and neuropathic pain in rodent models of formalin-induced paw licking, tail-flicking, acetic acid-induced writhing, and hot plate test. It showed a better analgesic effect than morphine in inflammatory pain and equipotent effect to morphine in neuropathic pain. These findings demonstrate that µ-TRTX-Hl1a might be a valuable tool for physiology studies on NaV1.8 and a promising lead molecule for pain therapeutics. PMID:28035974

  11. Asp residues of the Glu-Glu-Asp-Asp pore filter contribute to ion permeation and selectivity of the Ca(v)3.2 T-type channel.

    PubMed

    Park, Hyun-Jee; Park, So-Jung; Ahn, Eun-Joo; Lee, So-Young; Seo, Haengsoo; Lee, Jung-Ha

    2013-09-01

    Voltage-activated Ca2+ channels are membrane protein machinery performing selective permeation of external calcium ions. The main Ca2+ selective filters of all high-voltage-activated Ca2+ channel isoforms are commonly composed of four Glu residues (EEEE), while those of low-voltage-activated T-type Ca2+ channel isoforms are made up of two Glu and two Asp residues (EEDD). We here investigate how the Asp residues at the pore loops of domains III and IV affect biophysical properties of the Ca(v)3.2 channel. Electrophysiological characterization of the pore mutant channels in which the pore Asp residue(s) were replaced with Glu, showed that both Asp residues critically control the biophysical properties of Ca(v)3.2, including relative permeability between Ba2+ and Ca2+, anomalous mole fraction effect (AMFE), voltage dependency of channel activation, Cd2+ blocking sensitivity, and pH effects, in distinctive ways.

  12. Distinct interactions of Na{sup +} and Ca{sup 2+} ions with the selectivity filter of the bacterial sodium channel Na{sub V}Ab

    SciTech Connect

    Ke, Song; Zangerl, Eva-Maria; Stary-Weinzinger, Anna

    2013-01-25

    Highlights: ► Ca{sup 2+} translocates slowly in the filter, due to lack of “loose” knock-on mechanism. ► Identification of a high affinity binding site in Na{sub V}Ab selectivity filter. ► Changes of EEEE locus triggered by electrostatic interactions with Ca{sup 2+} ions. -- Abstract: Rapid and selective ion transport is essential for the generation and regulation of electrical signaling pathways in living organisms. In this study, we use molecular dynamics simulations and free energy calculations to investigate how the bacterial sodium channel Na{sub V}Ab (Arcobacter butzleri) differentiates between Na{sup +} and Ca{sup 2+} ions. Multiple nanosecond molecular dynamics simulations revealed distinct binding patterns for these two cations in the selectivity filter and suggested a high affinity calcium binding site formed by backbone atoms of residues Leu-176 and Thr-175 (S{sub CEN}) in the sodium channel selectivity filter.

  13. A Rational Design of a Selective Inhibitor for Kv1.1 Channels Prevalent in Demyelinated Nerves That Improves Their Impaired Axonal Conduction.

    PubMed

    Al-Sabi, Ahmed; Daly, Declan; Hoefer, Patrick; Kinsella, Gemma K; Metais, Charles; Pickering, Mark; Herron, Caroline; Kaza, Seshu Kumar; Nolan, Kieran; Dolly, J Oliver

    2017-03-23

    K(+) channels containing Kv1.1 α subunits, which become prevalent at internodes in demyelinated axons, may underlie their dysfunctional conduction akin to muscle weakness in multiple sclerosis. Small inhibitors were sought with selectivity for the culpable hyper-polarizing K(+) currents. Modeling of interactions with the extracellular pore in a Kv1.1-deduced structure identified diaryldi(2-pyrrolyl)methane as a suitable scaffold with optimized alkyl ammonium side chains. The resultant synthesized candidate [2,2'-((5,5'(di-p-topyldiaryldi(2-pyrrolyl)methane)bis(2,2'carbonyl)bis(azanediyl)) diethaneamine·2HCl] (8) selectively blocked Kv1.1 channels (IC50 ≈ 15 μM) recombinantly expressed in mammalian cells, induced a positive shift in the voltage dependency of K(+) current activation, and slowed its kinetics. It preferentially inhibited channels containing two or more Kv1.1 subunits regardless of their positioning in concatenated tetramers. In slices of corpus callosum from mice subjected to a demyelination protocol, this novel inhibitor improved neuronal conduction, highlighting its potential for alleviating symptoms in multiple sclerosis.

  14. Interference in spectrum of radiation from doubly scattered charged particle

    NASA Astrophysics Data System (ADS)

    Bondarenco, M. V.; Shul'ga, N. F.

    2017-03-01

    Existence of different types of interference in the spectrum of radiation emitted by a doubly hard scattered electron is demonstrated. The spectrum develops oscillations in two regions: the hard, where they depend on the electron Lorentz factor, and the soft, where the oscillations depend on the electron scattering angles. This interference pattern owes to the presence of jetlike radiation configurations, formed by a piecewise-rectilinearly moving electron and the accompanying photon. The corresponding nondipole decomposition relation is derived. Notions describing proper field formation and interference, and presumably being applicable more generally, are discussed in detail.

  15. Image estimation using doubly stochastic gaussian random field models.

    PubMed

    Woods, J W; Dravida, S; Mediavilla, R

    1987-02-01

    The two-dimensional (2-D) doubly stochastic Gaussian (DSG) model was introduced by one of the authors to provide a complete model for spatial filters which adapt to the local structure in an image signal. Here we present the optimal estimator and 2-D fixed-lag smoother for this DSG model extending earlier work of Ackerson and Fu. As the optimal estimator has an exponentially growing state space, we investigate suboptimal estimators using both a tree and a decision-directed method. Experimental results are presented.

  16. Numerical conformal mapping methods for exterior and doubly connected regions

    SciTech Connect

    DeLillo, T.K.; Pfaltzgraff, J.A.

    1996-12-31

    Methods are presented and analyzed for approximating the conformal map from the exterior of the disk to the exterior a smooth, simple closed curve and from an annulus to a bounded, doubly connected region with smooth boundaries. The methods are Newton-like methods for computing the boundary correspondences and conformal moduli similar to Fornberg`s method for the interior of the disk. We show that the linear systems are discretizations of the identity plus a compact operator and, hence, that the conjugate gradient method converges superlinearly.

  17. Coherence properties of a doubly resonant monolithic optical parametric oscillator

    NASA Technical Reports Server (NTRS)

    Nabors, C. D.; Yang, S. T.; Day, T.; Byer, R. L.

    1990-01-01

    A doubly resonant optical parametric oscillator (DRO) pumped with the second harmonic of a narrow-linewidth Nd:YAG laser is described. The linewidth of the DRO signal was less than 13 kHz, the DRO was shown to generate a phase-locked subharmonic of the pump at degeneracy, and the signal and the idler were shown to be mutually coherent with the pump and to be phase-anticorrelated with each other away from degeneracy. The signal-idler heterodyne linewidth was 500 Hz, and pump phase modulation was shown to transfer to the DRO phase at degeneracy.

  18. Species diversity and peptide toxins blocking selectivity of ether-a-go-go-related gene subfamily K+ channels in the central nervous system.

    PubMed

    Restano-Cassulini, Rita; Korolkova, Yuliya V; Diochot, Sylvie; Gurrola, Georgina; Guasti, Leonardo; Possani, Lourival D; Lazdunski, Michel; Grishin, Eugene V; Arcangeli, Annarosa; Wanke, Enzo

    2006-05-01

    The ether-à-go-go-related gene (erg) K+ channels are known to be crucial for life in Caenorhabditis elegans (mating), Drosophila melanogaster (seizure), and humans (LQT syndrome). The erg genes known to date (erg1, erg2, and erg3) are highly expressed in various areas of the rat and mouse central nervous system (CNS), and ERG channel blockers alter firing accommodation. To assign physiological roles to each isoform, it is necessary to design pharmacological strategies to distinguish individual currents. To this purpose, we have investigated the blocking properties of specific peptide inhibitors of hERG1 channels on the human and rat isoforms. In particular, we have tested ErgTx1 (from the scorpion Centruroides noxious), BeKm-1 (from the scorpion Buthus eupeus), and APETx1 (from the sea anemone Anthopleura elegantissima). Because these peptides had different species-specific effects on the six different channels, we have also carried out a biophysical characterization of hERG2 and hERG3 channels that turned out to be different from the rat homologs. It emerged that APETx1 is exquisitely selective for ERG1 and does not compete with the other two toxins. BeKm-1 discriminates well among the three rat members. ErgTx1 is unable to block hERG2, but blocks rERG2 and has the lowest KD for hERG3. BeKm-1 and ErgTx1 compete for hERG3 but not for rERG2 blockade. Our findings should be helpful for structure-function studies and for novel CNS ERG-specific drug design.

  19. Structure and function of hainantoxin-III, a selective antagonist of neuronal tetrodotoxin-sensitive voltage-gated sodium channels isolated from the Chinese bird spider Ornithoctonus hainana.

    PubMed

    Liu, Zhonghua; Cai, Tianfu; Zhu, Qi; Deng, Meichun; Li, Jiayan; Zhou, Xi; Zhang, Fan; Li, Dan; Li, Jing; Liu, Yu; Hu, Weijun; Liang, Songping

    2013-07-12

    In the present study, we investigated the structure and function of hainantoxin-III (HNTX-III), a 33-residue polypeptide from the venom of the spider Ornithoctonus hainana. It is a selective antagonist of neuronal tetrodotoxin-sensitive voltage-gated sodium channels. HNTX-III suppressed Nav1.7 current amplitude without significantly altering the activation, inactivation, and repriming kinetics. Short extreme depolarizations partially activated the toxin-bound channel, indicating voltage-dependent inhibition of HNTX-III. HNTX-III increased the deactivation of the Nav1.7 current after extreme depolarizations. The HNTX-III·Nav1.7 complex was gradually dissociated upon prolonged strong depolarizations in a voltage-dependent manner, and the unbound toxin rebound to Nav1.7 after a long repolarization. Moreover, analysis of chimeric channels showed that the DIIS3-S4 linker was critical for HNTX-III binding to Nav1.7. These data are consistent with HNTX-III interacting with Nav1.7 site 4 and trapping the domain II voltage sensor in the closed state. The solution structure of HNTX-III was determined by two-dimensional NMR and shown to possess an inhibitor cystine knot motif. Structural analysis indicated that certain basic, hydrophobic, and aromatic residues mainly localized in the C terminus may constitute an amphiphilic surface potentially involved in HNTX-III binding to Nav1.7. Taken together, our results show that HNTX-III is distinct from β-scorpion toxins and other β-spider toxins in its mechanism of action and binding specificity and affinity. The present findings contribute to our understanding of the mechanism of toxin-sodium channel interaction and provide a useful tool for the investigation of the structure and function of sodium channel isoforms and for the development of analgesics.

  20. Hydroxyproline-induced Helical Disruption in Conantokin Rl-B Affects Subunit-selective Antagonistic Activities toward Ion Channels of N-Methyl-d-aspartate Receptors*

    PubMed Central

    Kunda, Shailaja; Yuan, Yue; Balsara, Rashna D.; Zajicek, Jaroslav; Castellino, Francis J.

    2015-01-01

    Conantokins are ∼20-amino acid peptides present in predatory marine snail venoms that function as allosteric antagonists of ion channels of the N-methyl-d-aspartate receptor (NMDAR). These peptides possess a high percentage of post-/co-translationally modified amino acids, particularly γ-carboxyglutamate (Gla). Appropriately spaced Gla residues allow binding of functional divalent cations, which induces end-to-end α-helices in many conantokins. A smaller number of these peptides additionally contain 4-hydroxyproline (Hyp). Hyp should prevent adoption of the metal ion-induced full α-helix, with unknown functional consequences. To address this disparity, as well as the role of Hyp in conantokins, we have solved the high resolution three-dimensional solution structure of a Gla/Hyp-containing 18-residue conantokin, conRl-B, by high field NMR spectroscopy. We show that Hyp10 disrupts only a small region of the α-helix of the Mn2+·peptide complex, which displays cation-induced α-helices on each terminus of the peptide. The function of conRl-B was examined by measuring its inhibition of NMDA/Gly-mediated current through NMDAR ion channels in mouse cortical neurons. The conRl-B displays high inhibitory selectivity for subclasses of NMDARs that contain the functionally important GluN2B subunit. Replacement of Hyp10 with N8Q results in a Mg2+-complexed end-to-end α-helix, accompanied by attenuation of NMDAR inhibitory activity. However, replacement of Hyp10 with Pro10 allowed the resulting peptide to retain its inhibitory property but diminished its GluN2B specificity. Thus, these modified amino acids, in specific peptide backbones, play critical roles in their subunit-selective inhibition of NMDAR ion channels, a finding that can be employed to design NMDAR antagonists that function at ion channels of distinct NMDAR subclasses. PMID:26048991

  1. No evidence for induction or selection of mutant sodium channel expression in the copepod Acartia husdsonica challenged with the toxic dinoflagellate Alexandrium fundyense

    PubMed Central

    Finiguerra, Michael; Avery, David E; Dam, Hans G

    2014-01-01

    Some species in the dinoflagellate genus Alexandrium spp. produce a suite of neurotoxins that block sodium channels, known as paralytic shellfish toxins (PST), which have deleterious effects on grazers. Populations of the ubiquitous copepod grazer Acartia hudsonica that have co-occurred with toxic Alexandrium spp. are better adapted than naïve populations. The mechanism of adaptation is currently unknown. We hypothesized that a mutation in the sodium channel could account for the grazer adaptation. We tested two hypotheses: (1) Expression of the mutant sodium channel could be induced by exposure to toxic Alexandrium fundyense; (2) in the absence of induction, selection exerted by toxic A. fundyense would favor copepods that predominantly express the mutant isoform. In the copepod A. hudsonica, both isoforms are expressed in all individuals in varying proportions. Thus, in addition to comparing expression ratios of wild-type to mutant isoforms for individual copepods, we also partitioned copepods into three groups: those that predominantly express the mutant (PMI) isoform, the wild-type (PWI) isoform, or both isoforms approximately equally (EI). There were no differences in isoform expression between individuals that were fed toxic and nontoxic food after three and 6 days; induction of mutant isoform expression did not occur. Furthermore, the hypothesis that mutant isoform expression responds to toxic food was also rejected. That is, no consistent evidence showed that the wild-type to mutant isoform ratios decreased, or that the relative proportion of PMI individuals increased, due to the consumption of toxic food over four generations. However, in the selected line that was continuously exposed to toxic food sources, egg production rate increased, which suggested that adaptation occurred but was unrelated to sodium channel isoform expression. PMID:25535562

  2. A-803467, a potent and selective Nav1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat

    PubMed Central

    Jarvis, Michael F.; Honore, Prisca; Shieh, Char-Chang; Chapman, Mark; Joshi, Shailen; Zhang, Xu-Feng; Kort, Michael; Carroll, William; Marron, Brian; Atkinson, Robert; Thomas, James; Liu, Dong; Krambis, Michael; Liu, Yi; McGaraughty, Steve; Chu, Katharine; Roeloffs, Rosemarie; Zhong, Chengmin; Mikusa, Joseph P.; Hernandez, Gricelda; Gauvin, Donna; Wade, Carrie; Zhu, Chang; Pai, Madhavi; Scanio, Marc; Shi, Lei; Drizin, Irene; Gregg, Robert; Matulenko, Mark; Hakeem, Ahmed; Gross, Michael; Johnson, Matthew; Marsh, Kennan; Wagoner, P. Kay; Sullivan, James P.; Faltynek, Connie R.; Krafte, Douglas S.

    2007-01-01

    Activation of tetrodotoxin-resistant sodium channels contributes to action potential electrogenesis in neurons. Antisense oligonucleotide studies directed against Nav1.8 have shown that this channel contributes to experimental inflammatory and neuropathic pain. We report here the discovery of A-803467, a sodium channel blocker that potently blocks tetrodotoxin-resistant currents (IC50 = 140 nM) and the generation of spontaneous and electrically evoked action potentials in vitro in rat dorsal root ganglion neurons. In recombinant cell lines, A-803467 potently blocked human Nav1.8 (IC50 = 8 nM) and was >100-fold selective vs. human Nav1.2, Nav1.3, Nav1.5, and Nav1.7 (IC50 values ≥1 μM). A-803467 (20 mg/kg, i.v.) blocked mechanically evoked firing of wide dynamic range neurons in the rat spinal dorsal horn. A-803467 also dose-dependently reduced mechanical allodynia in a variety of rat pain models including: spinal nerve ligation (ED50 = 47 mg/kg, i.p.), sciatic nerve injury (ED50 = 85 mg/kg, i.p.), capsaicin-induced secondary mechanical allodynia (ED50 ≈ 100 mg/kg, i.p.), and thermal hyperalgesia after intraplantar complete Freund's adjuvant injection (ED50 = 41 mg/kg, i.p.). A-803467 was inactive against formalin-induced nociception and acute thermal and postoperative pain. These data demonstrate that acute and selective pharmacological blockade of Nav1.8 sodium channels in vivo produces significant antinociception in animal models of neuropathic and inflammatory pain. PMID:17483457

  3. Identification and Analysis of Genome-Wide SNPs Provide Insight into Signatures of Selection and Domestication in Channel Catfish (Ictalurus punctatus)

    PubMed Central

    Sun, Luyang; Liu, Shikai; Wang, Ruijia; Jiang, Yanliang; Zhang, Yu; Zhang, Jiaren; Bao, Lisui; Kaltenboeck, Ludmilla; Dunham, Rex; Waldbieser, Geoff; Liu, Zhanjiang

    2014-01-01

    Domestication and selection for important performance traits can impact the genome, which is most often reflected by reduced heterozygosity in and surrounding genes related to traits affected by selection. In this study, analysis of the genomic impact caused by domestication and artificial selection was conducted by investigating the signatures of selection using single nucleotide polymorphisms (SNPs) in channel catfish (Ictalurus punctatus). A total of 8.4 million candidate SNPs were identified by using next generation sequencing. On average, the channel catfish genome harbors one SNP per 116 bp. Approximately 6.6 million, 5.3 million, 4.9 million, 7.1 million and 6.7 million SNPs were detected in the Marion, Thompson, USDA103, Hatchery strain, and wild population, respectively. The allele frequencies of 407,861 SNPs differed significantly between the domestic and wild populations. With these SNPs, 23 genomic regions with putative selective sweeps were identified that included 11 genes. Although the function for the majority of the genes remain unknown in catfish, several genes with known function related to aquaculture performance traits were included in the regions with selective sweeps. These included hypoxia-inducible factor 1β· HIFιβ ¨ and the transporter gene ATP-binding cassette sub-family B member 5 (ABCB5). HIF1β· is important for response to hypoxia and tolerance to low oxygen levels is a critical aquaculture trait. The large numbers of SNPs identified from this study are valuable for the development of high-density SNP arrays for genetic and genomic studies of performance traits in catfish. PMID:25313648

  4. Sodium leak channel, non-selective contributes to the leak current in human myometrial smooth muscle cells from pregnant women

    PubMed Central

    Reinl, Erin L.; Cabeza, Rafael; Gregory, Ismail A.; Cahill, Alison G.; England, Sarah K.

