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Sample records for doubly selective channels

  1. Joint Channel Estimation and Signal Detection for the OFDM System Without Cyclic Prefix Over Doubly-Selective Channels

    NASA Astrophysics Data System (ADS)

    Song, Lijun; Lei, Xia; Jin, Maozhu; Lv, Zhihan

    2015-12-01

    In the high-speed railway wireless communication, a joint channel estimation and signal detection algorithm is proposed for the orthogonal frequency division multiplexing (OFDM) system without cyclic prefix in the doubly-selective fading channels. Our proposed method first combines the basis expansion model (BEM) and the inter symbol interference (ISI) cancellation to overcome the situation that exists with the fast time-varying channel and the normalized maximum multipath channel exceeding the length of the cyclic prefix (CP). At first, the channel estimation and signal detection can be approximated without considering the ISI. Then, the channel parameters and signal detection are updated through ISI cancellation and circular convolution reconstruction from the frequency domain. The simulations show the algorithm can improve the performance of channel estimation and signal detection.

  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. 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. PMID:22280593

  4. SINR Analysis of Hexagonal Multicarrier Transmission Systems in the Presence of Insufficient Synchronization for Doubly Dispersive Channel

    NASA Astrophysics Data System (ADS)

    Xu, Kui; Xu, Youyun; Zhang, Dongmei

    2011-07-01

    This paper analyzes the effect of the insufficient synchronization (carrier frequency offset, timing offset) on hexagonal multicarrier transmission (HMT) systems for doubly dispersive channel. Exact SINR and demodulated symbol expressions for HMT systems in the presence of insufficient synchronization transmission conditions over doubly dispersive channel with exponential delay power profile and U-shape Doppler power spectrum and uniform delay power profile and uniform Doppler power spectrum are derived, respectively. Theoretical analysis shows that similar degradations on symbol amplitude and phase caused by insufficient synchronization are incurred as in traditional cyclic-prefix orthogonal frequency division multiplexing (CP-OFDM) transmission. HMT systems outperform traditional OFDM systems with respect to signal to interference-plus-noise-ratio (SINR) against inter-symbol interference (ISI) and inter-carrier interference (ICI) caused by insufficient synchronization and doubly dispersive(DD) channel. The BER performance of the HMT systems using Monte Carlo simulation match with the conclusion given by the proposed exact SINR expression.

  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. Production of the doubly magic nucleus Sn100 in fusion and quasifission reactions via light particle and cluster emission channels

    NASA Astrophysics Data System (ADS)

    Kalandarov, Sh. A.; Adamian, G. G.; Antonenko, N. V.; Wieleczko, J. P.

    2014-08-01

    The possibilities of production of the doubly magic nucleus Sn100 in complete fusion and quasifission reactions with stable and radioactive ion beams are investigated within a dinuclear system model. The excitation functions for production of the exotic nuclei 100-103Sn and 112,114Ba via xn, pxn, αxn, and 12,14Cxn emission channels are predicted for future experiments.

  7. Genetic Response To Selection In Channel Catfish

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Channel catfish selected solely for fast growth (fast growing) were compared to USDA103, USDA403, and industry pool groups of channel catfish for growth, body composition, and stress response. All fish were fed daily for 8 wks followed by an acute 10-minute dewatering stress. By wk 4, feed intake ...

  8. The VDAC channel: Molecular basis for selectivity.

    PubMed

    Colombini, Marco

    2016-10-01

    The voltage dependent anion-selective channel, VDAC, is the major permeability pathway by which molecules and ion cross the mitochondrial outer membrane. This pathway has evolved to optimize the flow of these substances and to control this flow by a gating process that is influenced by a variety of factors including transmembrane voltage. The permeation pathway formed through the membrane by VDAC is complex. Small ion flow is primarily influenced by the charged surface of the inner walls of the channel. Channel closure changes this landscape resulting in a change from a channel that favors anions to one that favors cations. Molecular ions interact more intimately with the inner walls of the channel and are selected by their 3-dimensional structure, not merely by their size and charge. Molecular ions typically found in cells are greatly favored over those that are not. For these larger structures the channel may form a low-energy translocation path that complements the structure of the permeant. This article is part of a Special Issue entitled: Mitochondrial Channels edited by Pierre Sonveaux, Pierre Maechler and Jean-Claude Martinou. PMID:26826035

  9. 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.

  10. Structure and selectivity in bestrophin ion channels

    DOE PAGESBeta

    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 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. 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.

  12. Highly sensitive and doubly orientated selective molecularly imprinted electrochemical sensor for Cu(2.).

    PubMed

    Li, Jianping; Zhang, Lianming; Wei, Ge; Zhang, Yun; Zeng, Ying

    2015-07-15

    Studies on molecularly imprinted electrochemical sensors for metal ions determination have been widely reported. However, the sensitivity and selectivity of the sensors needs to be improved urgently. In the current work, a novel molecularly imprinted electrochemical sensor was originally developed for selective determination of ultratrace Cu(2+) by combining the metal-ligand chelate orientated recognition with enzyme amplification effect. The detection relied on a competition reaction between Cu(2+)-glycine (Cu-Gly) and horse radish peroxidase (HRP)-labeled Cu-Gly on the imprinted polymer membrane modified electrode. The sensitivity of this sensor was promoted by enzyme amplification. Selectivity was improved by the double-specificity derived from ligand-to-metal ion and metal-ligand chelate orientated recognition of 3D imprinted cavities. This technique was quantitatively sensitive to Cu(2+) concentrations ranging from 0.5nmol/L to 30nmol/L, with a detection limit of 42.4pmol/L. which was lower than those in most of the reported methods. The allowable amounts of interference ions were higher when it compared to other common molecularly imprinted sensors. Moreover, the results of assaying several real samples have proven its feasibility for practical applications. PMID:25771304

  13. Anion, cation, and zwitterion selectivity of phospholemman channel molecules.

    PubMed Central

    Kowdley, G C; Ackerman, S J; Chen, Z; Szabo, G; Jones, L R; Moorman, J R

    1997-01-01

    Phospholemman (PLM), a 72-amino acid membrane protein with a single transmembrane domain, forms taurine-selective ion channels in lipid bilayers. Because taurine forms zwitterions, a taurine-selective channel might have binding sites for both anions and cations. Here we show that PLM channels indeed allow fluxes of both cations and anions, making instantaneous and voltage-dependent transitions among conformations with drastically different ion selectivity characteristics. This surprising and novel ion channel behavior offers a molecular explanation for selective taurine flux across cell membranes and may explain why molecules in the phospholemman family can induce cation- or anion-selective conductances when expressed in Xenopus oocytes. PMID:8994599

  14. Channel selective tunnelling through a nanographene assembly.

    PubMed

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

    2012-03-01

    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. PMID:22322294

  15. 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 inter-annual 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

  16. Using the Doubly Charged Selected Ion Coupled with MS/MS Fragments Monitoring (DCSI-MS/MS) Mode for the Identification of Gelatin Species.

    PubMed

    Cheng, Xian-Long; Wei, Feng; Chen, Jia; Li, Ming-Hua; Zhang, Lei; Zhao, Ying-Yong; Xiao, Xin-Yue; Ma, Shuang-Cheng; Lin, Rui-Chao

    2014-01-01

    In electrospray ionization (ESI) mode, peptides and proteins can be multiply charged ions; in this situation a doubly charged selected ion (DCSI) coupled with mass spectrometry (MS/MS) fragments monitoring (DCSI-MS/MS) method is the most suitable scanning mode to detect known peptides in complex samples when an ion-trap mass spectrometer is the instrument used for the analysis. In this mode, the MS detector is programmed to only select a doubly charged ion as a precursor and to perform continuous MS/MS on one or more of the selected precursors, either during a specific time interval or along the whole chromatographic run. Gelatin is a mixture of high molecular weight polypeptides from the hydrolysis of collagen. In this study, the DCSI-MS/MS monitoring mode was applied to the detection of previously characterized species-specific peptides from different gelatins. The proposed methodology makes use of tryptic digestion for sample preparation and peptide separation and identification by rapid resolution liquid chromatography coupled to an ion trap working in the DCSI-MS/MS mode for the analysis. This methodology was applied to the differential classification of five commercial, homological species of gelatins and proved to be an excellent tool for gelatin product authentication. PMID:24744960

  17. 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.

  18. [Model of the selective calcium channel of characean algae].

    PubMed

    Lunevskiĭ, V Z; Zherelova, O M; Aleksandrov, A A; Vinokurov, M G; Berestovskiĭ, G N

    1980-01-01

    The present work was intended to further investigate the selective filter of calcium channel on both a cell membrane and reconstructed channels. For the studies on cell membranes, an inhibitor of chloride channels was chosen (ethacrynic acid) to pass currents only through the calcium channels. On both the cells and reconstructed channels, permeability of ions of different crystal radii and valencies was investigated. The obtained results suggest that the channel represents a wide water pore with a diameter larger than 8 A into which ions go together with the nearest water shell. The values of the maximal currents are given by electrostatic interaction of the ions with the anion center of the channel. A phenomenological two-barrier model of the channel is given which describes the movement of all the ions studied. PMID:6251921

  19. Channel Selection Methods for the P300 Speller

    PubMed Central

    Colwell, K. A.; Ryan, D. B.; Throckmorton, C. S.; Sellers, E. W.; Collins, L. M.

    2014-01-01

    The P300 Speller brain-computer interface (BCI) allows a user to communicate without muscle activity by reading electrical signals on the scalp via electroencephalogram. Modern BCI systems use multiple electrodes (“channels”) to collect data, which has been shown to improve speller accuracy; however, system cost and setup time can increase substantially with the number of channels in use, so it is in the user’s interest to use a channel set of modest size. This constraint increases the importance of using an effective channel set, but current systems typically utilize the same channel montage for each user. We examine the effect of active channel selection for individuals on speller performance, using generalized standard feature-selection methods, and present a new channel selection method, termed Jumpwise Regression, that extends the Stepwise Linear Discriminant Analysis classifier. Simulating the selections of each method on real P300 Speller data, we obtain results demonstrating that active channel selection can improve speller accuracy for most users relative to a standard channel set, with particular benefit for users who experience low performance using the standard set. Of the methods tested, Jumpwise Regression offers accuracy gains similar to the best-performing feature-selection methods, and is robust enough for online use. PMID:24797224

  20. 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.

  1. 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

  2. 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. PMID:26779604

  3. 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.

  4. Ion selectivity and gating mechanisms of FNT channels

    PubMed Central

    Waight, Andrew B.; Czyzewski, Bryan K.; Wang, Da-Neng

    2013-01-01

    The phospholipid bilayer has evolved to be a protective and selective barrier by which the cell maintains high concentrations of life sustaining organic and inorganic material. As gatekeepers responsible for an immense amount of bidirectional chemical traffic between the cytoplasm and extracellular milieu, ion channels have been studied in detail since their postulated existence nearly three-quarters of a century ago. Over the past fifteen years, we have begun to understand how selective permeability can be achieved for both cationic and anionic ions. Our mechanistic knowledge has expanded recently with studies of a large family of anion channels, the Formate Nitrite Transport (FNT) family. This family has proven amenable to structural studies at a resolution high enough to reveal intimate details of ion selectivity and gating. With five representative members having yielded a total of 15 crystal structures, this family represents one of the richest sources of structural information for anion channels. PMID:23773802

  5. Sodium and potassium competition in potassium-selective and non-selective channels

    NASA Astrophysics Data System (ADS)

    Sauer, David B.; Zeng, Weizhong; Canty, John; Lam, Yeeling; Jiang, Youxing

    2013-11-01

    Potassium channels selectively conduct K+, primarily to the exclusion of Na+, despite the fact that both ions can bind within the selectivity filter. Here we perform crystallographic titration and single-channel electrophysiology to examine the competition of Na+ and K+ binding within the filter of two NaK channel mutants; one is the potassium-selective NaK2K mutant and the other is the non-selective NaK2CNG, a CNG channel pore mimic. With high-resolution structures of these engineered NaK channel constructs, we explicitly describe the changes in K+ occupancy within the filter upon Na+ competition by anomalous diffraction. Our results demonstrate that the non-selective NaK2CNG still retains a K+-selective site at equilibrium, whereas the NaK2K channel filter maintains two high-affinity K+ sites. A double-barrier mechanism is proposed to explain K+ channel selectivity at low K+ concentrations.

  6. Surface potentials and the calculated selectivity of ion channels.

    PubMed Central

    Miedema, Henk

    2002-01-01

    Ion channels catalyze the transport of ions across biological membranes. A proper understanding of ion-channel functioning is essential to our knowledge of cell physiology, and, in this context, ion-channel selectivity is a key concept. The extent to which a channel permeates two ion species, a and b, is expressed by the permeability ratio, P(a)/P(b). This paper addresses a complication in the calculation of P(a)/P(b) that is related to the existence of surface potentials (psi) and that so far has not been fully appreciated. This paper shows the rather surprising effect of psi on the calculated P(a)/P(b) of a channel that is permeable to two ion species of different valence. If we ignore psi, we conclude, for instance, P(a) > P(b). If we implement psi in the calculation of P(a)/P(b), we may, however, conclude exactly the reverse, i.e., P(a) < P(b). Because electrostatic potentials arise at the surface of essentially all biological membranes, this paper argues for a more critical evaluation of ion channel selectivity measurements. PMID:11751304

  7. Flux, coupling, and selectivity in ionic channels of one conformation.

    PubMed Central

    Chen, D P; Eisenberg, R S

    1993-01-01

    Ions crossing biological membranes are described as a concentration of charge flowing through a selective open channel of one conformation and analyzed by a combination of Poisson and Nernst-Planck equations and boundary conditions, called the PNP theory for short. The ion fluxes in this theory interact much as ion fluxes interact in biological channels and mediated transporters, provided the theoretical channel contains permanent charge and has selectivity created by (electro-chemical) resistance at its ends. Interaction occurs because the flux of different ionic species depends on the same electric field. That electric field is a variable, changing with experimental conditions because the screening (i.e., shielding) of the permanent charge within the channel changes with experimental conditions. For example, the screening of charge and the shape of the electric field depend on the concentration of all ionic species on both sides of the channel. As experimental interventions vary the screening, the electric field varies, and thus the flux of each ionic species varies conjointly, and is, in that sense, coupled. Interdependence and interaction are the rule, independence is the exception, in this channel. PMID:7693003

  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. Doubly Distributed Transactions

    Energy Science and Technology Software Center (ESTSC)

    2014-08-25

    Doubly Distributed Transactions (D2T) offers a technique for managing operations from a set of parallel clients with a collection of distributed services. It detects and manages faults. Example code with a test harness is also provided

  10. 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.

  11. Ionic Selectivity and Permeation Properties of Human PIEZO1 Channels

    PubMed Central

    Gnanasambandam, Radhakrishnan; Bae, Chilman; Gottlieb, Philip A.; Sachs, Frederick

    2015-01-01

    Members of the eukaryotic PIEZO family (the human orthologs are noted hPIEZO1 and hPIEZO2) form cation-selective mechanically-gated channels. We characterized the selectivity of human PIEZO1 (hPIEZO1) for alkali ions: K+, Na+, Cs+ and Li+; organic cations: TMA and TEA, and divalents: Ba2+, Ca2+, Mg2+ and Mn2+. All monovalent ions permeated the channel. At a membrane potential of -100 mV, Cs+, Na+ and K+ had chord conductances in the range of 35–55 pS with the exception of Li+, which had a significantly lower conductance of ~ 23 pS. The divalents decreased the single-channel permeability of K+, presumably because the divalents permeated slowly and occupied the open channel for a significant fraction of the time. In cell-attached mode, 90 mM extracellular divalents had a conductance for inward currents carried by the divalents of: 25 pS for Ba2+ and 15 pS for Ca2+ at -80 mV and 10 pS for Mg2+ at -50 mV. The organic cations, TMA and TEA, permeated slowly and attenuated K+ currents much like the divalents. As expected, the channel K+ conductance increased with K+ concentration saturating at ~ 45 pS and the KD of K+ for the channel was 32 mM. Pure divalent ion currents were of lower amplitude than those with alkali ions and the channel opening rate was lower in the presence of divalents than in the presence of monovalents. Exposing cells to the actin disrupting reagent cytochalasin D increased the frequency of openings in cell-attached patches probably by reducing mechanoprotection. PMID:25955826

  12. Frequency selective tunable spin wave channeling in the magnonic network

    NASA Astrophysics Data System (ADS)

    Sadovnikov, A. V.; Beginin, E. N.; Odincov, S. A.; Sheshukova, S. E.; Sharaevskii, Yu. P.; Stognij, A. I.; Nikitov, S. A.

    2016-04-01

    Using the space-resolved Brillouin light scattering spectroscopy, we study the frequency and wavenumber selective spin-wave channeling. We demonstrate the frequency selective collimation of spin-wave in an array of magnonic waveguides, formed between the adjacent magnonic crystals on the surface of yttrium iron garnet film. We show the control over spin-wave propagation length by the orientation of an in-plane bias magnetic field. Fabricated array of magnonic crystal can be used as a magnonic platform for multidirectional frequency selective signal processing applications in magnonic networks.

  13. Principles of selective ion transport in channels and pumps.

    PubMed

    Gouaux, Eric; Mackinnon, Roderick

    2005-12-01

    The transport of ions across the membranes of cells and organelles is a prerequisite for many of life's processes. Transport often involves very precise selectivity for specific ions. Recently, atomic-resolution structures have been determined for channels or pumps that are selective for sodium, potassium, calcium, and chloride: four of the most abundant ions in biology. From these structures we can begin to understand the principles of selective ion transport in terms of the architecture and detailed chemistry of the ion conduction pathways. PMID:16322449

  14. Canonical analysis for increased classification speed and channel selection

    NASA Technical Reports Server (NTRS)

    Eppler, W.

    1976-01-01

    The quadratic form can be expressed as a monotonically increasing sum of squares when the inverse covariance matrix is represented in canonical form. This formulation has the advantage that, in testing a particular class hypothesis, computations can be discontinued when the partial sum exceeds the smallest value obtained for other classes already tested. A method for channel selection is presented which arranges the original input measurements in that order which minimizes the expected number of computations. The classification algorithm was tested on data from LARS Flight Line C1 and found to reduce the sum-of-products operations by a factor of 6.7 in comparison with the conventional approach. In effect, the accuracy of a twelve-channel classification was achieved using only that CPU time required for a conventional four-channel classification.

  15. 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

  16. 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.

  17. Lipoamide channel-binding sulfonamides selectively inhibit mycobacterial lipoamide dehydrogenase†,#

    PubMed Central

    Bryk, Ruslana; Arango, Nancy; Maksymiuk, Christina; Balakrishnan, Anand; Wu, Ying-Ta; Wong, Chi-Huey; Masquelin, Thierry; Hipskind, Philip; Lima, Christopher D.; Nathan, Carl

    2014-01-01

    Tuberculosis remains a global health emergency that calls for treatment regimens directed at new targets. Here we explored lipoamide dehydrogenase, a metabolic and detoxifying enzyme in Mycobacterium tuberculosis whose deletion drastically impairs Mtb's ability to establish infection in the mouse. Upon screening over 1,600,000 compounds, we identified N-methylpyridine 3-sulfonamides as potent and species-selective inhibitors of Mtb Lpd, affording over 1,000-fold selectivity versus the human homolog. The sulfonamides demonstrated low nanomolar affinity and bound at the lipoamide channel in an Lpd-inhibitor co-crystal. Their selectivity could be attributed, at least partially, to hydrogen bonding of the sulfonamide amide oxygen with the species-variant Arg93 in the lipoamide channel. Although potent and selective, the sulfonamides did not enter mycobacteria, as determined by their inability to accumulate in Mtb to effective levels and produce changes in intracellular metabolites. This work demonstrates that high potency and selectivity can be achieved at the lipoamide binding site of Mtb Lpd, a site different from the NAD+/NADH pocket targeted by previously reported species-selective triazaspirodimethoxybenzoyl inhibitors. PMID:24251446

  18. Production of Stable Isotopes by Selective Channel Photofission of Pd

    NASA Astrophysics Data System (ADS)

    Takahashi, Akito; Ohta, Masayuki; Mizuno, Tadahiko

    2001-12-01

    A conservative modeling and analysis were attempted to explain the presence of nonradioactive fission-like products with nonnatural isotopic ratios observed in some D2O/Pd electrolysis experiments. The collective deformation of a Pd nucleus by multiphoton E1 resonance absorption in a dynamic PdDx lattice was assumed to induce low-energy photofissions via the selective scission channels within the lowest band (11-20 MeV) of channel-dependent fission barriers. Values of channel dependent fission barriers were calculated by using liquid drop model potentials for Pd isotopes. Fission products were analyzed in detail. Major fission products (FPs) are stable isotopes and the isotopic ratios of FP elements are very different from those of natural abundances. The present theoretical results have shown good agreement with the experimental data of Mizuno ηl. [Denki Kagaku 64 (1996) 1660] and others in terms of Z-distribution, mass distribution and isotopic ratios. Selective channel photofissions with positive Q-values are possible for A>90 nuclei, which may provide us with a clean method for the incineration for the radio isotope (RI) waste of nuclear plants.

  19. Synthesis of the doubly magic deformed nucleus 108270Hs162 in the decay of 274Hs* formed via hot fusion reactions: Entrance-channel effects and role of magicity of 48Ca and 270Hs

    NASA Astrophysics Data System (ADS)

    Niyti, Gupta, Raj K.

    2014-01-01

    Quantum mechanical fragmentation theory (QMFT) is used to look for all possible target-projectile (t,p) combinations forming the "cold" compound nucleus (CN) 274Hs* at the CN excitation energy E* of "hot, compact" configuration. The predicted reactions, referring to potential energy minima, include all the three reactions 248Cm + 26Mg, 238U + 36S, and 226Ra + 48Ca already used in experiments, and a few more. The optimum "cold" and "compact" (t,p) combination, corresponding to lowest interaction barrier and smallest interaction radius, is one with largest mass asymmetry, but because of the doubly magic 48Ca nucleus, the evaporation residue cross sections for the 226Ra + 48Ca reaction are shown to be further enhanced. For the decay of CN 274Hs*, synthesizing 269-271Hs via 3n-5n emission, we use the dynamical cluster-decay model (DCM) with effects of quadrupole deformations and "hot" compact orientations included in it, which support symmetric fission, in agreement with experiments. The fusion evaporation residue cross sections σxn, for x =3, 4, and 5 neutrons emission from the above-mentioned three entrance channels, are calculated within one parameter fitting, namely, the neck length. For best fitted neck-length parameter, the roles of entrance channel and that of magic shells are analyzed. In spite of different entrance channels resulting in different evaporation residue cross sections, the neck-length parameter at a given E* is shown to be independent of the entrance channel. The role of magic shells is shown in enhancing evaporation residue cross sections, not only for the entrance channel 226Ra + 48Ca, but also for the residue 270Hs, compared to its neighboring isotopes 269,271Hs. The fusion evaporation residue cross sections for the proposed new reactions, in synthesizing CN 274Hs*, are also estimated for future new experiments.

  20. Deciphering Subtype-Selective Modulations in TRPA1 Biosensor Channels

    PubMed Central

    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. PMID:26411770

  1. Doubly robust survival trees.

    PubMed

    Steingrimsson, Jon Arni; Diao, Liqun; Molinaro, Annette M; Strawderman, Robert L

    2016-09-10

    Estimating a patient's mortality risk is important in making treatment decisions. Survival trees are a useful tool and employ recursive partitioning to separate patients into different risk groups. Existing 'loss based' recursive partitioning procedures that would be used in the absence of censoring have previously been extended to the setting of right censored outcomes using inverse probability censoring weighted estimators of loss functions. In this paper, we propose new 'doubly robust' extensions of these loss estimators motivated by semiparametric efficiency theory for missing data that better utilize available data. Simulations and a data analysis demonstrate strong performance of the doubly robust survival trees compared with previously used methods. Copyright © 2016 John Wiley & Sons, Ltd. PMID:27037609

  2. Selection of optimal muscle set for 16-channel standing neuroprosthesis

    PubMed Central

    Gartman, Steven J.; Audu, Musa L.; Kirsch, Robert F.; Triolo, Ronald J.

    2009-01-01

    The Case Western Reserve University/Department of Veterans Affairs 8-channel lower-limb neuroprosthesis can restore standing to selected individuals with paraplegia by application of functional electrical stimulation. The second generation of this system will include 16 channels of stimulation and a closed-loop control scheme to provide automatic postural corrections. This study used a musculoskeletal model of the legs and trunk to determine which muscles to target with the new system in order to maximize the range of postures that can be statically maintained, which should increase the system’s ability to provide adequate support to maintain standing when the user’s posture moves away from a neutral stance, either by an external disturbance or a volitional change in posture by the user. The results show that the prime muscle targets should be the medial gastrocnemius, tibialis anterior, vastus lateralis, semimembranosus, gluteus maximus, gluteus medius, adductor magnus, and erector spinae. This set of 16 muscles supports 42 percent of the standing postures that are attainable by the nondisabled model. Coactivation of the lateral gastrocnemius and peroneus longus with the medial gastrocnemius and of the peroneus tertius with the tibialis anterior increased the percentage of feasible postures to 71 percent. PMID:16847793

  3. 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.

  4. 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.

  5. Altered and dynamic ion selectivity of K+ channels in cell development and excitability

    PubMed Central

    Chen, Haijun; Chatelain, Franck C.; Lesage, Florian

    2015-01-01

    K+ channels play a key role in regulating cellular excitability. It was thought that the strong K+-selectivity of these channels was static, only altered by mutations in their selectivity filter, which can cause severe genetic disorders. Recent studies demonstrate that selectivity of K+ channels can also exhibit dynamic changes. Under acidic conditions or in low extracellular K+ concentrations, the two-pore domain K+ channel (K2P) TWIK1 becomes permeable to Na+, shifting from an inhibitory role to an excitatory role. This phenomenon is responsible for the paradoxical depolarization of human cardiomyocytes in pathological hypokalemia, and therefore may contribute to cardiac arrhythmias. In other cell types, TWIK1 produces depolarizing leak currents under physiological conditions. Dynamic ion selectivity also occurs in other K2P channels. Here we review evidence that dynamic selectivity of K2P channels constitutes a new regulatory mechanism of cellular excitability, whose significance is only now becoming appreciated. PMID:25023607

  6. 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

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

    PubMed

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

    2000-06-01

    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

  8. 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.

  9. 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.

  10. Non-equilibrium dynamics contribute to ion selectivity in the KcsA channel.

    PubMed

    Ngo, Van; Stefanovski, Darko; 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

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

    PubMed Central

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

    2015-01-01

    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. PMID:26598654

  12. Electrostatic Tuning of Permeation and Selectivity in Aquaporin Water Channels

    PubMed Central

    Jensen, Morten Ø.; Tajkhorshid, Emad; Schulten, Klaus

    2003-01-01

    Water permeation and electrostatic interactions between water and channel are investigated in the Escherichia coli glycerol uptake facilitator GlpF, a member of the aquaporin water channel family, by molecular dynamics simulations. A tetrameric model of the channel embedded in a 16:0/18:1c9-palmitoyloleylphosphatidylethanolamine membrane was used for the simulations. During the simulations, water molecules pass through the channel in single file. The movement of the single file water molecules through the channel is concerted, and we show that it can be described by a continuous-time random-walk model. The integrity of the single file remains intact during the permeation, indicating that a disrupted water chain is unlikely to be the mechanism of proton exclusion in aquaporins. Specific hydrogen bonds between permeating water and protein at the channel center (at two conserved Asp-Pro-Ala “NPA” motifs), together with the protein electrostatic fields enforce a bipolar water configuration inside the channel with dipole inversion at the NPA motifs. At the NPA motifs water-protein electrostatic interactions facilitate this inversion. Furthermore, water-water electrostatic interactions are in all regions inside the channel stronger than water-protein interactions, except near a conserved, positively charged Arg residue. We find that variations of the protein electrostatic field through the channel, owing to preserved structural features, completely explain the bipolar orientation of water. This orientation persists despite water translocation in single file and blocks proton transport. Furthermore, we find that for permeation of a cation, ion-protein electrostatic interactions are more unfavorable at the conserved NPA motifs than at the conserved Arg, suggesting that the major barrier against proton transport in aquaporins is faced at the NPA motifs. PMID:14581193

  13. Electrostatic tuning of permeation and selectivity in aquaporin water channels.

    PubMed

    Jensen, Morten Ø; Tajkhorshid, Emad; Schulten, Klaus

    2003-11-01

    Water permeation and electrostatic interactions between water and channel are investigated in the Escherichia coli glycerol uptake facilitator GlpF, a member of the aquaporin water channel family, by molecular dynamics simulations. A tetrameric model of the channel embedded in a 16:0/18:1c9-palmitoyloleylphosphatidylethanolamine membrane was used for the simulations. During the simulations, water molecules pass through the channel in single file. The movement of the single file water molecules through the channel is concerted, and we show that it can be described by a continuous-time random-walk model. The integrity of the single file remains intact during the permeation, indicating that a disrupted water chain is unlikely to be the mechanism of proton exclusion in aquaporins. Specific hydrogen bonds between permeating water and protein at the channel center (at two conserved Asp-Pro-Ala "NPA" motifs), together with the protein electrostatic fields enforce a bipolar water configuration inside the channel with dipole inversion at the NPA motifs. At the NPA motifs water-protein electrostatic interactions facilitate this inversion. Furthermore, water-water electrostatic interactions are in all regions inside the channel stronger than water-protein interactions, except near a conserved, positively charged Arg residue. We find that variations of the protein electrostatic field through the channel, owing to preserved structural features, completely explain the bipolar orientation of water. This orientation persists despite water translocation in single file and blocks proton transport. Furthermore, we find that for permeation of a cation, ion-protein electrostatic interactions are more unfavorable at the conserved NPA motifs than at the conserved Arg, suggesting that the major barrier against proton transport in aquaporins is faced at the NPA motifs. PMID:14581193

  14. 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.