    2015-01-01

    Uterine contractions are tightly regulated by the electrical activity of myometrial smooth muscle cells (MSMCs). These cells require a depolarizing current to initiate Ca2+ influx and induce contraction. Cationic leak channels, which permit a steady flow of cations into a cell, are known to cause membrane depolarization in many tissue types. Previously, a Gd3+-sensitive, Na+-dependent leak current was identified in the rat myometrium, but the presence of such a current in human MSMCs and the specific ion channel conducting this current was unknown. Here, we report the presence of a Na+-dependent leak current in human myometrium and demonstrate that the Na+-leak channel, NALCN, contributes to this current. We performed whole-cell voltage-clamp on fresh and cultured MSMCs from uterine biopsies of term, non-laboring women and isolated the leak currents by using Ca2+ and K+ channel blockers in the bath solution. Ohmic leak currents were identified in freshly isolated and cultured MSMCs with normalized conductances of 14.6 pS/pF and 10.0 pS/pF, respectively. The myometrial leak current was significantly reduced (P < 0.01) by treating cells with 10 μM Gd3+ or by superfusing the cells with a Na+-free extracellular solution. Reverse transcriptase PCR and immunoblot analysis of uterine biopsies from term, non-laboring women revealed NALCN messenger RNA and protein expression in the myometrium. Notably, ∼90% knockdown of NALCN protein expression with lentivirus-delivered shRNA reduced the Gd3+-sensitive leak current density by 42% (P < 0.05). Our results reveal that NALCN, in part, generates the leak current in MSMCs and provide the basis for future research assessing NALCN as a potential molecular target for modulating uterine excitability. PMID:26134120

  5. Sodium leak channel, non-selective contributes to the leak current in human myometrial smooth muscle cells from pregnant women.

    PubMed

    Reinl, Erin L; Cabeza, Rafael; Gregory, Ismail A; Cahill, Alison G; England, Sarah K

    2015-10-01

    Uterine contractions are tightly regulated by the electrical activity of myometrial smooth muscle cells (MSMCs). These cells require a depolarizing current to initiate Ca(2+) influx and induce contraction. Cationic leak channels, which permit a steady flow of cations into a cell, are known to cause membrane depolarization in many tissue types. Previously, a Gd(3+)-sensitive, Na(+)-dependent leak current was identified in the rat myometrium, but the presence of such a current in human MSMCs and the specific ion channel conducting this current was unknown. Here, we report the presence of a Na(+)-dependent leak current in human myometrium and demonstrate that the Na(+)-leak channel, NALCN, contributes to this current. We performed whole-cell voltage-clamp on fresh and cultured MSMCs from uterine biopsies of term, non-laboring women and isolated the leak currents by using Ca(2+) and K(+) channel blockers in the bath solution. Ohmic leak currents were identified in freshly isolated and cultured MSMCs with normalized conductances of 14.6 pS/pF and 10.0 pS/pF, respectively. The myometrial leak current was significantly reduced (P < 0.01) by treating cells with 10 μM Gd(3+) or by superfusing the cells with a Na(+)-free extracellular solution. Reverse transcriptase PCR and immunoblot analysis of uterine biopsies from term, non-laboring women revealed NALCN messenger RNA and protein expression in the myometrium. Notably, ∼90% knockdown of NALCN protein expression with lentivirus-delivered shRNA reduced the Gd(3+)-sensitive leak current density by 42% (P < 0.05). Our results reveal that NALCN, in part, generates the leak current in MSMCs and provide the basis for future research assessing NALCN as a potential molecular target for modulating uterine excitability.

  6. Channel-pattern and cross-section changes in selected reaches of Elkhead Creek, northwestern Colorado, 1938-2009

    USGS Publications Warehouse

    Elliott, John G.; Char, Steven J.

    2012-01-01

    Elkhead Creek near Craig, Colorado, is a sinuous, meandering stream whose lower 9 river miles have been regulated by Elkhead Reservoir and Dam since 1974. The U.S. Geological Survey, in cooperation with the Colorado River Water Conservation District, conducted a study from 2009 to 2010 that evaluated channel-pattern and cross-section changes and identified possible causes of streambank erosion in Elkhead Creek that could have been affected by Elkhead Dam and Reservoir. Aerial photographs taken from 1937 through 2009, streamflow records from water years 1953 through 2009, and channel surveys and sediment measurements made in 1997 and 2009 were used to analyze streambed and streambank erosion both downstream and upstream from the reservoir. Erosional trends were evaluated by calculating meander migration rates determined from analyses of georectified aerial photographs and from replicate channel surveys at monumented cross sections established in a previous study. The aerial photography dates defined four periods of roughly equal lengths for which mean meander migration rates were determined. Two periods were prior to and two periods were after Elkhead Reservoir was constructed.

  7. Molecular basis of the remarkable species selectivity of an insecticidal sodium channel toxin from the African spider Augacephalus ezendami

    NASA Astrophysics Data System (ADS)

    Herzig, Volker; Ikonomopoulou, Maria; Smith, Jennifer J.; Dziemborowicz, Sławomir; Gilchrist, John; Kuhn-Nentwig, Lucia; Rezende, Fernanda Oliveira; Moreira, Luciano Andrade; Nicholson, Graham M.; Bosmans, Frank; King, Glenn F.

    2016-07-01

    The inexorable decline in the armament of registered chemical insecticides has stimulated research into environmentally-friendly alternatives. Insecticidal spider-venom peptides are promising candidates for bioinsecticide development but it is challenging to find peptides that are specific for targeted pests. In the present study, we isolated an insecticidal peptide (Ae1a) from venom of the African spider Augacephalus ezendami (family Theraphosidae). Injection of Ae1a into sheep blowflies (Lucilia cuprina) induced rapid but reversible paralysis. In striking contrast, Ae1a was lethal to closely related fruit flies (Drosophila melanogaster) but induced no adverse effects in the recalcitrant lepidopteran pest Helicoverpa armigera. Electrophysiological experiments revealed that Ae1a potently inhibits the voltage-gated sodium channel BgNaV1 from the German cockroach Blattella germanica by shifting the threshold for channel activation to more depolarized potentials. In contrast, Ae1a failed to significantly affect sodium currents in dorsal unpaired median neurons from the American cockroach Periplaneta americana. We show that Ae1a interacts with the domain II voltage sensor and that sensitivity to the toxin is conferred by natural sequence variations in the S1–S2 loop of domain II. The phyletic specificity of Ae1a provides crucial information for development of sodium channel insecticides that target key insect pests without harming beneficial species.

  8. Molecular basis of the remarkable species selectivity of an insecticidal sodium channel toxin from the African spider Augacephalus ezendami.

    PubMed

    Herzig, Volker; Ikonomopoulou, Maria; Smith, Jennifer J; Dziemborowicz, Sławomir; Gilchrist, John; Kuhn-Nentwig, Lucia; Rezende, Fernanda Oliveira; Moreira, Luciano Andrade; Nicholson, Graham M; Bosmans, Frank; King, Glenn F

    2016-07-07

    The inexorable decline in the armament of registered chemical insecticides has stimulated research into environmentally-friendly alternatives. Insecticidal spider-venom peptides are promising candidates for bioinsecticide development but it is challenging to find peptides that are specific for targeted pests. In the present study, we isolated an insecticidal peptide (Ae1a) from venom of the African spider Augacephalus ezendami (family Theraphosidae). Injection of Ae1a into sheep blowflies (Lucilia cuprina) induced rapid but reversible paralysis. In striking contrast, Ae1a was lethal to closely related fruit flies (Drosophila melanogaster) but induced no adverse effects in the recalcitrant lepidopteran pest Helicoverpa armigera. Electrophysiological experiments revealed that Ae1a potently inhibits the voltage-gated sodium channel BgNaV1 from the German cockroach Blattella germanica by shifting the threshold for channel activation to more depolarized potentials. In contrast, Ae1a failed to significantly affect sodium currents in dorsal unpaired median neurons from the American cockroach Periplaneta americana. We show that Ae1a interacts with the domain II voltage sensor and that sensitivity to the toxin is conferred by natural sequence variations in the S1-S2 loop of domain II. The phyletic specificity of Ae1a provides crucial information for development of sodium channel insecticides that target key insect pests without harming beneficial species.

  9. Molecular basis of the remarkable species selectivity of an insecticidal sodium channel toxin from the African spider Augacephalus ezendami

    PubMed Central

    Herzig, Volker; Ikonomopoulou, Maria; Smith, Jennifer J.; Dziemborowicz, Sławomir; Gilchrist, John; Kuhn-Nentwig, Lucia; Rezende, Fernanda Oliveira; Moreira, Luciano Andrade; Nicholson, Graham M.; Bosmans, Frank; King, Glenn F.

    2016-01-01

    The inexorable decline in the armament of registered chemical insecticides has stimulated research into environmentally-friendly alternatives. Insecticidal spider-venom peptides are promising candidates for bioinsecticide development but it is challenging to find peptides that are specific for targeted pests. In the present study, we isolated an insecticidal peptide (Ae1a) from venom of the African spider Augacephalus ezendami (family Theraphosidae). Injection of Ae1a into sheep blowflies (Lucilia cuprina) induced rapid but reversible paralysis. In striking contrast, Ae1a was lethal to closely related fruit flies (Drosophila melanogaster) but induced no adverse effects in the recalcitrant lepidopteran pest Helicoverpa armigera. Electrophysiological experiments revealed that Ae1a potently inhibits the voltage-gated sodium channel BgNaV1 from the German cockroach Blattella germanica by shifting the threshold for channel activation to more depolarized potentials. In contrast, Ae1a failed to significantly affect sodium currents in dorsal unpaired median neurons from the American cockroach Periplaneta americana. We show that Ae1a interacts with the domain II voltage sensor and that sensitivity to the toxin is conferred by natural sequence variations in the S1–S2 loop of domain II. The phyletic specificity of Ae1a provides crucial information for development of sodium channel insecticides that target key insect pests without harming beneficial species. PMID:27383378

  10. Is the mobility of the pore walls and water molecules in the selectivity filter of KcsA channel functionally important?

    PubMed

    Kraszewski, Sebastian; Yesylevskyy, Semen O; Boiteux, Céline; Ramseyer, Christophe; Kharkyanen, Valery N

    2008-04-28

    We performed in-depth analysis of the forces which act on the K(+) ions in the selectivity filter of the KcsA channel in order to estimate the relative importance of static and dynamic influence of the filter wall and water molecules on ion permeation and selectivity. The forces were computed using the trajectories of all-atom molecular dynamics simulations. It is shown that the dynamics of the selectivity filter contributes about 3% to the net force acting on the ions and can be neglected in the studies focused on the macroscopic properties of the channel, such as the current. Among the filter atoms, only the pore-forming carbonyl groups can be considered as dynamic in the studies of microscopic events of conduction, while the dynamic effects from all other atoms are negligible. We also show that the dynamics of the water molecules in the filter can not be neglected. The fluctuating forces from the water molecules can be as strong as net forces from the pore walls and can effectively drive the ions through the local energy barriers in the filter.

  11. Habitat selection of the channel darter, Percina (Cottogaster) copelandi, a surrogate for the imperiled pearl darter, Percina aurora

    USGS Publications Warehouse

    Schofield, P.J.; Ross, Stephen T.

    2003-01-01

    Percina (Cottogaster) aurora is an imperiled species under consideration for listing by the U.S. Fish and Wildlife Service. To better understand habitat Use of P. aurora, we studied a related and more abundant Cottogaster species, Percina copelandi, from the Ouachita River, Arkansas. We used a laboratory stream system to examine mesohabitat selection (pools versus riffles) and microhabitat selection (substratum particle size) of P. copelandi over three temperature regimes (summer, spring, and winter). Percina copelandi selected pool habitats over riffles and selected pools with coarse substrata (e.g., cobble) over free substrata (e.g., gravel). In riffles, P. copelandi selected large substrata during winter and spring but did not show particle size selection during summer. These data, and various published and unpublished field data for P. aurora, suggest that habitat use of P. aurora is also centered around deep runs and pools, with large substrata likely being more important at low water temperatures.

  12. Subcellular localization of the K+ channel subunit Kv3.1b in selected rat CNS neurons.

    PubMed

    Sekirnjak, C; Martone, M E; Weiser, M; Deerinck, T; Bueno, E; Rudy, B; Ellisman, M

    1997-08-22

    Voltage-gated potassium channels constitute the largest group of heteromeric ion channels discovered to date. Over 20 genes have been isolated, encoding different channel subunit proteins which form functional tetrameric K+ channels. We have analyzed the subcellular localization of subunit Kv3.1b, a member of the Kv3 (Shaw-like) subfamily, in rat brain at the light and electron microscopic level, using immunocytochemical detection. Detailed localization was carried out in specific neurons of the neocortex, hippocampus and cerebellum. The identity of Kv3.1b-positive neurons was established using double labeling with markers for specific neuronal populations. In the neocortex, the Kv3.1b subunit was expressed in most parvalbumin-containing bipolar, basket or chandelier cells, and in some bipolar or double bouquet neurons containing calbindin. In the hippocampus, Kv3.1b was expressed in many parvalbumin-containing basket cells, as well as in calbindin-positive neurons in the stratum oriens, and in a small number of interneurons that did not stain for either parvalbumin or calbindin. Kv3.1b protein was not present in pyramidal cells in the neocortex and the hippocampus, but these cells were outlined by labeled presynaptic terminals from interneuron axons that surround the postsynaptic cell. In the cerebellar cortex, granule cells were the only population expressing the channel protein. Careful examination of individual granule cells revealed a non-uniform distribution of Kv3.1 staining on the somata: circular bands of labeling were present in the vicinity of the axon hillock. In cortical and hippocampal interneurons, as well as in cerebellar granule cells, the Kv3.1b subunit was present in somatic and unmyelinated axonal membranes and adjacent cytoplasm, as well as in the most proximal portion of dendritic processes, but not throughout most of the dendrite. Labeling was also seen in the terminals of labeled axons, but not at a higher concentration than in other parts

  13. Nonlinear vibrations of functionally graded doubly curved shallow shells

    NASA Astrophysics Data System (ADS)

    Alijani, F.; Amabili, M.; Karagiozis, K.; Bakhtiari-Nejad, F.

    2011-03-01

    Nonlinear forced vibrations of FGM doubly curved shallow shells with a rectangular base are investigated. Donnell's nonlinear shallow-shell theory is used and the shell is assumed to be simply supported with movable edges. The equations of motion are reduced using the Galerkin method to a system of infinite nonlinear ordinary differential equations with quadratic and cubic nonlinearities. Using the multiple scales method, primary and subharmonic resonance responses of FGM shells are fully discussed and the effect of volume fraction exponent on the internal resonance conditions, softening/hardening behavior and bifurcations of the shallow shell when the excitation frequency is (i) near the fundamental frequency and (ii) near two times the fundamental frequency is shown. Moreover, using a code based on arclength continuation method, a bifurcation analysis is carried out for a special case with two-to-one internal resonance between the first and second doubly symmetric modes with respect to the panel's center ( ω13≈2 ω11). Bifurcation diagrams and Poincaré maps are obtained through direct time integration of the equations of motion and chaotic regions are shown by calculating Lyapunov exponents and Lyapunov dimension.

  14. Structure of dipole bands in doubly odd 102Ag

    NASA Astrophysics Data System (ADS)

    Singh, V.; Sihotra, S.; Malik, S. S.; Bhat, G. H.; Palit, R.; Sheikh, J. A.; Kumar, S.; Singh, N.; Singh, K.; Goswamy, J.; Sethi, J.; Saha, S.; Trivedi, T.; Mehta, D.

    2016-10-01

    Excited states in the transitional doubly odd 102Ag nucleus were populated in the 75As(31P,p 3 n ) fusion-evaporation reaction using the 125 MeV incident 31P beam. The subsequent deexcitations were investigated through in-beam γ -ray spectroscopic techniques using the Indian National Gamma Array spectrometer equipped with 21 clover Ge detectors. The level scheme in 102Ag has been established up to excitation energy ˜6.5 MeV and angular momentum 19 ℏ . The earlier reported level scheme is considerably extended and modified to result in a pair of nearly degenerate negative-parity dipole bands. Lifetime measurements for the states of these two dipole bands have been performed by using the Doppler-shift attenuation method. The two nearly degenerate bands exhibit different features with regard to kinetic moment of inertia, and the reduced transition probabilities B (M 1 ) and B (E 2 ) , which do not favor these to be chiral partners. These bands are discussed in the framework of the hybrid version of tilted-axis cranking (tac) model calculations and assigned the π g9 /2⊗ν h11 /2 and π g9 /2⊗ν h11 /2(d5/2/g7 /2) 2 configurations. The tac model calculations are extended to the nearly degenerate bands observed in the heavier doubly odd Ag-108104 isotopes.

  15. Spectroscopy of doubly charmed baryons from lattice QCD

    SciTech Connect

    Padmanath, M.; Edwards, Robert G.; Mathur, Nilmani; Peardon, Michael

    2015-05-06

    This study presents the ground and excited state spectra of doubly charmed baryons from lattice QCD with dynamical quark fields. Calculations are performed on anisotropic lattices of size 16³ × 128, with inverse spacing in temporal direction at⁻¹=5.67(4) GeV and with a pion mass of about 390 MeV. A large set of baryonic operators that respect the symmetries of the lattice yet which retain a memory of their continuum analogues are used. These operators transform as irreducible representations of SU(3)F symmetry for flavor, SU(4) symmetry for Dirac spins of quarks and O(3) for spatial symmetry. The distillation method is utilized to generate baryon correlation functions which are analyzed using the variational fitting method to extract excited states. The lattice spectra obtained have baryonic states with well-defined total spins up to 7/2 and the pattern of low-lying states does not support the diquark picture for doubly charmed baryons. On the contrary the calculated spectra are remarkably similar to the expectations from models with an SU(6)×O(3) symmetry. Various spin-dependent energy splittings between the extracted states are also evaluated.

  16. Doubly charged vector leptons and the Higgs portal

    NASA Astrophysics Data System (ADS)

    Li, Wen Jun; Ng, J. N.

    2016-11-01

    Using a bottom up phenomenological approach we constructed a simple doubly charged vector lepton E±± model for the possible 750 GeV diphoton resonance Φ at the LHC assuming it to be a scalar particle. Since no stable doubly charged leptons are seen, to facilitate their decays we complete the model by adding a charged standard model (SM) electroweak scalar S± . Φ is a SM singlet and can be either an inert scalar or a Higgs field. In the inert case more than one vector lepton is required to account for the photon fusion production of the resonance if the model is to remain perturbative. For a Higgs boson case S± can assist the production mechanism without using more than one such lepton. We also found that precision measurements constrain the couplings of E±± and S± to SM particles to be small. This raises the possibility that they can be fairly long lived and can give rise to displaced vertices if produced at the LHC.

  17. Quantum phase transition in ultra small doubly connected superconducting cylinders

    NASA Astrophysics Data System (ADS)

    Sternfeld, I.; Koret, R.; Shtrikman, H.; Tsukernik, A.; Karpovski, M.; Palevski, A.

    2008-02-01

    The kinetic energy of Cooper pairs, in doubly connected superconducting cylinders, is a function of the applied flux and the ratio between the diameter of the cylinder and the zero temperature coherence length d/ ξ(0). If d >ξ(0) the known Little-Parks oscillations are observed. On the other hand if d <ξ(0), the superconducting state is energetically not favored around odd multiples of half flux quanta even at T∼0, resulting in the so called destructive regime [Y. Liu, et al., Science 294 (2001) 2332]. We developed a novel technique to fabricate superconducting doubly connected nanocylinders with both diameter and thickness less than 100 nm, and performed magnetoresistance measurements on such Nb and Al cylinders. In the Nb cylinders, where d >ξ(0), we observed the LP oscillations. In the Al cylinders we did not observe a transition to the superconducting state due to the proximity effect, resulted from an Au layer coating the Al. However, we did observe Altshuler-Aronov-Spivak (h/2e) oscillations in these cylinders.

  18. Spectroscopy of doubly charmed baryons from lattice QCD

    NASA Astrophysics Data System (ADS)

    Padmanath, M.; Edwards, Robert G.; Mathur, Nilmani; Peardon, Michael; Hadron Spectrum Collaboration

    2015-05-01

    We present the ground and excited state spectra of doubly charmed baryons from lattice QCD with dynamical quark fields. Calculations are performed on anisotropic lattices of size 1 63×128 , with inverse spacing in temporal direction at-1=5.67 (4 ) GeV and with a pion mass of about 390 MeV. A large set of baryonic operators that respect the symmetries of the lattice yet which retain a memory of their continuum analogues are used. These operators transform as irreducible representations of SU(3 ) F symmetry for flavor, SU(4) symmetry for Dirac spins of quarks and O(3) for spatial symmetry. The distillation method is utilized to generate baryon correlation functions which are analyzed using the variational fitting method to extract excited states. The lattice spectra obtained have baryonic states with well-defined total spins up to 7 /2 and the pattern of low-lying states does not support the diquark picture for doubly charmed baryons. On the contrary the calculated spectra are remarkably similar to the expectations from models with an SU (6 )×O (3 ) symmetry. Various spin-dependent energy splittings between the extracted states are also evaluated.

  19. A novel substituted aminoquinoline selectively targets voltage-sensitive sodium channel isoforms and NMDA receptor subtypes and alleviates chronic inflammatory and neuropathic pain.

    PubMed

    Tabakoff, Boris; Ren, Wenhua; Vanderlinden, Lauren; Snell, Lawrence D; Matheson, Christopher J; Wang, Ze-Jun; Levinson, Rock; Smothers, C Thetford; Woodward, John J; Honse, Yumiko; Lovinger, David; Rush, Anthony M; Sather, William A; Gustafson, Daniel L; Hoffman, Paula L

    2016-08-05

    Recent understanding of the systems that mediate complex disease states, has generated a search for molecules that simultaneously modulate more than one component of a pathologic pathway. Chronic pain syndromes are etiologically connected to functional changes (sensitization) in both peripheral sensory neurons and in the central nervous system (CNS). These functional changes involve modifications of a significant number of components of signal generating, signal transducing and signal propagating pathways. Our analysis of disease-related changes which take place in sensory neurons during sensitization led to the design of a molecule that would simultaneously inhibit peripheral NMDA receptors and voltage sensitive sodium channels. In the current report, we detail the selectivity of N,N-(diphenyl)-4-ureido-5,7-dichloro-2-carboxy-quinoline (DCUKA) for action at NMDA receptors composed of different subunit combinations and voltage sensitive sodium channels having different α subunits. We show that DCUKA is restricted to the periphery after oral administration, and that circulating blood levels are compatible with its necessary concentrations for effects at the peripheral cognate receptors/channels that were assayed in vitro. Our results demonstrate that DCUKA, at concentrations circulating in the blood after oral administration, can modulate systems which are upregulated during peripheral sensitization, and are important for generating and conducting pain information to the CNS. Furthermore, we demonstrate that DCUKA ameliorates the hyperalgesia of chronic pain without affecting normal pain responses in neuropathic and inflammation-induced chronic pain models.

  20. Channel-lining residues of the AMPA receptor M2 segment: structural environment of the Q/R site and identification of the selectivity filter.

    PubMed

    Kuner, T; Beck, C; Sakmann, B; Seeburg, P H

    2001-06-15

    In AMPA receptor channels, a single amino acid residue (Q/R site) of the M2 segment controls permeation of calcium ions, single-channel conductance, blockade by intracellular polyamines, and permeation of anions. The structural environment of the Q/R site and its positioning with regard to a narrow constriction were probed with the accessibility of substituted cysteines to positively and negatively charged methanethiosulfonate reagents, applied from the extracellular and cytoplasmic sides of the channel. The accessibility patterns confirm that the M2 segment forms a pore loop with the Q/R site positioned at the tip of the loop (position 0) facing the extracellular vestibule. Cytoplasmically accessible residues on the N- and C-terminal sides of position 0 form the ascending alpha-helical (-8 to -1) and descending random coil (+1 to +6) components of the loop, respectively. Substitution of a glycine residue at position +2 with alanine strongly decreased the permeability of organic cations, indicating that position +2 contributes to the narrow constriction. The anionic 2-sulfonatoethyl-methanethiosufonate reacted with a cysteine at position 0 only from the external side and with cysteines at positions +1 to +4 only from the cytoplasmic side. These results suggest that charge selectivity occurs external to the constriction (+2) and possibly involves interactions of ions with the negative electrostatic potential created by the dipole of the alpha-helix formed by the ascending limb of the loop.

  1. Stapled Voltage-Gated Calcium Channel (CaV) α-Interaction Domain (AID) Peptides Act As Selective Protein-Protein Interaction Inhibitors of CaV Function.

    PubMed

    Findeisen, Felix; Campiglio, Marta; Jo, Hyunil; Abderemane-Ali, Fayal; Rumpf, Christine H; Pope, Lianne; Rossen, Nathan D; Flucher, Bernhard E; DeGrado, William F; Minor, Daniel L

    2017-03-17

    For many voltage-gated ion channels (VGICs), creation of a properly functioning ion channel requires the formation of specific protein-protein interactions between the transmembrane pore-forming subunits and cystoplasmic accessory subunits. Despite the importance of such protein-protein interactions in VGIC function and assembly, their potential as sites for VGIC modulator development has been largely overlooked. Here, we develop meta-xylyl (m-xylyl) stapled peptides that target a prototypic VGIC high affinity protein-protein interaction, the interaction between the voltage-gated calcium channel (CaV) pore-forming subunit α-interaction domain (AID) and cytoplasmic β-subunit (CaVβ). We show using circular dichroism spectroscopy, X-ray crystallography, and isothermal titration calorimetry that the m-xylyl staples enhance AID helix formation are structurally compatible with native-like AID:CaVβ interactions and reduce the entropic penalty associated with AID binding to CaVβ. Importantly, electrophysiological studies reveal that stapled AID peptides act as effective inhibitors of the CaVα1:CaVβ interaction that modulate CaV function in an CaVβ isoform-selective manner. Together, our studies provide a proof-of-concept demonstration of the use of protein-protein interaction inhibitors to control VGIC function and point to strategies for improved AID-based CaV modulator design.

  2. A semi-microscopic Monte Carlo study of permeation energetics in a gramicidin-like channel: the origin of cation selectivity.

    PubMed Central

    Dorman, V; Partenskii, M B; Jordan, P C

    1996-01-01

    The influence of a gramicidin-like channel former on ion free energy barriers is studied using Monte Carlo simulation. The model explicitly describes the ion, the water dipoles, and the peptide carbonyls; the remaining degrees of freedom, bulk electrolyte, non-polar lipid and peptide regions, and electronic (high frequency) permittivity, are treated in continuum terms. Contributions of the channel waters and peptide COs are studied both separately and collectively. We found that if constrained to their original orientations, the COs substantially increase the cationic permeation free energy; with or without water present, CO reorientation is crucial for ion-CO interaction to lower cation free energy barriers; the translocation free energy profiles for potassium-, rubidium-, and cesium-like cations exhibit no broad barriers; the lipid-bound peptide interacts more effectively with anions than cations; anionic translocation free energy profiles exhibit well defined maxima. Using experimental data to estimate transfer free energies of ions and water from bulk electrolyte to a non-polar dielectric (continuum lipid), we found reasonable ion permeation profiles; cations bind and permeate, whereas anions cannot enter the channel. Cation selectivity arises because, for ions of the same size and charge, anions bind hydration water more strongly. PMID:8770192

  3. New Exotic Meson and Baryon Resonances from Doubly Heavy Hadronic Molecules.

    PubMed

    Karliner, Marek; Rosner, Jonathan L

    2015-09-18

    We predict several new exotic doubly heavy hadronic resonances, inferring from the observed exotic bottomoniumlike and charmoniumlike narrow states X(3872), Z_{b}(10610), Z_{b}(10650), Z_{c}(3900), and Z_{c}(4020/4025). We interpret the binding mechanism as mostly molecularlike isospin-exchange attraction between two heavy-light mesons in a relative S-wave state. We then generalize it to other systems containing two heavy hadrons which can couple through isospin exchange. The new predicted states include resonances in meson-meson, meson-baryon, baryon-baryon, and baryon-antibaryon channels. These include those giving rise to final states involving a heavy quark Q=c,b and antiquark Q[over ¯]^{'}=c[over ¯],b[over ¯], namely, DD[over ¯]^{*}, D^{*}D[over ¯]^{*}, D^{*}B^{*}, B[over ¯]B^{*}, B[over ¯]^{*}B^{*}, Σ_{c}D[over ¯]^{*}, Σ_{c}B^{*}, Σ_{b}D[over ¯]^{*}, Σ_{b}B^{*}, Σ_{c}Σ[over ¯]_{c}, Σ_{c}Λ[over ¯]_{c}, Σ_{c}Λ[over ¯]_{b}, Σ_{b}Σ[over ¯]_{b}, Σ_{b}Λ[over ¯]_{b}, and Σ_{b}Λ[over ¯]_{c}, as well as corresponding S-wave states giving rise to QQ^{'} or Q[over ¯]Q[over ¯]^{'}.

  4. On the intermolecular Coulombic decay of singly and doubly ionized states of water dimer.

    PubMed

    Stoychev, Spas D; Kuleff, Alexander I; Cederbaum, Lorenz S

    2010-10-21

    A semiquantitative study of the intermolecular Coulombic decay (ICD) of singly and doubly ionized water dimer has been carried out with the help of ab initio computed ionization spectra and potential energy curves (PECs). These PECs are particular cuts through the (H(2)O)(2), (H(2)O)(2) (+), and (H(2)O)(2) (++) hypersurfaces along the distance between the two oxygen atoms. A comparison with the recently published experimental data for the ICD in singly ionized water dimers [T. Jahnke, H. Sann, T. Havermeier et al., Nat. Phys. 6, 139 (2010)] and in large water clusters [M. Mucke, M. Braune, S. Barth et al., Nat. Phys. 6, 143 (2010)] shows that such a simplified description in which the internal degrees of freedom of the water molecules are frozen gives surprisingly useful results. Other possible decay channels of the singly ionized water dimer are also investigated and the influence of the H-atom participating in the hydrogen bond on the spectra of the proton-donor and proton-acceptor molecules in the dimer is discussed. Importantly, the decay processes of one-site dicationic states of water dimer are discussed and an estimate of the ICD-electron spectra is made. More than 33% of the dications produced by Auger decay are found to undergo ICD. The qualitative results show that the ICD following Auger decay in water is also expected to be an additional source of low-energy electrons proven to be extremely important for causing damages to living tissues.

  5. Four basic residues critical for the ion selectivity and pore blocker sensitivity of TMEM16A calcium-activated chloride channels.

    PubMed

    Peters, Christian J; Yu, Haibo; Tien, Jason; Jan, Yuh Nung; Li, Min; Jan, Lily Yeh

    2015-03-17

    TMEM16A (transmembrane protein 16) (Anoctamin-1) forms a calcium-activated chloride channel (CaCC) that regulates a broad array of physiological properties in response to changes in intracellular calcium concentration. Although known to conduct anions according to the Eisenman type I selectivity sequence, the structural determinants of TMEM16A anion selectivity are not well-understood. Reasoning that the positive charges on basic residues are likely contributors to anion selectivity, we performed whole-cell recordings of mutants with alanine substitution for basic residues within the putative pore region and identified four residues on four different putative transmembrane segments that significantly increased the permeability of the larger halides and thiocyanate relative to that of chloride. Because TMEM16A permeation properties are known to shift with changes in intracellular calcium concentration, we further examined the calcium dependence of anion selectivity. We found that WT TMEM16A but not mutants with alanine substitution at those four basic residues exhibited a clear decline in the preference for larger anions as intracellular calcium was increased. Having implicated these residues as contributing to the TMEM16A pore, we scrutinized candidate small molecules from a high-throughput CaCC inhibitor screen to identify two compounds that act as pore blockers. Mutations of those four putative pore-lining basic residues significantly altered the IC50 of these compounds at positive voltages. These findings contribute to our understanding regarding anion permeation of TMEM16A CaCC and provide valuable pharmacological tools to probe the channel pore.

  6. Four basic residues critical for the ion selectivity and pore blocker sensitivity of TMEM16A calcium-activated chloride channels

    PubMed Central

    Peters, Christian J.; Yu, Haibo; Tien, Jason; Jan, Yuh Nung; Li, Min; Jan, Lily Yeh

    2015-01-01

    TMEM16A (transmembrane protein 16) (Anoctamin-1) forms a calcium-activated chloride channel (CaCC) that regulates a broad array of physiological properties in response to changes in intracellular calcium concentration. Although known to conduct anions according to the Eisenman type I selectivity sequence, the structural determinants of TMEM16A anion selectivity are not well-understood. Reasoning that the positive charges on basic residues are likely contributors to anion selectivity, we performed whole-cell recordings of mutants with alanine substitution for basic residues within the putative pore region and identified four residues on four different putative transmembrane segments that significantly increased the permeability of the larger halides and thiocyanate relative to that of chloride. Because TMEM16A permeation properties are known to shift with changes in intracellular calcium concentration, we further examined the calcium dependence of anion selectivity. We found that WT TMEM16A but not mutants with alanine substitution at those four basic residues exhibited a clear decline in the preference for larger anions as intracellular calcium was increased. Having implicated these residues as contributing to the TMEM16A pore, we scrutinized candidate small molecules from a high-throughput CaCC inhibitor screen to identify two compounds that act as pore blockers. Mutations of those four putative pore-lining basic residues significantly altered the IC50 of these compounds at positive voltages. These findings contribute to our understanding regarding anion permeation of TMEM16A CaCC and provide valuable pharmacological tools to probe the channel pore. PMID:25733897

  7. Bounds on LFV Higgs decays in a vector-like lepton model and searching for doubly charged leptons at the LHC

    NASA Astrophysics Data System (ADS)

    Chen, Chuan-Hung; Nomura, Takaaki

    2016-06-01

    The Higgs-portal lepton flavor violation is studied in a vector-like lepton model. To avoid the constraints from rare Z→ ℓ ^± _i ℓ ^∓ _j decays, we introduce two triplet vector-like leptons, (1,3)_{-1} and (1,3)0. The resultant branching ratio for h→ μ τ can be up to 10^{-4} when the constraints from the invisible Z decays are applied. As a result, the signal strength for the τ τ channel has a 12 % deviation from the standard model prediction, while the muon g-2 is two orders of magnitude smaller than the data, and BR(τ → μ γ ) is of the order of 10^{-12}. A predicted doubly charged lepton in pp collisions at √{s}=13 TeV is analyzed, and it is found that the interesting production channels are pp→ (Ψ ^{- -}1 Ψ ^{++}_1, Ψ ^{± ± }_1 Ψ ^∓ _1). Both single and pair production cross sections of Ψ ^{++}_1 are comparable, and can be a few hundred fb. The main decay channels for the doubly charged lepton are Ψ ^{± ± } → ℓ ^± W^± , and for the heavy singly charged lepton they are Ψ ^± _1 → ν W^± , ℓ ^± Z. The numerical analysis is carried out with regard to 13 TeV LHC with 100 fb^{-1} luminosity.

  8. Coordination numbers of K(+) and Na(+) Ions inside the selectivity filter of the KcsA potassium channel: insights from first principles molecular dynamics.

    PubMed

    Bucher, Denis; Guidoni, Leonardo; Carloni, Paolo; Rothlisberger, Ursula

    2010-05-19

    Quantum mechanics/molecular mechanics (QM/MM) Car-Parrinello simulations were performed to estimate the coordination numbers of K(+) and Na(+) ions in the selectivity filter of the KcsA channel, and in water. At the DFT/BLYP level, K(+) ions were found to display an average coordination number of 6.6 in the filter, and 6.2 in water. Na(+) ions displayed an average coordination number of 5.2 in the filter, and 5.0 in water. A comparison was made with the average coordination numbers obtained from using classical molecular dynamics (6.7 for K(+) in the filter, 6.6 for K(+) in water, 6.0 for Na(+) in the filter, and 5.2 for Na(+) in water). The observation that different coordination numbers were displayed by the ions in QM/MM simulations and in classical molecular dynamics is relevant to the discussion of selectivity in K-channels.