  15. Unexpected doubly-magic nucleus.

    SciTech Connect

    Janssens, R. V. F.; Physics

    2009-01-01

    Nuclei with a 'magic' number of both protons and neutrons, dubbed doubly magic, are particularly stable. The oxygen isotope {sup 24}O has been found to be one such nucleus - yet it lies just at the limit of stability.

  16. 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.

  17. 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.

  18. A Portable MIMO Testbed and Selected Channel Measurements

    NASA Astrophysics Data System (ADS)

    Goud, Paul, Jr.; Hang, Robert; Truhachev, Dmitri; Schlegel, Christian

    2006-12-01

    A portable[InlineEquation not available: see fulltext.] multiple-input multiple-output (MIMO) testbed that is based on field programmable gate arrays (FPGAs) and which operates in the 902-928 MHz industrial, scientific, and medical (ISM) band has been developed by the High Capacity Digital Communications (HCDC) Laboratory at the University of Alberta. We present a description of the HCDC testbed along with MIMO channel capacities that were derived from measurements taken with the HCDC testbed for three special locations: a narrow corridor, an athletics field that is surrounded by a metal fence, and a parkade. These locations are special because the channel capacities are different from what is expected for a typical indoor or outdoor channel. For two of the cases, a ray-tracing analysis has been performed and the simulated channel capacity values closely match the values calculated from the measured data. A ray-tracing analysis, however, requires accurate geometrical measurements and sophisticated modeling for each specific location. A MIMO testbed is ideal for quickly obtaining accurate channel capacity information.

  19. Cation Selectivity in Biological Cation Channels Using Experimental Structural Information and Statistical Mechanical Simulation.

    PubMed

    Finnerty, Justin John; Peyser, Alexander; Carloni, Paolo

    2015-01-01

    Cation selective channels constitute the gate for ion currents through the cell membrane. Here we present an improved statistical mechanical model based on atomistic structural information, cation hydration state and without tuned parameters that reproduces the selectivity of biological Na+ and Ca2+ ion channels. The importance of the inclusion of step-wise cation hydration in these results confirms the essential role partial dehydration plays in the bacterial Na+ channels. The model, proven reliable against experimental data, could be straightforwardly used for designing Na+ and Ca2+ selective nanopores. PMID:26460827

  20. Cation Selectivity in Biological Cation Channels Using Experimental Structural Information and Statistical Mechanical Simulation

    PubMed Central

    Finnerty, Justin John

    2015-01-01

    Cation selective channels constitute the gate for ion currents through the cell membrane. Here we present an improved statistical mechanical model based on atomistic structural information, cation hydration state and without tuned parameters that reproduces the selectivity of biological Na+ and Ca2+ ion channels. The importance of the inclusion of step-wise cation hydration in these results confirms the essential role partial dehydration plays in the bacterial Na+ channels. The model, proven reliable against experimental data, could be straightforwardly used for designing Na+ and Ca2+ selective nanopores. PMID:26460827

  1. Toxicity of Selected Mosquito Sprays to Channel Catfish Sac Fry

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In the spring when channel catfish, Ictalurus punctatus, hatcheries are in full operation, the associated moisture and warm temperatures provide a haven for mosquitoes. Large swarms of biting mosquitoes in a hatchery can make the tedious work of egg-picking (i.e., removing dead and fungus-infested e...

  2. Spatial localization of the K+ channel selectivity filter by mutant cycle-based structure analysis.

    PubMed

    Ranganathan, R; Lewis, J H; MacKinnon, R

    1996-01-01

    The structurally well-characterized scorpion toxin Agitoxin2 inhibits ion permeation through Shaker K+ channels by binding to the external pore entryway. Scanning mutagenesis identified a set of inhibitor residues critical for making energetic contacts with the channel. Using thermodynamic mutant cycle analysis, we have mapped channel residues relative to the known inhibitor structure. This study constrains the position of multiple channel residues within the pore-forming loops; in one stretch, we have been able to map five out of seven contiguous residues to the inhibitor interaction surface, including those involved in ion selectivity. One interaction in particular, that of K27M on the inhibitor with Y445F on the channel, is unique in that it depends on the K+ ion concentration. These results reveal a shallow vestibule formed by the pore loops at the K+ channel entryway. The selectivity filter is located at the center of the vestibule close to (approximately 5 A) the extracellular solution. PMID:8562077

  3. Comparison of Growth, Body Composition, and Stress Response of Three Select Lines and Industry Channel Catfish

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Improvement in growth and resistance to stress has been identified as traits of interest for genetic improvement. Channel catfish selected solely for fast growth (fast growing) were compared to USDA103, USDA403, and industry pool groups of channel catfish for growth, body composition, and stress re...

  4. 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.

  5. Role of protein dynamics in ion selectivity and allosteric coupling in the NaK channel

    PubMed Central

    Brettmann, Joshua B.; Urusova, Darya; Tonelli, Marco; Silva, Jonathan R.; Henzler-Wildman, Katherine A.

    2015-01-01

    Flux-dependent inactivation that arises from functional coupling between the inner gate and the selectivity filter is widespread in ion channels. The structural basis of this coupling has only been well characterized in KcsA. Here we present NMR data demonstrating structural and dynamic coupling between the selectivity filter and intracellular constriction point in the bacterial nonselective cation channel, NaK. This transmembrane allosteric communication must be structurally different from KcsA because the NaK selectivity filter does not collapse under low-cation conditions. Comparison of NMR spectra of the nonselective NaK and potassium-selective NaK2K indicates that the number of ion binding sites in the selectivity filter shifts the equilibrium distribution of structural states throughout the channel. This finding was unexpected given the nearly identical crystal structure of NaK and NaK2K outside the immediate vicinity of the selectivity filter. Our results highlight the tight structural and dynamic coupling between the selectivity filter and the channel scaffold, which has significant implications for channel function. NaK offers a distinct model to study the physiologically essential connection between ion conduction and channel gating. PMID:26621745

  6. 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...

  7. 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

  8. 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.

  9. 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

    2016-04-01

    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.

  10. Voltage-Gated Potassium Channels: A Structural Examination of Selectivity and Gating.

    PubMed

    Kim, Dorothy M; Nimigean, Crina M

    2016-01-01

    Voltage-gated potassium channels play a fundamental role in the generation and propagation of the action potential. The discovery of these channels began with predictions made by early pioneers, and has culminated in their extensive functional and structural characterization by electrophysiological, spectroscopic, and crystallographic studies. With the aid of a variety of crystal structures of these channels, a highly detailed picture emerges of how the voltage-sensing domain reports changes in the membrane electric field and couples this to conformational changes in the activation gate. In addition, high-resolution structural and functional studies of K(+) channel pores, such as KcsA and MthK, offer a comprehensive picture on how selectivity is achieved in K(+) channels. Here, we illustrate the remarkable features of voltage-gated potassium channels and explain the mechanisms used by these machines with experimental data. PMID:27141052

  11. 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

  12. 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.

  13. M2 pore mutations convert the glycine receptor channel from being anion- to cation-selective.

    PubMed Central

    Keramidas, A; Moorhouse, A J; French, C R; Schofield, P R; Barry, P H

    2000-01-01

    Three mutations in the M2 transmembrane domains of the chloride-conducting alpha1 homomeric glycine receptor (P250Delta, A251E, and T265V), which normally mediate fast inhibitory neurotransmission, produced a cation-selective channel with P(Cl)/P(Na), = 0.27 (wild-type P(Cl)/P(Na) = 25), a permeability sequence P(Cs) > P(K) > P(Na) > P(Li), an impermeability to Ca(2+), and a reduced glycine sensitivity. Outside-out patch measurements indicated reversed and accentuated rectification with extremely low mean single channel conductances of 3 pS (inward current) and 11 pS (outward current). The three inverse mutations, to those analyzed in this study, have previously been shown to make the alpha7 acetylcholine receptor channel anion-selective, indicating a common location for determinants of charge selectivity of inhibitory and excitatory ligand-gated ion channels. PMID:10866951

  14. Simulation Studies of Ion Permeation and Selectivity in Voltage-Gated Sodium Channels.

    PubMed

    Ing, C; Pomès, R

    2016-01-01

    Voltage-gated ion channels are responsible for the generation and propagation of action potentials in electrically excitable cells. Molecular dynamics simulations have become a useful tool to study the molecular basis of ion transport in atomistic models of voltage-gated ion channels. The elucidation of several three-dimensional structures of bacterial voltage-gated sodium channels (Nav) in 2011 and 2012 opened the way to detailed computational investigations of this important class of membrane proteins. Here we review the numerous simulation studies of Na(+) permeation and selectivity in bacterial Nav channels published in the past 5years. These studies use a variety of simulation methodologies differing in force field parameters, molecular models, sampling algorithms, and simulation times. Although results disagree on the details of ion permeation mechanisms, they concur in the presence of two primary Na(+) binding sites in the selectivity filter and support a loosely coupled knock-on mechanism of Na(+) permeation. Comparative studies of Na(+), K(+), and Ca(2+) permeation reveal sites within Nav channels that are Na(+) selective, yet a consensus model of selectivity has not been established. We discuss the agreement between simulation and experimental results and propose strategies that may be used to resolve discrepancies between simulation studies in order to improve future computational studies of permeation and selectivity in ion channels. PMID:27586286

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

    PubMed

    Li, Yang; Liu, Huihui; Xia, Mengdie; Gong, Haipeng

    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

  16. Selection of sounding channels for the High Resolution Dynamics Limb Sounder

    NASA Astrophysics Data System (ADS)

    Barnett, John J.; Edwards, David P.; Gille, John C.; Bailey, Paul L.

    1995-10-01

    We describe the scientific design work behind the selection of the IR spectral passbands for the 21 sounding channels of the High Resolution Dynamics Limb Sounder (HIRDLS), which is scheduled to fly aboard the Earth Observing System chemistry platform at the beginning of the next century. At least one radiometer channel must be used for each gas that is being measured. Preferably the interfering contributions to the radiance by other gases in a channel should be small, but the principal requirements are that the desired emission be measured with high signal-to-noise ratio and that there be separate channels for the measurement of interfering species. However, more than one channel is required for providing full altitude coverage of those target gases such as CO2, H2O, and O3, which have emission bands whose centers become optically thick in the middle atmosphere. Further channels, in which gaseous absorption is low, are required for the characterization of aerosol effects. We describe the HIRDLS channels selected for each gas, with emphasis on signal-to-noise considerations and altitude coverage, the elimination of contaminating signal between channels, and nonlocal thermodynamic equilibrium processes for high-altitude sounding and space view definition.

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

    PubMed

    Schwent, V L; Hillyard, S A

    1975-02-01

    Ten subjects were presented with a random sequence of 50 msec tone pips at a rapid rate (averaging one tone every 225 msec). The tones came from four different sound sources or sensory "channels" each having a different pitch (2000,4000,1000, and 500 c/sec respectively) and perceived spatial position (spaced equidistant across the head). Within each sensory "channel" a random 10% of the tones were of a slightly higher pitch (designated as "targets"). The subject attended to one channel at a time for 7.5 min and counted the targets in that channel. The auditory evoked vertex potential elicited by a channel of stimuli when attended was compared with the mean vertex potential elicited by those same stimuli when the other three channels were being attended. The N1 component (latency 80130 msec) measured re a baseline revealed an increase with attention (82% in the baselineN1 measure, P less than 10-). It was concluded that: (1) this N1 enhancement could not be attributed to peripheral mechanisms acting on sensory transmission; (2) this N1 enhancement reflects a "finely tuned" selective attention to one channel of stimuli among several concurrent and competing channels; and (3) a probable relationship exists between the information load on the subject and the magnitude of this EP enhancement with selective attention. PMID:45943

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

    PubMed Central

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

    2016-01-01

    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. PMID:26861347

  19. 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

    2016-01-01

    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. PMID:26861347

  20. Ion selectivity of the anthrax toxin channel and its effect on protein translocation

    PubMed Central

    Anderson, Damon; Finkelstein, Alan

    2015-01-01

    Anthrax toxin consists of three ∼85-kD proteins: lethal factor (LF), edema factor (EF), and protective antigen (PA). PA63 (the 63-kD, C-terminal portion of PA) forms heptameric channels ((PA63)7) in planar phospholipid bilayer membranes that enable the translocation of LF and EF across the membrane. These mushroom-shaped channels consist of a globular cap domain and a 14-stranded β-barrel stem domain, with six anionic residues lining the interior of the stem to form rings of negative charges. (PA63)7 channels are highly cation selective, and, here, we investigate the effects on both cation selectivity and protein translocation of mutating each of these anionic residues to a serine. We find that although some of these mutations reduce cation selectivity, selectivity alone does not directly predict the rate of protein translocation; local changes in electrostatic forces must be considered as well. PMID:26170174

  1. 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.

  2. 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.

  3. Discovery of novel tetrahydroisoquinoline derivatives as orally active N-type calcium channel blockers with high selectivity for hERG potassium channels.

    PubMed

    Ogiyama, Takashi; Inoue, Makoto; Honda, Shugo; Yamada, Hiroyoshi; Watanabe, Toshihiro; Gotoh, Takayasu; Kiso, Tetsuo; Koakutsu, Akiko; Kakimoto, Shuichiro; Shishikura, Jun-ichi

    2014-12-15

    N-type calcium channels represent a promising target for the treatment of neuropathic pain. The selective N-type calcium channel blocker ziconotide ameliorates severe chronic pain but has a narrow therapeutic window and requires intrathecal administration. We identified tetrahydroisoquinoline derivative 1a as a novel potent N-type calcium channel blocker. However, this compound also exhibited potent inhibitory activity against hERG channels. Structural optimizations led to identification of (1S)-(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-{[(1-hydroxycyclohexyl)methyl]amino}ethanone ((S)-1h), which exhibited high selectivity for hERG channels while retaining potency for N-type calcium channel inhibition. (S)-1h went on to demonstrate in vivo efficacy as an orally available N-type calcium channel blocker in a rat spinal nerve ligation model of neuropathic pain. PMID:25456079

  4. Sodium channel selectivity and conduction: Prokaryotes have devised their own molecular strategy

    PubMed Central

    Finol-Urdaneta, Rocio K.; Wang, Yibo; Al-Sabi, Ahmed; Zhao, Chunfeng

    2014-01-01

    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

  5. 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.

  6. 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. PMID:27197631

  7. 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.

  8. 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. PMID:21263644

  9. Structural and Thermodynamic Properties of Selective Ion Binding in a K+ Channel

    SciTech Connect

    Lockless,S.; Zhou, M.; MacKinnon, R.

    2007-01-01

    Thermodynamic measurements of ion binding to the Streptomyces lividans K+ channel were carried out using isothermal titration calorimetry, whereas atomic structures of ion-bound and ion-free conformations of the channel were characterized by x-ray crystallography. Here we use these assays to show that the ion radius dependence of selectivity stems from the channel's recognition of ion size (i.e., volume) rather than charge density. Ion size recognition is a function of the channel's ability to adopt a very specific conductive structure with larger ions (K+, Rb+, Cs+, and Ba2+) bound and not with smaller ions (Na+, Mg2+, and Ca2+). The formation of the conductive structure involves selectivity filter atoms that are in direct contact with bound ions as well as protein atoms surrounding the selectivity filter up to a distance of 15 Angstroms from the ions. We conclude that ion selectivity in a K+ channel is a property of size-matched ion binding sites created by the protein structure.

  10. Structural and Thermodynamic Properties of Selective Ion Binding in a K+ Channel

    PubMed Central

    Lockless, Steve W; Zhou, Ming; MacKinnon, Roderick

    2007-01-01

    Thermodynamic measurements of ion binding to the Streptomyces lividans K+ channel were carried out using isothermal titration calorimetry, whereas atomic structures of ion-bound and ion-free conformations of the channel were characterized by x-ray crystallography. Here we use these assays to show that the ion radius dependence of selectivity stems from the channel's recognition of ion size (i.e., volume) rather than charge density. Ion size recognition is a function of the channel's ability to adopt a very specific conductive structure with larger ions (K+, Rb+, Cs+, and Ba2+) bound and not with smaller ions (Na+, Mg2+, and Ca2+). The formation of the conductive structure involves selectivity filter atoms that are in direct contact with bound ions as well as protein atoms surrounding the selectivity filter up to a distance of 15 Å from the ions. We conclude that ion selectivity in a K+ channel is a property of size-matched ion binding sites created by the protein structure. PMID:17472437

  11. Low-Complexity User Selection for Rate Maximization in MIMO Broadcast Channels with Downlink Beamforming

    PubMed Central

    Silva, Adão; Gameiro, Atílio

    2014-01-01

    We present in this work a low-complexity algorithm to solve the sum rate maximization problem in multiuser MIMO broadcast channels with downlink beamforming. Our approach decouples the user selection problem from the resource allocation problem and its main goal is to create a set of quasiorthogonal users. The proposed algorithm exploits physical metrics of the wireless channels that can be easily computed in such a way that a null space projection power can be approximated efficiently. Based on the derived metrics we present a mathematical model that describes the dynamics of the user selection process which renders the user selection problem into an integer linear program. Numerical results show that our approach is highly efficient to form groups of quasiorthogonal users when compared to previously proposed algorithms in the literature. Our user selection algorithm achieves a large portion of the optimum user selection sum rate (90%) for a moderate number of active users. PMID:24574928

  12. Stereodivergent catalytic doubly diastereoselective nitroaldol reactions using heterobimetallic complexes.

    PubMed

    Sohtome, Yoshihiro; Kato, Yuko; Handa, Shinya; Aoyama, Naohiro; Nagawa, Keita; Matsunaga, Shigeki; Shibasaki, Masakatsu

    2008-06-01

    Stereodivergent construction of three contiguous stereocenters in catalytic doubly diastereoselective nitroaldol reactions of alpha-chiral aldehydes with nitroacetaldehyde dimethyl acetal using two types of heterobimetallic catalysts is described. A La-Li-BINOL (LLB) catalyst afforded anti,syn-nitroaldol products in >20:1-14:1 selectivity, and a Pd/La/Schiff base catalyst afforded complimentary syn,syn-nitroaldol products in 10:1-5:1 selectivity. PMID:18465868

  13. Reduced Complexity in Antenna Selection for Polarized MIMO System with SVD for the Practical MIMO Communication Channel Environment

    NASA Astrophysics Data System (ADS)

    Sann Maw, Maung; Sasase, Iwao

    In the conventional multi-input multi-output (MIMO) communication systems, most of the antenna selection methods considered are suitable only for spatially separated uni-polarized system under Rayleigh fading channel in non-line of sight (NLOS) condition. There have a few antenna selection schemes for the cross-polarized system in LOS condition and Ricean fading channel, and no antenna selection scheme for the MIMO channel with both LOS and NLOS. In the practical MIMO channel case, influence of LOS and NLOS conditions in the channel can vary from time to time according to the channel parameters and user movement in the system. Based on these influences and channel condition, uni-polarized system may outperform a cross-polarized. Thus, we should consider this kind of practical MIMO channel environment when developing the antenna selection scheme. Moreover, no research work has been done on reducing the complexity of antenna selection for this kind of practical MIMO channel environment. In this paper, reduced complexity in antenna selection is proposed to give the higher throughput in the practical MIMO channel environment. In the proposed scheme, suitable polarized antennas are selected based on the calculation of singular value decomposition (SVD) of channel matrix and then adaptive bit loading is applied. Simulation results show that throughput of the system can be improved under the constraint of target BER and total transmit power of the MIMO system.

  14. 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). PMID:25882406

  15. K+-Dependent Selectivity and External Ca2+ Block of Shab K+ Channels

    PubMed Central

    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, Nao/Ki or Nao/Rbi, conditions. However, when internal K+ is replaced by Cs+ (Nao/Csi), 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. PMID:25798591

  16. A channel-selection criterion for suppressing reverberation in cochlear implants.

    PubMed

    Kokkinakis, Kostas; Hazrati, Oldooz; Loizou, Philipos C

    2011-05-01

    Little is known about the extent to which reverberation affects speech intelligibility by cochlear implant (CI) listeners. Experiment 1 assessed CI users' performance using Institute of Electrical and Electronics Engineers (IEEE) sentences corrupted with varying degrees of reverberation. Reverberation times of 0.30, 0.60, 0.80, and 1.0 s were used. Results indicated that for all subjects tested, speech intelligibility decreased exponentially with an increase in reverberation time. A decaying-exponential model provided an excellent fit to the data. Experiment 2 evaluated (offline) a speech coding strategy for reverberation suppression using a channel-selection criterion based on the signal-to-reverberant ratio (SRR) of individual frequency channels. The SRR reflects implicitly the ratio of the energies of the signal originating from the early (and direct) reflections and the signal originating from the late reflections. Channels with SRR larger than a preset threshold were selected, while channels with SRR smaller than the threshold were zeroed out. Results in a highly reverberant scenario indicated that the proposed strategy led to substantial gains (over 60 percentage points) in speech intelligibility over the subjects' daily strategy. Further analysis indicated that the proposed channel-selection criterion reduces the temporal envelope smearing effects introduced by reverberation and also diminishes the self-masking effects responsible for flattened formants. PMID:21568424

  17. 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.

  18. Nanoscale ion sequestration to determine the polarity selectivity of ion conductance in carriers and channels.

    PubMed

    Cranfield, Charles G; Bettler, Taren; Cornell, Bruce

    2015-01-01

    The nanoscale spacing between a tethered lipid bilayer membrane (tBLM) and its supporting gold electrode can be utilized to determine the polarity selectivity of the conduction of ion channels and ion carriers embedded in a membrane. The technique relies upon a bias voltage sequestering or eliminating ions, of a particular polarity, into or out of the aqueous electrolyte region between the gold electrode and the tethered membrane. A demonstration is given, using ac swept frequency impedance spectrometry, of the bias polarity dependence of the ionophore conductance of gramicidin A, a cationic selective channel, and valinomycin, a potassium ion selective carrier. We further use pulsed amperometry to show that the intrinsic voltage dependence of the ion conduction is actually selective of the polarity of the transported ion and not simply of the direction of the ionic current flow. PMID:25474616

  19. Zn(2+) modulation of neuronal transient K(+) current: fast and selective binding to the deactivated channels

    PubMed Central

    Kuo, CC; Chen, FP

    1999-01-01

    Modulation of voltage-dependent transient K(+) currents (A type K(+) or K(A) current) by Zn(2+) was studied in rat hippocampal neurons by the whole-cell patch-clamp technique. It is found that Zn(2+) selectively binds to the resting (deactivated or closed) K(A) channels with a dissociation constant (K(d)) of approximately 3 &mgr;M, whereas the affinity between Zn(2+) and the inactivated K(A) channels is 1000-fold lower. Zn(2+) therefore produces a concentration-dependent shift of the K(A) channel inactivation curve and enhances the K(A) current elicited from relatively positive holding potentials. It is also found that the kinetics of Zn(2+) action are fast enough to compete with the transition rates between different gating states of the channel. The rapid and selective binding of Zn(2+) to the closed K(A) channels keeps the channel in the closed state and explains the ion's concentration-dependent slowing effect on the activation of K(A) current. This in turn accounts for the inhibitory effect of Zn(2+) on the K(A) current elicited from hyperpolarized holding potentials. Because the molecular mechanisms underlying these gating changes are kinetic interactions between the binding-unbinding of Zn(2+) and the intrinsic gating processes of the channel, the shift of the inactivation curve and slowing of K(A) channel activation are quantitatively correlated with ambient Zn(2+) over a wide concentration range without "saturation"; i.e., The effects are already manifest in micromolar Zn(2+), yet are not saturated even in millimolar Zn(2+). Because the physiological concentration of Zn(2+) could vary over a similarly wide range according to neural activities, Zn(2+) may be a faithful physiological "fine tuner," controlling and controlled by neural activities through its effect on the K(A) current. PMID:10545356

  20. Selecting Ions by Size in a Calcium Channel: The Ryanodine Receptor Case Study

    PubMed Central

    Gillespie, Dirk; Xu, Le; Meissner, Gerhard

    2014-01-01

    Many calcium channels can distinguish between ions of the same charge but different size. For example, when cations are in direct competition with each other, the ryanodine receptor (RyR) calcium channel preferentially conducts smaller cations such as Li+ and Na+ over larger ones such as K+ and Cs+. Here, we analyze the physical basis for this preference using a previously established model of RyR permeation and selectivity. Like other calcium channels, RyR has four aspartate residues in its GGGIGDE selectivity filter. These aspartates have their terminal carboxyl group in the pore lumen, which take up much of the available space for permeating ions. We find that small ions are preferred by RyR because they can fit into this crowded environment more easily. PMID:25418295

  1. Electrostatics of aquaporin and aquaglyceroporin channels correlates with their transport selectivity

    PubMed Central

    Oliva, Romina; Calamita, Giuseppe; Thornton, Janet M.; Pellegrini-Calace, Marialuisa

    2010-01-01

    Aquaporins are homotetrameric channel proteins, which allow the diffusion of water and small solutes across biological membranes. According to their transport function, aquaporins can be divided into “orthodox aquaporins”, which allow the flux of water molecules only, and “aquaglyceroporins”, which facilitate the diffusion of glycerol and other small solutes in addition to water. The contribution of individual residues in the pore to the selectivity of orthodox aquaporins and aquaglyceroporins is not yet fully understood. To gain insights into aquaporin selectivity, we focused on the sequence variation and electrostatics of their channels. The continuum Poisson-Boltzmann electrostatic potential along the channel was calculated and compared for ten three-dimensional-structures which are representatives of different aquaporin subfamilies, and a panel of functionally characterized mutants, for which high-accuracy three-dimensional-models could be derived. Interestingly, specific electrostatic profiles associated with the main selectivity to water or glycerol could be identified. In particular: (i) orthodox aquaporins showed a distinctive electrostatic potential maximum at the periplasmic side of the channel around the aromatic/Arg (ar/R) constriction site; (ii) aquaporin-0 (AQP0), a mammalian aquaporin with considerably low water permeability, had an additional deep minimum at the cytoplasmic side; (iii) aquaglyceroporins showed a rather flat potential all along the channel; and (iv) the bifunctional protozoan PfAQP had an unusual all negative profile. Evaluation of electrostatics of the mutants, along with a thorough sequence analysis of the aquaporin pore-lining residues, illuminated the contribution of specific residues to the electrostatics of the channels and possibly to their selectivity. PMID:20147624

  2. 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.