  9. Search for doubly charged Higgs bosons decaying to dileptons in pp collisions at square root of s=1.96 TeV.

    PubMed

    Acosta, D; Affolder, T; Akimoto, T; Albrow, M G; Ambrose, D; Amerio, S; Amidei, D; Anastassov, A; Anikeev, K; Annovi, A; Antos, J; Aoki, M; Apollinari, G; Arisawa, T; Arguin, J-F; Artikov, A; Ashmanskas, W; Attal, A; Azfar, F; Azzi-Bacchetta, P; Bacchetta, N; Bachacou, H; Badgett, W; Barbaro-Galtieri, A; Barker, G J; Barnes, V E; Barnett, B A; Baroiant, S; Barone, M; Bauer, G; Bedeschi, F; Behari, S; Belforte, S; Bellettini, G; Bellinger, J; Benjamin, D; Beretvas, A; Bhatti, A; Binkley, M; Bisello, D; Bishai, M; Blair, R E; Blocker, C; Bloom, K; Blumenfeld, B; Bocci, A; Bodek, A; Bolla, G; Bolshov, A; Booth, P S L; Bortoletto, D; Boudreau, J; Bourov, S; Bromberg, C; Brubaker, E; Budagov, J; Budd, H S; Burkett, K; Busetto, G; Bussey, P; Byrum, K L; Cabrera, S; Calafiura, P; Campanelli, M; Campbell, M; Canepa, A; Casarsa, M; Carlsmith, D; Carron, S; Carosi, R; Cavalli-Sforza, M; Castro, A; Catastini, P; Cauz, D; Cerri, A; Cerri, C; Cerrito, L; Chapman, J; Chen, C; Chen, Y C; Chertok, M; Chiarelli, G; Chlachidze, G; Chlebana, F; Cho, I; Cho, K; Chokheli, D; Chu, M L; Chuang, S; Chung, J Y; Chung, W-H; Chung, Y S; Ciobanu, C I; Ciocci, M A; Clark, A G; Clark, D; Coca, M; Connolly, A; Convery, M; Conway, J; Cooper, B; Cordelli, M; Cortiana, G; Cranshaw, J; Cuevas, J; Culbertson, R; Currat, C; Cyr, D; Dagenhart, D; Da Ronco, S; D'Auria, S; de Barbaro, P; De Cecco, S; De Lentdecker, G; Dell'agnello, S; Dell'orso, M; Demers, S; Demortier, L; Deninno, M; De Pedis, D; Derwent, P F; Dionisi, C; Dittmann, J R; Doksus, P; Dominguez, A; Donati, S; Donega, M; Donini, J; D'Onofrio, M; Dorigo, T; Drollinger, V; Ebina, K; Eddy, N; Ely, R; Erbacher, R; Erdmann, M; Errede, D; Errede, S; Eusebi, R; Fang, H-C; Farrington, S; Fedorko, I; Feild, R G; Feindt, M; Fernandez, J P; Ferretti, C; Field, R D; Fiori, I; Flanagan, G; Flaugher, B; Flores-Castillo, L R; Foland, A; Forrester, S; Foster, G W; Franklin, M; Freeman, J; Frisch, H; Fujii, Y; Furic, I; Gajjar, A; Gallas, A; Galyardt, J; Gallinaro, M; Garcia-Sciveres, M; Garfinkel, A F; Gay, C; Gerberich, H; Gerdes, D W; Gerchtein, E; Giagu, S; Giannetti, P; Gibson, A; Gibson, K; Ginsburg, C; Giolo, K; Giordani, M; Giurgiu, G; Glagolev, V; Glenzinski, D; Gold, M; Goldschmidt, N; Goldstein, D; Goldstein, J; Gomez, G; Gomez-Ceballos, G; Goncharov, M; González, O; Gorelov, I; Goshaw, A T; Gotra, Y; Goulianos, K; Gresele, A; Grosso-Pilcher, C; Guenther, M; Guimaraes da Costa, J; Haber, C; Hahn, K; Hahn, S R; Halkiadakis, E; Handler, R; Happacher, F; Hara, K; Hare, M; Harr, R F; Harris, R M; Hartmann, F; Hatakeyama, K; Hauser, J; Hays, C; Hayward, H; Heider, E; Heinemann, B; Heinrich, J; Hennecke, M; Herndon, M; Hill, C; Hirschbuehl, D; Hocker, A; Hoffman, K D; Holloway, A; Hou, S; Houlden, M A; Huffman, B T; Huang, Y; Hughes, R E; Huston, J; Ikado, K; Incandela, J; Introzzi, G; Iori, M; Ishizawa, Y; Issever, C; Ivanov, A; Iwata, Y; Iyutin, B; James, E; Jang, D; Jarrell, J; Jeans, D; Jensen, H; Jeon, E J; Jones, M; Joo, K K; Jun, S; Junk, T; Kamon, T; Kang, J; Karagoz Unel, M; Karchin, P E; Kartal, S; Kato, Y; Kemp, Y; Kephart, R; Kerzel, U; Khotilovich, V; Kilminster, B; Kim, D H; Kim, H S; Kim, J E; Kim, M J; Kim, M S; Kim, S B; Kim, S H; Kim, T H; Kim, Y K; King, B T; Kirby, M; Kirsch, L; Klimenko, S; Knuteson, B; Ko, B R; Kobayashi, H; Koehn, P; Kong, D J; Kondo, K; Konigsberg, J; Kordas, K; Korn, A; Korytov, A; Kotelnikov, K; Kotwal, A V; Kovalev, A; Kraus, J; Kravchenko, I; Kreymer, A; Kroll, J; Kruse, M; Krutelyov, V; Kuhlmann, S E; Kuznetsova, N; Laasanen, A T; Lai, S; Lami, S; Lammel, S; Lancaster, J; Lancaster, M; Lander, R; Lannon, K; Lath, A; Latino, G; Lauhakangas, R; Lazzizzera, I; Le, Y; Lecci, C; Lecompte, T; Lee, J; Lee, J; Lee, S W; Leonardo, N; Leone, S; Lewis, J D; Li, K; Lin, C; Lin, C S; Lindgren, M; Liss, T M; Litvintsev, D O; Liu, T; Liu, Y; Lockyer, N S; Loginov, A; Loreti, M; Loverre, P; Lu, R-S; Lucchesi, D; Lujan, P; Lukens, P; Lyons, L; Lys, J; Lysak, R; Macqueen, D; Madrak, R; Maeshima, K; Maksimovic, P; Malferrari, L; Manca, G; Marginean, R; Martin, M; Martin, A; Martin, V; Martínez, M; Maruyama, T; Matsunaga, H; Mattson, M; Mazzanti, P; McFarland, K S; McGivern, D; McIntyre, P M; McNamara, P; McNulty, R; Menzemer, S; Menzione, A; Merkel, P; Mesropian, C; Messina, A; Miao, T; Miladinovic, N; Miller, L; Miller, R; Miller, J S; Miquel, R; Miscetti, S; Mitselmakher, G; Miyamoto, A; Miyazaki, Y; Moggi, N; Mohr, B; Moore, R; Morello, M; Moulik, T; Movilla Fernandez, P A; Mukherjee, A; Mulhearn, M; Muller, T; Mumford, R; Munar, A; Murat, P; Nachtman, J; Nahn, S; Nakamura, I; Nakano, I; Napier, A; Napora, R; Naumov, D; Necula, V; Niell, F; Nielsen, J; Nelson, C; Nelson, T; Neu, C; Neubauer, M S; Newman-Holmes, C; Nicollerat, A-S; Nigmanov, T; Nodulman, L; Norniella, O; Oesterberg, K; Ogawa, T; Oh, S H; Oh, Y D; Ohsugi, T; Okusawa, T; Oldeman, R; Orava, R; Orejudos, W; Pagliarone, C; Palmonari, F; Paoletti, R; Papadimitriou, V; Pashapour, S; Patrick, J; Pauletta, G; Paulini, M; Pauly, T; Paus, C; Pellett, D; Penzo, A; Phillips, T J; Piacentino, G; Piedra, J; Pitts, K T; Plager, C; Pompos, A; Pondrom, L; Pope, G; Poukhov, O; Prakoshyn, F; Pratt, T; Pronko, A; Proudfoot, J; Ptohos, F; Punzi, G; Rademacker, J; Rakitine, A; Rappoccio, S; Ratnikov, F; Ray, H; Reichold, A; Reisert, B; Rekovic, V; Renton, P; Rescigno, M; Rimondi, F; Rinnert, K; Ristori, L; Robertson, W J; Robson, A; Rodrigo, T; Rolli, S; Rosenson, L; Roser, R; Rossin, R; Rott, C; Russ, J; Ruiz, A; Ryan, D; Saarikko, H; Safonov, A; St Denis, R; Sakumoto, W K; Salamanna, G; Saltzberg, D; Sanchez, C; Sansoni, A; Santi, L; Sarkar, S; Sato, K; Savard, P; Savoy-Navarro, A; Schemitz, P; Schlabach, P; Schmidt, E E; Schmidt, M P; Schmitt, M; Scodellaro, L; Scribano, A; Scuri, F; Sedov, A; Seidel, S; Seiya, Y; Semeria, F; Sexton-Kennedy, L; Sfiligoi, I; Shapiro, M D; Shears, T; Shepard, P F; Shimojima, M; Shochet, M; Shon, Y; Shreyber, I; Sidoti, A; Siegrist, J; Siket, M; Sill, A; Sinervo, P; Sisakyan, A; Skiba, A; Slaughter, A J; Sliwa, K; Smirnov, D; Smith, J R; Snider, F D; Snihur, R; Somalwar, S V; Spalding, J; Spezziga, M; Spiegel, L; Spinella, F; Spiropulu, M; Squillacioti, P; Stadie, H; Stefanini, A; Stelzer, B; Stelzer-Chilton, O; Strologas, J; Stuart, D; Sukhanov, A; Sumorok, K; Sun, H; Suzuki, T; Taffard, A; Tafirout, R; Takach, S F; Takano, H; Takashima, R; Takeuchi, Y; Takikawa, K; Tanaka, M; Tanaka, R; Tanimoto, N; Tapprogge, S; Tecchio, M; Teng, P K; Terashi, K; Tesarek, R J; Tether, S; Thom, J; Thompson, A S; Thomson, E; Tipton, P; Tiwari, V; Tkaczyk, S; Toback, D; Tollefson, K; Tomura, T; Tonelli, D; Tönnesmann, M; Torre, S; Torretta, D; Trischuk, W; Tseng, J; Tsuchiya, R; Tsuno, S; Tsybychev, D; Turini, N; Turner, M; Ukegawa, F; Unverhau, T; Uozumi, S; Usynin, D; Vacavant, L; Vaiciulis, A; Varganov, A; Vataga, E; Vejcik, S; Velev, G; Veramendi, G; Vickey, T; Vidal, R; Vila, I; Vilar, R; Volobouev, I; von der Mey, M; Wagner, R G; Wagner, R L; Wagner, W; Wallny, R; Walter, T; Yamashita, T; Yamamoto, K; Wan, Z; Wang, M J; Wang, S M; Warburton, A; Ward, B; Waschke, S; Waters, D; Watts, T; Weber, M; Wester, W C; Whitehouse, B; Wicklund, A B; Wicklund, E; Williams, H H; Wilson, P; Winer, B L; Wittich, P; Wolbers, S; Wolter, M; Worcester, M; Worm, S; Wright, T; Wu, X; Würthwein, F; Wyatt, A; Yagil, A; Yang, U K; Yao, W; Yeh, G P; Yi, K; Yoh, J; Yoon, P; Yorita, K; Yoshida, T; Yu, I; Yu, S; Yu, Z; Yun, J C; Zanello, L; Zanetti, A; Zaw, I; Zetti, F; Zhou, J; Zsenei, A; Zucchelli, S

    2004-11-26

    We present the results of a search for doubly charged Higgs bosons (H+/-+/-) decaying to dileptons (ll(')) using approximately 240 pb(-1) of pp collision data collected by the CDF II experiment at the Fermilab Tevatron. In our search region, given by same-sign ll(') mass m(ll('))>80 GeV/c(2) (100 GeV/c(2) for ee channel), we observe no evidence for H+/-+/- production. We set limits on sigma(pp -->H++H---->l(+)l('+)l(-)l('-)) as a function of the mass of the H+/-+/- and the chirality of its couplings. Assuming exclusive same-sign dilepton decays, we derive lower mass limits on H(+/-+/-)(L) of 133, 136, and 115 GeV/c(2) in the ee, mumu, and emu channels, respectively, and a lower mass limit of 113 GeV/c(2) on H(+/-+/-)(R) in the mumu channel, all at the 95% confidence level.

  10. Detection of singly- and doubly-charged quaternary ammonium drugs in equine urine by liquid chromatography/tandem mass spectrometry.

    PubMed

    Ho, Emmie N M; Kwok, W H; Wong, April S Y; Wan, Terence S M

    2012-01-13

    Quaternary ammonium drugs (QADs) are anticholinergic agents some of which are known to have been abused or misused in equine sports. A recent review of literature shows that the screening methods reported thus far for QADs mainly cover singly-charged QADs. Doubly-charged QADs are extremely polar substances which are difficult to be extracted and poorly retained on reversed-phase columns. It would be ideal if a comprehensive method can be developed which can detect both singly- and doubly-charged QADs. This paper describes an efficient liquid chromatography/tandem mass spectrometry (LC/MS/MS) method for the simultaneous detection and confirmation of 38 singly- and doubly-charged QADs at sub-parts-per-billion (ppb) to low-ppb levels in equine urine after solid-phase extraction. Quaternary ammonium drugs were extracted from equine urine by solid-phase extraction (SPE) using an ISOLUTE(®) CBA SPE column and analysed by LC/MS/MS in the positive electrospray ionisation mode. Separation of the 38 QADs was achieved on a polar group embedded C18 LC column with a mixture of aqueous ammonium formate (pH 3.0, 10 mM) and acetonitrile as the mobile phase. Detection and confirmation of the 38 QADs at sub-ppb to low-ppb levels in equine urine could be achieved within 16 min using selected reaction monitoring (SRM). Matrix interference of the target transitions at the expected retention times was not observed. Other method validation data, including precision and recovery, were acceptable. The method was successfully applied to the analyses of drug-administration samples.

  11. Water-surface elevations and channel characteristics for a selected reach of the Applegate River, Jackson County, Oregon

    USGS Publications Warehouse

    Harris, David Dell; Alexander, Clyde W.

    1970-01-01

    In land-use planning for the Applegate River and its flood plain, consideration should be given to (1) preservation of the recreational attributes of the area, (2) allowance for optimum development of the flood plain's natural resources, and (3) protection of the rights of private landowners. Major factors that influence evaluation of the above considerations are the elevations and characteristics of floods. Heretofore, such flood data for the Applegate River have been inadequate to evaluate the flood potential or to use as a basis for delineating reasonable land-use zones. Therefore, at the request of Jackson County, this study was made to provide flood elevations, water-surface profiles, and channel characteristics (geometry and slope) for a reach of the Applegate River from the Jackson-Josephine County line upstream to the Applegate damsite (fig. 1). A similar study was previously made for reaches of adjacent Rogue River and Elk Creek (Harris, 1970).

  12. Expression of acid-sensing ion channels and selection of reference genes in mouse and naked mole rat.

    PubMed

    Schuhmacher, Laura-Nadine; Smith, Ewan St John

    2016-12-13

    Acid-sensing ion channels (ASICs) are a family of ion channels comprised of six subunits encoded by four genes and they are expressed throughout the peripheral and central nervous systems. ASICs have been implicated in a wide range of physiological and pathophysiological processes: pain, breathing, synaptic plasticity and excitotoxicity. Unlike mice and humans, naked mole-rats do not perceive acid as a noxious stimulus, even though their sensory neurons express functional ASICs, likely an adaptation to living in a hypercapnic subterranean environment. Previous studies of ASIC expression in the mammalian nervous system have often not examined all subunits, or have failed to adequately quantify expression between tissues; to date there has been no attempt to determine ASIC expression in the central nervous system of the naked mole-rat. Here we perform a geNorm study to identify reliable housekeeping genes in both mouse and naked mole-rat and then use quantitative real-time PCR to estimate the relative amounts of ASIC transcripts in different tissues of both species. We identify RPL13A (ribosomal protein L13A) and CANX (calnexin), and β-ACTIN and EIF4A (eukaryotic initiation factor 4a) as being the most stably expressed housekeeping genes in mouse and naked mole-rat, respectively. In both species, ASIC3 was most highly expressed in dorsal root ganglia (DRG), and ASIC1a, ASIC2b and ASIC3 were more highly expressed across all brain regions compared to the other subunits. We also show that ASIC4, a proton-insensitive subunit of relatively unknown function, was highly expressed in all mouse tissues apart from DRG and hippocampus, but was by contrast the lowliest expressed ASIC in all naked mole-rat tissues.

  13. Molecular level model for the agonist/antagonist selectivity of the 1,4-dihydropyridine calcium channel receptor

    NASA Astrophysics Data System (ADS)

    Langs, David A.; Kwon, Yong Wha; Strong, Phyllis D.; Triggle, David J.

    1991-04-01

    Crystal structures of the 1,4-dihydropyridine (1,4-DHP) calcium channel activators Bay K 8643 [methyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(3-nitrophenyl)-pyridine-5-carboxylate], Bay O 8495 [methyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(3-trifluoromethylphenyl)-pyridine-5-carboxylate], and Bay O 9507 [methyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(4-nitrophenyl)-pyridine-5-carboxylate] were determined. The conformations of the 1,4-DHP rings of these activator analogues of Bay K 8644 [methyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)-pyridine-5- carboxylate] do not suggest that their activator properties are as strongly correlated with the degree of 1,4-DHP ring flattening as was indicated for members of the corresponding antagonist series. The solid state hydrogen bonding of the N(1)-H groups of the activators is not, unlike that of their antagonist counterparts, to acceptors that are directly in line with the donor. Rather, acceptor groups are positioned within ± 60 degrees of the N(1)-H bond in the vertical plane of the 1,4-DHP ring. Previously determined structure-activity relationships have indicated the importance of this N(1)-H group to the activity of the 1,4-DHP antagonists. Based on these observations, a model is advanced to describe the 1,4-DHP binding site of the voltage-gated Ca2+ channel and its ability to accommodate both antagonist and activator ligands.

  14. High-efficiency frequency upconversion of 1.5 μm laser based on a doubly resonant external ring cavity with a low finesse for signal field

    NASA Astrophysics Data System (ADS)

    Tan, Wei; Qiu, Xiaodong; Zhao, Gang; Jia, Mengyuan; Ma, Weiguang; Yan, Xiaojuan; Dong, Lei; Zhang, Lei; Tong, Zhaomin; Yin, Wangbao; Feng, Xiaoxia; Xiao, Liantuan; Axner, Ove; Jia, Suotang

    2017-02-01

    A doubly resonant external ring cavity with a low finesse for the signal field is used to improve the frequency upconversion efficiency of a weak 1583 nm signal laser to 636 nm by mixing with a resonance power enhanced 1064 nm pump laser in a 25 mm periodically poled lithium niobate crystal. The process of frequency upconversion is described and optimized by the doubly resonant cavity-enhanced sum frequency generation theory under the condition of undepleted pump approximation. By selecting the suitable reflectivity of the signal input mirror and the incident pump power, a cavity-enhanced frequency conversion efficiency of 94.6% was obtained for signal powers up to 25 mW with an input pump power of 780 mW.

  15. Outage Performance Analysis of Relay Selection Schemes in Wireless Energy Harvesting Cooperative Networks over Non-Identical Rayleigh Fading Channels

    PubMed Central

    Do, Nhu Tri; Bao, Vo Nguyen Quoc; An, Beongku

    2016-01-01

    In this paper, we study relay selection in decode-and-forward wireless energy harvesting cooperative networks. In contrast to conventional cooperative networks, the relays harvest energy from the source’s radio-frequency radiation and then use that energy to forward the source information. Considering power splitting receiver architecture used at relays to harvest energy, we are concerned with the performance of two popular relay selection schemes, namely, partial relay selection (PRS) scheme and optimal relay selection (ORS) scheme. In particular, we analyze the system performance in terms of outage probability (OP) over independent and non-identical (i.n.i.d.) Rayleigh fading channels. We derive the closed-form approximations for the system outage probabilities of both schemes and validate the analysis by the Monte-Carlo simulation. The numerical results provide comprehensive performance comparison between the PRS and ORS schemes and reveal the effect of wireless energy harvesting on the outage performances of both schemes. Additionally, we also show the advantages and drawbacks of the wireless energy harvesting cooperative networks and compare to the conventional cooperative networks. PMID:26927119

  16. Near yrast states in doubly odd [sup 214]Fr

    SciTech Connect

    Debray, M.E.; Kreiner, A.J.; Kesque, J.M.; Ozafran, M.; Romo, A.; Somacal, H.; Vazquez, M.E. ); Davidson, J.; Davidson, M. ); Ahn, K.; Fossan, D.B.; Liang, Y.; Ma, R.; Paul, E.S.; Piel, W.F. Jr.; Xu, N. )

    1993-11-01

    High spin states of doubly odd [sup 214]Fr[sub 127] have been investigated using in-beam [gamma]-ray and conversion electron spectroscopy techniques through the [sup 206]Pb([sup 11]B, 3[ital n]) and [sup 208]Pb([sup 11]B, 5[ital n]) fusion-evaporation reactions. Completely new spectrocopic information has been obtained. The yrast level structure is established up to spin (19[sup +]) and some information on [gamma] transitions from higher-lying levels is also obtained. Two new isomers [ital T][sub 1/2]=174(20) ns and [ital T][sub 1/2]=11(2) ns were found. Configuration assignments for the low-lying levels are discussed. Information on residual proton-neutron interactions is extracted.

  17. Doubly Robust Learning for Estimating Individualized Treatment with Censored Data

    PubMed Central

    Zhao, Y. Q.; Zeng, D.; Laber, E. B.; Song, R.; Yuan, M.; Kosorok, M. R.

    2014-01-01

    Summary Individualized treatment rules recommend treatments based on individual patient characteristics in order to maximize clinical benefit. When the clinical outcome of interest is survival time, estimation is often complicated by censoring. We develop nonparametric methods for estimating an optimal individualized treatment rule in the presence of censored data. To adjust for censoring, we propose a doubly robust estimator which requires correct specification of either the censoring model or survival model, but not both; the method is shown to be Fisher consistent when either model is correct. Furthermore, we establish the convergence rate of the expected survival under the estimated optimal individualized treatment rule to the expected survival under the optimal individualized treatment rule. We illustrate the proposed methods using simulation study and data from a Phase III clinical trial on non-small cell lung cancer. PMID:25937641

  18. Triple differential cross sections of magnesium in doubly symmetric geometry

    NASA Astrophysics Data System (ADS)

    S, Y. Sun; X, Y. Miao; Xiang-Fu, Jia

    2016-01-01

    A dynamically screened three-Coulomb-wave (DS3C) method is applied to study the single ionization of magnesium by electron impact. Triple differential cross sections (TDCS) are calculated in doubly symmetric geometry at incident energies of 13.65, 17.65, 22.65, 27.65, 37.65, 47.65, 57.65, and 67.65 eV. Comparisons are made with experimental data and theoretical predictions from a three-Coulomb-wave function (3C) approach and distorted-wave Born approximation (DWBA). The overall agreement between the predictions of the DS3C model and the DWBA approach with the experimental data is satisfactory. Project supported by the National Natural Science Foundation of China (Grant No. 11274215).

  19. Properties of Doubly Heavy Baryons in the Relativistic Quark Model

    SciTech Connect

    Ebert, D.; Faustov, R.N.; Galkin, V.O.; Martynenko, A.P.

    2005-05-01

    Mass spectra and semileptonic decay rates of baryons consisting of two heavy (b or c) and one light quark are calculated in the framework of the relativistic quark model. The doubly heavy baryons are treated in the quark-diquark approximation. The ground and excited states of both the diquark and quark-diquark bound systems are considered. The quark-diquark potential is constructed. The light quark is treated completely relativistically, while the expansion in the inverse heavy-quark mass is used. The weak transition amplitudes of heavy diquarks bb and bc going, respectively, to bc and cc are explicitly expressed through the overlap integrals of the diquark wave functions in the whole accessible kinematic range. The relativistic baryon wave functions of the quark-diquark bound system are used for the calculation of the decay matrix elements, the Isgur-Wise function, and decay rates in the heavy-quark limit.

  20. Doubly infinite separation of quantum information and communication

    NASA Astrophysics Data System (ADS)

    Liu, Zi-Wen; Perry, Christopher; Zhu, Yechao; Koh, Dax Enshan; Aaronson, Scott

    2016-01-01

    We prove the existence of (one-way) communication tasks with a subconstant versus superconstant asymptotic gap, which we call "doubly infinite," between their quantum information and communication complexities. We do so by studying the exclusion game [C. Perry et al., Phys. Rev. Lett. 115, 030504 (2015), 10.1103/PhysRevLett.115.030504] for which there exist instances where the quantum information complexity tends to zero as the size of the input n increases. By showing that the quantum communication complexity of these games scales at least logarithmically in n , we obtain our result. We further show that the established lower bounds and gaps still hold even if we allow a small probability of error. However in this case, the n -qubit quantum message of the zero-error strategy can be compressed polynomially.

  1. Nonsnaking doubly diffusive convectons and the twist instability

    SciTech Connect

    Beaume, Cédric Knobloch, Edgar; Bergeon, Alain

    2013-11-15

    Doubly diffusive convection in a three-dimensional horizontally extended domain with a square cross section in the vertical is considered. The fluid motion is driven by horizontal temperature and concentration differences in the transverse direction. When the buoyancy ratio N = −1 and the Rayleigh number is increased the conduction state loses stability to a subcritical, almost two-dimensional roll structure localized in the longitudinal direction. This structure exhibits abrupt growth in length near a particular value of the Rayleigh number but does not snake. Prior to this filling transition the structure becomes unstable to a secondary twist instability generating a pair of stationary, spatially localized zigzag states. In contrast to the primary branch these states snake as they grow in extent and eventually fill the whole domain. The origin of the twist instability and the properties of the resulting localized structures are investigated for both periodic and no-slip boundary conditions in the extended direction.

  2. Doubly responsive polymer-microgel composites: rheology and structure.

    PubMed

    Monti, Fabrice; Fu, Shang-Yi; Iliopoulos, Ilias; Cloitre, Michel

    2008-10-21

    Mixtures of alkali swellable microgels and linear PNIPAm chains exhibit doubly responsive properties both with pH and temperature. Below the lower critical solution temperature (LCST), the linear chains of PNIPAm are soluble and increase the osmotic pressure outside the microgels, which causes them to deswell. Above the LCST, the PNIPAm chains become insoluble and form spherical colloidal particles confined between the microgels that subsequently reswell. The swelling and deswelling of the microgels change the rheological properties of the composites, providing a unique way to tune the elasticity of the composites with temperature. The structure of the composites above the LCST is studied using multiple light scattering and fluorescence confocal microscopy. The phase separation of PNIPAm above the LCST is strongly affected by the confinement of the PNIPAm chains between the microgels.

  3. Regional Relations in Bankfull Channel Characteristics determined from flow measurements at selected stream-gaging stations in West Virginia, 1911-2002

    USGS Publications Warehouse

    Messinger, Terence; Wiley, Jeffrey B.

    2004-01-01

    Three bankfull channel characteristics?cross-sectional area, width, and depth?were significantly correlated with drainage area in regression equations developed for two regions in West Virginia. Channel characteristics were determined from analysis of flow measurements made at 74 U.S. Geological Survey stream-gaging stations at flows between 0.5 and 5.0 times bankfull flow between 1911 and 2002. Graphical and regression analysis were used to delineate an 'Eastern Region' and a 'Western Region,' which were separated by the boundary between the Appalachian Plateaus and Valley and Ridge Physiographic Provinces. Streams that drained parts of both provinces had channel characteristics typical of the Eastern Region, and were grouped with it. Standard error for the six regression equations, three for each region, ranged between 8.7 and 16 percent. Cross-sectional area and depth were greater relative to drainage area for the Western Region than they were for the Eastern Region. Regression equations were defined for streams draining between 46.5 and 1,619 square miles for the Eastern Region, and between 2.78 and 1,354 square miles for the Western Region. Stream-gaging stations with two or more cross sections where flow had been measured at flows between 0.5 and 5.0 times the 1.5-year flow showed poor replication of channel characteristics compared to the 95-percent confidence intervals of the regression, suggesting that within-reach variability for the stream-gaging stations may be substantial. A disproportionate number of the selected stream-gaging stations were on large (drainage area greater than 100 square miles) streams in the central highlands of West Virginia, and only one stream-gaging station that met data-quality criteria was available to represent the region within about 50 miles of the Ohio River north of Parkersburg, West Virginia. Many of the cross sections were at bridges, which can change channel shape. Although the data discussed in this report may not be

  4. Human trypanolytic factor APOL1 forms pH-gated cation-selective channels in planar lipid bilayers: Relevance to trypanosome lysis

    PubMed Central

    Thomson, Russell; Finkelstein, Alan

    2015-01-01

    Apolipoprotein L-1 (APOL1), the trypanolytic factor of human serum, can lyse several African trypanosome species including Trypanosoma brucei brucei, but not the human-infective pathogens T. brucei rhodesiense and T. brucei gambiense, which are resistant to lysis by human serum. Lysis follows the uptake of APOL1 into acidic endosomes and is apparently caused by colloid-osmotic swelling due to an increased ion permeability of the plasma membrane. Here we demonstrate that nanogram quantities of full-length recombinant APOL1 induce ideally cation-selective macroscopic conductances in planar lipid bilayers. The conductances were highly sensitive to pH: their induction required acidic pH (pH 5.3), but their magnitude could be increased 3,000-fold upon alkalinization of the milieu (pKa = 7.1). We show that this phenomenon can be attributed to the association of APOL1 with the bilayer at acidic pH, followed by the opening of APOL1-induced cation-selective channels upon pH neutralization. Furthermore, the conductance increase at neutral pH (but not membrane association at acidic pH) was prevented by the interaction of APOL1 with the serum resistance-associated protein, which is produced by T. brucei rhodesiense and prevents trypanosome lysis by APOL1. These data are consistent with a model of lysis that involves endocytic recycling of APOL1 and the formation of cation-selective channels, at neutral pH, in the parasite plasma membrane. PMID:25730870

  5. Kinetic Analysis of Membrane Potential Dye Response to NaV1.7 Channel Activation Identifies Antagonists with Pharmacological Selectivity against NaV1.5.

    PubMed

    Finley, Michael; Cassaday, Jason; Kreamer, Tony; Li, Xinnian; Solly, Kelli; O'Donnell, Greg; Clements, Michelle; Converso, Antonella; Cook, Sean; Daley, Chris; Kraus, Richard; Lai, Ming-Tain; Layton, Mark; Lemaire, Wei; Staas, Donnette; Wang, Jixin

    2016-06-01

    The NaV1.7 voltage-gated sodium channel is a highly valued target for the treatment of neuropathic pain due to its expression in pain-sensing neurons and human genetic mutations in the gene encoding NaV1.7, resulting in either loss-of-function (e.g., congenital analgesia) or gain-of-function (e.g., paroxysmal extreme pain disorder) pain phenotypes. We exploited existing technologies in a novel manner to identify selective antagonists of NaV1.7. A full-deck high-throughput screen was developed for both NaV1.7 and cardiac NaV1.5 channels using a cell-based membrane potential dye FLIPR assay. In assay development, known local anesthetic site inhibitors produced a decrease in maximal response; however, a subset of compounds exhibited a concentration-dependent delay in the onset of the response with little change in the peak of the response at any concentration. Therefore, two methods of analysis were employed for the screen: one to measure peak response and another to measure area under the curve, which would capture the delay-to-onset phenotype. Although a number of compounds were identified by a selective reduction in peak response in NaV1.7 relative to 1.5, the AUC measurement and a subsequent refinement of this measurement were able to differentiate compounds with NaV1.7 pharmacological selectivity over NaV1.5 as confirmed in electrophysiology.

  6. Selective cognitive deficits and reduced hippocampal brain-derived neurotrophic factor mRNA expression in small-conductance calcium-activated K+ channel deficient mice.

    PubMed

    Jacobsen, J P R; Redrobe, J P; Hansen, H H; Petersen, S; Bond, C T; Adelman, J P; Mikkelsen, J D; Mirza, N R

    2009-09-29

    Small-conductance calcium-activated K(+) channels 1-3 (SK1-3) are important for neuronal firing regulation and are considered putative CNS drug targets. For instance non-selective SK blockers improve performance in animal models of cognition. The SK subtype(s) involved herein awaits identification and the question is difficult to address pharmacologically due to the lack of subtype-selective SK-channel modulators. In this study, we used doxycycline-induced conditional SK3-deficient (T/T) mice to address the cognitive consequences of selective SK3 deficiency. In T/T mice SK3 protein is near-eliminated from the brain following doxycycline treatment. We tested T/T and wild type (WT) littermate mice in five distinct learning and memory paradigms. In Y-maze spontaneous alternations and five-trial inhibitory avoidance the performance of T/T mice was markedly inferior to WT mice. In contrast, T/T and WT mice performed equally well in passive avoidance, object recognition and the Morris water maze. Thus, some aspects of working/short-term memory are disrupted in T/T mice. Using in situ hybridization, we further found the cognitive deficits in T/T mice to be paralleled by reduced brain-derived neurotrophic factor (BDNF) mRNA expression in the dentate gyrus and CA3 of the hippocampus. BDNF mRNA levels in the frontal cortex were not affected. BDNF has been crucially implicated in many cognitive processes. Hence, the biological substrate for the cognitive impairments in T/T mice could conceivably entail reduced trophic support of the hippocampus.

  7. Molecular determinants of agonist selectivity in glutamate-gated chloride channels which likely explain the agonist selectivity of the vertebrate glycine and GABAA-ρ receptors.

    PubMed

    Blarre, Thomas; Bertrand, Hugues-Olivier; Acher, Francine C; Kehoe, JacSue

    2014-01-01

    Orthologous Cys-loop glutamate-gated chloride channels (GluClR's) have been cloned and described electrophysiologically and pharmacologically in arthropods and nematodes (both members of the invertebrate ecdysozoan superphylum). Recently, GluClR's from Aplysia californica (a mollusc from the lophotrochozoan superphylum) have been cloned and similarly studied. In spite of sharing a common function, the ecdysozoan and lophotrochozoan receptors have been shown by phylogenetic analyses to have evolved independently. The recent crystallization of the GluClR from C. elegans revealed the binding pocket of the nematode receptor. An alignment of the protein sequences of the nematode and molluscan GluClRs showed that the Aplysia receptor does not contain all of the residues defining the binding mode of the ecdysozoan receptor. That the two receptors have slightly different binding modes is not surprising since earlier electrophysiological and pharmacological experiments had suggested that they were differentially responsive to certain agonists. Knowledge of the structure of the C. elegans GluClR has permitted us to generate a homology model of the binding pocket of the Aplysia receptor. We have analyzed the differences between the two binding modes and evaluated the relative significance of their non-common residues. We have compared the GluClRs electrophysiologically and pharmacologically and we have used site-directed mutagenesis on both receptor types to test predictions made from the model. Finally, we propose an explanation derived from the model for why the nematode receptors are gated only by glutamate, whereas the molluscan receptors can also be activated by β-alanine, GABA and taurine. Like the Aplysia receptor, the vertebrate glycine and GABAA-ρ receptors also respond to these other agonists. An alignment of the sequences of the molluscan and vertebrate receptors shows that the reasons we have given for the ability of the other agonists to activate the Aplysia

  8. Doubly charged CO2 clusters formed by ionization of doped helium nanodroplets☆

    PubMed Central

    Daxner, Matthias; Denifl, Stephan; Scheier, Paul; Echt, Olof

    2014-01-01

    Helium nanodroplets are doped with carbon dioxide and ionized by electrons. Doubly charged cluster ions are, for the first time, identified based on their characteristic patterns of isotopologues. Thanks to the high mass resolution, large dynamic range, and a novel method to eliminate contributions from singly charged ions from the mass spectra, we are able to observe doubly charged cluster ions that are smaller than the ones reported in the past. The likely mechanism by which doubly charged ions are formed in doped helium droplets is discussed. PMID:25844051

  9. Doubly heavy baryons and quark-diquark symmetry in quenched and partially quenched chiral perturbation theory

    SciTech Connect

    Thomas Mehen; Brian C. Tiburzi

    2006-07-17

    We extend the chiral Lagrangian with heavy quark-diquark symmetry to quenched and partially quenched theories. These theories are used to derive formulae for the chiral extrapolation of masses and hyperfine splittings of doubly heavy baryons in lattice QCD simulations. A quark-diquark symmetry prediction for the hyperfine splittings of heavy mesons and doubly heavy baryons is rather insensitive to chiral corrections in both quenched and partially quenched QCD. Extrapolation formulae for the doubly heavy baryon electromagnetic transition moments are also determined for the partially quenched theory.

  10. Ab initio Approach to Effective Single-Particle Energies in Doubly Closed Shell Nuclei

    SciTech Connect

    Duguet, T.

    2012-01-01

    The present work discusses, from an ab initio standpoint, the definition, the meaning, and the usefulness of effective single-particle energies (ESPEs) in doubly closed shell nuclei. We perform coupled-cluster calculations to quantify to what extent selected closed-shell nuclei in the oxygen and calcium isotopic chains can effectively be mapped onto an effective independent-particle picture. To do so, we revisit in detail the notion of ESPEs in the context of strongly correlated many-nucleon systems and illustrate the necessity of extracting ESPEs through the diagonalization of the centroid matrix, as originally argued by Baranger. For the purpose of illustration, we analyze the impact of correlations on observable one-nucleon separation energies and nonobservable ESPEs in selected closed-shell oxygen and calcium isotopes. We then state and illustrate the nonobservability of ESPEs. Similarly to spectroscopic factors, ESPEs can indeed be modified by a redefinition of inaccessible quantities while leaving actual observables unchanged. This leads to the absolute necessity of employing consistent structure and reaction models based on the same nuclear Hamiltonian to extract the shell structure in a meaningful fashion from experimental data.

  11. Polymodal sensory function of the Caenorhabditis elegans OCR-2 channel arises from distinct intrinsic determinants within the protein and is selectively conserved in mammalian TRPV proteins.

    PubMed

    Sokolchik, Irina; Tanabe, Takahiro; Baldi, Pierre F; Sze, Ji Ying

    2005-01-26

    Caenorhabditis elegans OCR-2 (OSM-9 and capsaicin receptor-related) is a TRPV (vanilloid subfamily of transient receptor potential channel) protein that regulates serotonin (5-HT) biosynthesis in chemosensory neurons and also mediates olfactory and osmotic sensation. Here, we identify the molecular basis for the polymodal function of OCR-2 in its native cellular environment. We show that OCR-2 function in 5-HT production and osmotic sensing is governed by its N-terminal region upstream of the ankyrin repeats domain, but the diacetyl sensitivity is mediated by independent mechanisms. The ocr-2(yz5) mutation results in a glycine-to-glutamate substitution (G36E) within the N-terminal region. The G36E substitution causes dramatic downregulation of 5-HT synthesis in the ADF neurons, eliminates osmosensation mediated by the ASH neurons, but does not affect the response to the odorant diacetyl mediated by the AWA neurons. Conversely, wild-type sequence of the N-terminal segment confers osmotic sensitivity and upregulation of 5-HT production to a normally insensitive C. elegans homolog, OCR-4, but this chimeric channel does not respond to diacetyl stimuli. Furthermore, expression of either the mouse or human TRPV2 gene under the ocr-2 promoter can substantially restore 5-HT biosynthesis in ocr-2-null mutants but cannot improve the deficits in osmotic or olfactory sensation, suggesting that TRPV2 can substitute for the role of OCR-2 only in serotonergic neurons. Thus, different sensory functions of OCR-2 arise from separable intrinsic determinants, and specific functional properties of TRPV channel proteins may be selectively conserved across phyla.

  12. Development of regional curves relating bankfull-channel geometry and discharge to drainage area for streams in Pennsylvania and selected areas of Maryland

    USGS Publications Warehouse

    Chaplin, Jeffrey J.

    2005-01-01

    Natural-stream designs are commonly based on the dimensions of the bankfull channel, which is capable of conveying discharges that transport sediment without excessive erosion or deposition. Regional curves relate bankfull-channel geometry and discharge to drainage area in watersheds with similar runoff characteristics and commonly are utilized by practitioners of natural-stream design to confirm or refute selection of the field-identified bankfull channel. Data collected from 66 streamflow-gaging stations and associated stream reaches between December 1999 and December 2003 were used in one-variable ordinary least-squares regression analyses to develop regional curves relating drainage area to cross-sectional area, discharge, width, and mean depth of the bankfull channel. Watersheds draining to these stations are predominantly within the Piedmont, Ridge and Valley, and Appalachian Plateaus Physiographic Provinces of Pennsylvania and northern Maryland. Statistical analyses of physiography, percentage of watershed area underlain by carbonate bedrock, and percentage of watershed area that is glaciated indicate that carbonate bedrock, not physiography or glaciation, has a controlling influence on the slope of regional curves. Regional curves developed from stations in watersheds underlain by 30 percent or less carbonate bedrock generally had steeper slopes than the corresponding relations developed from watersheds underlain by greater than 30 percent carbonate bedrock. In contrast, there is little evidence to suggest that regional curves developed from stations in the Piedmont or Ridge and Valley Physiographic Province are different from the corresponding relations developed from stations in the Appalachian Plateaus Physiographic Province. On the basis of these findings, regional curves are presented to represent two settings that are independent of physiography: (1) noncarbonate settings characterized by watersheds with carbonate bedrock underlying 30 percent or less

  13. LIGHT MODULATION: Quasi-collinear tunable acousto-optic paratellurite crystal filters for wavelength division multiplexing and optical channel selection

    NASA Astrophysics Data System (ADS)

    Molchanov, V. Ya; Voloshinov, V. B.; Makarov, O. Yu

    2009-04-01

    Quasi-collinear acousto-optic interaction is studied in acoustically and optically anisotropic paratellurite crystals. The possible applications of this interaction in acousto-optic tunable filters with a high spectral resolution are discussed. Different modifications of devices are compared and variants of devices intended for processing light beams and selection of light signals in fibreoptic communication systems with wavelength division multiplexing (WDM) at λ simeq 1550 nm are considered.

  14. Optimal frequency selection of multi-channel O2-band different absorption barometric radar for air pressure measurements

    NASA Astrophysics Data System (ADS)

    Lin, Bing; Min, Qilong

    2017-02-01

    Through theoretical analysis, optimal selection of frequencies for O2 differential absorption radar systems on air pressure field measurements is achieved. The required differential absorption optical depth between a radar frequency pair is 0.5. With this required value and other considerations on water vapor absorption and the contamination of radio wave transmission, frequency pairs of present considered radar system are obtained. Significant impacts on general design of differential absorption remote sensing systems are expected from current results.