  3. Selectivity in K+ channels is due to topological control of the permeant ion's coordinated state.

    PubMed

    Bostick, David L; Brooks, Charles L

    2007-05-29

    The selectivity filter of K+ channels provides specific coordinative interactions between dipolar carbonyl ligands, water, and the permeant cation, which allow for selective flow of K+ over (most importantly) Na+ across the cell membrane. Although a structural viewpoint attributes K+ selectivity to coordination geometry provided by the filter, recent molecular dynamics simulation studies attribute it to dynamic and unique chemical/electrostatic properties of the filter's carbonyl ligands. Here we provide a simple theoretical analysis of K+ and Na+ complexation with water in the context of simplified binding site models and bulk solution. Our analysis reveals that water molecules and carbonyl groups can both provide K+ selective environments if equivalent constraints are imposed on the coordination number of the complex. Absence of such constraints annihilates selectivity, demonstrating that whether a coordinating ligand is a water molecule or a carbonyl group, "external" or "topological" constraints/forces must be imposed on an ion-coordinated complex to elicit selective binding. These forces must inevitably originate from the channel protein, because in bulk water, which, by definition, presents a nonselective medium, the coordination number is allowed to relax to suit the ion. We show that the coordination geometry of K+ channel binding sites is replicated by 8-fold complexation of K+ in both water and simplified binding site models due to dominance of local interactions within a complex and is thus a requirement for topologically constraining the coordination number to a specific value. PMID:17519335

  4. Plants Do It Differently. A New Basis for Potassium/Sodium Selectivity in the Pore of an Ion Channel1

    PubMed Central

    Hua, Bao-Guang; Mercier, Richard W.; Leng, Qiang; Berkowitz, Gerald A.

    2003-01-01

    Understanding of the molecular architecture necessary for selective K+ permeation through the pore of ion channels is based primarily on analysis of the crystal structure of the bacterial K+ channel KcsA, and structure:function studies of cloned animal K+ channels. Little is known about the conduction properties of a large family of plant proteins with structural similarities to cloned animal cyclic nucleotide-gated channels (CNGCs). Animal CNGCs are nonselective cation channels that do not discriminate between Na+ and K+ permeation. These channels all have the same triplet of amino acids in the channel pore ion selectivity filter, and this sequence is different from that of the selectivity filter found in K+-selective channels. Plant CNGCs have unique pore selectivity filters; unlike those found in any other family of channels. At present, the significance of the unique pore selectivity filters of plant CNGCs, with regard to discrimination between Na+ and K+ permeation is unresolved. Here, we present an electrophysiological analysis of several members of this protein family; identifying the first cloned plant channel (AtCNGC1) that conducts Na+. Another member of this ion channel family (AtCNGC2) is shown to have a selectivity filter that provides a heretofore unknown molecular basis for discrimination between K+ and Na+ permeation. Specific amino acids within the AtCNGC2 pore selectivity filter (Asn-416, Asp-417) are demonstrated to facilitate K+ over Na+ conductance. The selectivity filter of AtCNGC2 represents an alternative mechanism to the well-known GYG amino acid triplet of K+ channels that has been identified as the critical basis for K+ over Na+ permeation through the pore of ion channels. PMID:12857817

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

    NASA Astrophysics Data System (ADS)

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

    2015-01-01

    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.

  6. 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.

  7. 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. PMID:24329301

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

    NASA Astrophysics Data System (ADS)

    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 Qf at its selectivity filter. We are thus able to reconcile the discrete calcium conduction bands recently revealed in our BD simulations, M0 (Qf=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 Qf for the sodium-calcium channels family. An increase of Qf 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 Qf(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 Ca2+/Na+ valence selectivity of calcium and sodium ion channels. The model and results could be also applicable to biomimetic nanopores with charged walls.

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

    PubMed Central

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

    2015-01-01

    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. PMID:25955978

  10. 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.

  11. Lipid and stress dependence of amphotericin B ion selective channels in sterol-free membranes.

    PubMed

    Ruckwardt, T; Scott, A; Scott, J; Mikulecky, P; Hartsel, S C

    1998-07-17

    The idea that amphotericin B (AmB) may not require sterols to form ion selective channels has recently been criticized on the grounds that egg phospholipids commonly used in experiments may contain small amounts of sterol which associate with AmB to form AmB/sterol pore channel structures. It was recently shown in this laboratory that modest osmotic stress can enhance the formation of AmB channels in sterol-free egg phosphatidylcholine (eggPC) membranes. We have tested AmB's ability to form ion channels/defects in synthetic palmitoyl oleoyl (POPC), dieicosenyl (DEPC) and natural eggPC osmotically stressed large unilamellar vesicles (LUV) using pyranine fluorescence detected ion/H+ exchange. These sterol-free POPC LUV exhibit greatly increased sensitivity to cation selective AmB channel formation when osmotically stressed; even more than eggPC. Under these stressed conditions, AmB activity was observed at [AmB]/POPC ratios as low as 3.5x10(-4), corresponding to about 34 AmB molecules/vesicle. DEPC vesicles were almost completely unresponsive, demonstrating a strong bilayer thickness dependence. These results prove conclusively that AmB can form sterol-free channels and do so within therapeutic concentration ranges (>0.5-10x10(-6) M) in a stress-dependent manner. This phenomenon may allow us to use osmotic stress changes in simple model systems to spectroscopically isolate and characterize the thus-far elusive AmB channel forming aggregate. In addition, this stress dependence may be responsible for the potentiation of renal toxicity of AmB in the ascending branch of the loop of Henle which is under greatest osmotic stress. PMID:9675313

  12. Selectivity and permeation of alkali metal ions in K+-channels.

    PubMed

    Furini, Simone; Domene, Carmen

    2011-06-24

    Ion conduction in K(+)-channels is usually described in terms of concerted movements of K(+) progressing in a single file through a narrow pore. Permeation is driven by an incoming ion knocking on those ions already inside the protein. A fine-tuned balance between high-affinity binding and electrostatic repulsive forces between permeant ions is needed to achieve efficient conduction. While K(+)-channels are known to be highly selective for K(+) over Na(+), some K(+) channels conduct Na(+) in the absence of K(+). Other ions are known to permeate K(+)-channels with a more moderate preference and unusual conduction features. We describe an extensive computational study on ion conduction in K(+)-channels rendering free energy profiles for the translocation of three different alkali ions and some of their mixtures. The free energy maps for Rb(+) translocation show at atomic level why experimental Rb(+) conductance is slightly lower than that of K(+). In contrast to K(+) or Rb(+), external Na(+) block K(+) currents, and the sites where Na(+) transport is hindered are characterized. Translocation of K(+)/Na(+) mixtures is energetically unfavorable owing to the absence of equally spaced ion-binding sites for Na(+), excluding Na(+) from a channel already loaded with K(+). PMID:21540036

  13. 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.

  14. Streaming potentials reveal a short ryanodine-sensitive selectivity filter in cardiac Ca2+ release channel.

    PubMed Central

    Tu, Q; Vélez, P; Brodwick, M; Fill, M

    1994-01-01

    Single cardiac sarcoplasmic reticulum Ca2+ release channels were reconstituted into planar bilayer membranes. Streaming potentials were measured in osmotically asymmetric solutions as a shift in the reversal potential. Potential changes induced by water movement through the bilayer (concentration polarization) and reduced ion activity in the concentrated non-electrolyte solutions were determined using valinomycin. In 400 mM symmetrical CsCH3SO3, the average streaming potential was 2.74 +/- 0.2 mV (n = 5, mean +/- SE; 2 osmol/kg) and independent of the osmoticant used (sucrose or diglycine). Identical streaming potential magnitudes were obtained regardless of which side of the membrane the nonelectrolyte was placed. This suggests that the narrow part of the pore where single file diffusion occurs is relatively short (i.e., accommodates a minimum of 3 H2O molecules). This value is comparable to similar measurements in a variety of surface membrane channels. Ryanodine-modified channels had no measurable streaming potential, an increased Tris+ permeability relative to Cs+, and decreased divalent selectivity (PCs/PTris 5.1 +/- 1.1 to 1.7 +/- 0.3, n = 3; PBa/PCs 8.2 +/- 0.7 to 1.8 +/- 0.5, n = 4). Cation/anion selectivity was essentially unaltered in ryanodine-modified channels. These results suggests that the narrow region of the permeation pathway (i.e., the selectivity filter) is relatively short and widens after ryanodine modification. PMID:7696468

  15. 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.

  16. 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.

  17. The doubly compactified Schwinger model

    SciTech Connect

    Linares, R.; Urrutia, L. F.; Vergara, J. D.

    1999-10-25

    In this note we summarize the exact solution of the doubly compactified Schwinger model (CSM), defined by the condition that the domain of the electromagnetic degree of freedom c=1/L{integral}{sub 0}{sup L}dxA{sub 1} is -c-bar

  18. 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. PMID:24844608

  19. Evaluating State Dependence and Subtype Selectivity of Calcium Channel Modulators in Automated Electrophysiology Assays

    PubMed Central

    Kuryshev, Yuri A.; Brown, Arthur M.; Duzic, Emir

    2014-01-01

    Abstract Voltage-gated Ca2+ channels play essential roles in control of neurosecretion and muscle contraction. The pharmacological significance of Cav channels stem from their identification as the molecular targets of calcium blockers used in the treatment of cardiovascular diseases, such as hypertension, angina, and arrhythmia, and neurologic diseases, such as pain and seizure. It has been proposed that state-dependent Cav inhibitors, that is, those that preferentially bind to channels in open or inactivated states, may improve the therapeutic window over relatively state-independent Cav inhibitors. High-throughput fluorescent-based functional assays have been useful in screening chemical libraries to identify Cav inhibitors. However, hit confirmation, mechanism of action, and subtype selectivity are better suited to automated patch clamp assays that have sufficient capacity to handle the volume of compounds identified during screening, even of modest sized libraries (≤500,000 compounds), and the flexible voltage control that allows evaluation of state-dependent drug blocks. IonWorks™ Barracuda (IWB), the newest generation of IonWorks instruments, provides the opportunity to accelerate the Cav drug discovery studies in an automated patch clamp platform in 384-well format capable of medium throughput screening and profiling studies. We have validated hCav1.2, hCav2.1, hCav2.2, and hCav3.2 channels assays on the IWB platform (population patch clamp mode) and demonstrated that the biophysical characteristics of the channels (activation, inactivation, and steady-state inactivation) obtained with the IWB system are consistent with known subtype-specific characteristics. Using standard reference compounds (nifedipine, BAY K8644, verapamil, mibefradil, and pimozide), we demonstrated subtype-selective and state- and use-dependent characteristics of drug–channel interactions. Here we describe the design and validation of novel robust high-throughput Cav channel

  20. 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…

  1. Isomeric Selective Studies of the Dominant Addition Channel in OH Initiated Oxidation of Isoprene

    NASA Astrophysics Data System (ADS)

    Ghosh, B.; Bugarin, A.; Connell, B.; North, S. W.

    2009-12-01

    We report the first isomeric selective study of the dominant isomeric pathway in the OH initiated oxidation of isoprene in the presence of O2 and NO using the Laser Photolysis-Laser Induced Fluorescence (LP-LIF) technique. The photolysis of monodeuterated/non deuterated 2-iodo-2-methyl-but-3-en-1-ol results exclusively in the dominant OH-isoprene addition product, providing important insight into the oxidation mechanism. Based on kinetic analysis of OH cycling experiments we have determined the rate constant for O2 addition to the hydroxy alkyl radical to be (1.0±0.5) × 10^(-12) cm^(3) s^(-1) and we find a value of (8.05±2.3) × 10^(-12) cm^(3) s^(-1) for the overall reaction rate constant of the hydroxy peroxy radical with NO. We also report the first clear experimental evidence of the (E-) form of the δ-hydroxyalkoxy channel through isotopic labeling experiments and quantify its branching ratio to be 0.1±0.025. Since it corresponds to missing carbon balance in isoprene oxidation, we have been able to identify some of the missing carbon balance. Since our measured isomeric selective rate constants for the dominant outer channel in OH initiated isoprene chemistry are similar to the overall rate constants derived from non isomeric kinetics, we predict that the remaining outer addition channel will have similar reactivity. We have extended this study to the OH initiated oxidation of 1,3-butadiene. We have obtained isomeric selective rate constants on the dominant channel of the butadiene oxidation chemistry and measured the branching ratio for the δ-hydroxyalkoxy channel. These results on butadiene studies will be discussed.

  2. Selective T-Type Calcium Channel Blockade Alleviates Hyperalgesia in ob/ob Mice

    PubMed Central

    Latham, Janelle R.; Pathirathna, Sriyani; Jagodic, Miljen M.; Joo Choe, Won; Levin, Michaela E.; Nelson, Michael T.; Yong Lee, Woo; Krishnan, Kathiresan; Covey, Douglas F.; Todorovic, Slobodan M.; Jevtovic-Todorovic, Vesna

    2009-01-01

    OBJECTIVE Morbid obesity may be accompanied by diabetes and painful diabetic neuropathy, a poorly understood condition that is manifested by mechanical or thermal allodynia and hyperalgesia. Recent studies have highlighted the importance of T-type calcium channels (T-channels) in peripheral nociception; therefore, our goal was to examine the function of these channels in the pathophysiology and development of painful diabetic neuropathy. RESEARCH DESIGN AND METHODS In vivo testing of mechanical and thermal sensation, morphometric peripheral nerve studies, and electrophysiological and biochemical measurements were used to characterize the role of T-channels and the development of painful diabetic neuropathy in leptin-deficient (ob/ob) mice. RESULTS We found that ob/ob mice developed significant mechanical and thermal hypersensitivity early in life that coincided with hyperglycemia and was readily reversed with insulin therapy. These disturbances were accompanied by significant biophysical and biochemical modulation of T-channels in dorsal root ganglion neurons as measured by a large increase in the amplitude of T-currents and the expression of mRNA. The most prevalent subtype, α1H (Cav3.2), was most strongly affected. Moreover, (3β,5α,17β)-17-hydroxyestrane-3-carbonitrile (ECN), a novel neuroactive steroid and selective T-channel antagonist, provided dose-dependent alleviation of neuropathic thermal and mechanical hypersensitivity in diabetic ob/ob mice. CONCLUSIONS Our results indicate that pharmacological antagonism of T-channels is potentially an important novel therapeutic approach for the management of painful diabetic neuropathy. PMID:19651818

  3. Transient Receptor Potential Canonical 7 (TRPC7): A Diacylglycerol-Activated Non-Selective Cation Channel

    PubMed Central

    Zhang, Xuexin

    2016-01-01

    Transient receptor potential canonical 7 (TRPC7) channel is the seventh member of the mammalian TRPC channel family. TRPC7 mRNA, protein and channel activity have been detected in many tissues and organs from mouse, rat and human. TRPC7 has high sequence homology with TRPC3 and TRPC6 and all three channels are activated by membrane receptors that couple to isoforms of phospholipase C (PLC) and mediate non-selective cation currents. TRPC7, along with TRPC3 and TRPC6 can be activated by direct exogenous application of diacylglycerol (DAG) analogs and by pharmacological maneuvers that increase endogenous DAG in cells. TRPC7 shows distinct properties of activation, such as constitutive activity, susceptibility to negative regulation by extracellular Ca2+ and by protein kinase C. TRPC7 can form heteromultimers with TRPC3 and TRPC6. Although TRPC7 remains one of the least studied TRPC channel, its role in various cell types and physiological and pathophysiological conditions is begining to emerge. PMID:24756707

  4. Ionic selectivity and thermal adaptations within the voltage-gated sodium channel family of alkaliphilic Bacillus.

    PubMed

    DeCaen, Paul G; Takahashi, Yuka; Krulwich, Terry A; Ito, Masahiro; Clapham, David E

    2014-01-01

    Entry and extrusion of cations are essential processes in living cells. In alkaliphilic prokaryotes, high external pH activates voltage-gated sodium channels (Nav), which allows Na(+) to enter and be used as substrate for cation/proton antiporters responsible for cytoplasmic pH homeostasis. Here, we describe a new member of the prokaryotic voltage-gated Na(+) channel family (NsvBa; Non-selective voltage-gated, Bacillus alcalophilus) that is nonselective among Na(+), Ca(2+) and K(+) ions. Mutations in NsvBa can convert the nonselective filter into one that discriminates for Na(+) or divalent cations. Gain-of-function experiments demonstrate the portability of ion selectivity with filter mutations to other Bacillus Nav channels. Increasing pH and temperature shifts their activation threshold towards their native resting membrane potential. Furthermore, we find drugs that target Bacillus Nav channels also block the growth of the bacteria. This work identifies some of the adaptations to achieve ion discrimination and gating in Bacillus Nav channels. PMID:25385530

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

    PubMed

    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

    2016-06-23

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

  6. Multistep Mechanism of Chloride Translocation in a Strongly Anion-Selective Porin Channel

    PubMed Central

    Zachariae, Ulrich; Helms, Volkhard; Engelhardt, Harald

    2003-01-01

    The strongly anion-selective porin channel Omp32 from the bacterium Delftia acidovorans differs from other unspecific porins by its pronounced selectivity for anions and its particularly small channel cross-section. Multinanosecond molecular dynamics simulations of chloride ion movement in this pore protein suggest that translocated anions interact intimately with the charges of a “basic ladder”, whose dynamics lead the anions in a stepwise manner through the constriction zone of the channel. The ladder-steps comprise the central clustered arginine groups and flanking basic residues at its exoplasmic and periplasmic sides. The computed free energy profile of ion movement in and around the constriction zone shows a corresponding succession of free energy minima and barriers. A number of polar atoms from other amino acids contribute to the coordination of Cl− at certain sites and to its temporary immobilization in the channel. A special binding site occurs at the transition of the constriction zone to the periplasmic funnel, binding the chloride ion over significant lengths of time. The results from our MD study offer a possible explanation for the nonlinear conductance properties and unusual salt-dependent characteristics of Omp32 observed earlier in experimental measurements. PMID:12885642

  7. 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.

  8. Thermal Responsive Ion Selectivity of Uranyl Peroxide Nanocages: An Inorganic Mimic of K(+) Ion Channels.

    PubMed

    Gao, Yunyi; Szymanowski, Jennifer E S; Sun, Xinyu; Burns, Peter C; Liu, Tianbo

    2016-06-01

    An actinyl peroxide cage cluster, Li48+m K12 (OH)m [UO2 (O2 )(OH)]60 (H2 O)n (m≈20 and n≈310; U60 ), discriminates precisely between Na(+) and K(+) ions when heated to certain temperatures, a most essential feature for K(+) selective filters. The U60 clusters demonstrate several other features in common with K(+) ion channels, including passive transport of K(+) ions, a high flux rate, and the dehydration of U60 and K(+) ions. These qualities make U60 (a pure inorganic cluster) a promising ion channel mimic in an aqueous environment. Laser light scattering (LLS) and isothermal titration calorimetry (ITC) studies revealed that the tailorable ion selectivity of U60 clusters is a result of the thermal responsiveness of the U60 hydration shells. PMID:27105921

  9. Selection and design of the secondary electron channel of the time-of-flight mass spectrometer

    NASA Astrophysics Data System (ADS)

    Fishkova, T. Ya.; Basalaev, A. A.; Kuz'michev, V. V.

    2016-03-01

    Computer simulation is carried out for selecting a compact electron-optical system of the channel for detecting secondary electrons formed during the interaction of xenon atoms or ions with energy of 1-30 keV with Xe atoms. The solid angle of passage of secondary electron beams in a wide range of their initial energies is calculated. The energy spectrum of secondary electrons with various energies is determined by constructing their deceleration curve.

  10. 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.

  11. 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

  12. Mutations in the channel domain of a neuronal nicotinic receptor convert ion selectivity from cationic to anionic.

    PubMed

    Galzi, J L; Devillers-Thiéry, A; Hussy, N; Bertrand, S; Changeux, J P; Bertrand, D

    1992-10-01

    Introduction by site-directed mutagenesis of three amino acids from the MII segment of glycine or gamma-aminobutyric acid (GABAA) receptors into the MII segment of alpha 7 nicotinic receptor was sufficient to convert a cation-selective channel into an anion-selective channel gated by acetylcholine. A critical mutation was the insertion of an uncharged residue at the amino-terminal end of MII, stressing the importance of protein geometrical constraints on ion selectivity. PMID:1383829

  13. A Novel Variable Selection Method Based on a Partial KL Information Measure and Its Application to Channel Selection for Bioelectric Signal Classification

    NASA Astrophysics Data System (ADS)

    Shibanoki, Taro; Shima, Keisuke; Tsuji, Toshio; Takaki, Takeshi; Otsuka, Akira; Chin, Takaaki

    This paper proposes a novel variable selection method based on the KL information measure, and applies it to optimal channel selection for bioelectric signal classification. Generally, the accuracy of classifcation for bioelectric signals is greatly influenced by measuring positions of the signals as well as individual physical abilities of a user. Therefore, it is effective for classification to select optimal positions for each user in advance. In the proposed method, the probability density functions (pdfs) of measured data are estimated through learning of a multidimensional probabilistic neural network (PNN) based on the KL information theory. Then, a partial KL information measure is newly defined to evaluate contribution of each dimension in the data. The effective dimensions can be selected eliminating ineffective ones based on the partial KL information in a one-by-one manner. In the experiments, the proposed method was applied to EMG electrode selection with six subjects (including an amputee), and the effective channels were selected from all channels attached to each subject's forearm. Experimental results showed that the number of channels was reduced with 36.1±12.5 [%], and the average classification rate using selected channels by the proposed method was 98.99±1.31 [%]. These results indicated that the proposed method is capable to select effective channels (optimal or semi-optimal) for accurate classification.

  14. Mechanism for phosphoinositide selectivity and activation of TRPV1 ion channels

    PubMed Central

    Ufret-Vincenty, Carmen A.; Klein, Rebecca M.; Collins, Marcus D.; Rosasco, Mario G.; Martinez, Gilbert Q.

    2015-01-01

    Although PI(4,5)P2 is believed to play an essential role in regulating the activity of numerous ion channels and transporters, the mechanisms by which it does so are unknown. Here, we used the ability of the TRPV1 ion channel to discriminate between PI(4,5)P2 and PI(4)P to localize the region of TRPV1 sequence that interacts directly with the phosphoinositide. We identified a point mutation in the proximal C-terminal region after the TRP box, R721A, that inverted the selectivity of TRPV1. Although the R721A mutation produced only a 30% increase in the EC50 for activation by PI(4,5)P2, it decreased the EC50 for activation by PI(4)P by more than two orders of magnitude. We used chemically induced and voltage-activated phosphatases to determine that PI(4)P continued to support TRPV1 activity even after depletion of PI(4,5)P2 from the plasma membrane. Our data cannot be explained by a purely electrostatic mechanism for interaction between the phosphoinositide and the protein, similar to that of the MARCKS (myristoylated alanine-rich C kinase substrate) effector domain or the EGF receptor. Rather, conversion of a PI(4,5)P2-selective channel to a PI(4)P-selective channel indicates that a structured phosphoinositide-binding site mediates the regulation of TRPV1 activity and that the amino acid at position 721 likely interacts directly with the moiety at the 5′ position of the phosphoinositide. PMID:25918361

  15. Mechanism for phosphoinositide selectivity and activation of TRPV1 ion channels.

    PubMed

    Ufret-Vincenty, Carmen A; Klein, Rebecca M; Collins, Marcus D; Rosasco, Mario G; Martinez, Gilbert Q; Gordon, Sharona E

    2015-05-01

    Although PI(4,5)P2 is believed to play an essential role in regulating the activity of numerous ion channels and transporters, the mechanisms by which it does so are unknown. Here, we used the ability of the TRPV1 ion channel to discriminate between PI(4,5)P2 and PI(4)P to localize the region of TRPV1 sequence that interacts directly with the phosphoinositide. We identified a point mutation in the proximal C-terminal region after the TRP box, R721A, that inverted the selectivity of TRPV1. Although the R721A mutation produced only a 30% increase in the EC50 for activation by PI(4,5)P2, it decreased the EC50 for activation by PI(4)P by more than two orders of magnitude. We used chemically induced and voltage-activated phosphatases to determine that PI(4)P continued to support TRPV1 activity even after depletion of PI(4,5)P2 from the plasma membrane. Our data cannot be explained by a purely electrostatic mechanism for interaction between the phosphoinositide and the protein, similar to that of the MARCKS (myristoylated alanine-rich C kinase substrate) effector domain or the EGF receptor. Rather, conversion of a PI(4,5)P2-selective channel to a PI(4)P-selective channel indicates that a structured phosphoinositide-binding site mediates the regulation of TRPV1 activity and that the amino acid at position 721 likely interacts directly with the moiety at the 5' position of the phosphoinositide. PMID:25918361

  16. Doubly rotated contoured quartz resonators.

    PubMed

    Sinha, B K

    2001-09-01

    Doubly rotated contoured quartz resonators are used in the design of temperature-compensated stable clocks and dual-mode sensors for simultaneous measurements of pressure and temperature. The design of these devices is facilitated by models that can predict frequency spectra associated with the three thickness modes and temperature and stress-induced frequency changes as a function of crystalline orientation. The Stevens-Tiersten technique for the analysis of the C-mode of a doubly rotated contoured quartz resonator is extended to include the other two thickness modes. Computational results for harmonic and anharmonic overtones of all three thickness modes of such resonators help in optimizing the radius of curvature of the contour and electrode shape for suppression of unwanted modes and prevention of activity dips. The temperature and stress-induced changes in thickness-mode resonator frequencies are calculated from a perturbation technique for small dynamic fields superposed on a static bias. The static bias refers to either a temperature or stress-induced static deformation of the resonator plate. Phenomenological models are also used for calculating the temperature and stress-induced changes in resonant frequencies as a function of crystalline orientation. Results for the SBTC-cut quartz plate with a spherical convex contour of 260 mm indicate that normal trapping occurs for the third (n = 3) and fifth (n = 5) harmonic of the A-mode, the fundamental (n = 1) and third (n = 3) harmonic of the B-mode, and the fundamental (n = 1) and fifth (n = 5) harmonic of the C-mode. PMID:11570746

  17. 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

  18. Accessibility, reactivity, and selectivity of side chains within a channel of de novo peptide assembly.

    PubMed

    Burton, Antony J; Thomas, Franziska; Agnew, Christopher; Hudson, Kieran L; Halford, Stephen E; Brady, R Leo; Woolfson, Derek N

    2013-08-28

    Ab initio design of enzymes requires precise and predictable positioning of reactive functional groups within accessible and controlled environments of de novo protein scaffolds. Here we show that multiple thiol moieties can be placed within a central channel, with approximate dimensions 6 × 42 Å, of a de novo, six-helix peptide assembly (CC-Hex). Layers of six cysteine residues are introduced at two different sites ~6 (the "L24C" mutant) and ~17 Å (L17C) from the C-terminal opening of the channel. X-ray crystal structures confirm the mutant structures as hexamers with internal free thiol, rather than disulfide-linked cysteine residues. Both mutants are hexa-alkylated upon addition of iodoacetamide, demonstrating accessibility and full reactivity of the thiol groups. Comparison of the alkylation and unfolding rates of the hexamers indicates that access is directly through the channel and not via dissociation and unfolding of the assembly. Moreover, neither mutant reacts with iodoacetic acid, demonstrating selectivity of the largely hydrophobic channel. These studies show that it is possible to engineer reactive side chains with both precision and control into a de novo scaffold to produce protein-like structures with chemoselective reactivity. PMID:23924058

  19. 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. PMID:23531832

  20. 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.

  1. 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. PMID:27129258

  2. 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.

  3. 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

  4. Two conserved arginine residues from the SK3 potassium channel outer vestibule control selectivity of recognition by scorpion toxins.