  15. Selection of Mother Wavelet Functions for Multi-Channel EEG Signal Analysis during a Working Memory Task

    PubMed Central

    Al-Qazzaz, Noor Kamal; Hamid Bin Mohd Ali, Sawal; Ahmad, Siti Anom; Islam, Mohd Shabiul; Escudero, Javier

    2015-01-01

    We performed a comparative study to select the efficient mother wavelet (MWT) basis functions that optimally represent the signal characteristics of the electrical activity of the human brain during a working memory (WM) task recorded through electro-encephalography (EEG). Nineteen EEG electrodes were placed on the scalp following the 10–20 system. These electrodes were then grouped into five recording regions corresponding to the scalp area of the cerebral cortex. Sixty-second WM task data were recorded from ten control subjects. Forty-five MWT basis functions from orthogonal families were investigated. These functions included Daubechies (db1–db20), Symlets (sym1–sym20), and Coiflets (coif1–coif5). Using ANOVA, we determined the MWT basis functions with the most significant differences in the ability of the five scalp regions to maximize their cross-correlation with the EEG signals. The best results were obtained using “sym9” across the five scalp regions. Therefore, the most compatible MWT with the EEG signals should be selected to achieve wavelet denoising, decomposition, reconstruction, and sub-band feature extraction. This study provides a reference of the selection of efficient MWT basis functions. PMID:26593918

  16. Selective Activation of Nociceptor TRPV1 Channel and Reversal of Inflammatory Pain in Mice by a Novel Coumarin Derivative Muralatin L from Murraya alata*

    PubMed Central

    Wei, Ning-Ning; Lv, Hai-Ning; Wu, Yang; Yang, Shi-Long; Sun, Xiao-Ying; Lai, Ren; Jiang, Yong; Wang, KeWei

    2016-01-01

    Coumarin and its derivatives are fragrant natural compounds isolated from the genus Murraya that are flowering plants widely distributed in East Asia, Australia, and the Pacific Islands. Murraya plants have been widely used as medicinal herbs for relief of pain, such as headache, rheumatic pain, toothache, and snake bites. However, little is known about their analgesic components and the molecular mechanism underlying pain relief. Here, we report the bioassay-guided fractionation and identification of a novel coumarin derivative, named muralatin L, that can specifically activate the nociceptor transient receptor potential vanilloid 1 (TRPV1) channel and reverse the inflammatory pain in mice through channel desensitization. Muralatin L was identified from the active extract of Murraya alata against TRPV1 transiently expressed in HEK-293T cells in fluorescent calcium FlexStation assay. Activation of TRPV1 current by muralatin L and its selectivity were further confirmed by whole-cell patch clamp recordings of TRPV1-expressing HEK-293T cells and dorsal root ganglion neurons isolated from mice. Furthermore, muralatin L could reverse inflammatory pain induced by formalin and acetic acid in mice but not in TRPV1 knock-out mice. Taken together, our findings show that muralatin L specifically activates TRPV1 and reverses inflammatory pain, thus highlighting the potential of coumarin derivatives from Murraya plants for pharmaceutical and medicinal applications such as pain therapy. PMID:26515068

  17. Selective underexpression of Kv3.2 and Kv3.4 channels in the cortex of rats exposed to ethanol during early postnatal life.

    PubMed

    Tavian, Daniela; De Giorgio, Andrea; Granato, Alberto

    2011-08-01

    The expression of voltage-gated potassium channels belonging to the Kv3 family has been studied in the sensori-motor cortex of rats exposed to alcohol inhalation during the first postnatal week (P2-P6). The study was carried out using comparative RT-PCR. At P9, a significant reduction of the expression of Kv3.2 and Kv3.4 subunits occurred in alcohol-treated animals, as compared with controls. The expression of the Kv3.4a splicing variant, which is thought to be critically involved in the high-frequency firing of some cortical interneurons, was also correspondingly reduced. The downregulation of Kv3.2 and Kv3.4a subunits represented a long-lasting effect of alcohol exposure, since it was also observed in P24 animals. The expression of both Kv3.1 and Kv3.3 channels appeared to be not significantly affected by alcohol exposure. An increased susceptibility to apoptotic neuronal death after early postnatal exposure to ethanol was confirmed by the lower bcl-2/bax ratio observed in alcohol-treated animals. Although Kv3.4 subunits are thought to trigger apoptosis, the lack of upregulation in our model argues against their involvement in the mechanism leading to alcohol-induced apoptosis. The possible consequences of the selective downregulation of Kv3 subunits on the cortical function, as well as their relevance for the genesis of fetal alcohol effects, are discussed.

  18. Allosteric coupling between proximal C-terminus and selectivity filter is facilitated by the movement of transmembrane segment 4 in TREK-2 channel

    PubMed Central

    Zhuo, Ren-Gong; Peng, Peng; Liu, Xiao-Yan; Yan, Hai-Tao; Xu, Jiang-Ping; Zheng, Jian-Quan; Wei, Xiao-Li; Ma, Xiao-Yun

    2016-01-01

    TREK-2, a member of two-pore-domain potassium channel family, regulates cellular excitability in response to diverse stimuli. However, how such stimuli control channel function remains unclear. Here, by characterizing the responses of cytosolic proximal C-terminus deletant (ΔpCt) and transmembrane segment 4 (M4)-glycine hinge mutant (G312A) to 2-Aminoethoxydiphenyl borate (2-APB), an activator of TREK-2, we show that the transduction initiated from pCt domain is allosterically coupled with the conformation of selectivity filter (SF) via the movements of M4, without depending on the original status of SF. Moreover, ΔpCt and G312A also exhibited blunted responses to extracellular alkalization, a model to induce SF conformational transition. These results suggest that the coupling between pCt domain and SF is bidirectional, and M4 movements are involved in both processes. Further mechanistic exploration reveals that the function of Phe316, a residue close to the C-terminus of M4, is associated with such communications. However, unlike TREK-2, M4-hinge of TREK-1 only controls the transmission from pCt to SF, rather than SF conformational changes triggered by pHo changes. Together, our findings uncover the unique gating properties of TREK-2, and elucidate the mechanisms for how the extracellular and intracellular stimuli harness the pore gating allosterically. PMID:26879043

  19. Selective Activation of Nociceptor TRPV1 Channel and Reversal of Inflammatory Pain in Mice by a Novel Coumarin Derivative Muralatin L from Murraya alata.

    PubMed

    Wei, Ning-Ning; Lv, Hai-Ning; Wu, Yang; Yang, Shi-Long; Sun, Xiao-Ying; Lai, Ren; Jiang, Yong; Wang, KeWei

    2016-01-08

    Coumarin and its derivatives are fragrant natural compounds isolated from the genus Murraya that are flowering plants widely distributed in East Asia, Australia, and the Pacific Islands. Murraya plants have been widely used as medicinal herbs for relief of pain, such as headache, rheumatic pain, toothache, and snake bites. However, little is known about their analgesic components and the molecular mechanism underlying pain relief. Here, we report the bioassay-guided fractionation and identification of a novel coumarin derivative, named muralatin L, that can specifically activate the nociceptor transient receptor potential vanilloid 1 (TRPV1) channel and reverse the inflammatory pain in mice through channel desensitization. Muralatin L was identified from the active extract of Murraya alata against TRPV1 transiently expressed in HEK-293T cells in fluorescent calcium FlexStation assay. Activation of TRPV1 current by muralatin L and its selectivity were further confirmed by whole-cell patch clamp recordings of TRPV1-expressing HEK-293T cells and dorsal root ganglion neurons isolated from mice. Furthermore, muralatin L could reverse inflammatory pain induced by formalin and acetic acid in mice but not in TRPV1 knock-out mice. Taken together, our findings show that muralatin L specifically activates TRPV1 and reverses inflammatory pain, thus highlighting the potential of coumarin derivatives from Murraya plants for pharmaceutical and medicinal applications such as pain therapy.

  20. Flood-plain and channel aggradation of selected bridge sites in the Iowa and Skunk River basins, Iowa

    USGS Publications Warehouse

    Eash, D.A.

    1996-01-01

    Flood-plain and channel-aggradation rates were estimated at 10 bridge sites on the Iowa River upstream of Coralville Lake and at two bridge sites in the central part of the Skunk River Basin. Four measurement methods were used to quantify aggradation rates: (1) a dendrogeomorphic method that used tree-age data and sediment-deposition depths, (2) a bridge-opening cross-section method that compared historic and recent cross sections of bridge openings, (3) a stage-discharge rating-curve method that compared historic and recent stages for the 5-year flood discharge and the average discharge, and (4) nine sediment pads that were installed on the Iowa River flood plain at three bridge sites in the vicinity of Marshalltown. The sediment pads were installed prior to overbank flooding in 1993. Sediments deposited on the pads as a result of the 1993 flood ranged in depth from 0.004 to 2.95 feet. Measurement periods used to estimate average aggradation rates ranged from 1 to 98 years and varied among methods and sites. The highest aggradation rates calculated for the Iowa River Basin using the dendrogeomorphic and rating- curve measurement methods were for the State Highway 14 crossing at Marshalltown, where these highest rates were 0.045 and 0.124 feet per year, respectively. The highest aggradation rates calculated for the Skunk River Basin were for the U.S. Highway 63 crossing of the South Skunk River near Oskaloosa, where these highest rates were 0.051 and 0.298 feet per year, respectively.

  1. High-efficient photo-electron transport channel in SiC constructed by depositing cocatalysts selectively on specific surface sites for visible-light H2 production

    NASA Astrophysics Data System (ADS)

    Wang, Da; Peng, Yuan; Wang, Qi; Pan, Nanyan; Guo, Zhongnan; Yuan, Wenxia

    2016-04-01

    Control cocatalyst location on a metal-free semiconductor to promote surface charge transfer for decreasing the electron-hole recombination is crucial for enhancing solar energy conversion. Based on the findings that some metals have an affinity for bonding with the specific atoms of polar semiconductors at a heterostructure interface, we herein control Pt deposition selectively on the Si sites of a micro-SiC photocatalyst surface via in-situ photo-depositing. The Pt-Si bond forming on the interface constructs an excellent channel, which is responsible for accelerating photo-electron transfer from SiC to Pt and then reducing water under visible-light. The hydrogen production is enhanced by two orders of magnitude higher than that of bare SiC, and 2.5 times higher than that of random-depositing nano-Pt with the same loading amount.

  2. Production of the doubly charmed baryons at the SELEX experiment - The double intrinsic charm approach

    NASA Astrophysics Data System (ADS)

    Koshkarev, Sergey; Anikeev, Vladimir

    2017-02-01

    The high production rate and > 0.33 of the doubly charmed baryons measured by the SELEX experiment is not amenable to perturbative QCD analysis. In this paper we calculate the production of the doubly heavy baryons with the double intrinsic charm Fock states whose existence is rigorously predicted by QCD. The production rate and the longitudinal momentum distribution are both reproduced. We also show that the production rates of the doubly charmed baryons and double J / ψ production observed by NA3 collaboration are comparable. Recent experimental results are reviewed. The production cross section of the doubly charmed baryons at a fixed-target experiment at the LHC is presented.

  3. Measurement of the top quark pair production cross section in the dilepton channel using lepton+track selection

    SciTech Connect

    Wagner, Robert Emil

    2008-11-01

    The production cross section for t$\\bar{t}$ pairs decaying into two lepton final states was measured using data from the D0 detector at Fermilab. The measurement was made using a lepton+track selection, where one lepton is fully identified and the second lepton is observed as an isolated track. This analysis is designed to complement similar studies using two fully identified leptons [1]. The cross section for the lepton+track selection was found to be σ = 5.2-1.4+1.6(stat)-0.8+0.9(syst) ± 0.3(lumi) pb. The combined cross section using both the lepton+track data and the data from the electron+electron, electron+muon, and muon+muon samples is: σ = 6.4-0.9+0.9(stat)-0.7+0.8(syst) ± 0.4(lumi) pb.

  4. Search for doubly charged Higgs bosons in like-sign dilepton final states at √s¯= 7 TeV with the ATLAS detector

    DOE PAGES

    Aad, G.

    2012-12-04

    A search for doubly-charged Higgs bosons decaying to pairs of electrons and/or muons is presented. The search is performed using a data sample corresponding to an integrated luminosity of 4.7 fb-1 of pp collisions at √s¯ = 7 TeV collected by the ATLAS detector at the LHC. Pairs of prompt, isolated, high-pT leptons with the same electric charge (e±e±, e±μ±, μ±μ±) are selected, and their invariant mass distribution is searched for a narrow resonance. No significant excess over Standard Model background expectations is observed, and limits are placed on the cross section times branching ratio for pair production of doubly-chargedmore » Higgs bosons. The masses of doubly-charged Higgs bosons are constrained depending on the branching ratio into these leptonic final states. Assuming pair production, coupling to left-handed fermions, and a branching ratio of 100% for each final state, masses below 409 GeV, 375 GeV, and 398 GeV are excluded for e±e±, e±μ±, and μ±μ±, respectively.« less

  5. Search for doubly charged Higgs bosons in like-sign dilepton final states at √s¯= 7 TeV with the ATLAS detector

    SciTech Connect

    Aad, G.

    2012-12-04

    A search for doubly-charged Higgs bosons decaying to pairs of electrons and/or muons is presented. The search is performed using a data sample corresponding to an integrated luminosity of 4.7 fb-1 of pp collisions at √s¯ = 7 TeV collected by the ATLAS detector at the LHC. Pairs of prompt, isolated, high-pT leptons with the same electric charge (e±e±, e±μ±, μ±μ±) are selected, and their invariant mass distribution is searched for a narrow resonance. No significant excess over Standard Model background expectations is observed, and limits are placed on the cross section times branching ratio for pair production of doubly-charged Higgs bosons. The masses of doubly-charged Higgs bosons are constrained depending on the branching ratio into these leptonic final states. Assuming pair production, coupling to left-handed fermions, and a branching ratio of 100% for each final state, masses below 409 GeV, 375 GeV, and 398 GeV are excluded for e±e±, e±μ±, and μ±μ±, respectively.

  6. Wind Turbine Power Generation Emulation Via Doubly Fed Induction Generator Control

    DTIC Science & Technology

    2009-12-01

    AND ACRONYMS BNC Bayonette Neil-Concelamn connector DFIG Doubly Fed Induction Generator FPGA Field Programmable Gate Array IGBT Insulated Gate...Width Modulation ( PWM ) in which an algorithm involving space vectors are used to control the on and off times of pulsed signals. The generated signals...Clare, and G. M. Asher, “Doubly fed induction generator using back-to-back PWM converters and its application to variable speed wind-energy

  7. High Performance Variable Speed Drive System and Generating System with Doubly Fed Machines

    NASA Astrophysics Data System (ADS)

    Tang, Yifan

    Doubly fed machines are another alternative for variable speed drive systems. The doubly fed machines, including doubly fed induction machine, self-cascaded induction machine and doubly excited brushless reluctance machine, have several attractive advantages for variable speed drive applications, the most important one being the significant cost reduction with a reduced power converter rating. With a better understanding, improved machine design, flexible power converters and innovated controllers, the doubly fed machines could favorably compete for many applications, which may also include variable speed power generations. The goal of this research is to enhance the attractiveness of the doubly fed machines for both variable speed drive and variable speed generator applications. Recognizing that wind power is one of the favorable clean, renewable energy sources that can contribute to the solution to the energy and environment dilemma, a novel variable-speed constant-frequency wind power generating system is proposed. By variable speed operation, energy capturing capability of the wind turbine is improved. The improvement can be further enhanced by effectively utilizing the doubly excited brushless reluctance machine in slip power recovery configuration. For the doubly fed machines, a stator flux two -axis dynamic model is established, based on which a flexible active and reactive power control strategy can be developed. High performance operation of the drive and generating systems is obtained through advanced control methods, including stator field orientation control, fuzzy logic control and adaptive fuzzy control. System studies are pursued through unified modeling, computer simulation, stability analysis and power flow analysis of the complete drive system or generating system with the machine, the converter and the control. Laboratory implementations and tested results with a digital signal processor system are also presented.

  8. Atrial-selective Inhibition of Sodium Channel Current by Wenxin Keli is Effective in Suppressing Atrial Fibrillation

    PubMed Central

    Burashnikov, Alexander; Petroski, Alyssa; Hu, Dan; Barajas-Martinez, Hector; Antzelevitch, Charles

    2011-01-01

    BACKGROUND Wenxin Keli is a Chinese herb extract reported to be of benefit in the treatment of cardiac arrhythmias, cardiac inflammation and heart failure. METHODS AND RESULTS We evaluated the electrophysiologic effects of Wenxin Keli in isolated canine arterially-perfused right atrial preparations with a rim of right ventricular tissue (n=11). Transmembrane action potentials and a pseudo-electrocardiogram were simultaneously recorded. Acetylcholine (ACh, 1 μM) was used to induce atrial fibrillation (AF) and to test the anti-AF potential of Wenxin Keli (5 g/L). Wenxin Keli produced preferential abbreviation of action potential duration (APD90) in atria, but caused atrial-selective prolongation of effective refractory period, due to development of post-repolarization refractoriness. The maximum rate of rise of the action potential upstroke (Vmax) was preferentially reduced in atria. Diastolic threshold of excitation increased in both atria and ventricles, but much more in atria. The duration of the “P wave” (index of atrial conduction time) was prolonged to a much greater extent than the duration of the “QRS complex” (index of ventricular conduction time). Wenxin Keli significantly reduced INa and shifted steady-state inactivation to more negative potentials in HEK293 cells stably expressing SCN5A. Wenxin Keli prevented induction of persistent AF in 100% atria (6/6) and, in another experimental series was found to terminate persistent ACh-mediated AF in 100% of atria (3/3). CONCLUSION Wenxin Keli produces atrial-selective depression of INa-dependent parameters in canine isolated coronary perfused preparations via a unique mechanism and is effective in suppressing AF and preventing its induction, with minimal effects on ventricular electrophysiology. PMID:21884675

  9. Performance optimization for doubly-fed generation systems

    NASA Astrophysics Data System (ADS)

    Bhowmik, Shibashis

    A variable speed generation (VSG) system converts energy from a variable resource such as wind or water flow into variable rotational mechanical energy of a turbine or a similar device that converts translational kinetic energy into rotational mechanical energy. The mechanical energy is then converted into electrical energy by an electrical generator. Presently available and proposed generators include systems based mainly on dc machines, synchronous and induction machine technology as well as reluctance machines. While extracting more energy from the resource, most proposed VSG systems suffer a cost disadvantage due to the required rating of the power electronic interface. This cost penalty may eventually render the additional energy capture meaningless. Thus, reducing the cost of the power electronic hardware is essential for VSG systems to achieve viable and competitive $/kWh ratios when compared to fossil fuel-based generating systems. A variable speed constant frequency (VSCF) system and controller are proposed that utilize a doubly-fed machine (DFM) as the energy conversion device. The system includes a power converter that provides the current excitation for the control winding of the DFM. Both the magnitude and frequency of the excitation is determined by an adaptive model-based controller which maximizes the power flow from the mechanical turbine to the electrical grid and reduces the generator losses by maintaining the maximum efficiency point throughout the mechanical input power range. The proposed strategy has been experimentally verified in controlled laboratory conditions for a proof-of-concept brushless doubly-fed machine (BDFM) system of 1500 Watts power rating. Issues relating to power converter development and its incorporation in the system have been investigated. The controller and circuit design of a four quadrant, AC/AC power converter is presented and a novel sensorless current controller for the active rectifier stage is presented in detail

  10. Observations of Coulomb explosion in doubly charged atomic and molecular clusters

    NASA Astrophysics Data System (ADS)

    Gotts, N. G.; Lethbridge, P. G.; Stace, A. J.

    1992-01-01

    Coulomb explosion has been promoted in a range of doubly charged atomic and molecular clusters. In these new experiments, mass selected clusters of Ar2+n, (CO2)2+n, (H2O)2+n, (H2O)nH2+2, (CH3CN)nH2+2, and (C6H6)2+n have been subjected to collisional activation with a background gas. For species close to the Coulomb cutoff, each collision removes sufficient atoms or molecules (approximately six) as to render the clusters unstable. As a result, charge separation occurs and part (≂30%) of the Coulomb repulsion energy is released in the form of center of mass kinetic energy in the fragments. The remaining Coulomb energy appears as internal excitation in the fragments and subsequently leads to extensive evaporation. It is shown that the latter process is continuing even 10-6 s after Coulomb explosion. All the molecular systems studied show evidence of asymmetric charge separation, with some singly charged fragments containing up to 65% of the initial cluster mass. A detailed quantitative analysis of the results is made difficult by the very broad range of fragment ion sizes.

  11. Discovery of four doubly imaged quasar lenses from the Sloan digital sky survey

    SciTech Connect

    Inada, Naohisa; Oguri, Masamune; Rusu, Cristian E.; Kayo, Issha; Morokuma, Tomoki

    2014-06-01

    We report the discovery of four doubly imaged quasar lenses. All the four systems are selected as lensed quasar candidates from the Sloan Digital Sky Survey data. We confirm their lensing hypothesis with additional imaging and spectroscopic follow-up observations. The discovered lenses are SDSS J0743+2457 with the source redshift z{sub s} = 2.165, the lens redshift z{sub l} = 0.381, and the image separation θ = 1.''034, SDSS J1128+2402 with z{sub s} = 1.608 and θ = 0.''844, SDSS J1405+0959 with z{sub s} = 1.810, z{sub l} ≈ 0.66, and θ = 1.''978, and SDSS J1515+1511 with z{sub s} = 2.054, z{sub l} = 0.742, and θ = 1.''989. It is difficult to estimate the lens redshift of SDSS J1128+2402 from the current data. Two of the four systems (SDSS J1405+0959 and SDSS J1515+1511) are included in our final statistical lens sample to derive constraints on dark energy and the evolution of massive galaxies.

  12. Low-dose combination of Rho kinase and L-type Ca(2+) channel antagonists for selective inhibition of depolarization-induced sustained arterial contraction.

    PubMed

    Porras-González, Cristina; González-Rodríguez, Patricia; Calderón-Sánchez, Eva; López-Barneo, José; Ureña, Juan

    2014-06-05

    L-type Ca(2+) channels (LTCCs) are involved in the maintenance of tonic arterial contractions and regulate the RhoA/Rho-associated kinase (ROCK) sensitization cascade. We have tested effects of individual and combined low concentrations of LTCCs and ROCK inhibitors to produce arterial relaxation without the adverse side effects of LTCCs antagonists. We have also studied whether this pharmacological strategy alters Ca(2+)-dependent electrical properties of isolated arterial and cardiac myocytes as well as cardiac contractility. Rat basilar, human carotid and coronary arterial rings were mounted on a small-vessel myograph to measure isometric tension and cardiac contractility was measured in Langendorff-perfused rat heart. Simultaneous cytosolic Ca(2+) concentration and arterial diameter were measured in intact pressurized arteries loaded with Fura-2. Patch-clamp techniques were used to measure electrical properties in isolated cardiac and arterial myocytes. Low concentrations of LTCCs and ROCK inhibitors reduced the tonic component of moderate depolarization-evoked contraction, leaving the phasic component practically unaltered. This selective vasorelaxant effect was more marked when the LTCCs and ROCK inhibitors were applied together. In the concentration range used (nM), Ca(2+) currents in arterial myocytes, cardiac action potentials and heart contractility were unaffected by this pharmacological approach. In conclusion, low doses of LTCCs and ROCK inhibitors could be used to selectively relax precontracted arteries in pathologic conditions such as hypertension, and cerebral or coronary spasms with minor side effects on physiological contractile properties of vascular and cardiac myocytes.

  13. Control aspects of the brushless doubly-fed machine

    NASA Astrophysics Data System (ADS)

    Lauw, H. K.; Krishnan, S.

    1990-09-01

    This report covers the investigations into the control aspects of a variable-speed generation (VSG) system using a brushless double-fed generator excited by a series-resonant converter. The brushless double-fed machine comprises two sets of stator 3-phase systems which are designed with common windings. The rotor is a cage rotor resembling the low-cost and robust squirrel cage of a conventional induction machine. The system was actually designed and set up in the Energy Laboratory of the Department of Electrical and Computer Engineering at Oregon State University. The series-resonant converter designed to achieve effective control for variable-speed generation with the brushless doubly-fed generator was adequate in terms of required time response and regulation as well as in providing for adequate power quality. The three elements of the VSG controller, i.e., voltage or reactive power controller, the efficiency maximizer and the stabilizer, could be designed using conventional microprocessor elements with a processing time well within the time period required for sampling the variables involved with executing the control tasks. The report treats in detail the stability problem encountered in running the machine at certain speed regions, even if requirements for steady-state stability are satisfied. In this unstable region, shut down of the VSG system is necessary unless proper stabilization controls are provided for. The associated measures to be taken are presented.

  14. Brushless Doubly-Fed Machine system development program, phase 3

    NASA Astrophysics Data System (ADS)

    Alexander, G. C.; Spee, R.; Wallace, A. K.

    Since the inception of the Brushless Doubly-Fed Machine (BDFM) System Development Program in 1989, the value of BDFM technology has become apparent. The BDFM provides for adjustable speed, synchronous operation while keeping costs associated with the required power conversion equipment lower than in competing technologies. This provides for an advantage in initial as well as maintenance expenses over conventional drive system. Thus, the BDFM enables energy efficient, adjustable speed process control for applications where established drive technology has not been able to deliver satisfactory returns on investment. At the same time, the BDFM challenges conventional drive technologies in established markets by providing for improved performance at lower cost. BDFM converter rating is kept at a minimum, which significantly improves power quality at the utility interface over competing power conversion equipment. In summary, BDFM technology can be expected to provide significant benefits to utilities as well as their customers. This report discusses technical research and development activities related to Phase 3 of the BDFM System Development Program, including work made possible by supplemental funds for laboratory improvement and prototype construction.

  15. Fragmentation network of doubly charged methionine: Interpretation using graph theory.

    PubMed

    Ha, D T; Yamazaki, K; Wang, Y; Alcamí, M; Maeda, S; Kono, H; Martín, F; Kukk, E

    2016-09-07

    The fragmentation of doubly charged gas-phase methionine (HO2CCH(NH2)CH2CH2SCH3) is systematically studied using the self-consistent charge density functional tight-binding molecular dynamics (MD) simulation method. We applied graph theory to analyze the large number of the calculated MD trajectories, which appears to be a highly effective and convenient means of extracting versatile information from the large data. The present theoretical results strongly concur with the earlier studied experimental ones. Essentially, the dication dissociates into acidic group CO2H and basic group C4NSH10. The former may carry a single or no charge and stays intact in most cases, whereas the latter may hold either a single or a double charge and tends to dissociate into smaller fragments. The decay of the basic group is observed to follow the Arrhenius law. The dissociation pathways to CO2H and C4NSH10 and subsequent fragmentations are also supported by ab initio calculations.

  16. Study of doubly strange systems using stored antiprotons

    NASA Astrophysics Data System (ADS)

    Singh, B.; Erni, W.; Krusche, B.; Steinacher, M.; Walford, N.; Liu, B.; Liu, H.; Liu, Z.; Shen, X.; Wang, C.; Zhao, J.; Albrecht, M.; Erlen, T.; Fink, M.; Heinsius, F.; Held, T.; Holtmann, T.; Jasper, S.; Keshk, I.; Koch, H.; Kopf, B.; Kuhlmann, M.; Kümmel, M.; Leiber, S.; Mikirtychyants, M.; Musiol, P.; Mustafa, A.; Pelizäus, M.; Pychy, J.; Richter, M.; Schnier, C.; Schröder, T.; Sowa, C.; Steinke, M.; Triffterer, T.; Wiedner, U.; Ball, M.; Beck, R.; Hammann, C.; Ketzer, B.; Kube, M.; Mahlberg, P.; Rossbach, M.; Schmidt, C.; Schmitz, R.; Thoma, U.; Urban, M.; Walther, D.; Wendel, C.; Wilson, A.; Bianconi, A.; Bragadireanu, M.; Caprini, M.; Pantea, D.; Patel, B.; Czyzycki, W.; Domagala, M.; Filo, G.; Jaworowski, J.; Krawczyk, M.; Lisowski, E.; Lisowski, F.; Michałek, M.; Poznański, P.; Płażek, J.; Korcyl, K.; Kozela, A.; Kulessa, P.; Lebiedowicz, P.; Pysz, K.; Schäfer, W.; Szczurek, A.; Fiutowski, T.; Idzik, M.; Mindur, B.; Przyborowski, D.; Swientek, K.; Biernat, J.; Kamys, B.; Kistryn, S.; Korcyl, G.; Krzemien, W.; Magiera, A.; Moskal, P.; Psyzniak, A.; Rudy, Z.; Salabura, P.; Smyrski, J.; Strzempek, P.; Wronska, A.; Augustin, I.; Böhm, R.; Lehmann, I.; Nicmorus Marinescu, D.; Schmitt, L.; Varentsov, V.; Al-Turany, M.; Belias, A.; Deppe, H.; Dzhygadlo, R.; Ehret, A.; Flemming, H.; Gerhardt, A.; Götzen, K.; Gromliuk, A.; Gruber, L.; Karabowicz, R.; Kliemt, R.; Krebs, M.; Kurilla, U.; Lehmann, D.; Löchner, S.; Lühning, J.; Lynen, U.; Orth, H.; Patsyuk, M.; Peters, K.; Saito, T.; Schepers, G.; Schmidt, C. J.; Schwarz, C.; Schwiening, J.; Täschner, A.; Traxler, M.; Ugur, C.; Voss, B.; Wieczorek, P.; Wilms, A.; Zühlsdorf, M.; Abazov, V. M.; Alexeev, G.; Arefiev, A.; Astakhov, V. I.; Barabanov, M. Yu.; Batyunya, B. V.; Davydov, Yu. I.; Dodokhov, V. Kh.; Efremov, A. A.; Fechtchenko, A.; Fedunov, A. G.; Galoyan, A.; Grigoryan, S.; Koshurnikov, E. K.; Lobanov, V. I.; Lobanov, Y. Yu.; Makarov, A. F.; Malinina, L. V.; Malyshev, V. L.; Olshevskiy, A.; Perevalova, E.; Piskun, A. A.; Pocheptsov, T.; Pontecorvo, G.; Rodionov, V.; Rogov, Y.; Salmin, R.; Samartsev, A.; Sapozhnikov, M. G.; Shabratova, G.; Skachkov, N. B.; Skachkova, A. N.; Strokovsky, E. A.; Suleimanov, M.; Teshev, R.; Tokmenin, V.; Uzhinsky, V.; Vodopyanov, A.; Zaporozhets, S. A.; Zhuravlev, N. I.; Zorin, A. G.; Branford, D.; Glazier, D.; Watts, D.; Böhm, M.; Britting, A.; Eyrich, W.; Lehmann, A.; Pfaffinger, M.; Uhlig, F.; Dobbs, S.; Seth, K.; Tomaradze, A.; Xiao, T.; Bettoni, D.; Carassiti, V.; Cotta Ramusino, A.; Dalpiaz, P.; Drago, A.; Fioravanti, E.; Garzia, I.; Savriè, M.; Akishina, V.; Kisel, I.; Kozlov, G.; Pugach, M.; Zyzak, M.; Gianotti, P.; Guaraldo, C.; Lucherini, V.; Bersani, A.; Bracco, G.; Macri, M.; Parodi, R. F.; Biguenko, K.; Brinkmann, K.; Di Pietro, V.; Diehl, S.; Dormenev, V.; Drexler, P.; Düren, M.; Etzelmüller, E.; Galuska, M.; Gutz, E.; Hahn, C.; Hayrapetyan, A.; Kesselkaul, M.; Kühn, W.; Kuske, T.; Lange, J. S.; Liang, Y.; Metag, V.; Nanova, M.; Nazarenko, S.; Novotny, R.; Quagli, T.; Reiter, S.; Rieke, J.; Rosenbaum, C.; Schmidt, M.; Schnell, R.; Stenzel, H.; Thöring, U.; Ullrich, M.; Wagner, M. N.; Wasem, T.; Wohlfarth, B.; Zaunick, H.; Ireland, D.; Rosner, G.; Seitz, B.; Deepak, P. N.; Kulkarni, A.; Apostolou, A.; Babai, M.; Kavatsyuk, M.; Lemmens, P.; Lindemulder, M.; Loehner, H.; Messchendorp, J.; Schakel, P.; Smit, H.; Tiemens, M.; van der Weele, J. C.; Veenstra, R.; Vejdani, S.; Dutta, K.; Kalita, K.; Kumar, A.; Roy, A.; Sohlbach, H.; Bai, M.; Bianchi, L.; Büscher, M.; Cao, L.; Cebulla, A.; Dosdall, R.; Gillitzer, A.; Goldenbaum, F.; Grunwald, D.; Herten, A.; Hu, Q.; Kemmerling, G.; Kleines, H.; Lehrach, A.; Nellen, R.; Ohm, H.; Orfanitski, S.; Prasuhn, D.; Prencipe, E.; Pütz, J.; Ritman, J.; Schadmand, S.; Sefzick, T.; Serdyuk, V.; Sterzenbach, G.; Stockmanns, T.; Wintz, P.; Wüstner, P.; Xu, H.; Zambanini, A.; Li, S.; Li, Z.; Sun, Z.; Xu, H.; Rigato, V.; Isaksson, L.; Achenbach, P.; Corell, O.; Denig, A.; Distler, M.; Hoek, M.; Karavdina, A.; Lauth, W.; Liu, Z.; Merkel, H.; Müller, U.; Pochodzalla, J.; Schlimme, S.; Sfienti, C.; Thiel, M.; Ahmadi, H.; Ahmed, S.; Bleser, S.; Capozza, L.; Cardinali, M.; Dbeyssi, A.; Deiseroth, M.; Feldbauer, F.; Fritsch, M.; Fröhlich, B.; Jasinski, P.; Kang, D.; Khaneft, D.; Klasen, R.; Leithoff, H. H.; Lin, D.; Maas, F.; Maldaner, S.; Martìnez Rojo, M.; Marta, M.; Michel, M.; Mora Espì, M. C.; Morales Morales, C.; Motzko, C.; Nerling, F.; Noll, O.; Pflüger, S.; Pitka, A.; Rodríguez Piñeiro, D.; Sanchez Lorente, A.; Steinen, M.; Valente, R.; Weber, T.; Zambrana, M.; Zimmermann, I.; Fedorov, A.; Korjik, M.; Missevitch, O.; Boukharov, A.; Malyshev, O.; Marishev, I.; Balanutsa, P.; Balanutsa, V.; Chernetsky, V.; Demekhin, A.; Dolgolenko, A.; Fedorets, P.; Gerasimov, A.; Goryachev, V.; Chandratre, V.; Datar, V.; Dutta, D.; Jha, V.; Kumawat, H.; Mohanty, A. K.; Parmar, A.; Roy, B.; Sonika, G.; Fritzsch, C.; Grieser, S.; Hergemöller, A. K.; Hetz, B.; Hüsken, N.; Khoukaz, A.; Wessels, J. P.; Khosonthongkee, K.; Kobdaj, C.; Limphirat, A.; Srisawad, P.; Yan, Y.; Barnyakov, M.; Barnyakov, A. Yu.; Beloborodov, K.; Blinov, A. E.; Blinov, V. E.; Bobrovnikov, V. S.; Kononov, S.; Kravchenko, E. A.; Kuyanov, I. A.; Martin, K.; Onuchin, A. P.; Serednyakov, S.; Sokolov, A.; Tikhonov, Y.; Atomssa, E.; Kunne, R.; Marchand, D.; Ramstein, B.; Van de Wiele, J.; Wang, Y.; Boca, G.; Costanza, S.; Genova, P.; Montagna, P.; Rotondi, A.; Abramov, V.; Belikov, N.; Bukreeva, S.; Davidenko, A.; Derevschikov, A.; Goncharenko, Y.; Grishin, V.; Kachanov, V.; Kormilitsin, V.; Levin, A.; Melnik, Y.; Minaev, N.; Mochalov, V.; Morozov, D.; Nogach, L.; Poslavskiy, S.; Ryazantsev, A.; Ryzhikov, S.; Semenov, P.; Shein, I.; Uzunian, A.; Vasiliev, A.; Yakutin, A.; Tomasi-Gustafsson, E.; Roy, U.; Yabsley, B.; Belostotski, S.; Gavrilov, G.; Izotov, A.; Manaenkov, S.; Miklukho, O.; Veretennikov, D.; Zhdanov, A.; Makonyi, K.; Preston, M.; Tegner, P.; Wölbing, D.; Bäck, T.; Cederwall, B.; Rai, A. K.; Godre, S.; Calvo, D.; Coli, S.; De Remigis, P.; Filippi, A.; Giraudo, G.; Lusso, S.; Mazza, G.; Mignone, M.; Rivetti, A.; Wheadon, R.; Balestra, F.; Iazzi, F.; Introzzi, R.; Lavagno, A.; Olave, J.; Amoroso, A.; Bussa, M. P.; Busso, L.; De Mori, F.; Destefanis, M.; Fava, L.; Ferrero, L.; Greco, M.; Hu, J.; Lavezzi, L.; Maggiora, M.; Maniscalco, G.; Marcello, S.; Sosio, S.; Spataro, S.; Birsa, R.; Bradamante, F.; Bressan, A.; Martin, A.; Calen, H.; Ikegami Andersson, W.; Johansson, T.; Kupsc, A.; Marciniewski, P.; Papenbrock, M.; Pettersson, J.; Schönning, K.; Wolke, M.; Galnander, B.; Diaz, J.; Pothodi Chackara, V.; Chlopik, A.; Kesik, G.; Melnychuk, D.; Slowinski, B.; Trzcinski, A.; Wojciechowski, M.; Wronka, S.; Zwieglinski, B.; Bühler, P.; Marton, J.; Steinschaden, D.; Suzuki, K.; Widmann, E.; Zmeskal, J.; Gerl, Jürgen; Kojouharov, Ivan; Kojouharova, Jasmina

    2016-10-01

    Bound nuclear systems with two units of strangeness are still poorly known despite their importance for many strong interaction phenomena. Stored antiprotons beams in the GeV range represent an unparalleled factory for various hyperon-antihyperon pairs. Their outstanding large production probability in antiproton collisions will open the floodgates for a series of new studies of systems which contain two or even more units of strangeness at the P ‾ ANDA experiment at FAIR. For the first time, high resolution γ-spectroscopy of doubly strange ΛΛ-hypernuclei will be performed, thus complementing measurements of ground state decays of ΛΛ-hypernuclei at J-PARC or possible decays of particle unstable hypernuclei in heavy ion reactions. High resolution spectroscopy of multistrange Ξ--atoms will be feasible and even the production of Ω--atoms will be within reach. The latter might open the door to the | S | = 3 world in strangeness nuclear physics, by the study of the hadronic Ω--nucleus interaction. For the first time it will be possible to study the behavior of Ξ‾+ in nuclear systems under well controlled conditions.

  17. Doubly Differential Multiple Ionization of Neon by Electron Impact*

    NASA Astrophysics Data System (ADS)

    Santos, A. C. F.; Dubois, R. D.; Hasan, A.

    2003-05-01

    Absolute doubly differential cross sections for single, double and triple ionization of Ne atoms have been measured for 750 eV electron impact as a function of projectile energy loss and scattering angle. Angular distributions between 0 and +/- 12 degrees were obtained for energy losses between 0 and 600 eV. In this energy-loss range only L shell electrons are available for target ionization. The data were normalized to total ionization cross sections available in the literature. A comparison is made with photoionization data as well as with argon data taken using similar methods in order to study the role played by the static target potential. 1- R. D. DuBois, C. Doudna, C. Lloyd, M. Kahveci, Kh Khayyat, Y. Zhou, and D. H. Madison, J. Phys. B 34 (2001) L783-L789. 2- R. D. DuBois, Kh Khayyat, C. Doudna, C. Lloyd, NIM B 192 (2002) 63-66. 3- A. C. F. Santos, A. Hasan, T. Yates, R. D. DuBois, submitted to Phys. Rev. A (2003).

  18. Interactions of intrathecally administered ziconotide, a selective blocker of neuronal N-type voltage-sensitive calcium channels, with morphine on nociception in rats.