    PubMed

    Feng, Jing; Hu, Youtian; Yi, Hong; Yin, Shijin; Han, Song; Hu, Jun; Chen, Zongyun; Yang, Weishan; Cao, Zhijian; De Waard, Michel; Sabatier, Jean-Marc; Li, Wenxin; Wu, Yingliang

    2013-05-01

    Potassium channel functions are often deciphered by using selective and potent scorpion toxins. Among these toxins, only a limited subset is capable of selectively blocking small conductance Ca(2+)-activated K(+) (SK) channels. The structural bases of this selective SK channel recognition remain unclear. In this work, we demonstrate the key role of the electric charges of two conserved arginine residues (Arg-485 and Arg-489) from the SK3 channel outer vestibule in the selective recognition by the SK3-blocking BmP05 toxin. Indeed, individually substituting these residues with histidyl or lysyl (maintaining the positive electric charge partially or fully), although decreasing BmP05 affinity, still preserved the toxin sensitivity profile of the SK3 channel (as evidenced by the lack of recognition by many other types of potassium channel-sensitive charybdotoxin). In contrast, when Arg-485 or Arg-489 of the SK3 channel was mutated to an acidic (Glu) or alcoholic (Ser) amino acid residue, the channel lost its sensitivity to BmP05 and became susceptible to the "new" blocking activity by charybdotoxin. In addition to these SK3 channel basic residues important for sensitivity, two acidic residues, Asp-492 and Asp-518, also located in the SK3 channel outer vestibule, were identified as being critical for toxin affinity. Furthermore, molecular modeling data indicate the existence of a compact SK3 channel turret conformation (like a peptide screener), where the basic rings of Arg-485 and Arg-489 are stabilized by strong ionic interactions with Asp-492 and Asp-518. In conclusion, the unique properties of Arg-485 and Arg-489 (spatial orientations and molecular interactions) in the SK3 channel account for its toxin sensitivity profile. PMID:23511633

  5. Dimensions and ion selectivity of recombinant AMPA and kainate receptor channels and their dependence on Q/R site residues.

    PubMed Central

    Burnashev, N; Villarroel, A; Sakmann, B

    1996-01-01

    1. Recombinant alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptor (AMPAR) subunits (GluR-A or GluR-B) and kainate receptor (KAR) subunit (GluR-6) in their unedited (Q)- and edited (R)-forms were expressed in HEK 293 cells. To estimate the dimensions of the narrow portion of these channels, biionic reversal potentials for organic cations of different mean diameters were determined with Cs+ as the internal reference ion. 2. Homomeric channels assembled from Q-form subunits were cation selective. The relation between the relative permeability and the mean size of different organic cations suggests that the diameter of the narrow portion of Q-form channels is approximately 0.78 nm for AMPAR and 0.75 nm for KAR channels. 3. Homomeric channels assembled from R-form subunits were permeant for anions and cations. When probed with CsC1 gradients the relative chloride permeability (PC1/PCs) was estimated as 0.14 for GluR-B(R) and 0.74 for GluR-6(R)-subunit channels. The permeability versus mean size relation for large cations measured with the weakly permeant F- as anion, indicates that for the R-form KAR channels the apparent pore diameter is close to 0.76 nm. 4. Heteromeric AMPAR and KAR channels co-assembled from Q- and R-form subunits were cation selective. The diameter of the narrow portion of these channels is estimated to be in the range between 0.70 and 0.74 nm. 5. The results indicated that the diameters of the narrow portion of AMPAR and KAR channels of different subunit composition and of widely different ion selectivity are comparable. Therefore, the differences in the anion versus cation selectivity, in Ca2+ permeability and in channel conductance are likely to be determined by the difference in charge density of the channel. PMID:8910205

  6. Overcoming mutagenicity and ion channel activity: optimization of selective spleen tyrosine kinase inhibitors.

    PubMed

    Ellis, J Michael; Altman, Michael D; Bass, Alan; Butcher, John W; Byford, Alan J; Donofrio, Anthony; Galloway, Sheila; Haidle, Andrew M; Jewell, James; Kelly, Nancy; Leccese, Erica K; Lee, Sandra; Maddess, Matthew; Miller, J Richard; Moy, Lily Y; Osimboni, Ekundayo; Otte, Ryan D; Reddy, M Vijay; Spencer, Kerrie; Sun, Binyuan; Vincent, Stella H; Ward, Gwendolyn J; Woo, Grace H C; Yang, Chiming; Houshyar, Hani; Northrup, Alan B

    2015-02-26

    Development of a series of highly kinome-selective spleen tyrosine kinase (Syk) inhibitors with favorable druglike properties is described. Early leads were discovered through X-ray crystallographic analysis, and a systematic survey of cores within a selected chemical space focused on ligand binding efficiency. Attenuation of hERG ion channel activity inherent within the initial chemotype was guided through modulation of physicochemical properties including log D, PSA, and pKa. PSA proved most effective for prospective compound design. Further profiling of an advanced compound revealed bacterial mutagenicity in the Ames test using TA97a Salmonella strain, and subsequent study demonstrated that this mutagenicity was pervasive throughout the series. Identification of intercalation as a likely mechanism for the mutagenicity-enabled modification of the core scaffold. Implementation of a DNA binding assay as a prescreen and models in DNA allowed resolution of the mutagenicity risk, affording molecules with favorable potency, selectivity, pharmacokinetic, and off-target profiles. PMID:25625541

  7. Phospholamban spontaneously reconstitutes into giant unilamellar vesicles where it generates a cation selective channel.

    PubMed

    Smeazzetto, S; Tadini-Buoninsegni, F; Thiel, G; Berti, D; Montis, C

    2016-01-21

    Phospholamban (PLN) is a small integral membrane protein, which modulates the activity of the Sarcoplasmic Reticulum Ca(2+)-ATPase (SERCA) of cardiac myocytes. PLN, as a monomer, can directly interact and tune SERCA activity, but the physiological function of the pentameric form is not yet fully understood and still debated. In this work, we reconstituted PLN in Giant Unilamellar Vesicles (GUVs), a simple and reliable experimental model system to monitor the activity of proteins in membranes. By Laser Scanning Confocal Microscopy (LSCM) and Fluorescence Correlation Spectroscopy (FCS) we verified a spontaneous reconstitution of PLN into the phospholipid bilayer. In parallel experiments, we measured with the patch clamp technique canonical ion channel fluctuations, which highlight a preference for Cs(+) over K(+) and do not conduct Ca(2+). The results prove that PLN forms, presumably in its pentameric form, a cation selective ion channel. PMID:26673394

  8. Robust fetal QRS detection from noninvasive abdominal electrocardiogram based on channel selection and simultaneous multichannel processing.

    PubMed

    Ghaffari, Ali; Mollakazemi, Mohammad Javad; Atyabi, Seyyed Abbas; Niknazar, Mohammad

    2015-12-01

    The purpose of this study is to provide a new method for detecting fetal QRS complexes from non-invasive fetal electrocardiogram (fECG) signal. Despite most of the current fECG processing methods which are based on separation of fECG from maternal ECG (mECG), in this study, fetal heart rate (FHR) can be extracted with high accuracy without separation of fECG from mECG. Furthermore, in this new approach thoracic channels are not necessary. These two aspects have reduced the required computational operations. Consequently, the proposed approach can be efficiently applied to different real-time healthcare and medical devices. In this work, a new method is presented for selecting the best channel which carries strongest fECG. Each channel is scored based on two criteria of noise distribution and good fetal heartbeat visibility. Another important aspect of this study is the simultaneous and combinatorial use of available fECG channels via the priority given by their scores. A combination of geometric features and wavelet-based techniques was adopted to extract FHR. Based on fetal geometric features, fECG signals were divided into three categories, and different strategies were employed to analyze each category. The method was validated using three datasets including Noninvasive fetal ECG database, DaISy and PhysioNet/Computing in Cardiology Challenge 2013. Finally, the obtained results were compared with other studies. The adopted strategies such as multi-resolution analysis, not separating fECG and mECG, intelligent channels scoring and using them simultaneously are the factors that caused the promising performance of the method. PMID:26462679

  9. 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.

  10. Channel

    NASA Technical Reports Server (NTRS)

    2006-01-01

    [figure removed for brevity, see original site] Context image for PIA03693 Channel

    This channel is located south of Iani Chaos.

    Image information: VIS instrument. Latitude -10.9N, Longitude 345.5E. 17 meter/pixel resolution.

    Note: this THEMIS visual image has not been radiometrically nor geometrically calibrated for this preliminary release. An empirical correction has been performed to remove instrumental effects. A linear shift has been applied in the cross-track and down-track direction to approximate spacecraft and planetary motion. Fully calibrated and geometrically projected images will be released through the Planetary Data System in accordance with Project policies at a later time.

    NASA's Jet Propulsion Laboratory manages the 2001 Mars Odyssey mission for NASA's Office of Space Science, Washington, D.C. The Thermal Emission Imaging System (THEMIS) was developed by Arizona State University, Tempe, in collaboration with Raytheon Santa Barbara Remote Sensing. The THEMIS investigation is led by Dr. Philip Christensen at Arizona State University. Lockheed Martin Astronautics, Denver, is the prime contractor for the Odyssey project, and developed and built the orbiter. Mission operations are conducted jointly from Lockheed Martin and from JPL, a division of the California Institute of Technology in Pasadena.

  11. Multi-ion free energy landscapes underscore the microscopic mechanism of ion selectivity in the KcsA channel.

    PubMed

    Medovoy, David; Perozo, Eduardo; Roux, Benoît

    2016-07-01

    Potassium (K(+)) channels are transmembrane proteins that passively and selectively allow K(+) ions to flow through them, after opening in response to an external stimulus. One of the most critical functional aspects of their function is their ability to remain very selective for K(+) over Na(+) while allowing high-throughput ion conduction at a rate close to the diffusion limit. Classically, it is assumed that the free energy difference between K(+) and Na(+) in the pore relative to the bulk solution is the critical quantity at the origin of selectivity. This is the thermodynamic view of ion selectivity. An alternative view assumes that kinetic factors play the dominant role. Recent results from a number of studies have also highlighted the great importance of the multi-ion single file on the selectivity of K(+) channels. The data indicate that having multiple K(+) ions bound simultaneously is required for selective K(+) conduction, and that a reduction in the number of bound K(+) ions destroys the multi-ion selectivity mechanism utilized by K(+) channels. In the present study, multi-ion potential of mean force molecular dynamics computations are carried out to clarify the mechanism of ion selectivity in the KcsA channel. The computations show that the multi-ion character of the permeation process is a critical element for establishing the selective ion conductivity through K(+)-channels. This article is part of a Special Issue entitled: Membrane Proteins edited by J.C. Gumbart and Sergei Noskov. PMID:26896693

  12. Multi-ion free energy landscapes underscore the microscopic mechanism of ion selectivity in the KcsA channel

    PubMed Central

    Medovoy, David; Perozo, Eduardo; Roux, Benoît

    2016-01-01

    Potassium (K+) channels are transmembrane proteins that passively and selectively allow K+ ions to flow through them, after opening in response to an external stimulus. One of the most critical functional aspects of their function is their ability to remain very selective for K+ over Na+ while allowing high-throughput ion conduction at a rate close to the diffusion limit. Classically, it is assumed that the free energy difference between K+ and Na+ in the pore relative to the bulk solution is the critical quantity at the origin of selectivity. This is the thermodynamic view of ion selectivity. An alternative view assumes that kinetic factor play the dominant role. Recent results from a number of studies have also highlighted the great importance of the multi-ion single file on the selectivity of K+ channels. The data indicate that having multiple K+ ions bound simultaneously is required for selective K+ conduction, and that a reduction in the number of bound K+ ions destroys the multi-ion selectivity mechanism utilized by K+ channels. In the present study, multi-ion potential of mean force molecular dynamics computations are carried out to clarify the mechanism of ion selectivity in the KcsA channel. The computations show that the multi-ion character of the permeation process is a critical element for establishing the selective ion conductivity through K+-channels. PMID:26896693

  13. Phosphatidylinositol 4,5-bisphosphate alters pharmacological selectivity for epilepsy-causing KCNQ potassium channels

    PubMed Central

    Zhou, Pingzheng; Yu, Haibo; Gu, Min; Nan, Fa-jun; Gao, Zhaobing; Li, Min

    2013-01-01

    Pharmacological augmentation of neuronal KCNQ muscarinic (M) currents by drugs such as retigabine (RTG) represents a first-in-class therapeutic to treat certain hyperexcitatory diseases by dampening neuronal firing. Whereas all five potassium channel subtypes (KCNQ1–KCNQ5) are found in the nervous system, KCNQ2 and KCNQ3 are the primary players that mediate M currents. We investigated the plasticity of subtype selectivity by two M current effective drugs, retigabine and zinc pyrithione (ZnPy). Retigabine is more effective on KCNQ3 than KCNQ2, whereas ZnPy is more effective on KCNQ2 with no detectable effect on KCNQ3. In neurons, activation of muscarinic receptor signaling desensitizes effects by retigabine but not ZnPy. Importantly, reduction of phosphatidylinositol 4,5-bisphosphate (PIP2) causes KCNQ3 to become sensitive to ZnPy but lose sensitivity to retigabine. The dynamic shift of pharmacological selectivity caused by PIP2 may be induced orthogonally by voltage-sensitive phosphatase, or conversely, abolished by mutating a PIP2 site within the S4–S5 linker of KCNQ3. Therefore, whereas drug-channel binding is a prerequisite, the drug selectivity on M current is dynamic and may be regulated by receptor signaling pathways via PIP2. PMID:23650395

  14. Phosphatidylinositol 4,5-bisphosphate alters pharmacological selectivity for epilepsy-causing KCNQ potassium channels.

    PubMed

    Zhou, Pingzheng; Yu, Haibo; Gu, Min; Nan, Fa-jun; Gao, Zhaobing; Li, Min

    2013-05-21

    Pharmacological augmentation of neuronal KCNQ muscarinic (M) currents by drugs such as retigabine (RTG) represents a first-in-class therapeutic to treat certain hyperexcitatory diseases by dampening neuronal firing. Whereas all five potassium channel subtypes (KCNQ1-KCNQ5) are found in the nervous system, KCNQ2 and KCNQ3 are the primary players that mediate M currents. We investigated the plasticity of subtype selectivity by two M current effective drugs, retigabine and zinc pyrithione (ZnPy). Retigabine is more effective on KCNQ3 than KCNQ2, whereas ZnPy is more effective on KCNQ2 with no detectable effect on KCNQ3. In neurons, activation of muscarinic receptor signaling desensitizes effects by retigabine but not ZnPy. Importantly, reduction of phosphatidylinositol 4,5-bisphosphate (PIP2) causes KCNQ3 to become sensitive to ZnPy but lose sensitivity to retigabine. The dynamic shift of pharmacological selectivity caused by PIP2 may be induced orthogonally by voltage-sensitive phosphatase, or conversely, abolished by mutating a PIP2 site within the S4-S5 linker of KCNQ3. Therefore, whereas drug-channel binding is a prerequisite, the drug selectivity on M current is dynamic and may be regulated by receptor signaling pathways via PIP2. PMID:23650395

  15. High-order derivative spectroscopy for selecting spectral regions and channels for remote sensing algorithm development

    NASA Astrophysics Data System (ADS)

    Bostater, Charles R., Jr.

    1999-12-01

    A remote sensing reflectance model, which describes the transfer of irradiant light within a plant canopy or water column has previously been used to simulate the nadir viewing reflectance of vegetation canopies and leaves under solar induced or an artificial light source and the water surface reflectance. Wavelength dependent features such as canopy reflectance leaf absorption and canopy bottom reflectance as well as water absorption and water bottom reflectance have been used to simulate or generate synthetic canopy and water surface reflectance signatures. This paper describes how derivative spectroscopy can be utilized to invert the synthetic or modeled as well as measured reflectance signatures with the goal of selecting the optimal spectral channels or regions of these environmental media. Specifically, in this paper synthetic and measured reflectance signatures are used for selecting vegetative dysfunction variables for different plant species. The measured reflectance signatures as well as model derived or synthetic signatures are processed using extremely fast higher order derivative processing techniques which filter the synthetic/modeled or measured spectra and automatically selects the optimal channels for automatic and direct algorithm application. The higher order derivative filtering technique makes use of a translating and dilating, derivative spectroscopy signal processing (TDDS-SPR) approach based upon remote sensing science and radiative transfer theory. Thus the technique described, unlike other signal processing techniques being developed for hyperspectral signatures and associated imagery, is based upon radiative transfer theory instead of statistical or purely mathematical operational techniques such as wavelets.

  16. Cooperation of Hydrophobic Gating, Knock-on Effect, and Ion Binding Determines Ion Selectivity in the p7 Channel.

    PubMed

    Padhi, Siladitya; Priyakumar, U Deva

    2016-05-19

    Ion channels selectively allow certain ions to pass through at much higher rates than others, and thereby modulate ionic concentrations across cell membranes. The current molecular dynamics study elucidates the intricate mechanisms that render ion selectivity to the viral channel p7 by employing free energy calculations. Free energy barriers of 5.4 and 19.4 kcal mol(-1) for K(+) and Ca(2+), respectively, explain the selectivity of the channel reported in experiments. Initially, the permeating ions encounter a hydrophobic barrier followed by stabilization in an ion-binding site. Electrostatic repulsion between the permeating ions propels one of the ions out of the binding site to complete the process of permeation. K(+) and Ca(2+) are seen to exhibit different modes of binding toward a ring of asparagine residues, which serves as the binding site. The findings illustrate how the overall selectivity of a channel can be achieved by a combination of subtle differences. PMID:27111292

  17. 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.

  18. Major intrinsic protein superfamily: channels with unique structural features and diverse selectivity filters.

    PubMed

    Verma, Ravi Kumar; Gupta, Anjali Bansal; Sankararamakrishnan, Ramasubbu

    2015-01-01

    Members of the superfamily of major intrinsic proteins (MIPs) facilitate water and solute permeability across cell membranes and are found in sources ranging from bacteria to humans. Aquaporin and aquaglyceroporin channels are the prominent members of the MIP superfamily. Experimental studies show that MIPs are involved in important physiological processes in mammals and plants. They are implicated in several human diseases and are considered to be attractive drug targets for a wide range of diseases such as cancer, brain edema, epilepsy, glaucoma, and congestive heart failure. Three-dimensional structures of MIP channels from diverse sources reveal that MIPs adopt a unique conserved hourglass helical fold consisting of six transmembrane helices (TM1-TM6) and two half-helices (LB and LE). Conserved NPA motifs near the center and the aromatic/arginine selectivity filter (Ar/R SF) toward the extracellular side constitute two narrow constriction regions within the channel. Structural knowledge combined with simulation studies have helped to investigate the role of these two constriction regions in the transport and selectivity of the solutes. With the availability of many genome sequences from diverse species, a large number of MIP genes have been identified. Homology models of 1500 MIP channels have been used to derive structure-based sequence alignment of TM1-TM6 helices and the two half-helices LB and LE. Thirteen residues are highly conserved in different transmembrane helices and half-helices. High group conservation of small and weakly polar residues is observed in 27 positions at the interface of two interacting helices. Thus, although the MIP sequences are diverse, the hourglass helical fold is maintained during evolution with the conservation of these 40 positions within the transmembrane region. We have proposed a generic structure-based numbering scheme for the MIP channels that will facilitate easier comparison of the MIP sequences. Analysis of Ar/R SF in

  19. Discovery and characterization of a potent and selective inhibitor of Aedes aegypti inward rectifier potassium channels.

    PubMed

    Raphemot, Rene; Rouhier, Matthew F; Swale, Daniel R; Days, Emily; Weaver, C David; Lovell, Kimberly M; Konkel, Leah C; Engers, Darren W; Bollinger, Sean R; Bollinger, Sean F; Hopkins, Corey; Piermarini, Peter M; Denton, Jerod S

    2014-01-01

    Vector-borne diseases such as dengue fever and malaria, which are transmitted by infected female mosquitoes, affect nearly half of the world's population. The emergence of insecticide-resistant mosquito populations is reducing the effectiveness of conventional insecticides and threatening current vector control strategies, which has created an urgent need to identify new molecular targets against which novel classes of insecticides can be developed. We previously demonstrated that small molecule inhibitors of mammalian Kir channels represent promising chemicals for new mosquitocide development. In this study, high-throughput screening of approximately 30,000 chemically diverse small-molecules was employed to discover potent and selective inhibitors of Aedes aegypti Kir1 (AeKir1) channels heterologously expressed in HEK293 cells. Of 283 confirmed screening 'hits', the small-molecule inhibitor VU625 was selected for lead optimization and in vivo studies based on its potency and selectivity toward AeKir1, and tractability for medicinal chemistry. In patch clamp electrophysiology experiments of HEK293 cells, VU625 inhibits AeKir1 with an IC50 value of 96.8 nM, making VU625 the most potent inhibitor of AeKir1 described to date. Furthermore, electrophysiology experiments in Xenopus oocytes revealed that VU625 is a weak inhibitor of AeKir2B. Surprisingly, injection of VU625 failed to elicit significant effects on mosquito behavior, urine excretion, or survival. However, when co-injected with probenecid, VU625 inhibited the excretory capacity of mosquitoes and was toxic, suggesting that the compound is a substrate of organic anion and/or ATP-binding cassette (ABC) transporters. The dose-toxicity relationship of VU625 (when co-injected with probenecid) is biphasic, which is consistent with the molecule inhibiting both AeKir1 and AeKir2B with different potencies. This study demonstrates proof-of-concept that potent and highly selective inhibitors of mosquito Kir channels can

  20. Discovery and Characterization of a Potent and Selective Inhibitor of Aedes aegypti Inward Rectifier Potassium Channels

    PubMed Central

    Raphemot, Rene; Rouhier, Matthew F.; Swale, Daniel R.; Days, Emily; Weaver, C. David; Lovell, Kimberly M.; Konkel, Leah C.; Engers, Darren W.; Bollinger, Sean F.; Hopkins, Corey; Piermarini, Peter M.; Denton, Jerod S.

    2014-01-01

    Vector-borne diseases such as dengue fever and malaria, which are transmitted by infected female mosquitoes, affect nearly half of the world's population. The emergence of insecticide-resistant mosquito populations is reducing the effectiveness of conventional insecticides and threatening current vector control strategies, which has created an urgent need to identify new molecular targets against which novel classes of insecticides can be developed. We previously demonstrated that small molecule inhibitors of mammalian Kir channels represent promising chemicals for new mosquitocide development. In this study, high-throughput screening of approximately 30,000 chemically diverse small-molecules was employed to discover potent and selective inhibitors of Aedes aegypti Kir1 (AeKir1) channels heterologously expressed in HEK293 cells. Of 283 confirmed screening ‘hits’, the small-molecule inhibitor VU625 was selected for lead optimization and in vivo studies based on its potency and selectivity toward AeKir1, and tractability for medicinal chemistry. In patch clamp electrophysiology experiments of HEK293 cells, VU625 inhibits AeKir1 with an IC50 value of 96.8 nM, making VU625 the most potent inhibitor of AeKir1 described to date. Furthermore, electrophysiology experiments in Xenopus oocytes revealed that VU625 is a weak inhibitor of AeKir2B. Surprisingly, injection of VU625 failed to elicit significant effects on mosquito behavior, urine excretion, or survival. However, when co-injected with probenecid, VU625 inhibited the excretory capacity of mosquitoes and was toxic, suggesting that the compound is a substrate of organic anion and/or ATP-binding cassette (ABC) transporters. The dose-toxicity relationship of VU625 (when co-injected with probenecid) is biphasic, which is consistent with the molecule inhibiting both AeKir1 and AeKir2B with different potencies. This study demonstrates proof-of-concept that potent and highly selective inhibitors of mosquito Kir channels

  1. Doubly charmful baryonic B decays

    SciTech Connect

    Cheng, H.-Y.; Chua, C.-K.; Tsai, S.-Y.

    2006-04-01

    There are two apparent puzzles connected with the two-body and three-body doubly charmed baryonic B decays. First, earlier calculations based on QCD sum rules or the diquark model predict B(B{sup 0}{yields}{xi}{sub c}{sup +}{lambda}{sub c}{sup -}){approx_equal}B(B{sup 0}{yields}B{sub c}N), while experimentally the former has a rate 2 orders of magnitude larger than the latter. Second, a naive estimate of the branching ratio O(10{sup -9}) for the color-suppressed three-body decay B{yields}{lambda}{sub c}{sup +}{lambda}{sub c}{sup -}K, which is highly suppressed by phase space, is too small by 5 to 6 orders of magnitude compared to the experiment. We show that the great suppression for the {lambda}{sub c}{sup +}{lambda}{sub c}{sup -}K production can be alleviated provided that there exists a narrow hidden charm bound state with a mass near the {lambda}{sub c}{lambda}{sub c} threshold. This new state that couples strongly to the charmed baryon pair can be searched for in B decays and in pp collisions by studying the mass spectrum of D{sup (*)}D{sup (*)} or {lambda}{sub c}{lambda}{sub c}. The doubly charmful decay B{yields}{xi}{sub c}{lambda}{sub c} has a configuration more favorable than the singly charmful one such as B{sup 0}{yields}{lambda}{sub c}p since no hard gluon is needed to produce the energetic {xi}{sub c}{lambda}{sub c} pair in the former decay, while two hard gluons are needed for the latter process. Assuming that a soft qq quark pair is produced through the {sigma} and {pi} meson exchanges in the configuration for B{yields}{xi}{sub c}{lambda}{sub c}, it is found that its branching ratio is of order 10{sup -3}, in agreement with the experiment.

  2. Chemical rescue of histidine selectivity filter mutants of the M2 ion channel of influenza A virus.

    PubMed

    Venkataraman, Padmavati; Lamb, Robert A; Pinto, Lawrence H

    2005-06-01

    The influenza virus M2 proton-selective ion channel activity facilitates virus uncoating, a process that occurs in the acidic environment of the endosome. The M2 channel causes acidification of the interior of the virus particle, which results in viral protein-protein dissociation. The M2 protein is a homotetramer that contains in its aqueous pore a histidine residue (His-37) that acts as a selectivity filter and a tryptophan residue (Trp-41) that acts as a channel gate. Substitution of His-37 modifies M2 ion channel properties drastically. However, the results of such experiments are difficult to interpret because substitution of His-37 could cause gross structural changes to the channel pore. We described here experiments in which partial or, in some cases, full rescue of specific M2 ion channel properties of His-37 substitution mutants was achieved by addition of imidazole to the bathing medium. Chemical rescue was demonstrated for three histidine substitution mutant ion channels (M2-H37G, M2-H37S, and M2-H37T) and for two double mutants in which the Trp-41 channel gate was also mutated (H37G/W41Y and H37G/W41A). Currents of the M2-H37G mutant ion channel were inhibited by Cu(II), which has been shown to coordinate with His-37 in the wild-type channel. Chemical rescue was very specific for imidazole. Buffer molecules that were neutral when protonated (4-morpholineethanesulfonic acid and 3-morpholino-2-hydroxypropanesulfonic acid) did not rescue ion channel activity of the M2-H37G mutant ion channel, but 1-methylimidazole did provide partial rescue of function. These results were consistent with a model for proton transport through the pore of the wild-type channel in which the imidazole side chain of His-37 acted as an intermediate proton acceptor/donor group. PMID:15784624

  3. 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

  4. 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

  5. High Guanidinium Permeability Reveals Dehydration-Dependent Ion Selectivity in the Plasmodial Surface Anion Channel

    PubMed Central

    Bokhari, Abdullah A. B.; Mita-Mendoza, Neida K.; Fuller, Alexandra; Pillai, Ajay D.; Desai, Sanjay A.

    2014-01-01

    Malaria parasites grow within vertebrate erythrocytes and increase host cell permeability to access nutrients from plasma. This increase is mediated by the plasmodial surface anion channel (PSAC), an unusual ion channel linked to the conserved clag gene family. Although PSAC recognizes and transports a broad range of uncharged and charged solutes, it must efficiently exclude the small Na+ ion to maintain infected cell osmotic stability. Here, we examine possible mechanisms for this remarkable solute selectivity. We identify guanidinium as an organic cation with high permeability into human erythrocytes infected with Plasmodium falciparum, but negligible uptake by uninfected cells. Transport characteristics and pharmacology indicate that this uptake is specifically mediated by PSAC. The rank order of organic and inorganic cation permeabilities suggests cation dehydration as the rate-limiting step in transport through the channel. The high guanidinium permeability of infected cells also allows rapid and stringent synchronization of parasite cultures, as required for molecular and cellular studies of this pathogen. These studies provide important insights into how nutrients and ions are transported via PSAC, an established target for antimalarial drug development. PMID:25243175

  6. Wavenumber selection for small-wavelength Goertler vortices in curved channel flows

    NASA Technical Reports Server (NTRS)

    Dando, Andrew; Hall, Philip

    1995-01-01

    The problem of wavenumber selection for fully nonlinear, small-wavelength Goertler vortices in a curved channel flow is considered. These types of Goertler vortices were first considered by Hall & Lakin (1988) for an external boundary layer flow. They proved particularly amenable to asymptotic description, it was possible to consider vortices large enough so that the mean flow correction driven by them is as large as the basic state, and this prompted the authors to consider them in a curved channel flow as an initial application of the phase-equation approach to Goertler vortices. This involves the assumption that the phase variable of these Goertler vortices varies on slow spanwise and time scales, then an analysis of both inside and outside the core region, to which vortex activity is restricted, leads to a system of partial differential equations which can be solved numerically for the wavenumber. The authors consider in particular the effect on the wavenumber of the outer channel wall varying on the same slow spanwise scale as the phase variable.