    PubMed

    Wang, Y X; Gao, D; Pettus, M; Phillips, C; Bowersox, S S

    2000-02-01

    Ziconotide is a selective, potent and reversible blocker of neuronal N-type voltage-sensitive calcium channels (VSCCs). Morphine is an agonist of mu-opioid receptors and inhibits N-type VSCC channels via a G-protein coupling mechanism. Both agents are antinociceptive when they are administered intrathecally (spinally). The present study investigated the acute and chronic (7-day) interactions of intrathecally administered ziconotide and morphine on nociception in several animal models of pain. In the acute study, intrathecal bolus injections of morphine and ziconotide alone produced dose-dependent inhibition of formalin-induced tonic flinch responses and withdrawal responses to paw pressure. The combination of ziconotide and morphine produced an additive inhibition of formalin-induced tonic flinch responses and a significant leftward shift of the morphine dose-response curve in the paw pressure test. After chronic (7-day) intrathecal infusion, ziconotide enhanced morphine analgesia in the formalin test. In contrast, chronic intrathecal morphine infusion produced tolerance to analgesia, but did not affect ziconotide antinociception. Antinociception produced by ziconotide alone was the same as that observed when the compound was co-administered with morphine to morphine-tolerant rats. In the hot-plate and tail immersion tests, chronic intrathecal infusion of morphine lead to rapid tolerance whereas ziconotide produced sustained analgesia with no loss of potency throughout the infusion period. Although ziconotide in combination with morphine produced an apparent synergistic analgesic effects during the initial phase of continuous infusion, it did not prevent morphine tolerance to analgesia. These results demonstrate that (1) acute intrathecal administrations of ziconotide and morphine produce additive or synergistic analgesic effects; (2) chronic intrathecal morphine infusion results in tolerance to analgesia but does not produce cross-tolerance to ziconotide; (3

  19. Regionally selective alterations in local cerebral glucose utilization evoked by charybdotoxin, a blocker of central voltage-activated K+-channels.

    PubMed

    Cochran, S M; Harvey, A L; Pratt, J A

    2001-11-01

    The quantitative [14C]-2-deoxyglucose autoradiographic technique was employed to investigate the effect of charybdotoxin, a blocker of certain voltage-activated K+ channels, on functional activity, as reflected by changes in local rates of cerebral glucose utilization in rat brain. Intracerebroventricular administration of charybdotoxin, at doses below those producing seizure activity, produced a heterogeneous effect on glucose utilization throughout the brain. Out of the 75 brain regions investigated, 24 displayed alterations in glucose utilization. The majority of these changes were observed with the intermediate dose of charybdotoxin administered (12.5 pmol), with the lower (6.25 pmol) and higher (25 pmol) doses of charybdotoxin producing a much more restricted pattern of change in glucose utilization. In brain regions which displayed alterations in glucose at all doses of charybdotoxin administered, no dose dependency in terms of the magnitude of change was observed. The 21 brain regions which displayed altered functional activity after administration of 12.5 pmol charybdotoxin were predominantly limited to the hippocampus, limbic and motor structures. In particular, glucose utilization was altered within three pathways implicated within learning and memory processes, the septohippocampal pathway, Schaffer collaterals within the hippocampus and the Papez circuit. The nigrostriatal pathway also displayed altered local cerebral glucose utilization. These data indicate that charybdotoxin produces alterations in functional activity within selected pathways in the brain. Furthermore the results raise the possibility that manipulation of particular subtypes of Kv1 channels in the hippocampus and related structures may be a means of altering cognitive processes without causing global changes in neural activity throughout the brain.

  20. Asymptotic error-rate analysis of FSO links using transmit laser selection over gamma-gamma atmospheric turbulence channels with pointing errors.

    PubMed

    García-Zambrana, Antonio; Castillo-Vázquez, Beatriz; Castillo-Vázquez, Carmen

    2012-01-30

    Since free-space optical (FSO) systems are usually installed on high buildings and building sway may cause vibrations in the transmitted beam, an unsuitable alignment between transmitter and receiver together with fluctuations in the irradiance of the transmitted optical beam due to the atmospheric turbulence can severely degrade the performance of optical wireless communication systems. In this paper, asymptotic bit error-rate (BER) performance for FSO communication systems using transmit laser selection over atmospheric turbulence channels with pointing errors is analyzed. Novel closed-form asymptotic expressions are derived when the irradiance of the transmitted optical beam is susceptible to either a wide range of turbulence conditions (weak to strong), following a gamma-gamma distribution of parameters α and β, or pointing errors, following a misalignment fading model where the effect of beam width, detector size and jitter variance is considered. Obtained results provide significant insight into the impact of various system and channel parameters, showing that the diversity order is independent of the pointing error when the equivalent beam radius at the receiver is at least 2(min{α,β})(1/2) times the value of the pointing error displacement standard deviation at the receiver. Moreover, since proper FSO transmission requires transmitters with accurate control of their beamwidth, asymptotic expressions are used to find the optimum beamwidth that minimizes the BER at different turbulence conditions. Simulation results are further demonstrated to confirm the accuracy and usefulness of the derived results, showing that asymptotic expressions here obtained lead to simple bounds on the bit error probability that get tighter over a wider range of signal-to-noise ratio (SNR) as the turbulence strength increases.

  1. Molecular analysis of the sea anemone toxin Av3 reveals selectivity to insects and demonstrates the heterogeneity of receptor site-3 on voltage-gated Na+ channels

    PubMed Central

    Moran, Yehu; Kahn, Roy; Cohen, Lior; Gur, Maya; Karbat, Izhar; Gordon, Dalia; Gurevitz, Michael

    2007-01-01

    Av3 is a short peptide toxin from the sea anemone Anemonia viridis shown to be active on crustaceans and inactive on mammals. It inhibits inactivation of Navs (voltage-gated Na+ channels) like the structurally dissimilar scorpion α-toxins and type I sea anemone toxins that bind to receptor site-3. To examine the potency and mode of interaction of Av3 with insect Navs, we established a system for its expression, mutagenized it throughout, and analysed it in toxicity, binding and electrophysiological assays. The recombinant Av3 was found to be highly toxic to blowfly larvae (ED50=2.65±0.46 pmol/100 mg), to compete well with the site-3 toxin LqhαIT (from the scorpion Leiurus quinquestriatus) on binding to cockroach neuronal membranes (Ki=21.4±7.1 nM), and to inhibit the inactivation of Drosophila melanogaster channel, DmNav1, but not that of mammalian Navs expressed in Xenopus oocytes. Moreover, like other site-3 toxins, the activity of Av3 was synergically enhanced by ligands of receptor site-4 (e.g. scorpion β-toxins). The bioactive surface of Av3 was found to consist mainly of aromatic residues and did not resemble any of the bioactive surfaces of other site-3 toxins. These analyses have portrayed a toxin that might interact with receptor site-3 in a different fashion compared with other ligands of this site. This assumption was corroborated by a D1701R mutation in DmNav1, which has been shown to abolish the activity of all other site-3 ligands, except Av3. All in all, the present study provides further evidence for the heterogeneity of receptor site-3, and raises Av3 as a unique model for design of selective anti-insect compounds. PMID:17492942

  2. High-resolution single-channel seismic reflection surveys of Orange Lake and other selected sites of north central Florida

    USGS Publications Warehouse

    Kindinger, Jack G.; Davis, Jeffrey B.; Flocks, James G.

    1994-01-01

    and faulting. The largest and most important features in the lake are the collapse sinkholes found along the southwestern shore that provide conduits for exchange between the lake and subsurface aquifer. There are two basic differences between the southwest and other areas of the lake: (1) the features found towards the central part of the lake are smaller in scale (1to 10 m across) and tend to be singular structures compare to the southwest area where features combined to form larger sinkholes (>400 m), and; (2) the southwest area is the only site where collapse dolines were identified. These dolines are located along the southwestern shoreline adjacent to Heagy-Burry Park. The comparison of seismic profiles from the several other selected lake and river sites to the Orange Lake profiles showed that other study areas were constructed of one or two large subsidences or a combination of sinkholes to form one large sinkhole. Aside from the difference in scale the basic characteristics of the subsidence sinkholes were similar.

  3. Encoderless Model Predictive Control of Doubly-Fed Induction Generators in Variable-Speed Wind Turbine Systems

    NASA Astrophysics Data System (ADS)

    Abdelrahem, Mohamed; Hackl, Christoph; Kennel, Ralph

    2016-09-01

    In this paper, an encoderless finite-control-set model predictive control (FCS-MPC) strategy for doubly-fed induction generators (DFIGs) based on variable-speed wind turbine systems (WTSs) is proposed. According to the FCS-MPC concept, the discrete states of the power converter are taken into account and the future converter performance is predicted for each sampling period. Subsequently, the voltage vector that minimizes a predefined cost function is selected to be applied in the next sampling instant. Furthermore, a model reference adaptive system (MRAS) observer is used to estimate the rotor speed and position of the DFIG. Estimation and control performance of the proposed encoderless control method are validated by simulation results for all operation conditions. Moreover, the performance of the MRAS observer is tested under variations of the DFIG parameters.

  4. Holographic recording in a doubly doped lithium niobate crystal with two wavelengths: a blue laser diode and a green laser

    NASA Astrophysics Data System (ADS)

    Komori, Yuichi; Ishii, Yukihiro

    2010-08-01

    A doubly-doped LiNbO3 (LN) crystal has been well used as a nonvolatile two-wavelength recording material. By using two levels of the crystal, two-kind holograms can be recorded on one crystal; a hologram is recorded with a 405-nm blue laser diode (LD) for a deep Mn level, and another hologram is with a 532-nm green laser for a shallow Fe level. The recording capacity doubles. A 780-nm LD is non-volatile reconstructing source since the LD line is insensitive to both levels. Multiplexed reconstructed images are demonstrated by using a sharp angular selectivity of a volume LN crystal keeping Bragg condition with spherical reconstructions.

  5. The Torsional Spectrum of Doubly Deuterated Methanol CHD_2OH

    NASA Astrophysics Data System (ADS)

    Ndao, M.; Coudert, L. H.; Kwabia Tchana, F.; Barros, J.; Margulès, L.; Manceron, Laurent; Roy, P.

    2014-06-01

    Although the torsional spectrum of several isotopic species of methanol with a symmetrical CH_3 or CD_3 was analyzed some time ago, it is recently, and only for the monodeuterated species CH_2DOH, that such an analysis was extended to the case of an asymmetrical methyl group. In this talk, based on a Fourier transform high-resolution spectrum recorded in the 20 to 670 wn region, the first analysis of the torsional spectrum of doubly deuterated methanol CHD_2OH will be presented. The Q branch of many torsional subbands could be observed and their assignment was initiated using a theoretical torsion-rotation spectrum computed with an approach accounting for the torsion-rotation Coriolis coupling and for the dependence of the generalized inertia tensor on the angle of internal rotation. 46 torsional subbands were thus assigned. For 28 of them, their rotational structure could be assigned and fitted using an effective Hamiltonian expressed as a J(J+1) expansion; and for 2 of them microwave transitions within the lower torsional level could also be included in the analysis. In several cases these analysis revealed that the torsional levels are strongly perturbed. In the talk, the torsional parameters retrieved in the analysis of the torsional subband centers will be discussed. The results of the analysis of the rotational structure of the torsional subbands will be presented and we will also try to understand the nature of the perturbations. At last, preliminary results about the analysis of the microwave spectrum will be presented. El Hilali, Coudert, Konov, and Klee, J. Chem. Phys. 135 (2011) 194309 Lauvergnat, Coudert, Klee, and Smirnov, J. Mol. Spectrosc. 256 (2009) 204 Quade, Liu, Mukhopadhyay, and Su, J. Mol. Spectrosc. 192 (1998) 378 Pearson, Yu, and Drouin, J. Mol. Spectrosc. 280 (2012) 119

  6. Simultaneous marginal survival estimators when doubly censored data is present.

    PubMed

    Julià, Olga; Gómez, Guadalupe

    2011-07-01

    A doubly censoring scheme occurs when the lifetimes T being measured,from a well-known time origin, are exactly observed within a window [L, R] of observational time and are otherwise censored either from above (right-censored observations)or below (left-censored observations). Sample data consists on the pairs (U, δ)where U = min{R, max{T, L}} and δ indicates whether T is exactly observed (δ = 0),right-censored (δ = 1) or left-censored (δ = −1). We are interested in the estimation of the marginal behaviour of the three random variables T, L and R based on the observed pairs (U, δ).We propose new nonparametric simultaneous marginal estimators Ŝ(T) , Ŝ(L) and Ŝ(R) for the survival functions of T, L and R, respectively, by means of an inverse-probability-of-censoring approach. The proposed estimators Ŝ(T) , Ŝ(L) and Ŝ(R) are not computationally intensive, generalize the empirical survival estimator and reduce to the Kaplan-Meier estimator in the absence of left-censored data. Furthermore,Ŝ(T) is equivalent to a self-consistent estimator, is uniformly strongly consistent and asymptotically normal. The method is illustrated with data from a cohort of drug users recruited in a detoxification program in Badalona (Spain). For these data we estimate the survival function for the elapsed time from starting IV-drugs to AIDS diagnosis, as well as the potential follow-up time. A simulation study is discussed to assess the performance of the three survival estimators for moderate sample sizes and different censoring levels.

  7. Singly and Doubly Occupied Higher Quantum States in Nanocrystals.

    PubMed

    Jeong, Juyeon; Yoon, Bitna; Kwon, Young-Wan; Choi, Dongsun; Jeong, Kwang Seob

    2017-02-08

    Filling the lowest quantum state of the conduction band of colloidal nanocrystals with a single electron, which is analogous to the filling the lowest unoccupied molecular orbital in a molecule with a single electron, has attracted much attention due to the possibility of harnessing the electron spin for potential spin-based applications. The quantized energy levels of the artificial atom, in principle, make it possible for a nanocrystal to be filled with an electron if the Fermi-energy level is optimally tuned during the nanocrystal growth. Here, we report the singly occupied quantum state (SOQS) and doubly occupied quantum state (DOQS) of a colloidal nanocrystal in steady state under ambient conditions. The number of electrons occupying the lowest quantum state can be controlled to be zero, one (unpaired), and two (paired) depending on the nanocrystal growth time via changing the stoichiometry of the nanocrystal. Electron paramagnetic resonance spectroscopy proved the nanocrystals with single electron to show superparamagnetic behavior, which is a direct evidence of the SOQS, whereas the DOQS of the two- or zero-electron occupied nanocrystals in the 1Se exhibit diamagnetic behavior. In combination with the superconducting quantum interference device measurement, it turns out that the SOQS of the HgSe colloidal quantum dots has superparamagnetic property. The appearance and change of the steady-state mid-IR intraband absorption spectrum reflect the sequential occupation of the 1Se state with electrons. The magnetic property of the colloidal quantum dot, initially determined by the chemical synthesis, can be tuned from diamagnetic to superparamagnetic and vice versa by varying the number of electrons through postchemical treatment. The switchable magnetic property will be very useful for further applications such as colloidal nanocrystal based spintronics, nonvolatile memory, infrared optoelectronics, catalyst, imaging, and quantum computing.

  8. Basis set dependence of the doubly hybrid XYG3 functional

    NASA Astrophysics Data System (ADS)

    Zhang, Igor Ying; Luo, Yi; Xu, Xin

    2010-09-01

    In the present study, we investigated the basis set dependence of XYG3, a newly developed doubly hybrid functional [Y. Zhang, X. Xu, and W. A. Goddard III, Proc. Natl. Acad. Sci. U.S.A. 106, 4963 (2009)], in prediction of (1) heats of formation (HOFs), (2) bond dissociation enthalpies (BDEs), (3) reaction barrier heights (RBHs), and (4) nonbonded interactions (NBIs). We used basis sets of triple-zeta quality starting from 6-311+G(d,p) with increasing completeness of the polarization functions to the largest Pople-type basis set 6-311++G(3df,3pd) and found that there was a continued improvement with larger basis sets. We showed that while HOF predictions were prone to basis set deficiencies, the basis set dependences in calculating BDEs, RBHs, and NBIs were mild. All of them converged fast with the increase of basis set size. We extended XYG3 to propose the XYG3o functional which was specifically optimized for a particular basis set in order to enhance its performance when using basis set of moderate size. With the 6-311+G(2df,p) basis set, XYG3o led to MADs of 2.56 kcal/mol for HOFs of the G3/99 set, 1.17 kcal/mol for BDEs of the BDE92/07 set, 1.11 kcal/mol for RBHs of the NHTBH38/04 and HTBH38/04 sets, and 0.40 kcal/mol for NBIs of the NCIE31/05 set, being comparable to those obtained by using XYG3/6-311++G(3df,3pd).

  9. Continuum model for chiral induced spin selectivity in helical molecules

    SciTech Connect

    Medina, Ernesto; González-Arraga, Luis A.; Finkelstein-Shapiro, Daniel; Mujica, Vladimiro; Berche, Bertrand

    2015-05-21

    A minimal model is exactly solved for electron spin transport on a helix. Electron transport is assumed to be supported by well oriented p{sub z} type orbitals on base molecules forming a staircase of definite chirality. In a tight binding interpretation, the spin-orbit coupling (SOC) opens up an effective π{sub z} − π{sub z} coupling via interbase p{sub x,y} − p{sub z} hopping, introducing spin coupled transport. The resulting continuum model spectrum shows two Kramers doublet transport channels with a gap proportional to the SOC. Each doubly degenerate channel satisfies time reversal symmetry; nevertheless, a bias chooses a transport direction and thus selects for spin orientation. The model predicts (i) which spin orientation is selected depending on chirality and bias, (ii) changes in spin preference as a function of input Fermi level and (iii) back-scattering suppression protected by the SO gap. We compute the spin current with a definite helicity and find it to be proportional to the torsion of the chiral structure and the non-adiabatic Aharonov-Anandan phase. To describe room temperature transport, we assume that the total transmission is the result of a product of coherent steps.

  10. Inhibition of cell proliferation by a selective inhibitor of the Ca{sup 2+}-activated Cl{sup -} channel, Ano1

    SciTech Connect

    Mazzone, Amelia; Eisenman, Seth T.; Strege, Peter R.; Yao, Zhen; Ordog, Tamas; Gibbons, Simon J.; Farrugia, Gianrico

    2012-10-19

    Highlights: Black-Right-Pointing-Pointer T16A{sub inh}-A01 blocked Ano1 currents in HEK cells expressing Ano1. Black-Right-Pointing-Pointer T16A{sub inh}-A01 reduced proliferation in ICC primary cultures and CFPAC-1 cell line. Black-Right-Pointing-Pointer T16A{sub inh}-A01 reduced proliferation of ICC in intact smooth muscle strips. -- Abstract: Background: Ion channels play important roles in regulation of cellular proliferation. Ano1 (TMEM16A) is a Ca{sup 2+}-activated Cl{sup -} channel expressed in several tumors and cell types. In the muscle layers of the gastrointestinal tract Ano1 is selectively expressed in interstitial cells of Cajal (ICC) and appears to be required for normal gastrointestinal slow wave electrical activity. However, Ano1 is expressed in all classes of ICC, including those that do not generate slow waves suggesting that Ano1 may have other functions. Indeed, a role for Ano1 in regulating proliferation of tumors and ICC has been recently suggested. Recently, a high-throughput screen identified a small molecule, T16A{sub inh}-A01 as a specific inhibitor of Ano1. Aim: To investigate the effect of the T16A{sub inh}-A01 inhibitor on proliferation in ICC and in the Ano1-expressing human pancreatic cancer cell line CFPAC-1. Methods: Inhibition of Ano1 was demonstrated by whole cell voltage clamp recordings of currents in cells transfected with full-length human Ano1. The effect of T16A{sub inh}-A01 on ICC proliferation was examined in situ in organotypic cultures of intact mouse small intestinal smooth muscle strips and in primary cell cultures prepared from these tissues. ICC were identified by Kit immunoreactivity. Proliferating ICC and CFPAC-1 cells were identified by immunoreactivity for the nuclear antigen Ki67 or EdU incorporation, respectively. Results: T16A{sub inh}-A01 inhibited Ca{sup 2+}-activated Cl{sup -} currents by 60% at 10 {mu}M in a voltage-independent fashion. Proliferation of ICC was significantly reduced in primary cultures

  11. The vertical distribution of selected trace metals and organic compounds in bottom materials of the proposed lower Columbia River export channel, Oregon, 1984

    USGS Publications Warehouse

    Fuhrer, Gregory J.; Horowitz, Arthur J.

    1989-01-01

    A proposal to deepen the lower Columbia River navigation channel in Orego