  7. Diversity technique for DAPSK signal over the frequency-selective fading channel

    NASA Astrophysics Data System (ADS)

    Lee, Jong Y.; Chung, Young M.; Lee, Sang U.

    2001-10-01

    In this paper, a maximal ratio combining (MRC) and weighted maximal ratio combining (WMRC) diversity receiver are proposed. The MRC receiver makes a decision at each branch based on the minimum distance criterion. The performance of the MRC receiver is analyzed on the frequency-selective Rayleigh and Rician fading channels, in terms of the union bound for bit error probability. In addition, the WMRC receiver, which assigns weighting factors to the decision variable at each branch, based on the optimum decision boundaries, is proposed. The performance of the WMRC is investigated through the computer simulation and compared with those of MRC and equal gain combining (EGC). From the results, it is found that the performances of the WMRC and MRC are better than those of EGC on both the frequency-selective Rayleigh and Rician fading channels and performance improvements over the EGC are noticeable when the number of diversity branches is large as long as the root mean square (rms) delay is smaller than or equal to 10% of the symbol period.

  8. 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

  9. 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.

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

    DOE PAGESBeta

    Li, Zhan; Wang, Chunmei; Tian, Longlong; Bai, Jing; Yao, Huijun; Zhao, Yang; Zhang, Xin; Cao, Shiwei; Qi, Wei; Wang, Suomin; et al

    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

  11. 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.

  12. 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

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

    PubMed

    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 (84)Kr(25+), 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

  14. Luminal non-selective cation and outwardly rectifying chloride channels in cultured strial marginal cells from gerbil.

    PubMed

    Yeh, T; Van den Abbeele, T; Marianovski, R; Herman, P; Tran Ba Huy, P

    1995-10-01

    Ionic channels located on the luminal side of strial marginal cells (MCs) of gerbil in culture were investigated using the patch-clamp technique. Two types of channels were identified. The most frequently recorded single-channel activity corresponded to a non-selective cation (NSC) channel with a conductance of 23.7 +/- 0.2 pS (n = 18) in symmetrical NaCl conditions. The channel was activated by internal Ca2+ and inhibited by internal adenine nucleotides and flufenamic acid. Spontaneous activity of NSC channels was found in 16% of the cell-attached patches and with a very high density (9 +/- 2 levels/patch, n = 28) in 100% of the excised patches. An outwardly rectifying chloride (ORC) channel was also identified in 14% of the patches but only after excision. The channel exhibited at 0 mV a unit conductance of 26.8 +/- 1.3 pS (n = 8) and a strong outward rectification in symmetrical NaCl conditions, and the open probability increased with depolarization. The luminal NSC channel and the ORC channel evidenced in this study might participate in the production of endolymph. Although extrapolation of the presents results to the in vivo situation should be made with caution, this study suggests that culture of strial MCs may be a suitable model for investigation of endolymph physiology. PMID:8975008

  15. 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

    2015-07-01

    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

  16. 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

  17. Myrsinane, Premyrsinane, and Cyclomyrsinane Diterpenes from Euphorbia falcata as Potassium Ion Channel Inhibitors with Selective G Protein-Activated Inwardly Rectifying Ion Channel (GIRK) Blocking Effects.

    PubMed

    Vasas, Andrea; Forgo, Peter; Orvos, Péter; Tálosi, László; Csorba, Attila; Pinke, Gyula; Hohmann, Judit

    2016-08-26

    GIRK channels are activated by a large number of G protein-coupled receptors and regulate the electrical activity of neurons, cardiac atrial myocytes, and β-pancreatic cells. Abnormalities in GIRK channel function have been implicated in the pathophysiology of neuropathic pain, drug addiction, and cardiac arrhythmias. In the heart, GIRK channels are selectively expressed in the atrium, and their activation inhibits pacemaker activity, thereby slowing the heart rate. In the present study, 19 new diterpenes, falcatins A-S (1-19), and the known euphorprolitherin D (20) were isolated from Euphorbia falcata. The compounds were assayed on stable transfected HEK-hERG (Kv11.1) and HEK-GIRK1/4 (Kir3.1 and Kir3.4) cells. Blocking activity on GIRK channels was exerted by 13 compounds (61-83% at 10 μM), and, among them, five possessed low potency on the hERG channel (4-20% at 10 μM). These selective activities suggest that myrsinane-related diterpenes are potential lead compounds for the treatment of atrial fibrillation. PMID:27441737

  18. Selectivity of calcium channels in rat uterine smooth muscle: interactions between sodium, calcium and barium ions.

    PubMed

    Jmari, K; Mironneau, C; Mironneau, J

    1987-03-01

    1. Action potentials and membrane currents were recorded by means of a double sucrose-gap technique from Cs-loaded strips from pregnant rats superfused in Ca-free EGTA-containing solutions. 2. When external Ca was reduced below 1 microM in the presence of 1 mM-EGTA, step depolarizations from a holding potential close to the normal resting potential produced tetrodotoxin-resistant inward currents. These currents were suppressed after removal of external Na and blocked by a variety of Ca-channel blockers such as Mn, Co, Ni and nifedipine. 3. Inactivation of the inward Na current was studied using a double-pulse protocol. The degree of inactivation of the Na current was almost maximal for depolarizations of +50 mV. Application of stronger depolarizations did not significantly increase it and had no effect on recovery from inactivation. Similarly, increasing the duration of the conditioning pulse from 30 to 250 ms had no further effect on both amplitude and kinetics of the Na current. These results suggest that the Na current inactivation reflects a pure voltage-dependent mechanism. 4. The effects of external Ca were studied over a 10(9)-fold range in concentration. When external Ca was gradually increased from 1 nM to 1 microM, the inward Na current was reduced and finally abolished. As the external Ca was increased over 0.5 mM, inward current reappeared and increased as Ca became the charge carrier. 5. When Na was the charge carrier, external Ca was the most effective divalent cation in blocking the Ca channel with a half-blockage concentration of 0.1 microM. Addition of millimolar concentrations of Ca and Sr also reduced the Ba current while adding Ba to Ca-containing solution produced no increase in current. 6. Membrane currents in solutions containing both Ba and Ca ions were less than in solutions containing either Ca or Ba at the same concentration, suggesting that Ca channels are single-file multi-ion pores. 7. We conclude that the selectivity of uterine Ca

  19. Identification of R(−)-isomer of efonidipine as a selective blocker of T-type Ca2+ channels

    PubMed Central

    Furukawa, Taiji; Miura, Reiko; Honda, Mitsuyoshi; Kamiya, Natsuko; Mori, Yasuo; Takeshita, Satoshi; Isshiki, Takaaki; Nukada, Toshihide

    2004-01-01

    Efonidipine, a derivative of dihydropyridine Ca2+ antagonist, is known to block both L- and T-type Ca2+ channels. It remains to be clarified, however, whether efonidipine affects other voltage-dependent Ca2+ channel subtypes such as N-, P/Q- and R-types, and whether the optical isomers of efonidipine have different selectivities in blocking these Ca2+ channels, including L- and T-types. To address these issues, the effects of efonidipine and its R(−)- and S(+)-isomers on these Ca2+ channel subtypes were examined electrophysiologically in the expression systems using Xenopus oocytes and baby hamster kidney cells (BHK tk-ts13). Efonidipine, a mixture of R(−)- and S(+)-isomers, exerted blocking actions on L- and T-types, but no effects on N-, P/Q- and R-type Ca2+ channels. The selective blocking actions on L- and T-type channels were reproduced by the S(+)-efonidipine isomer. By contrast, the R(−)-efonidipine isomer preferentially blocked T-type channels. The blocking actions of efonidipine and its enantiomers were dependent on holding potentials. These findings indicate that the R(−)-isomer of efonidipine is a specific blocker of the T-type Ca2+ channel. PMID:15545287

  20. Identification of ML204, a Novel Potent Antagonist That Selectively Modulates Native TRPC4/C5 Ion Channels*

    PubMed Central

    Miller, Melissa; Shi, Jie; Zhu, Yingmin; Kustov, Maksym; Tian, Jin-bin; Stevens, Amy; Wu, Meng; Xu, Jia; Long, Shunyou; Yang, Pu; Zholos, Alexander V.; Salovich, James M.; Weaver, C. David; Hopkins, Corey R.; Lindsley, Craig W.; McManus, Owen; Li, Min; Zhu, Michael X.

    2011-01-01

    Transient receptor potential canonical (TRPC) channels are Ca2+-permeable nonselective cation channels implicated in diverse physiological functions, including smooth muscle contractility and synaptic transmission. However, lack of potent selective pharmacological inhibitors for TRPC channels has limited delineation of the roles of these channels in physiological systems. Here we report the identification and characterization of ML204 as a novel, potent, and selective TRPC4 channel inhibitor. A high throughput fluorescent screen of 305,000 compounds of the Molecular Libraries Small Molecule Repository was performed for inhibitors that blocked intracellular Ca2+ rise in response to stimulation of mouse TRPC4β by μ-opioid receptors. ML204 inhibited TRPC4β-mediated intracellular Ca2+ rise with an IC50 value of 0.96 μm and exhibited 19-fold selectivity against muscarinic receptor-coupled TRPC6 channel activation. In whole-cell patch clamp recordings, ML204 blocked TRPC4β currents activated through either μ-opioid receptor stimulation or intracellular dialysis of guanosine 5′-3-O-(thio)triphosphate (GTPγS), suggesting a direct interaction of ML204 with TRPC4 channels rather than any interference with the signal transduction pathways. Selectivity studies showed no appreciable block by 10–20 μm ML204 of TRPV1, TRPV3, TRPA1, and TRPM8, as well as KCNQ2 and native voltage-gated sodium, potassium, and calcium channels in mouse dorsal root ganglion neurons. In isolated guinea pig ileal myocytes, ML204 blocked muscarinic cation currents activated by bath application of carbachol or intracellular infusion of GTPγS, demonstrating its effectiveness on native TRPC4 currents. Therefore, ML204 represents an excellent novel tool for investigation of TRPC4 channel function and may facilitate the development of therapeutics targeted to TRPC4. PMID:21795696

  1. On the classical vibrational coherence of carbonyl groups in the selectivity filter backbone of the KcsA ion channel.

    PubMed

    Salari, V; Sajadi, M; Bassereh, H; Rezania, V; Alaei, M; Tuszynski, J A

    2015-06-01

    It has been suggested that quantum coherence in the selectivity filter of ion channel may play a key role in fast conduction and selectivity of ions. However, it has not been clearly elucidated yet why classical coherence is not sufficient for this purpose. In this paper, we investigate the classical vibrational coherence between carbonyl groups oscillations in the selectivity filter of KcsA ion channels based on the data obtained from molecular dynamics simulations. Our results show that classical coherence plays no effective role in fast ionic conduction. PMID:25990939

  2. 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.

  3. 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

  4. 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. PMID:21295166

  5. 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.

  6. Channel Selection and Feature Projection for Cognitive Load Estimation Using Ambulatory EEG

    PubMed Central

    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. PMID:18364990

  7. 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. PMID:25084457

  8. Gating-pore currents demonstrate selective and specific modulation of individual sodium channel voltage-sensors by biological toxins.

    PubMed

    Xiao, Yucheng; Blumenthal, Kenneth; Cummins, Theodore R

    2014-08-01

    Voltage-gated sodium channels are critical determinants of nerve and muscle excitability. Although numerous toxins and small molecules target sodium channels, identifying the mechanisms of action is challenging. Here we used gating-pore currents selectively generated in each of the voltage-sensors from the four α-subunit domains (DI-DIV) to monitor the activity of individual voltage-sensors and to investigate the molecular determinants of sodium channel pharmacology. The tarantula toxin huwentoxin-IV (HWTX-IV), which inhibits sodium channel current, exclusively enhanced inward gating-pore currents through the DII voltage-sensor. By contrast, the tarantula toxin ProTx-II, which also inhibits sodium channel currents, altered the gating-pore currents in multiple voltage-sensors in a complex manner. Thus, whereas HWTX-IV inhibits central-pore currents by selectively trapping the DII voltage-sensor in the resting configuration, ProTx-II seems to inhibit central-pore currents by differentially altering the configuration of multiple voltage-sensors. The sea anemone toxin anthopleurin B, which impairs open-channel inactivation, exclusively enhanced inward gating-pore currents through the DIV voltage-sensor. This indicates that trapping the DIV voltage-sensor in the resting configuration selectively impairs open-channel inactivation. Furthermore, these data indicate that although activation of all four voltage-sensors is not required for central-pore current generation, activation of the DII voltage-sensor is crucial. Overall, our data demonstrate that gating-pore currents can determine the mechanism of action for sodium channel gating modifiers with high precision. We propose this approach could be adapted to identify the molecular mechanisms of action for gating modifiers of various voltage-gated ion channels. PMID:24898004

  9. Gating-Pore Currents Demonstrate Selective and Specific Modulation of Individual Sodium Channel Voltage-Sensors by Biological Toxins

    PubMed Central

    Xiao, Yucheng; Blumenthal, Kenneth

    2014-01-01

    Voltage-gated sodium channels are critical determinants of nerve and muscle excitability. Although numerous toxins and small molecules target sodium channels, identifying the mechanisms of action is challenging. Here we used gating-pore currents selectively generated in each of the voltage-sensors from the four α-subunit domains (DI–DIV) to monitor the activity of individual voltage-sensors and to investigate the molecular determinants of sodium channel pharmacology. The tarantula toxin huwentoxin-IV (HWTX-IV), which inhibits sodium channel current, exclusively enhanced inward gating-pore currents through the DII voltage-sensor. By contrast, the tarantula toxin ProTx-II, which also inhibits sodium channel currents, altered the gating-pore currents in multiple voltage-sensors in a complex manner. Thus, whereas HWTX-IV inhibits central-pore currents by selectively trapping the DII voltage-sensor in the resting configuration, ProTx-II seems to inhibit central-pore currents by differentially altering the configuration of multiple voltage-sensors. The sea anemone toxin anthopleurin B, which impairs open-channel inactivation, exclusively enhanced inward gating-pore currents through the DIV voltage-sensor. This indicates that trapping the DIV voltage-sensor in the resting configuration selectively impairs open-channel inactivation. Furthermore, these data indicate that although activation of all four voltage-sensors is not required for central-pore current generation, activation of the DII voltage-sensor is crucial. Overall, our data demonstrate that gating-pore currents can determine the mechanism of action for sodium channel gating modifiers with high precision. We propose this approach could be adapted to identify the molecular mechanisms of action for gating modifiers of various voltage-gated ion channels. PMID:24898004

  10. Point Mutations in the Transmembrane Region of the Clic1 Ion Channel Selectively Modify Its Biophysical Properties

    PubMed Central

    Averaimo, Stefania; Abeti, Rosella; Savalli, Nicoletta; Brown, Louise J.; Curmi, Paul M. G.; Breit, Samuel N.; Mazzanti, Michele

    2013-01-01

    Chloride intracellular Channel 1 (CLIC1) is a metamorphic protein that changes from a soluble cytoplasmic protein into a transmembrane protein. Once inserted into membranes, CLIC1 multimerises and is able to form chloride selective ion channels. Whilst CLIC1 behaves as an ion channel both in cells and in artificial lipid bilayers, its structure in the soluble form has led to some uncertainty as to whether it really is an ion channel protein. CLIC1 has a single putative transmembrane region that contains only two charged residues: arginine 29 (Arg29) and lysine 37 (Lys37). As charged residues are likely to have a key role in ion channel function, we hypothesized that mutating them to neutral alanine to generate K37A and R29A CLIC1 would alter the electrophysiological characteristics of CLIC1. By using three different electrophysiological approaches: i) single channel Tip-Dip in artificial bilayers using soluble recombinant CLIC1, ii) cell-attached and iii) whole-cell patch clamp recordings in transiently transfected HEK cells, we determined that the K37A mutation altered the single-channel conductance while the R29A mutation affected the single-channel open probability in response to variation in membrane potential. Our results show that mutation of the two charged amino acids (K37 and R29) in the putative transmembrane region of CLIC1 alters the biophysical properties of the ion channel in both artificial bilayers and cells. Hence these charged residues are directly involved in regulating its ion channel activity. This strongly suggests that, despite its unusual structure, CLIC1 itself is able to form a chloride ion channel. PMID:24058583

  11. Free energy analysis of conductivity and charge selectivity of M2GlyR-derived synthetic channels.

    PubMed

    Chen, Jianhan; Tomich, John M

    2014-09-01

    Significant progresses have been made in the design, synthesis, modeling and in vitro testing of channel-forming peptides derived from the second transmembrane domain of the α-subunit of the glycine receptor (GlyR). The latest designs, including p22 (KKKKP ARVGL GITTV LTMTT QS), are highly soluble in water with minimal aggregation propensity and insert efficiently into cell membranes to form highly conductive ion channels. The last obstacle to a potential lead sequence for channel replacement treatment of CF patients is achieving adequate chloride selectivity. We have performed free energy simulation to analyze the conductance and charge selectivity of M2GlyR-derived synthetic channels. The results reveal that the pentameric p22 pore is non-selective. Moderate barriers for permeation of both K(+) and Cl(-) are dominated by the desolvation cost. Despite previous evidence suggesting a potential role of threonine side chains in anion selectivity, the hydroxyl group is not a good surrogate of water for coordinating these ions. We have also tested initial ideas of introducing additional rings of positive changes to various positions along the pore to increase anion selectivity. The results support the feasibility of achieving anion selectivity by modifying the electrostatic properties of the pore, but at the same time suggest that the peptide assembly and pore topology may also be dramatically modified, which could abolish the effects of modified electrostatics on anion selectivity. This was confirmed by subsequent two-electrode voltage clamp measurements showing that none of the tested mono-, di- and tri-Dap substituted sequences was selective. The current study thus highlights the importance of controlling channel topology besides modifying pore electrostatics for achieving anion selectivity. Several strategies are now being explored in our continued efforts to design an anion selective peptide channel with suitable biophysical, physiological and pharmacological

  12. Meroterpenoid Chrodrimanins Are Selective and Potent Blockers of Insect GABA-Gated Chloride Channels

    PubMed Central

    Ihara, Makoto; Ling, Yun; Yang, Xinling; Kai, Kenji; Hayashi, Hideo; Matsuda, Kazuhiko

    2015-01-01

    Meroterpenoid chrodrimanins, produced from Talaromyces sp. YO-2, are known to paralyze silkworm (Bombyx mori) larvae, but their target is unknown. We have investigated the actions of chrodrimanin B on ligand-gated ion channels of silkworm larval neurons using patch-clamp electrophysiology. Chrodrimanin B had no effect on membrane currents when tested alone at 1 μM. However, it completely blocked the γ-aminobutyric acid (GABA)-induced current and showed less pronounced actions on acetylcholine- and L-glutamate-induced currents, when delivered at 1 μM for 1 min prior to co-application with transmitter GABA. Thus, chrodrimanins were also tested on a wild-type isoform of the B. mori GABA receptor (GABAR) RDL using two-electrode voltage-clamp electrophysiology. Chrodrimanin B attenuated the peak current amplitude of the GABA response of RDL with an IC50 of 1.66 nM. The order of the GABAR-blocking potency of chrodrimanins B > D > A was in accordance with their reported insecticidal potency. Chrodrimanin B had no open channel blocking action when tested at 3 nM on the GABA response of RDL. Co-application with 3 nM chrodrimanin B shifted the GABA concentration response curve to a higher concentration and further increase of chrodrimanin B concentration to10 nM; it reduced maximum current amplitude of the GABA response, pointing to a high-affinity competitive action and a lower affinity non-competitive action. The A282S;T286V double mutation of RDL, which impairs the actions of fipronil, hardly affected the blocking action of chrodrimanin B, indicating a binding site of chrodrimanin B distinct from that of fipronil. Chrodrimanin B showed approximately 1,000-fold lower blocking action on human α1β2γ2 GABAR compared to RDL and thus is a selective blocker of insect GABARs. PMID:25902139

  13. Meroterpenoid Chrodrimanins Are Selective and Potent Blockers of Insect GABA-Gated Chloride Channels.

    PubMed

    Xu, Yan; Furutani, Shogo; Ihara, Makoto; Ling, Yun; Yang, Xinling; Kai, Kenji; Hayashi, Hideo; Matsuda, Kazuhiko

    2015-01-01

    Meroterpenoid chrodrimanins, produced from Talaromyces sp. YO-2, are known to paralyze silkworm (Bombyx mori) larvae, but their target is unknown. We have investigated the actions of chrodrimanin B on ligand-gated ion channels of silkworm larval neurons using patch-clamp electrophysiology. Chrodrimanin B had no effect on membrane currents when tested alone at 1 μM. However, it completely blocked the γ-aminobutyric acid (GABA)-induced current and showed less pronounced actions on acetylcholine- and L-glutamate-induced currents, when delivered at 1 μM for 1 min prior to co-application with transmitter GABA. Thus, chrodrimanins were also tested on a wild-type isoform of the B. mori GABA receptor (GABAR) RDL using two-electrode voltage-clamp electrophysiology. Chrodrimanin B attenuated the peak current amplitude of the GABA response of RDL with an IC50 of 1.66 nM. The order of the GABAR-blocking potency of chrodrimanins B > D > A was in accordance with their reported insecticidal potency. Chrodrimanin B had no open channel blocking action when tested at 3 nM on the GABA response of RDL. Co-application with 3 nM chrodrimanin B shifted the GABA concentration response curve to a higher concentration and further increase of chrodrimanin B concentration to 10 nM; it reduced maximum current amplitude of the GABA response, pointing to a high-affinity competitive action and a lower affinity non-competitive action. The A282S;T286V double mutation of RDL, which impairs the actions of fipronil, hardly affected the blocking action of chrodrimanin B, indicating a binding site of chrodrimanin B distinct from that of fipronil. Chrodrimanin B showed approximately 1,000-fold lower blocking action on human α1β2γ2 GABAR compared to RDL and thus is a selective blocker of insect GABARs. PMID:25902139

  14. A Change in the Ion Selectivity of Ligand-Gated Ion Channels Provides a Mechanism to Switch Behavior.

    PubMed

    Pirri, Jennifer K; Rayes, Diego; Alkema, Mark J

    2015-01-01

    Behavioral output of neural networks depends on a delicate balance between excitatory and inhibitory synaptic connections. However, it is not known whether network formation and stability is constrained by the sign of synaptic connections between neurons within the network. Here we show that switching the sign of a synapse within a neural circuit can reverse the behavioral output. The inhibitory tyramine-gated chloride channel, LGC-55, induces head relaxation and inhibits forward locomotion during the Caenorhabditis elegans escape response. We switched the ion selectivity of an inhibitory LGC-55 anion channel to an excitatory LGC-55 cation channel. The engineered cation channel is properly trafficked in the native neural circuit and results in behavioral responses that are opposite to those produced by activation of the LGC-55 anion channel. Our findings indicate that switches in ion selectivity of ligand-gated ion channels (LGICs) do not affect network connectivity or stability and may provide an evolutionary and a synthetic mechanism to change behavior. PMID:26348462

  15. On the Construction of Orthogonal Spreading Code Groups for MC-CDMA with FDE in a Frequency Selective Channel

    NASA Astrophysics Data System (ADS)

    Adachi, Koichi; Nakagawa, Masao

    The bit error rate (BER) performance of multicode multi-carrier code division multiple access (MC-CDMA) severely degrades due to the inter-code interference (ICI) in a strong frequency-selective channel. Recently a spreading code group construction method was proposed for MC-CDMA. The Walsh-Hadmard (WH) codes are divided into a number of code groups such that the code orthogonality can be maintained within each group even in a strong frequency-selective channel; any code pair taken from different groups is not orthogonal. The number of spreading codes in each group is determined by the maximum time delay difference of the channel. In this paper, we point out that the number of codes in each group is determined by the distribution of time delay differences among the propagation paths of the channel, not the maximum time delay difference. Based on that observation, we show that more orthogonal spreading codes can exist in each code group. The conditional BER is derived taking into account the interference from other code groups and the achievable downlink BER performance using the proposed spreading code group construction is numerically evaluated in a frequency-selective Rayleigh fading channel.

  16. Main-channel slopes of selected streams in Iowa for estimation of flood-frequency discharges

    USGS Publications Warehouse

    Eash, David A.

    2003-01-01

    This report describes a statewide study conducted to develop main-channel slope (MCS) curves for 138 selected streams in Iowa with drainage areas greater than 100 square miles. MCS values determined from the curves can be used in regression equations for estimating floodfrequency discharges. Multivariable regression equations previously developed for two of the three hydrologic regions defined for Iowa require the measurement of MCS. Main-channel slope is a difficult measurement to obtain for large streams using 1:24,000-scale topographic maps. The curves developed in this report provide a simplified method for determining MCS values for sites located along large streams in Iowa within hydrologic Regions 2 and 3. The curves were developed using MCS values quantified for 2,058 selected sites along 138 selected streams in Iowa. A geographic information system (GIS) technique and 1:24,000-scale topographic data were used to quantify MCS values for the stream sites. The sites were selected at about 5-mile intervals along the streams. River miles were quantified for each stream site using a GIS program. Data points for river-mile and MCS values were plotted and a best-fit curve was developed for each stream. An adjustment was applied to all 138 curves to compensate for differences in MCS values between manual measurements and GIS quantifications. The multivariable equations for Regions 2 and 3 were developed using manual measurements of MCS. A comparison of manual measurements and GIS quantifications of MCS indicates that manual measurements typically produce greater values of MCS compared to GIS quantifications. Median differences between manual measurements and GIS quantifications of MCS are 14.8 and 17.7 percent for Regions 2 and 3, respectively. Comparisons of percentage differences between flood-frequency discharges calculated using MCS values of manual measurements and GIS quantifications indicate that use of GIS values of MCS for Region 3 substantially

  17. Keeping active channels in their place: membrane phosphoinositides regulate TRPM channel activity in a compartment-selective manner.

    PubMed

    Braun, Andrew P

    2012-01-01

    We have long appreciated that the controlled movement of ions and solutes across the cell surface or plasma membrane affects every aspect of cell function, ranging from membrane excitability to metabolism to secretion, and is also critical for the long-term maintenance of cell viability. Studies examining these physiological transport processes have revealed a vast array of ion channels, transporters and ATPase-driven pumps that underlie these transmembrane ionic movements and how acquired or genetic disruption of these processes are linked to disease. More recently, it has become evident that the ongoing function of intracellular organelles and subcellular compartments also depends heavily on the controlled movement of ions to establish distinct pH or ionic environments. However, limited experimental access to these subcellular domains/structures has hampered scientific progress in this area, due in large part to the difficulty of applying proven functional assays, such as patch clamp and radiotracer methodologies, to these specialized membrane locations. Using both functional and immune-labeling assays, we now know that the types and complement of channels, transporters and pumps located within intracellular membranes and organelles often differ from those present on the plasma membrane. Moreover, it appears that this differential distribution is due to the presence of discrete tags/signals present within these transport proteins that dictate their sorting/trafficking to spatially discrete membrane compartments, where they may also interact with scaffolding proteins that help maintain their localization. Such targeting signals may thus operate in a manner analogous to the way a postal code is used to direct the delivery of a letter. PMID:23151432

  18. Targeting the Ion Channel Kv1.3 with Scorpion Venom Peptides Engineered for Potency, Selectivity, and Half-life

    PubMed Central

    Edwards, Wilson; Fung-Leung, Wai-Ping; Huang, Chichi; Chi, Ellen; Wu, Nancy; Liu, Yi; Maher, Michael P.; Bonesteel, Rachelle; Connor, Judith; Fellows, Ross; Garcia, Elena; Lee, Jerry; Lu, Lu; Ngo, Karen; Scott, Brian; Zhou, Hong; Swanson, Ronald V.; Wickenden, Alan D.

    2014-01-01

    Ion channels are an attractive class of drug targets, but progress in developing inhibitors for therapeutic use has been limited largely due to challenges in identifying subtype selective small molecules. Animal venoms provide an alternative source of ion channel modulators, and the venoms of several species, such as scorpions, spiders and snails, are known to be rich sources of ion channel modulating peptides. Importantly, these peptides often bind to hyper-variable extracellular loops, creating the potential for subtype selectivity rarely achieved with small molecules. We have engineered scorpion venom peptides and incorporated them in fusion proteins to generate highly potent and selective Kv1.3 inhibitors with long in vivo half-lives. Kv1.3 has been reported to play a role in human T cell activation, and therefore, these Kv1.3 inhibitor fusion proteins may have potential for the treatment of autoimmune diseases. Our results support an emerging approach to generating subtype selective therapeutic ion channel inhibitors. PMID:24939846

  19. Frequency-selective fading statistics of shallow-water acoustic communication channel with a few multipaths

    NASA Astrophysics Data System (ADS)

    Bae, Minja; Park, Jihyun; Kim, Jongju; Xue, Dandan; Park, Kyu-Chil; Yoon, Jong Rak

    2016-07-01

    The bit error rate of an underwater acoustic communication system is related to multipath fading statistics, which determine the signal-to-noise ratio. The amplitude and delay of each path depend on sea surface roughness, propagation medium properties, and source-to-receiver range as a function of frequency. Therefore, received signals will show frequency-dependent fading. A shallow-water acoustic communication channel generally shows a few strong multipaths that interfere with each other and the resulting interference affects the fading statistics model. In this study, frequency-selective fading statistics are modeled on the basis of the phasor representation of the complex path amplitude. The fading statistics distribution is parameterized by the frequency-dependent constructive or destructive interference of multipaths. At a 16 m depth with a muddy bottom, a wave height of 0.2 m, and source-to-receiver ranges of 100 and 400 m, fading statistics tend to show a Rayleigh distribution at a destructive interference frequency, but a Rice distribution at a constructive interference frequency. The theoretical fading statistics well matched the experimental ones.

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

    PubMed Central

    Cui, Yuanyuan; Yang, Fan; Cao, Xu; Yarov-Yarovoy, Vladimir

    2012-01-01

    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. PMID:22412190

  1. Selective deposition response to aeolian-fluvial sediment supply in the desert braided channel of the upper Yellow River, China

    NASA Astrophysics Data System (ADS)

    Wang, H.; Jia, X.; Li, Y.; Peng, W.

    2015-09-01

    Rivers flow across aeolian dunes and develop braided stream channels. Both aeolian and fluvial sediment supplies regulate sediment transport and deposition in such cross-dune braided rivers. Here we show a significant selective deposition in response to both aeolian and fluvial sediment supplies in the Ulan Buh desert braided channel. The Ulan Buh desert is the main coarse sediment source for this desert braided channel, and the mean percentage of the coarser (> 0.08 mm) grains on the aeolian dunes surface is 95.34 %. The lateral selective deposition process is developed by the interaction between the flows and the aeolian-fluvial sediment supplies, causing the coarser sediments (> 0.08 mm) from aeolian sand supply and bank erosion to accumulate in the channel centre and the finer fluvial sediments (< 0.08 mm) to be deposited on the bar and floodplain surfaces, forming a coarser-grained thalweg bed bounded by finer-grained floodplain surfaces. This lateral selective deposition reduces the downstream sediment transport and is a primary reason for the formation of an "above-ground" river in the braided reach of the upper Yellow River in response to aeolian and fluvial sediment supplies.

  2. Electrophysiological evidence for 4-isobutyl-3-isopropylbicyclophosphorothionate as a selective blocker of insect GABA-gated chloride channels.

    PubMed

    Akiyoshi, Yuki; Ju, Xiu-Lian; Furutani, Shogo; Matsuda, Kazuhiko; Ozoe, Yoshihisa

    2013-06-01

    Invertebrate γ-aminobutyric acid (GABA)-gated chloride channels (GABACls) and glutamate-gated chloride channels (GluCls), which function as inhibitory neurotransmitter receptors, are important targets of insecticides and antiparasitic agents. The antagonism of GABACls and GluCls by 4-isobutyl-3-isopropylbicyclophosphorothionate (PS-14) was examined in cultured cockroach and rat neurons using a whole-cell patch-clamp method. The results indicated that PS-14 selectively blocks cockroach GABACls relative to cockroach GluCls and rat GABACls. PS-14 represents a useful probe for the study of insect GABA receptors. PMID:23591113

  3. Isoform-selective physical coupling of TRPC3 channels to IP3 receptors in smooth muscle cells regulates arterial contractility

    PubMed Central

    Adebiyi, Adebowale; Zhao, Guiling; Narayanan, Damodaran; Thomas, Candice M.; Bannister, John P.; Jaggar, Jonathan H.

    2010-01-01

    Rationale Inositol 1,4,5-trisphosphate (IP3)-induced vasoconstriction can occur independently of intracellular Ca2+ release and via IP3 receptor (IP3R) and canonical transient receptor potential (TRPC) channel activation, but functional signaling mechanisms mediating this effect are unclear. Objectives Study mechanisms by which IP3Rs stimulate TRPC channels in myocytes of resistance-size cerebral arteries. Methods and Results Immunofluorescence resonance energy transfer (immuno-FRET) microscopy using isoform-selective antibodies indicated that endogenous type 1 IP3Rs (IP3R1) are in close spatial proximity to TRPC3, but distant from TRPC6 or TRPM4 channels in arterial myocytes. Endothelin-1 (ET-1), a phospholipase C-coupled receptor agonist, elevated immuno-FRET between IP3R1 and TRPC3, but not between IP3R1 and TRPC6 or TRPM4. TRPC3, but not TRPC6, co-immunoprecipitated with IP3R1. TRPC3 and TRPC6 antibodies selectively inhibited recombinant channels, but only the TRPC3 antibody blocked IP3-induced non-selective cation current (ICat) in myocytes. TRPC3 knockdown attenuated immuno-FRET between IP3R1 and TRPC3, IP3-induced ICat activation, and ET-1 and IP3-induced vasoconstriction, whereas TRPC6 channel knockdown had no effect. ET-1 did not alter total or plasma membrane-localized TRPC3, as determined using surface biotinylation. RT-PCR demonstrated that C-terminal calmodulin and IP3R binding (CIRB) domains are present in myocyte TRPC3 and TRPC6 channels. A peptide corresponding to the IP3R N-terminal region that can interact with TRPC channels activated ICat. A TRPC3 CIRB domain peptide attenuated IP3- and ET-1-induced ICat activation and vasoconstriction. Conclusions IP3 stimulates direct coupling between IP3R1 and membrane-resident TRPC3 channels in arterial myocytes, leading to ICat activation and vasoconstriction. Close spatial proximity between IP3R1 and TRPC3 establishes this isoform-selective functional interaction. PMID:20378853

  4. From Pan-Reactive KV7 Channel Opener to Subtype Selective Opener/Inhibitor by Addition of a Methyl Group

    PubMed Central

    Blom, Sigrid Marie; Rottländer, Mario; Kehler, Jan; Bundgaard, Christoffer; Schmitt, Nicole; Jensen, Henrik Sindal

    2014-01-01

    The voltage-gated potassium channels of the KV7 family (KV7.1–5) play important roles in controlling neuronal excitability and are therefore attractive targets for treatment of CNS disorders linked to hyperexcitability. One of the main challenges in developing KV7 channel active drugs has been to identify compounds capable of discriminating between the neuronally expressed subtypes (KV7.2–5), aiding the identification of the subunit composition of KV7 currents in various tissues, and possessing better therapeutic potential for particular indications. By taking advantage of the structure-activity relationship of acrylamide KV7 channel openers and the effects of these compounds on mutant KV7 channels, we have designed and synthesized a novel KV7 channel modulator with a unique profile. The compound, named SMB-1, is an inhibitor of KV7.2 and an activator of KV7.4. SMB-1 inhibits KV7.2 by reducing the current amplitude and increasing the time constant for the slow component of the activation kinetics. The activation of KV7.4 is seen as an increase in the current amplitude and a slowing of the deactivation kinetics. Experiments studying mutant channels with a compromised binding site for the KV7.2–5 opener retigabine indicate that SMB-1 binds within the same pocket as retigabine for both inhibition of KV7.2 and activation of KV7.4. SMB-1 may serve as a valuable tool for KV7 channel research and may be used as a template for further design of better subtype selective KV7 channel modulators. A compound with this profile could hold novel therapeutic potential such as the treatment of both positive and cognitive symptoms in schizophrenia. PMID:24956197

  5. Search for doubly charged Higgs bosons through vector boson fusion at the LHC and beyond

    NASA Astrophysics Data System (ADS)

    Bambhaniya, G.; Chakrabortty, J.; Gluza, J.; Jeliński, T.; Szafron, R.

    2015-07-01

    Production and decays of doubly charged Higgs bosons at the LHC and future hadron colliders triggered by a vector boson fusion mechanism are discussed in the context of the minimal left-right symmetric model. Our analysis is based on the Higgs boson mass spectrum compatible with available constraints which include flavor changing neutral current (FCNC) effects and vacuum stability of the scalar potential. Though the parity breaking scale vR is large (˜ few TeV) and scalar masses which contribute to FCNC effects are even larger, a consistent Higgs boson mass spectrum still allows us to keep doubly charged scalar masses below 1 TeV which is an interesting situation for LHC and future circular collider (FCC). We have shown that the allowed Higgs boson mass spectrum constrains the splittings (MH1±±-MH1± ), closing the possibility of H1±±→W1±H1± decays. Assuming that doubly charged Higgs bosons decay predominantly into a pair of same-sign charged leptons through the process p p →H1/2 ±±H1/2 ∓∓j j →ℓ±ℓ±ℓ∓ℓ∓j j , we find that for the LHC operating at √{s }=14 TeV with an integrated luminosity at the level of 3000 fb-1 (HL-LHC), there is practically no chance to detect such particles at the reasonable significance level through this channel. However, at 33 TeV HE-LHC and (or) 100 TeV FCC-hh, a wide region opens up for exploring the doubly charged Higgs boson mass spectrum. In FCC-hh, the doubly charged Higgs bosons mass up to 1 TeV can be easily probed.

  6. Decays of doubly charmed meson molecules

    NASA Astrophysics Data System (ADS)

    Molina, R.; Nagahiro, H.; Hosaka, A.

    2016-01-01

    If the X(3872), Y(3940) and X(4160) are D*D ¯+c .c ., D*D ¯* and DS*D¯S* molecules, respectively, there should be doubly charmed mesons (D(*)D(*)). In this talk we predict two states with JP = 1+ in the charm = 2 sector, one DD* state around 3850 MeV, other D*D* state with mass around 3970 MeV, and other two similar states in the (charm = 2; strangeness = sector. Besides that, we evaluate the decay widths of doubly charm mesons D*D*(1+), into DDπ and DDγ. These decays are mediated by anomalous couplings D*D* - DD*, with the subsequent decay of D* into Dπ or Dγ.

  7. Selectivity of a Singly Permeating Ion in Nonselective NaK Channel: Combined QM and MD Based Investigations.

    PubMed

    Sadhu, Biswajit; Sundararajan, Mahesh; Bandyopadhyay, Tusar

    2015-10-01

    Ion channels, such as potassium channels are known to discriminate ions to achieve remarkable selective transportation of K(+) over Na(+) through the membrane. The recently reported NaK ion channel, on the contrary, seems to be an exception, as it is observed to permeate most of the group IA alkali metal cations and hence is suggested to be nonselective in nature. However, does that correspond to a complete annihilation of selectivity inside the selectivity filter (SF) of the channel? What is the origin of such nonselectivity/selectivity, if any? The present computational study is an extensive multiscale modeling approach to find the probable answers to these intriguing questions. Here, we have used density functional theory (DFT) based calculations using a realistic truncated model of SF from the crystal structures of the NaK ion channel to evaluate the binding of various alkali metal ions (Na(+), K(+) and Cs(+)), free from "contamination" due to the absence any other "rivalry" cations, in its different binding sites. Among all of the possible binding sites, a vestibule is noticed to be nonselective and seen to act as a probable binding site only in the presence of multiple ions. Binding sites S3 and S4 are found to be selective for K(+) and Na(+), respectively. As an important observation, we find that calculations on oversimplified models using an isolated ion binding site may lead to an erroneous selectivity trend as it neglects the synergetics of consecutive binding sites on the final outcome. Energy decomposition analysis revealed ion-dipole electrostatics as the major contributing interaction in metal-bound binding sites. Our investigations find that although NaK is permeable to monovalent alkali metal ions, strongly "site specific" selectivity does exist at the three well-defined noncontiguous binding sites of the SF. Different important physicomechanical parameters (such as ligating environment, synergistic influence of binding sites, and topological

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

    SciTech Connect

    Valiyaveetil,F.; Sekedat, M.; MacKinnon, R.; Muir, T.

    2006-01-01

    The selectivity filter of K{sup +} channels comprises four contiguous ion binding sites, S1 through S4. Structural and functional data indicate that the filter contains on average two K{sup +} 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{sup +} 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{sup +}, Rb{sup +}, and Cs{sup +} within the filter, with the most dramatic change found for Rb{sup +}. 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{sup +} 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.

  9. 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

  10. 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…

  11. Filtering Characteristics of Doubly Sinusoidal Periodic Media

    NASA Astrophysics Data System (ADS)

    Dong, Tian-Lin; Chen, Ping

    2006-03-01

    Dispersion and filtering characteristics of doubly sinusoidal periodic (DSP) medium is investigated. Based on its feature different from singly sinusoidal periodic medium, a novel dual-band filter model is realized and measured. The results show that even a single unit cell of DSP medium can provide rather good filtering performance. And the filter is of perfect compatibility with regular waveguide and substrate integrated waveguide technology.

  12. Three-charge doubly rotating black ring

    SciTech Connect

    Gal'tsov, Dmitri V.; Scherbluk, Nikolai G.

    2010-02-15

    Using the recently proposed new solution generating technique, we construct the charged version of the Pomeranski-Senkov doubly rotating black ring in the U(1){sup 3} five-dimensional supergravity. For arbitrary values of charges the solution is unbalanced, but the Dirac-Misner string is removed when two of the charges are set to zero. In this particular case our solution can be uplifted to some solutions of six-dimensional vacuum gravity.

  13. Selective action of two aporphines at alpha 1-adrenoceptors and potential-operated Ca2+ channels.

    PubMed

    Ivorra, M D; Chuliá, S; Lugnier, C; D'Ocon, M P

    1993-02-01

    Contractions evoked by noradrenaline (1 microM) or a depolarizing solution of 60 mM KCl were concentration dependently depressed by the aporphine alkaloids (S)-boldine and (R)-apomorphine in rat aorta. Both drugs had a greater inhibitory potency on the contraction elicited by noradrenaline. Dose-response curves for noradrenaline were shifted to the right in presence of (S)-boldine. (R)-Apomorphine acted by a complex mechanism at alpha 1-adrenoceptors and its inhibitory effect was irreversible. The conformational features of these alkaloids may explain their different behaviour at alpha 1-adrenoceptors. In Ca(2+)-free solution, the alkaloids inhibited the contraction evoked by noradrenaline but did not modify (apomorphine) or increase (boldine) the contractile response induced by caffeine. Both alkaloids interacted with [3H]prazosin binding and with the benzothiazepine binding site of the Ca2+ entry receptor complex but had no effect at the dihydropyridine binding site in the rat cerebral cortex. Both drugs showed some selectivity as inhibitors of [3H]prazosin binding as opposed to [3H]d-cis diltiazem binding. (R)-Apomorphine slightly inhibited one of the two forms of the Ca(2+)-independent, low Km cyclic AMP-phosphodiesterase (type IV), whereas it did not have a significant effect on the other phosphodiesterase forms. (S)-Boldine had negligible inhibitory effects on all phosphodiesterase forms. The present study provides evidence that (S)-boldine and (R)-apomorphine have interesting properties as Ca2+ entry blockers (through the benzothiazepine receptor site in the Ca2+ channel) and at alpha 1-adrenoceptors. PMID:8384112

  14. Selective modulation of cellular voltage-dependent calcium channels by hyperbaric pressure-a suggested HPNS partial mechanism.

    PubMed

    Aviner, Ben; Gradwohl, Gideon; Mor Aviner, Merav; Levy, Shiri; Grossman, Yoram

    2014-01-01

    Professional deep sea divers experience motor and cognitive impairment, known as High Pressure Neurological Syndrome (HPNS), when exposed to pressures of 100 msw (1.1 MPa) and above, considered to be the result of synaptic transmission alteration. Previous studies have indicated modulation of presynaptic Ca(2+) currents at high pressure. We directly measured for the first time pressure effects on the currents of voltage dependent Ca(2+) channels (VDCCs) expressed in Xenopus oocytes. Pressure selectivity augmented the current in CaV1.2 and depressed it in CaV3.2 channels. Pressure application also affected the channels' kinetics, such as ƮRise, ƮDecay. Pressure modulation of VDCCs seems to play an important role in generation of HPNS signs and symptoms. PMID:24904281

  15. Selective modulation of cellular voltage-dependent calcium channels by hyperbaric pressure—a suggested HPNS partial mechanism

    PubMed Central

    Aviner, Ben; Gradwohl, Gideon; Mor Aviner, Merav; Levy, Shiri; Grossman, Yoram

    2014-01-01

    Professional deep sea divers experience motor and cognitive impairment, known as High Pressure Neurological Syndrome (HPNS), when exposed to pressures of 100 msw (1.1 MPa) and above, considered to be the result of synaptic transmission alteration. Previous studies have indicated modulation of presynaptic Ca2+ currents at high pressure. We directly measured for the first time pressure effects on the currents of voltage dependent Ca2+ channels (VDCCs) expressed in Xenopus oocytes. Pressure selectivity augmented the current in CaV1.2 and depressed it in CaV3.2 channels. Pressure application also affected the channels' kinetics, such as ƮRise, ƮDecay. Pressure modulation of VDCCs seems to play an important role in generation of HPNS signs and symptoms. PMID:24904281

  16. 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. PMID:25616853

  17. 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.

  18. Affinity and selectivity of ShK toxin for the Kv1 potassium channels from free energy simulations.

    PubMed

    Rashid, M Harunur; Kuyucak, Serdar

    2012-04-26

    The voltage-gated potassium channel Kv1.3 is an attractive target for treatment of autoimmune diseases. ShK toxin from sea anemone is one of the most potent blockers of Kv1.3, and therefore ShK and its analogues have been proposed as therapeutic leads for such diseases. Increasing the selectivity of the proposed leads for Kv1.3 over other Kv1 channels is a major issue in this endeavor. Here we study binding of ShK toxin to Kv1 channels using free energy simulation methods. Homology models for Kv1.1 and Kv1.3 channels are constructed using the crystal structure of Kv1.2. The initial poses for the Kv1.x-ShK complexes are obtained using HADDOCK, which are then refined via molecular dynamics simulations. The binding mode in each complex is characterized by identifying the strongly interacting residues, which compare well with available mutagenesis studies. For each complex, the potential of mean force is calculated from umbrella sampling simulations, and the corresponding absolute binding free energy is determined. The computed binding free energies are in good agreement with the experimental data, which increases the confidence on the model complexes. The insights gained on Kv1.x-ShK binding modes will be valuable in the development of new ShK analogues with better selectivity properties. PMID:22480371

  19. Bordetella pertussis major outer membrane porin protein forms small, anion-selective channels in lipid bilayer membranes.

    PubMed Central

    Armstrong, S K; Parr, T R; Parker, C D; Hancock, R E

    1986-01-01

    The major outer membrane protein of molecular weight 40,000 (the 40K protein) of a virulent isolate of Bordetella pertussis was purified to apparent homogeneity. The purified protein formed an oligomer band (of apparent molecular weight 90,000) on sodium dodecyl sulfate-polyacrylamide gels after solubilization at low temperatures. The porin function of this protein was characterized by the black lipid bilayer method. The 40K protein formed channels smaller than all other constitutive major outer membrane porins studied to date. The average single-channel conductance in 1 M KCl was 0.56 nS. This was less than a third of the conductance previously observed for Escherichia coli porins. Zero-current potential measurements made of the porin to determine its ion selectivity revealed the porin to be more than 100-fold selective for anions over cations. The single-channel conductance was measured as a function of salt concentration. The data could be fitted to a Lineweaver-Burk plot suggesting an anion binding site with a Kd of 1.17 M Cl- and a maximum possible conductance through the channel of 1.28 nS. Images PMID:2420780

  20. Peregrination of the selectivity filter delineates the pore of the human voltage-gated proton channel hHV1

    PubMed Central

    Morgan, Deri; Musset, Boris; Kulleperuma, Kethika; Smith, Susan M.E.; Rajan, Sindhu; Cherny, Vladimir V.; Pomès, Régis

    2013-01-01

    Extraordinary selectivity is crucial to all proton-conducting molecules, including the human voltage-gated proton channel (hHV1), because the proton concentration is >106 times lower than that of other cations. Here we use “selectivity filter scanning” to elucidate the molecular requirements for proton-specific conduction in hHV1. Asp112, in the middle of the S1 transmembrane helix, is an essential part of the selectivity filter in wild-type (WT) channels. After neutralizing Asp112 by mutating it to Ala (D112A), we introduced Asp at each position along S1 from 108 to 118, searching for “second site suppressor” activity. Surprisingly, most mutants lacked even the anion conduction exhibited by D112A. Proton-specific conduction was restored only with Asp or Glu at position 116. The D112V/V116D channel strikingly resembled WT in selectivity, kinetics, and ΔpH-dependent gating. The S4 segment of this mutant has similar accessibility to WT in open channels, because R211H/D112V/V116D was inhibited by internally applied Zn2+. Asp at position 109 allowed anion permeation in combination with D112A but did not rescue function in the nonconducting D112V mutant, indicating that selectivity is established externally to the constriction at F150. The three positions that permitted conduction all line the pore in our homology model, clearly delineating the conduction pathway. Evidently, a carboxyl group must face the pore directly to enable conduction. Molecular dynamics simulations indicate reorganization of hydrogen bond networks in the external vestibule in D112V/V116D. At both positions where it produces proton selectivity, Asp frequently engages in salt linkage with one or more Arg residues from S4. Surprisingly, mean hydration profiles were similar in proton-selective, anion-permeable, and nonconducting constructs. That the selectivity filter functions in a new location helps to define local environmental features required to produce proton-selective conduction. PMID

  1. Doubly Sparse Relevance Vector Machine for Continuous Facial Behavior Estimation.

    PubMed

    Kaltwang, Sebastian; Todorovic, Sinisa; Pantic, Maja

    2016-09-01

    Certain inner feelings and physiological states like pain are subjective states that cannot be directly measured, but can be estimated from spontaneous facial expressions. Since they are typically characterized by subtle movements of facial parts, analysis of the facial details is required. To this end, we formulate a new regression method for continuous estimation of the intensity of facial behavior interpretation, called Doubly Sparse Relevance Vector Machine (DSRVM). DSRVM enforces double sparsity by jointly selecting the most relevant training examples (a.k.a. relevance vectors) and the most important kernels associated with facial parts relevant for interpretation of observed facial expressions. This advances prior work on multi-kernel learning, where sparsity of relevant kernels is typically ignored. Empirical evaluation on challenging Shoulder Pain videos, and the benchmark DISFA and SEMAINE datasets demonstrate that DSRVM outperforms competing approaches with a multi-fold reduction of running times in training and testing. PMID:26595911

  2. 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.

  3. 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

  4. 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

  5. Adaptive Zero-Padding OFDM over Frequency-Selective Multipath Channels

    NASA Astrophysics Data System (ADS)

    Wang, Neng; Blostein, Steven D.

    2004-12-01

    We present a novel bandwidth (BW) efficient orthogonal frequency division multiplexing (OFDM) scheme with adaptive zero-padding (AZP-OFDM) for wireless transmission. Redundancy issues in OFDM based on cyclic prefix (CP), zero-padding (ZP), as well as no guard interval (NGI) systems are analyzed. A novel system design criterion based on the channel matrix condition is studied and applied to the design of an AZP-OFDM system. Simulation results have shown that the proposed AZP-OFDM offers performance similar to that of CP-OFDM, complexity similar to that of ZP-OFDM, with BW efficiency higher than that of both CP- and ZP-OFDM in channels with small to moderate delay spread. In channels with large delay spread, AZP scheme adaptively maintains high performance at the expense of BW efficiency. Essentially, AZP-OFDM offers a more flexible tradeoff between symbol recovery, BW efficiency, and complexity.

  6. 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

  7. 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

  8. 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.

  9. Kinetic properties and selectivity of calcium-permeable single channels in Aplysia neurones.

    PubMed Central

    Chesnoy-Marchais, D

    1985-01-01

    Two kinds of single channels, carrying inward currents even above the Na and Cl ion equilibrium potentials, were observed in outside-out patches from Aplysia neurones bathed in K-free internal and external solutions. The channel carrying the larger elementary current has been studied in detail. When the internal solution contained mainly CsCl, this channel usually inactivated during the first minutes following isolation of the membrane patch. However, when the internal solution contained NaCl instead of CsCl, the channel remained functional during several hours, thus allowing the present study. Na-Tris, NaCl-mannitol and Ca-Ba external substitution experiments showed that the channel studied is much more permeable to divalent cations than to sodium ions. Mono-exponential open-time distributions obtained under identical conditions from different membrane patches indicated either slow (in the order of 100 ms at 0 mV) or rapid (a few milliseconds at 0 mV) mean open-times. Biphasic open-time distributions could be obtained from other membrane patches under the same conditions. These results suggest the existence of two different gating modes. Both the open-time distribution and the closed-time distribution are voltage sensitive: membrane depolarization activates the channel by lengthening the openings and shortening the closures. The threshold of activation if any, is very low and the inactivation, if present, is never complete. Ca-Ba, Ca-Sr and Ca-Mg external substitution experiments showed that the elementary current amplitude is not very sensitive to the nature of the external divalent cation. The elementary current can be slightly larger when carried by Ba ions rather than by Ca ions, but is nearly identical whether carried by Ca, Sr or even Mg ions, which leads to the elementary conductance sequence: Ba greater than or equal to Ca = Sr congruent to Mg. In contrast, the mean open-time of the channel is very sensitive to the nature of the external permeant ion. The

  10. Mirroring Doubly Excited Resonances in Argon

    SciTech Connect

    Canton-Rogan, S. E.; Wills, A. A.; Gorczyca, T. W.; Wiedenhoeft, M.; Nayandin, O.; Liu, Chien-Nan; Berrah, N.

    2000-10-09

    New features are revealed in the low-energy photoionization spectrum of Ar by critically combining high photon resolution and differential photoelectron spectroscopic techniques. Two LS -forbidden doubly excited resonances are seen in the 3p{sup -1}{sub 3/2,1/2} partial cross sections which exhibit mirroring profiles, resulting in complete cancellation in the total photoionization cross section, as was predicted by Liu and Starace [Phys.Rev.A 59, R1731 (1999)]. These results demonstrate that a new class of weakly spin-orbit induced, mirroring resonances should be observable in partial, but not in total, collisional cross sections involving atoms, molecules, and solids in general.

  11. 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.

  12. 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

  13. Highly selective water channel activity measured by voltage clamp: Analysis of planar lipid bilayers reconstituted with purified AqpZ

    PubMed Central

    Pohl, Peter; Saparov, Sapar M.; Borgnia, Mario J.; Agre, Peter

    2001-01-01

    Aquaporins are membrane channels selectively permeated by water or water plus glycerol. Conflicting reports have described ion conductance associated with some water channels, raising the question of whether ion conductance is a general property of the aquaporin family. To clarify this question, a defined system was developed to simultaneously measure water permeability and ion conductance. The Escherichia coli water channel aquaporin-Z (AqpZ) was studied, because it is a highly stable tetramer. Planar lipid bilayers were formed from unilamellar vesicles containing purified AqpZ. The hydraulic conductivity of bilayers made from the total extract of E. coli lipids increased 3-fold if reconstituted with AqpZ, but electric conductance was unchanged. No channel activity was detected under voltage-clamp conditions, indicating that less than one in 109 transport events is electrogenic. Microelectrode measurements were simultaneously undertaken adjacent to the membrane. Changes in sodium concentration profiles accompanying transmembrane water flow permitted calculation of the activation energies: 14 kcal/mol for protein-free lipid bilayers and 4 kcal/mol for lipid bilayers containing AqpZ. Neither the water permeability nor the electric conductivity exhibited voltage dependence. This sensitive system demonstrated that AqpZ is permeated by water but not charged ions and should permit direct analyses of putative electrogenic properties of other aquaporins. PMID:11493683

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

    PubMed Central

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

    2014-01-01

    Magnesium is the most abundant divalent cation in living cells and is crucial to several biological processes. MgtE is a Mg2+ channel distributed in all domains of life that contributes to the maintenance of cellular Mg2+ homeostasis. Here we report the high-resolution crystal structures of the transmembrane domain of MgtE, bound to Mg2+, Mn2+ and Ca2+. The high-resolution Mg2+-bound crystal structure clearly visualized the hydrated Mg2+ 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 Mg2+ 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. PMID:25367295

  15. Analysis of channel confined selective area growth in evolutionary growth of GaN on SiO2

    NASA Astrophysics Data System (ADS)

    Leung, Benjamin; Tsai, Miao-Chan; Song, Jie; Zhang, Yu; Xiong, Kanglin; Yuan, Ge; Coltrin, Michael E.; Han, Jung

    2015-09-01

    Here, we analyze the chemical vapor deposition of semiconductor crystals by selective area growth in a non-planar geometry. Specifically, the growth process in laterally and vertically confined masks forming single-crystal GaN on SiO2 by metal-organic chemical vapor deposition is considered in detail. A textured AlN seed is used to initiate growth of oriented GaN selectively through the mask, allowing the reduction of degrees of freedom by the evolutionary grain selection process. As shown by measurements of growth rates within the mask, the sub micron length scale of the channel opening is comparable to the mean free path of precursors in the gas phase, resulting in transport characteristics that can be described by an intermediate flow regime between continuum and free-molecular. Mass transport is modeled through kinetic theory to explain the growth rate enhancements of more than a factor of two by changes in reactor pressure. The growth conditions that enable the modification of nucleation density within the channel are then discussed, and are measured by electron-back scatter diffraction of the nucleated grains on the AlN seed. Finally, the selectivity behavior using the low fill factor masks needed in these configurations has been optimized by control of precursor flow rates and the H2 enhanced etching of the polycrystalline GaN nuclei.

  16. 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. PMID:27130441

  17. Control of the Selectivity of the Aquaporin Water Channel Family by Global Orientational Tuning

    NASA Astrophysics Data System (ADS)

    Tajkhorshid, Emad; Nollert, Peter; Jensen, Morten Ø.; Miercke, Larry J. W.; O'Connell, Joseph; Stroud, Robert M.; Schulten, Klaus

    2002-04-01

    Aquaporins are transmembrane channels found in cell membranes of all life forms. We examine their apparently paradoxical property, facilitation of efficient permeation of water while excluding protons, which is of critical importance to preserving the electrochemical potential across the cell membrane. We have determined the structure of the Escherichia coli aquaglyceroporin GlpF with bound water, in native (2.7 angstroms) and in W48F/F200T mutant (2.1 angstroms) forms, and carried out 12-nanosecond molecular dynamics simulations that define the spatial and temporal probability distribution and orientation of a single file of seven to nine water molecules inside the channel. Two conserved asparagines force a central water molecule to serve strictly as a hydrogen bond donor to its neighboring water molecules. Assisted by the electrostatic potential generated by two half-membrane spanning loops, this dictates opposite orientations of water molecules in the two halves of the channel, and thus prevents the formation of a ``proton wire,'' while permitting rapid water diffusion. Both simulations and observations revealed a more regular distribution of channel water and an increased water permeability for the W48F/F200T mutant.

  18. Bit error rate performance of pi/4-DQPSK in a frequency-selective fast Rayleigh fading channel

    NASA Technical Reports Server (NTRS)

    Liu, Chia-Liang; Feher, Kamilo

    1991-01-01

    The bit error rate (BER) performance of pi/4-differential quadrature phase shift keying (DQPSK) modems in cellular mobile communication systems is derived and analyzed. The system is modeled as a frequency-selective fast Rayleigh fading channel corrupted by additive white Gaussian noise (AWGN) and co-channel interference (CCI). The probability density function of the phase difference between two consecutive symbols of M-ary differential phase shift keying (DPSK) signals is first derived. In M-ary DPSK systems, the information is completely contained in this phase difference. For pi/4-DQPSK, the BER is derived in a closed form and calculated directly. Numerical results show that for the 24 kBd (48 kb/s) pi/4-DQPSK operated at a carrier frequency of 850 MHz and C/I less than 20 dB, the BER will be dominated by CCI if the vehicular speed is below 100 mi/h. In this derivation, frequency-selective fading is modeled by two independent Rayleigh signal paths. Only one co-channel is assumed in this derivation. The results obtained are also shown to be valid for discriminator detection of M-ary DPSK signals.

  19. 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

  20. 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

  1. Designing and modeling doubly porous polymeric materials

    NASA Astrophysics Data System (ADS)

    Ly, H.-B.; Le Droumaguet, B.; Monchiet, V.; Grande, D.

    2015-07-01

    Doubly porous organic materials based on poly(2-hydroxyethyl methacrylate) are synthetized through the use of two distinct types of porogen templates, namely a macroporogen and a nanoporogen. Two complementary strategies are implemented by using either sodium chloride particles or fused poly(methyl methacrylate) beads as macroporogens, in conjunction with ethanol as a porogenic solvent. The porogen removal respectively allows for the generation of either non-interconnected or interconnected macropores with an average diameter of about 100-200 μm and nanopores with sizes lying within the 100 nm order of magnitude, as evidenced by mercury intrusion porosimetry and scanning electron microscopy. Nitrogen sorption measurements evidence the formation of materials with rather high specific surface areas, i.e. higher than 140 m2.g-1. This paper also addresses the development of numerical tools for computing the permeability of such doubly porous materials. Due to the coexistence of well separated scales between nanopores and macropores, a consecutive double homogenization approach is proposed. A nanoscopic scale and a mesoscopic scale are introduced, and the flow is evaluated by means of the Finite Element Method to determine the macroscopic permeability. At the nanoscopic scale, the flow is described by the Stokes equations with an adherence condition at the solid surface. At the mesoscopic scale, the flow obeys the Stokes equations in the macropores and the Darcy equation in the permeable polymer in order to account for the presence of the nanopores.

  2. Selective Modulation of Histaminergic Inputs on Projection Neurons of Cerebellum Rapidly Promotes Motor Coordination via HCN Channels.

    PubMed

    Zhang, Jun; Zhuang, Qian-Xing; Li, Bin; Wu, Guan-Yi; Yung, Wing-Ho; Zhu, Jing-Ning; Wang, Jian-Jun

    2016-03-01

    Insights into function of central histaminergic system, a general modulator originating from the hypothalamus for whole brain activity, in motor control are critical for understanding the mechanism underlying somatic-nonsomatic integration. Here, we show a novel selective role of histamine in the cerebellar nuclei, the final integrative center and output of the cerebellum. Histamine depolarizes projection neurons but not interneurons in the cerebellar nuclei via the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels coupled to histamine H2 receptors, which are exclusively expressed on glutamatergic and glycinergic projection neurons. Furthermore, blockage of HCN channels to block endogenous histaminergic afferent inputs in the cerebellar nuclei significantly attenuates motor balance and coordination. Therefore, through directly and quickly modulation on projection neurons but not interneurons in the cerebellar nuclei, central histaminergic system may act as a critical biasing force to not only promptly regulate ongoing movement but also realize a rapid integration of somatic and nonsomatic response. PMID:25633097

  3. Identification of a Peptide Toxin from Grammostola spatulata Spider Venom That Blocks Cation-Selective Stretch-Activated Channels

    PubMed Central

    Suchyna, Thomas M.; Johnson, Janice H.; Hamer, Katherine; Leykam, Joseph F.; Gage, Douglas A.; Clemo, Henry F.; Baumgarten, Clive M.; Sachs, Frederick

    2000-01-01

    We have identified a 35 amino acid peptide toxin of the inhibitor cysteine knot family that blocks cationic stretch-activated ion channels. The toxin, denoted GsMTx-4, was isolated from the venom of the spider Grammostola spatulata and has <50% homology to other neuroactive peptides. It was isolated by fractionating whole venom using reverse phase HPLC, and then assaying fractions on stretch-activated channels (SACs) in outside-out patches from adult rat astrocytes. Although the channel gating kinetics were different between cell-attached and outside-out patches, the properties associated with the channel pore, such as selectivity for alkali cations, conductance (∼45 pS at −100 mV) and a mild rectification were unaffected by outside-out formation. GsMTx-4 produced a complete block of SACs in outside-out patches and appeared specific since it had no effect on whole-cell voltage-sensitive currents. The equilibrium dissociation constant of ∼630 nM was calculated from the ratio of association and dissociation rate constants. In hypotonically swollen astrocytes, GsMTx-4 produces ∼40% reduction in swelling-activated whole-cell current. Similarly, in isolated ventricular cells from a rabbit dilated cardiomyopathy model, GsMTx-4 produced a near complete block of the volume-sensitive cation-selective current, but did not affect the anion current. In the myopathic heart cells, where the swell-induced current is tonically active, GsMTx-4 also reduced the cell size. This is the first report of a peptide toxin that specifically blocks stretch-activated currents. The toxin affect on swelling-activated whole-cell currents implicates SACs in volume regulation. PMID:10779316

  4. ML418: The First Selective, Sub-Micromolar Pore Blocker of Kir7.1 Potassium Channels.

    PubMed

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

    2016-07-20

    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 nonselective 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 h) and favorable CNS distribution (mouse brain/plasma Kp of 10.9 to support 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

  5. An overview on selected Middle Miocene slope channel complexes, offshore east Nile Delta of Egypt

    NASA Astrophysics Data System (ADS)

    F. Sharaf, Essam; Khaled, Khaled A.; Abushady, Ahmed I.

    2015-12-01

    Middle Miocene turbidite channel reservoirs offshore Nile Delta of Egypt are difficult to develop efficiently. The depositional mechanism of these channels defines sand bodies with variable thickness and quality over short distances. Akhen Field is a turbidite high pressure and high temperature reservoir offshore in the East Nile Delta, Egypt. The turbidite deposits at Akhen area reflect varied depositional fabrics from poorly to moderately sorted and non-graded to graded. Well logs and core data suggest at least 3 sand packages in a cyclic pattern. Each package exhibits variable sedimentological and petrophysical properties and forms a separate reservoir, sealed by shale. A conceptual geologic model showing facies geometry based on 3D seismic mapping and core analysis was used for evaluation of the reservoir quality of the Field. Integrating sedimentologic and other subsurface data such as seismic attributes, pressure data, core analysis, was crucial to predict the fluid flow between the different reservoir units.

  6. Adaptive Resource Allocation for the PB/MC-CDMA System in Frequency Selective Fading Channels

    NASA Astrophysics Data System (ADS)

    Lee, Kyujin; Lee, Kyesan

    We propose Adaptive Resource Allocation for the Partial Block MC-CDMA (ARA-PB/MC-CDMA) system. The ARA-PB/MC-CDMA system aims to improve total throughput performance and frequency efficiency across various channel conditions. It adaptively changes the number of blocks to improve the throughput performance and frequency efficiency according to the Signal to Interference Ratio (SIR). Therefore, the proposed system supports various Quality of Service (QoS) requirements for various SIR values.

  7. A peripherally acting, selective T-type calcium channel blocker, ABT-639, effectively reduces nociceptive and neuropathic pain in rats.

    PubMed

    Jarvis, Michael F; Scott, Victoria E; McGaraughty, Steve; Chu, Katharine L; Xu, Jun; Niforatos, Wende; Milicic, Ivan; Joshi, Shailen; Zhang, Qingwei; Xia, Zhiren

    2014-06-15

    Activation of T-type Ca²⁺ channels contributes to nociceptive signaling by facilitating action potential bursting and modulation of membrane potentials during periods of neuronal hyperexcitability. The role of T-type Ca²⁺ channels in chronic pain is supported by gene knockdown studies showing that decreased Ca(v)3.2 channel expression results in the loss of low voltage-activated (LVA) currents in dorsal root ganglion (DRG) neurons and attenuation of neuropathic pain in the chronic constriction injury (CCI) model. ABT-639 is a novel, peripherally acting, selective T-type Ca²⁺ channel blocker. ABT-639 blocks recombinant human T-type (Ca(v)3.2) Ca²⁺ channels in a voltage-dependent fashion (IC₅₀ = 2 μM) and attenuates LVA currents in rat DRG neurons (IC₅₀ = 8 μM). ABT-639 was significantly less active at other Ca²⁺ channels (e.g. Ca(v)1.2 and Ca(v)2.2) (IC₅₀ > 30 μM). ABT-639 has high oral bioavailability (%F = 73), low protein binding (88.9%) and a low brain:plasma ratio (0.05:1) in rodents. Following oral administration ABT-639 produced dose-dependent antinociception in a rat model of knee joint pain (ED₅₀ = 2 mg/kg, p.o.). ABT-639 (10-100 mg/kg, p.o.) also increased tactile allodynia thresholds in multiple models of neuropathic pain (e.g. spinal nerve ligation, CCI, and vincristine-induced). [corrected]. ABT-639 did not attenuate hyperalgesia in inflammatory pain models induced by complete Freund's adjuvant or carrageenan. At higher doses (e.g. 100-300 mg/kg) ABT-639 did not significantly alter hemodynamic or psychomotor function. The antinociceptive profile of ABT-639 provides novel insights into the role of peripheral T-type (Ca(v)3.2) channels in chronic pain states. PMID:24726441

  8. 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

  9. 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

    2015-01-01

    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. PMID:26650356

  10. 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.

  11. Neutron interaction with doubly-magic {sup 40}Ca

    SciTech Connect

    Smith, A.B. |

    1993-11-01

    Differential neutron elastic and inelastic-scattering cross sections of elemental calcium (96.94% doubly-magic {sup 40}Ca) are measured from {approx} 1.5 to 10 MeV with sufficient detail to determine their energy-averaged behavior in the highly fluctuating environment. These results, combined with values previously reported in the literature, are assessed in the contexts of optical-statistical, dispersive optical, and coupled-channels models, applicable to the energy domain 0 {yields} 30+ MeV, with particular emphasis on the lower energies where the interpretations are sensitive to the dispersion relationship and the effective mass. The interpretations define the energy dependencies of the potential parameters (resolving prior ambiguities), suggest that previous estimates of the prominent low-energy (n,p) and (n,a) reactions are too large, reasonably describe observables to at least 30 MeV, and provide a vehicle for extrapolation into the bound-state regime that gives a good description of hole- and particle-state binding energies. The resulting real-potential parameters (in contrast to many {sup 40}Ca parameters reported in the literature) are shown consistent with global trends.

  12. 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.

  13. MDIMP, a novel cardiac Ca(2+) channel blocker with atrial selectivity.

    PubMed

    Santamaria-Herrera, Mireille Aline; Ríos-Pérez, Erick Benjamín; de la Rosa, Juan Antonio Manuel; García-Castañeda, Maricela; Osornio-Garduño, Diana Stephanie; Ramos-Mondragón, Roberto; Mancilla-Percino, Teresa; Avila, Guillermo

    2016-06-15

    In cardiac muscle cells both T-and L-type Ca(2+) channels (TTCCs and LTCCs, respectively) are expressed, and the latter are relevant to a process known as excitation-contraction coupling (ECC). Evidence obtained from docking studies suggests that isoindolines derived from α-amino acids bind to the LTCC CaV1.2. In the present study, we investigated whether methyl (S)-2-(1,3-dihydroisoindol-2-yl)-4-methylpentanoate (MDIMP), which is derived from L-leucine, modulates both Ca(2+) channels and ECC. To this end, mechanical properties, as well as Ca(2+) transients and currents, were all investigated in isolated cardiac myocytes. The effects of MDIMP on CaV1.2 (transiently expressed in 293T/17 cells) were also studied. In this system, evidence was found for an inhibitory action that develops and recovers in min, with an IC50 of 450µM. With respect to myocytes: atrial-TTCCs, atrial-LTCCs, and ventricular-LTCCs were also inhibited, in that order of potency. Accordingly, Ca(2+) transients, contractions, and window currents of LTCCs were all reduced more strongly in atrial cells. Interestingly, while the modulation of LTCCs was state-independent in these cells, it was state-dependent, and dual, on the ventricular ones. Furthermore, practically all of the ventricular LTCCs were closed at resting membrane potentials. This could explain their resistance to MDIMP, as they were affected in only open or inactivated states. All these features in turn explain the preferential down-regulation of the atrial ECC. Thus, our results support the view that isoindolines bind to Ca(2+) channels, improve our knowledge of the corresponding structure-function relationship, and may be relevant for conditions where decreased atrial activity is desired. PMID:27089820

  14. Photoionization dominated by doubly excited resonances for Be and its isoelectronic sequence

    SciTech Connect

    Chang, T.N.; Zhu, L.

    1993-05-01

    We present the photoionization cross sections the ground and a few selected bound excited states of Be using a B-spline based configuration-interaction procedure for continuum (CIC). The resonant structures dominated by the doubly excited autoionization series will be examined in detail. Our calculation has shown that the strong overlap between the 2p(n+1)s and 2pnd {sup 1}P resonances seen in the ground state photoionization spectrum is completely removed in the spectrum originated from the bound excited state. Our calculated resonant widths vary smoothly as functions of the effective quantum number v and approach approximately an {nu}{sup 3}-dependence. We will also present the variation of the doubly excited resonance structures as Z increases along the Be-isoelectronic sequence.

  15. 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

  16. Selective modulation by membrane potential of desmethoxyverapamil binding to calcium channels in rat portal vein.

    PubMed

    Rakotoarisoa, L; Sayet, I; Mironneau, C; Mironneau, J

    1990-12-01

    (-)-[3H]Desmethoxyverapamil (D888) binds saturably to intact strips from rat portal vein bathed in physiological solution with a Kd value of 363 pM and a maximal binding capacity value of 15.6 fmol.mg-1 wet weight. Unlabeled dihydropyridines, phenylalkylamines and benzothiazepines inhibited (-)-[3H]D888 specific binding in a concentration-dependent manner. Scatchard analyses and dissociation kinetics of (-)-[3H]D888 binding revealed the existence of mutual allosteric interactions between (+)-isradipine, (+)-cis diltiazem and (-)-D888 binding sites in portal vein strips. When voltage-dependent Ca++ channels transported Ca++, Ba++, Sr++ or Na+ the binding capacity of (-)-[3H]D888 remained unchanged. In contrast, both depolarization (induced by elevation of external K+) and hyperpolarization (in the presence of cromakalim) induced a gradual decrease in (-)-D888 binding capacity. These observations suggest that membrane potential variation would change the conformational state of Ca++ channels, in such a way that it would be less favorable for access of (-)-[3H]D888 to the binding site. This would provide an experimental argument in favor of the "guarded receptor hypothesis" according to which membrane potential modulates ligand affinity by alteration of the amount of time during which the receptor binding site is available to (-)-[3H]D888. PMID:2175807

  17. RORγt+ cells selectively express redundant cation channels linked to the Golgi apparatus.

    PubMed

    Drujont, Lucile; Lemoine, Aurélie; Moreau, Aurélie; Bienvenu, Géraldine; Lancien, Mélanie; Cens, Thierry; Guillot, Flora; Bériou, Gaëlle; Bouchet-Delbos, Laurence; Fehling, Hans Jörg; Chiffoleau, Elise; Nicot, Arnaud B; Charnet, Pierre; Martin, Jérôme C; Josien, Régis; Cuturi, Maria Cristina; Louvet, Cédric

    2016-01-01

    Retinoid-related orphan receptor gamma t (RORγt) is a master transcription factor central to type 17 immunity involving cells such as T helper 17, group 3 innate lymphoid cells or IL-17-producing γδ T cells. Here we show that the intracellular ion channel TMEM176B and its homologue TMEM176A are strongly expressed in these RORγt(+) cells. We demonstrate that TMEM176A and B exhibit a similar cation channel activity and mainly colocalise in close proximity to the trans-Golgi network. Strikingly, in the mouse, the loss of Tmem176b is systematically associated with a strong upregulation of Tmem176a. While Tmem176b single-deficiency has no effect on the course of experimental autoimmune encephalomyelitis, T cell or DSS-induced colitis, it significantly reduces imiquimod-induced psoriasis-like skin inflammation. These findings shed light on a potentially novel specific process linked to post-Golgi trafficking for modulating the function of RORγt(+) cells and indicate that both homologues should be simultaneously targeted to clearly elucidate the role of this intracellular ion flow. PMID:27009467

  18. RORγt+ cells selectively express redundant cation channels linked to the Golgi apparatus

    PubMed Central

    Drujont, Lucile; Lemoine, Aurélie; Moreau, Aurélie; Bienvenu, Géraldine; Lancien, Mélanie; Cens, Thierry; Guillot, Flora; Bériou, Gaëlle; Bouchet-Delbos, Laurence; Fehling, Hans Jörg; Chiffoleau, Elise; Nicot, Arnaud B.; Charnet, Pierre; Martin, Jérôme C.; Josien, Régis; Cuturi, Maria Cristina; Louvet, Cédric

    2016-01-01

    Retinoid-related orphan receptor gamma t (RORγt) is a master transcription factor central to type 17 immunity involving cells such as T helper 17, group 3 innate lymphoid cells or IL-17-producing γδ T cells. Here we show that the intracellular ion channel TMEM176B and its homologue TMEM176A are strongly expressed in these RORγt+ cells. We demonstrate that TMEM176A and B exhibit a similar cation channel activity and mainly colocalise in close proximity to the trans-Golgi network. Strikingly, in the mouse, the loss of Tmem176b is systematically associated with a strong upregulation of Tmem176a. While Tmem176b single-deficiency has no effect on the course of experimental autoimmune encephalomyelitis, T cell or DSS-induced colitis, it significantly reduces imiquimod-induced psoriasis-like skin inflammation. These findings shed light on a potentially novel specific process linked to post-Golgi trafficking for modulating the function of RORγt+ cells and indicate that both homologues should be simultaneously targeted to clearly elucidate the role of this intracellular ion flow. PMID:27009467

  19. 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

  20. Screening for selective inhibitors of xanthine oxidase from Flos Chrysanthemum using ultrafiltration LC-MS combined with enzyme channel blocking.

    PubMed

    Song, Hui-Peng; Zhang, Hui; Fu, Yu; Mo, Hua-yan; Zhang, Mu; Chen, Jun; Li, Ping

    2014-06-15

    In this study, a new method based on ultrafiltration liquid chromatography-mass spectrometry (UF-LC-MS) combined with enzyme channel blocking (ECB) was developed to discover bioactive components from herbal medicines. Xanthine oxidase (XOD), a critical enzyme for treating gout, was employed as the target protein for screening. By comparing chromatographic profiles of the compounds binding to XOD before and after the ECB experiment, the selective ligands could be distinguished from the non-selective binders. In this experiment, febuxostat bound to the channel entering into the active site of the enzyme and prevented potential ligands from binding. Finally, four compounds, namely, luteolin-7-O-glucoside, apigenin-7-O-glucoside, luteolin and apigenin were screened and identified as the candidate XOD inhibitors based on the ultrafiltration chromatogram of Flos Chrysanthemum, a famous traditional Chinese medicine used in many prescriptions for gout treatment. To verify the compounds screened further, a microplate method was applied to evaluate their enzyme inhibitory activities. The IC50 values of the above 4 compounds were 23.61, 38.80, 1.54 and 1.96μM, respectively. The structure-function relationship was also estimated according to the in vitro assay. The results were in favor of the hypothesis that the Flos Chrysanthemum extract might be used for gout treatment by inhibiting XOD. PMID:24861872

  1. Selective loss of cone function in mice lacking the cyclic nucleotide-gated channel CNG3

    PubMed Central

    Biel, Martin; Seeliger, Mathias; Pfeifer, Alexander; Kohler, Konrad; Gerstner, Andrea; Ludwig, Andreas; Jaissle, Gesine; Fauser, Sascha; Zrenner, Eberhart; Hofmann, Franz

    1999-01-01

    Two types of photoreceptors, rods and cones, coexist in the vertebrate retina. An in-depth analysis of the retinal circuitry that transmits rod and cone signals has been hampered by the presence of intimate physical and functional connections between rod and cone pathways. By deleting the cyclic nucleotide-gated channel CNG3 we have generated a mouse lacking any cone-mediated photoresponse. In contrast, the rod pathway is completely intact in CNG3-deficient mice. The functional loss of cone function correlates with a progressive degeneration of cone photoreceptors but not of other retinal cell types. CNG3-deficient mice provide an animal model to dissect unequivocally the contribution of rod and cone pathways for normal retinal function. PMID:10377453

  2. An expert system for the selection of a suitable method for flow measurement in open channels

    NASA Astrophysics Data System (ADS)

    Simonovic, Slobodan P.

    1990-01-01

    The science of stream gaging has evolved through the years, mainly from the experiences and innovations of its practitioners. Stream-gaging procedures are standardized on the national and international level. However, the selection of a suitable method for flow measurement is still a fairly complex process. The knowledge-based system described in the paper is designed to aid the user in the selection process. Two aspects of selection are considered: physical characteristics of the gaging site and available equipment and/or structures at the gaging site. The system has been designed for the potential use in Environment Canada. The paper also discusses the rule-based expert system development tool, VP-Expert. Final conclusion of the research presented in the paper is that the expert system technology may help in the surface flow measurement process. The application seems to be natural, since stream gaging procedures are mainly derived from actual practice and experience.

  3. Analysis of K+/Na+ selectivity of KcsA potassium channel with reference interaction site model theory

    NASA Astrophysics Data System (ADS)

    Cui, Qizhi; Smith, Vedene H., Jr.

    2005-01-01

    As a preliminary approach, we have successfully analysed K+/Na+ selectivity of the KcsA potassium channel for the most selective ion occupancy state (1010) at the atomic level by using the reference interaction site model (RISM) integral equation theory [Q. Cui, V.H. Smith, Chem. Phys. Lett.365, 110 (2002)]. With similar methods, in this paper, we analyse seven other most relevant ion occupancy states: (0101), (0110), (1001), (1000), (0100), (0010) and (0001). By analysing all the most relevant states, we are able to characterize some dynamic properties of the systems. More detailed solvation structures of the selectivity filter are presented and more solvation energetic data are obtained and compared with the available molecular dynamics simulation data. We predict consistent results with the simulations in that ions are best dehydrated at binding site 2. For ion occupancy states of most interest, we obtain good relative solvation free energies in comparison with the simulation data. The results in this paper further support the conclusion in our previous paper that the selectivity filter favours K+ over Na+ from the point of view of solvation.

  4. 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

    2016-01-01

    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

  5. 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

    2016-04-01

    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

  6. Signatures of doubly-charged Higgsinos at colliders

    SciTech Connect

    Demir, D. A.; Frank, M.; Turan, I.; Huitu, K.; Rai, S. K.

    2008-11-23

    Several supersymmetric models with extended gauge structures predict light doubly-charged Higgsinos. Their distinctive signature at the large hadron collider is highlighted by studying its production and decay characteristics.

  7. 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.

  8. 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.

  9. Selective inhibition of a slow-inactivating voltage-dependent K+ channel in rat PC12 cells by hypoxia.

    PubMed

    Conforti, L; Millhorn, D E

    1997-07-15

    1. Electrophysiological (single-channel patch clamp) and molecular biological experiments (reverse transcriptase-polymerase chain reaction) were performed to attempt to identify the O2-sensitive K+ channel in rat phaeochromocytoma (PC12) cells. 2. Four types of K+ channels were recorded in PC12 cells: a small-conductance K+ channel (14 pS), a calcium-activated K+ channel (KCa; 102 pS) and two K+ channels with similar conductance (20 pS). These last two channels differed in their time-dependent inactivation: one was a slow-inactivating channel, while the other belonged to the family of fast transient K+ channels. 3. The slow-inactivating 20 pS K+ channel was inhibited by hypoxia. Exposure to hypoxia produced a 50% reduction in channel activity (number of active channels in the patch x open probability). Hypoxia had no effect on the 20 pS transient K+ channels, whereas reduced O2 stimulated the KCa channels. 4. The genes encoding the alpha-subunits of slow-inactivating K+ channels for two members of the Shaker subfamily of K+ channels (Kv1.2 and Kv1.3) together with the Kv2.1, Kv3.1 and Kv3.2 channel genes were identified in PC12 cells. 5. The expression of the Shaker Kv1.2, but none of the other K+ channel genes, increased in cells exposed to prolonged hypoxia (18 h). The same cells were more responsive to a subsequent exposure to hypoxia (35% inhibition of K+ current measured in whole-cell voltage clamp) compared with the cells maintained in normoxia (19% inhibition). 6. These results indicate that the O2-sensitive K+ channel in PC12 cells is a 20 pS slow-inactivating K+ channel that is upregulated by hypoxia. This channel appears to belong to the Shaker subfamily of voltage-gated K+ channels. PMID:9263911

  10. State-to-state mode selectivity in the HD + OH reaction: Perspectives from two product channels.

    PubMed

    Zhao, Bin; Sun, Zhigang; Guo, Hua

    2016-06-01

    The state-to-state quantum dynamics (Jtot = 0) of the HD + OH(υ2 = 0, 1) reaction is studied using a reactant coordinate based method, which allows the analysis of both the H + DOH and D + HOH channels with a single propagation. The stretching vibration of the newly formed bond, namely, the OD bond in DOH and one OH bond in HOH, is excited, thanks to its strong coupling with the reaction coordinate at the transition state. On the other hand, the vibrational energy deposited into the OH reactant (υ2 = 1) is sequestered during the reaction in the spectator OH mode. The combined effect leads to the excitation of both the OD and OH stretching modes in the DOH product, and the dominance of the (002) normal-mode state population in the HOH product, which in the local-mode picture corresponds to the excitation of both OH bonds with one quantum each. The energy flow in this prototypical tetratomic reaction can be understood in terms of the sudden vector projection model. PMID:27276953

  11. 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

  12. Characterization of selectivity and pharmacophores of type 1 sea anemone toxins by screening seven Na(v) sodium channel isoforms.

    PubMed

    Zaharenko, André Junqueira; Schiavon, Emanuele; Ferreira, Wilson Alves; Lecchi, Marzia; de Freitas, José Carlos; Richardson, Michael; Wanke, Enzo

    2012-03-01

    During their evolution, animals have developed a set of cysteine-rich peptides capable of binding various extracellular sites of voltage-gated sodium channels (VGSC). Sea anemone toxins that target VGSCs delay their inactivation process, but little is known about their selectivities. Here we report the investigation of three native type 1 toxins (CGTX-II, δ-AITX-Bcg1a and δ-AITX-Bcg1b) purified from the venom of Bunodosoma cangicum. Both δ-AITX-Bcg1a and δ-AITX-Bcg1b toxins were fully sequenced. The three peptides were evaluated by patch-clamp technique among Nav1.1-1.7 isoforms expressed in mammalian cell lines, and their preferential targets are Na(v)1.5>1.6>1.1. We also evaluated the role of some supposedly critical residues in the toxins which would interact with the channels, and observed that some substitutions are not critical as expected. In addition, CGTX-II and δ-AITX-Bcg1a evoke different shifts in activation/inactivation Boltzmann curves in Nav1.1 and 1.6. Moreover, our results suggest that the interaction region between toxins and VGSCs is not restricted to the supposed site 3 (S3-S4 linker of domain IV), and this may be a consequence of distinct surface of contact of each peptide vs. targeted channel. Our data suggest that the contact surfaces of each peptide may be related to their surface charges, as CGTX-II is more positive than δ-AITX-Bcg1a and δ-AITX-Bcg1b. PMID:21802465

  13. Vibrational excitons in ionophores: experimental probes for quantum coherence-assisted ion transport and selectivity in ion channels

    NASA Astrophysics Data System (ADS)

    Ganim, Ziad; Tokmakoff, Andrei; Vaziri, Alipasha

    2011-11-01

    Despite there being a large body of work, the exact molecular details underlying ion selectivity and transport in the potassium channel have not been fully uncovered. One major reason has been the lack of experimental methods that can probe these mechanisms dynamically on their biologically relevant timescales. Recently, it was suggested that quantum coherence and its interplay with thermal vibration might be involved in mediating ion selectivity and transport. In this paper, we present an experimental strategy for using time-resolved infrared spectroscopy to investigate these effects. We show the feasibility by demonstrating the infrared (IR) absorption and Raman spectroscopic signatures of the potassium-binding model molecules that mimic the transient interactions of potassium with binding sites of the selectivity filter during ion conduction. In addition to guiding our experiments on the real system, we have performed molecular dynamic-based simulations of the FTIR and two-dimensional IR (2DIR) spectra of the entire KcsA complex, which is the largest complex for which such modeling has been performed. We found that by combining isotope labeling with 2DIR spectroscopy, the signatures of potassium interaction with individual binding sites would be experimentally observable, and we identified specific labeling combinations that would maximize our expected experimental signatures.

  14. 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

    2015-01-01

    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

  15. 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

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

    PubMed

    Zhang, Xiao-Xue; Min, Xiao-Chun; Xu, Xu-Lin; Zheng, Min; Guo, Lian-Jun

    2016-05-01

    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 Ca(2+) concentration [Ca(2+)]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 [Ca(2+)]i in a concentration-dependent manner and reversed 8-Br-cAMP-mediated facilitation of these glutamate-induced [Ca(2+)]i rises. Our results suggest that ZD7288 inhibits hippocampal synaptic plasticity both glutamate release and resultant [Ca(2+)]i increases in rat hippocampal neurons. PMID:27335562

  17. 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

  18. 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

    2016-10-01

    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. PMID:27262660

  19. Parallel Multistage Decision Feedback Equalizer for Single-Carrier Layered Space-Time Systems in Frequency-Selective Channels

    NASA Astrophysics Data System (ADS)

    Xu, Jing; Wang, Haifeng; Cheng, Shixin; Chen, Ming

    2004-12-01

    Space-time transmission techniques can greatly increase the spectral efficiency. In this paper, a parallel multistage decision feedback equalizer (PMDFE) is proposed for single-carrier layered space-time systems with a fixed cyclic prefix over frequency-selective channels. It is composed of a parallel interference canceller, a multiple-input single-output decision feedback equalizer (MISO-DFE), and a linear combiner. The soft output of the MISO-DFE is linearly combined with the previous tentative soft decision. In addition, an algorithm is proposed to obtain tentative soft and hard decisions for initializing the equalizer. The initializing complexity of the PMDFE is lower than that of MIMO-OFDM. Simulation results show that the PMDFE outperforms MIMO-OFDM and previously existing equalizers for single-carrier layered space-time systems.

  20. 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.

  1. Observation of doubly excited levels in lithiumlike and beryliumlike titanium

    NASA Astrophysics Data System (ADS)

    Smith, A. J.; Beiersdorfer, P.; Harris, C. L.; Wong, K.; Chen, M.

    2002-10-01

    The satellite spectrum of heliumlike titanium has been studied using the Lawrence Livermore National Laboratory electron beam ion trap, EBIT II and a high resolution Bragg crystal spectrometer in von Hámos geometry. We initially ionize the titanium atoms to the heliumlike charge state, and then select an electron beam energy that overlaps the excitation energy for the KLM series of resonances. This allows us to populate doubly excited levels in lithiumlike TiXX as well as beryliumlike TiXIX by dielectronic remombination. We observe spectra of x-ray photons emitted at 90^rc to the electron beam. We have also calculated the photon energies, excitation energies, and resonance strengths of these resonances using an MCDF theory, and we find good agreement between the theoretical and experimental results. We gratefully acknwoledge support by the U. S. Office of Basic Energy Science, Chemical Sciences Division, and the LLNL Research Collaborations Program for HBCU's. This work was performed under the auspices of U. S. Department of Energy by Morehouse under contract No. DE-FG02-98ER14877, and by LLNL under contract No. W-7405-ENG-48.

  2. Research on seismic survey design for doubly complex areas

    NASA Astrophysics Data System (ADS)

    Zhao, Hu; Yin, Cheng; Wu, Ming-Sheng; Wu, Xiao-Hua; Pan, Shu-Lin

    2012-06-01

    The complex geological conditions in doubly complex areas tend to result in difficult surface survey operations and poor target layer imaging in the subsurface which has a great impact on seismic data quality. In this paper, we propose an optimal crooked line survey method for decreasing the surface survey operational difficulties and improving the sub-layer event continuity. The method concentrates on the surface shooting conditions, first, selecting the proper shot positions based on the specific surface topographic features to reduce the shot difficulties and then optimizing the receiver positioning to meet the prerequisite that the subsurface reflection points remain in a straight line. Using this method cannot only lower the shooting difficulty of rough surface condition areas but also overcome the subsurface reflection point bending problem appearing in the traditional crooked line survey method. On the other hand, we use local infill shooting rather than conventional overall infill shooting to improve sublayer event continuity and uniformity with lower survey operation cost. A model has been calculated and processed with the proposed optimal crooked line survey and local infill shooting design method workflow and the results show that this new method can work for seismic surveys in double complex areas.

  3. Wavelength-division multiplexing of nano-optomechanical doubly clamped beam systems.

    PubMed

    Sauer, Vincent T K; Diao, Zhu; Freeman, Mark R; Hiebert, Wayne K

    2015-05-01

    Wavelength-division multiplexing is demonstrated for a set of two doubly clamped beams. Using a single input/output waveguide in a nanophotonic detection system, the two mechanical beams are independently addressable using different wavelength channels as determined by their respective racetrack resonator detection cavities. The two cavities slightly overlap, which also enables the mechanical frequency of both beams to be detected simultaneously with a single wavelength. Finally, to physically map which wavelength channel corresponds to which specific device, a heating laser is targeted individually on each beam to create a reversible mechanical frequency shift. This multiplexing method would allow for the simpler detection of large arrays of nanomechanical devices in a sensor system. PMID:25927755

  4. 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

  5. Aromaticity of the doubly charged [8]circulenes.

    PubMed

    Baryshnikov, Gleb V; Valiev, Rashid R; Karaush, Nataliya N; Sundholm, Dage; Minaev, Boris F

    2016-04-01

    Magnetically induced current densities and current pathways have been calculated for a series of fully annelated dicationic and dianionic tetraphenylenes, which are also named [8]circulenes. The gauge including magnetically induced current (GIMIC) method has been employed for calculating the current density susceptibilities. The aromatic character and current pathways are deduced from the calculated current density susceptibilities showing that the neutral [8]circulenes have two concentric pathways with aromatic and antiaromatic character, respectively. The inner octatetraene core (the hub) is found to sustain a paratropic (antiaromatic) ring current, whereas the ring current along the outer part of the macrocycle (the rim) is diatropic (aromatic). The neutral [8]circulenes can be considered nonaromatic, because the sum of the ring-current strengths of the hub and the rim almost vanishes. The aromatic character of the doubly charged [8]circulenes is completely different: the dianionic [8]circulenes and the OC-, CH-, CH2-, SiH-, GeH-, SiH2-, and GeH2-containing dicationic species sustain net diatropic ring currents i.e., they are aromatic, whereas the O-, S-, Se-, NH-, PH- and AsH-containing dicationic [8]circulenes are strongly antiaromatic. The present study also shows that GIMIC calculations on the [8]circulenes provide more accurate information about the aromatic character than that obtained using local indices such as nuclear-independent chemical shifts (NICSs) and (1)H NMR chemical shifts. PMID:26964752

  6. 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

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

    PubMed

    Linsdell, P; Zheng, S X; Hanrahan, J W

    1998-10-01

    1. 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. 2. 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. 3. 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. 4. 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. Some remarks on the selection of exit channels in the theoretical description of dissociative recombination

    NASA Astrophysics Data System (ADS)

    Guberman, Steven L.

    2015-01-01

    The need for the careful selection of dissociative routes for inclusion in the theoretical calculation of accurate dissociative recombination (DR) cross sections and rate constants is discussed. For total energies corresponding to the sum of the "free" electron energy plus the ion vibrational energy, all neutral diabatic curves that fall between or near the turning points of the highest Rydberg vibrational levels with the same electronic symmetry need to be included in the calculation. This is especially the case if there are several dissociative routes of the same electronic symmetry that satisfy this criterion. Also, care must be exercised in the exclusion of dissociative routes having relatively small electron capture widths. Examples from theoretical studies of the dissociative recombination (DR) of N2+ are used as illustrations.

  9. 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. PMID:6324066

  10. 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

  11. 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.

  12. 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. PMID:25099151

  13. Isolation, synthesis and characterization of ω-TRTX-Cc1a, a novel tarantula venom peptide that selectively targets L-type Cav channels.

    PubMed

    Klint, Julie K; Berecki, Géza; Durek, Thomas; Mobli, Mehdi; Knapp, Oliver; King, Glenn F; Adams, David J; Alewood, Paul F; Rash, Lachlan D

    2014-05-15

    Spider venoms are replete with peptidic ion channel modulators, often with novel subtype selectivity, making them a rich source of pharmacological tools and drug leads. In a search for subtype-selective blockers of voltage-gated calcium (CaV) channels, we isolated and characterized a novel 39-residue peptide, ω-TRTX-Cc1a (Cc1a), from the venom of the tarantula Citharischius crawshayi (now Pelinobius muticus). Cc1a is 67% identical to the spider toxin ω-TRTX-Hg1a, an inhibitor of CaV2.3 channels. We assembled Cc1a using a combination of Boc solid-phase peptide synthesis and native chemical ligation. Oxidative folding yielded two stable, slowly interconverting isomers. Cc1a preferentially inhibited Ba(2+) currents (IBa) mediated by L-type (CaV1.2 and CaV1.3) CaV channels heterologously expressed in Xenopus oocytes, with half-maximal inhibitory concentration (IC50) values of 825nM and 2.24μM, respectively. In rat dorsal root ganglion neurons, Cc1a inhibited IBa mediated by high voltage-activated CaV channels but did not affect low voltage-activated T-type CaV channels. Cc1a exhibited weak activity at NaV1.5 and NaV1.7 voltage-gated sodium (NaV) channels stably expressed in mammalian HEK or CHO cells, respectively. Experiments with modified Cc1a peptides, truncated at the N-terminus (ΔG1-E5) or C-terminus (ΔW35-V39), demonstrated that the N- and C-termini are important for voltage-gated ion channel modulation. We conclude that Cc1a represents a novel pharmacological tool for probing the structure and function of L-type CaV channels. PMID:24561180

  14. Modulation by purines of calcium-activated non-selective cation channels in the outer hair cells of the guinea-pig cochlea.

    PubMed Central

    Van den Abbeele, T; Tran Ba Huy, P; Teulon, J

    1996-01-01

    1. The cell-attached and cell-free configurations of the patch-clamp technique were used to investigate whether external ATP and its derivatives modulate channel activity in outer hair cells freshly isolated from the guinea-pig cochlea. 2. Submicromolar concentrations of ATP stimulated a non-selective cation channel with a conductance of about 25 pS. The ATP-elicited stimulation was partly blocked by the membrane-permeant blocker 3',5-dichlorodiphenylamine-2-carboxylic acid (DCDPC), and mimicked by the calcium ionophore, ionomycin, suggesting that the channel activated by ATP is identical to a previously reported calcium-activated non-selective (CAN) cation channel. 3. The P2x agonist beta, gamma-methylene-ATP (beta, gamma-MeATP, 10 microM) and the P2Y agonist 2-methyl-thio-ATP (2-MeSATP, 1 microM) both activated CAN channels. The effect of ATP was inhibited by the P2 antagonist suramin but not by the P2Y antagonist Reactive Blue 2. These results suggest that both purinergic receptors are involved in the ATP-evoked response and that internal calcium acts as a second messenger for opening CAN channels. 4. In contrast, adenosine inhibited CAN channels. This effect was reproduced by the A2 agonist 5'-N-ethylcarboxyamidoadenosine (NECA) and the permeant cAMP analogue 8-bromo-adenosine 3',5'-cyclic monophosphate (8-Br-cAMP), but not by the A1 agonist N6-cyclo-hexyladenosine (CHA). CAN channels were also inhibited when the catalytic subunit of protein kinase A was applied internally on inside-out patches, suggesting that adenosine A2 receptor downregulates CAN channels via a cAMP-dependent phosphorylation. Images Figure 10 PMID:8814608

  15. Selective inhibition of a slow-inactivating voltage-dependent K+ channel in rat PC12 cells by hypoxia.

    PubMed Central

    Conforti, L; Millhorn, D E

    1997-01-01

    1. Electrophysiological (single-channel patch clamp) and molecular biological experiments (reverse transcriptase-polymerase chain reaction) were performed to attempt to identify the O2-sensitive K+ channel in rat phaeochromocytoma (PC12) cells. 2. Four types of K+ channels were recorded in PC12 cells: a small-conductance K+ channel (14 pS), a calcium-activated K+ channel (KCa; 102 pS) and two K+ channels with similar conductance (20 pS). These last two channels differed in their time-dependent inactivation: one was a slow-inactivating channel, while the other belonged to the family of fast transient K+ channels. 3. The slow-inactivating 20 pS K+ channel was inhibited by hypoxia. Exposure to hypoxia produced a 50% reduction in channel activity (number of active channels in the patch x open probability). Hypoxia had no effect on the 20 pS transient K+ channels, whereas reduced O2 stimulated the KCa channels. 4. The genes encoding the alpha-subunits of slow-inactivating K+ channels for two members of the Shaker subfamily of K+ channels (Kv1.2 and Kv1.3) together with the Kv2.1, Kv3.1 and Kv3.2 channel genes were identified in PC12 cells. 5. The expression of the Shaker Kv1.2, but none of the other K+ channel genes, increased in cells exposed to prolonged hypoxia (18 h). The same cells were more responsive to a subsequent exposure to hypoxia (35% inhibition of K+ current measured in whole-cell voltage clamp) compared with the cells maintained in normoxia (19% inhibition). 6. These results indicate that the O2-sensitive K+ channel in PC12 cells is a 20 pS slow-inactivating K+ channel that is upregulated by hypoxia. This channel appears to belong to the Shaker subfamily of voltage-gated K+ channels. Images Figure 4 Figure 7 PMID:9263911

  16. RESEARCH NOTE FROM COLLABORATION: Study of pair-produced doubly charged Higgs bosons with a four-muon final state with the CMS detector

    NASA Astrophysics Data System (ADS)

    Rommerskirchen, T.; Hebbeker, T.

    2007-03-01

    The discovery potential of doubly charged Higgs bosons pair-produced in Drell-Yan events at the CMS detector is presented in this note. The decay branching ratio into muon pairs is assumed to be 100%. The pure muonic decay channel yields a clear signal which is almost background free. Doubly charged Higgs bosons with masses in the range 100-800 GeV are studied, for a low luminosity scenario of \\mathcal{L} = 2\\times 10^{33} cm-2 s-1. The full detector simulation is used. Doubly charged Higgs bosons in this production and decay channel with masses m_{H^{\\pm\\pm}} \\le 650 GeV are expected to be observable at CMS with a significance exceeding 5σ at 10 fb-1 of integrated luminosity. If no signal will be detected for this integrated luminosity, the existence of a doubly charged Higgs boson with m_{H^{\\pm\\pm}} \\le 760 GeV can be excluded at 95% confidence level. This exceeds the current exclusion limit m_{H^{\\pm\\pm}} \\le 136 GeV, set by CDF at Tevatron Run II, by 624 GeV.

  17. ( sup 3 H)TA-3090, a selective benzothiazepine-type calcium channel receptor antagonist: In vitro characterization

    SciTech Connect

    Zobrist, R.H.; Mecca, T.E. )

    1990-05-01

    Binding of the new benzothiazepine calcium channel blocker, (+)-(2S,3S)-3-acetoxy-8-chloro-5-(2-(dimethylamino)ethyl)-2,3-dihydro-2- (4- methoxyphenyl)-1,5-benzothiazepine-4-(5H)-one maleate, (3H)TA-3090, was characterized and its specificity for rat myocardial benzothiazepine receptors described. Scatchard plots and nonlinear regression analysis of specific (3H)TA-3090 binding best fit a one-site binding model (Kd = 8.8 +/- 2.7 nM, Bmax = 132 +/- 38 fmol/mg protein). Kinetically derived affinity constants were in close agreement (Kd = 7.86 nM) with those obtained from analysis of equilibrium binding data. In comparison, under identical conditions (3H)diltiazem exhibited a Kd of 38 nM and Bmax, 106 fmol/mg protein. Specific binding was saturable, reversible and stereoselective (d-cis-TA-3090 Ki = 14 nM; 1-cis-TA-3090 Ki = 2700 nM). Competitions for (3H)TA-3090 binding were conducted with nifedipine, propranolol, prazosin, quinuclidinyl benzilate, verapamil and yohimbine. Only the calcium channel blockers nifedipine and verapamil inhibited specific (3H)TA-3090 binding. Nifedipine could maximally inhibit only 52% of specifically bound (3H)TA-3090 at 10 microM. In contrast, however, 10 microM verapamil completely inhibited specific radioligand binding (Ki = 93 +/- 28 nM) but with six times less efficacy than TA-3090. Thus, these data demonstrate that (3H)TA-3090 is a potent radioligand selective for the benzothiazepine binding site and is consistent with the hypothesis that (3H)TA-3090 interacts with a myocardial benzothiazepine receptor site.

  18. Subtype-selective activation of K(v)7 channels by AaTXKβ₂₋₆₄, a novel toxin variant from the Androctonus australis scorpion venom.

    PubMed

    Landoulsi, Zied; Miceli, Francesco; Palmese, Angelo; Amoresano, Angela; Marino, Gennaro; El Ayeb, Mohamed; Taglialatela, Maurizio; Benkhalifa, Rym

    2013-11-01

    K(v)7.4 channel subunits are expressed in central auditory pathways and in inner ear sensory hair cells and skeletal and smooth muscle cells. Openers of K(v)7.4 channels have been suggested to improve hearing loss, systemic or pulmonary arterial hypertension, urinary incontinence, gastrointestinal and neuropsychiatric diseases, and skeletal muscle disorders. Scorpion venoms are a large source of peptides active on K⁺ channels. Therefore, we have optimized a combined purification/screening procedure to identify specific modulator(s) of K(v)7.4 channels from the venom of the North African scorpion Androctonus australis (Aa). We report the isolation and functional characterization of AaTXKβ₂₋₆₄, a novel variant of AaTXKβ₁₋₆₄, in a high-performance liquid chromatography fraction from Aa venom (named P8), which acts as the first peptide activator of K(v)7.4 channels. In particular, in both Xenopus oocytes and mammalian Chinese hamster ovary cells, AaTXKβ₂₋₆₄, but not AaTXKβ₁₋₆₄, hyperpolarized the threshold voltage of current activation and increased the maximal currents of heterologously expressed K(v)7.4 channels. AaTXKβ₂₋₆₄ also activated K(v)7.3, K(v)7.2/3, and K(v)7.5/3 channels, whereas homomeric K(v)1.1, K(v)7.1, and K(v)7.2 channels were unaffected. We anticipate that these results may prove useful in unraveling the novel biologic roles of AaTXKβ₂₋₆₄-sensitive K(v)7 channels and developing novel pharmacologic tools that allow subtype-selective targeting of K(v)7 channels. PMID:24019223

  19. Corynebacterium jeikeium jk0268 Constitutes for the 40 Amino Acid Long PorACj, Which Forms a Homooligomeric and Anion-Selective Cell Wall Channel

    PubMed Central

    Norouzy, Amir; Schulz, Robert; Nau, Werner M.; Kleinekathöfer, Ulrich; Tauch, Andreas; Benz, Roland

    2013-01-01

    Corynebacterium jeikeium, a resident of human skin, is often associated with multidrug resistant nosocomial infections in immunodepressed patients. C. jeikeium K411 belongs to mycolic acid-containing actinomycetes, the mycolata and contains a channel-forming protein as judged from reconstitution experiments with artificial lipid bilayer experiments. The channel-forming protein was present in detergent treated cell walls and in extracts of whole cells using organic solvents. A gene coding for a 40 amino acid long polypeptide possibly responsible for the pore-forming activity was identified in the known genome of C. jeikeium by its similar chromosomal localization to known porH and porA genes of other Corynebacterium strains. The gene jk0268 was expressed in a porin deficient Corynebacterium glutamicum strain. For purification temporarily histidine-tailed or with a GST-tag at the N-terminus, the homogeneous protein caused channel-forming activity with an average conductance of 1.25 nS in 1M KCl identical to the channels formed by the detergent extracts. Zero-current membrane potential measurements of the voltage dependent channel implied selectivity for anions. This preference is according to single-channel analysis caused by some excess of cationic charges located in the channel lumen formed by oligomeric alpha-helical wheels. The channel has a suggested diameter of 1.4 nm as judged from the permeability of different sized hydrated anions using the Renkin correction factor. Surprisingly, the genome of C. jeikeium contained only one gene coding for a cell wall channel of the PorA/PorH type found in other Corynebacterium species. The possible evolutionary relationship between the heterooligomeric channels formed by certain Corynebacterium strains and the homooligomeric pore of C. jeikeium is discussed. PMID:24116064

  20. 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

  1. Performance Evaluation of Tunable Channel-Selective Wavelength Shift by Cascaded Sum- and Difference-Frequency Generation in Periodically Poled Lithium Niobate Waveguides

    NASA Astrophysics Data System (ADS)

    Gao, Shiming; Yang, Changxi; Xiao, Xiaosheng; Tian, Yu; You, Zheng; Jin, Guofan

    2007-03-01

    We theoretically evaluate the performance of tunable channel-selective wavelength shift based on cascaded sum- and difference-frequency generation by the use of two pump lights in periodically poled lithium niobate waveguides. In double-pass configurations, the functions of wavelength add/drop and wavelength shift are easy to integrate in the same waveguide. Analysis shows that a longer waveguide more competently adapts narrower channel spacing in wavelength-division-multiplexed (WDM) systems. This wavelength shifter is flexible due to the almost separable operations of the two pumps: The channel is selected by setting the first pump, and the wavelength-shifting value is tuned by adjusting the second pump. This wavelength shifter has a very large dynamic region. For a 2.56-cm-long waveguide, the maximum dynamic region is as broad as 67 nm in a 0.4-nm channel-spacing WDM system. The dynamic region is mainly dominated by the limitation of multiple-channel crosstalk in a dense WDM system. However, it is dominated by the limitation of single-channel efficiency fluctuation in a coarse one.

  2. Noseleaf pit in Egyptian slit-faced bat as a doubly curved reflector

    NASA Astrophysics Data System (ADS)

    Zhuang, Qiao; Wang, Xiao-Min; Li, Ming-Xuan; Mao, Jie; Wang, Fu-Xun

    2012-02-01

    Noseleaves in slit-faced bats have been hypothesized to affect the sonar beam. Using numerical methods, we show that the pit in the noseleaf of an Egyptian slit-faced bat has an effect on focusing the acoustic near field as well as shaping the radiation patterns and hence enhancing the directionality. The underlying physical mechanism suggested by the properties of the effect is that the pit acts as a doubly curved reflector. Thanks to the pit the beam shape is overall directional and more selectively widened at the high end of the biosonar frequency range to improve spatial coverage and detectability of targets.

  3. Alzheimer's disease amyloid beta-protein forms Zn(2+)-sensitive, cation-selective channels across excised membrane patches from hypothalamic neurons.

    PubMed Central

    Kawahara, M; Arispe, N; Kuroda, Y; Rojas, E

    1997-01-01

    We have previously shown that the 40-residue peptide termed amyloid beta-protein (A beta P[1-40]) in solution forms cation-selective channels across artificial phospholipid bilayer membranes. To determine whether A beta P[1-40] also forms channels across natural membranes, we used electrically silent excised membrane patches from a cell line derived from hypothalamic gonadotrophin-releasing hormone GnRH neurons. We found that exposing either the internal or the external side of excised membrane patches to A beta P[1-40] leads to the spontaneous formation of cation-selective channels. With Cs+ as the main cation in both the external as well as the internal saline, the amplitude of the A beta P[1-40] channel currents was found to follow the Cs+ gradient and to exhibit spontaneous conductance changes over a wide range (50-500 pS). We also found that free zinc (Zn2+), reported to bind to amyloid beta-protein in solution, can block the flow of Cs+ through the A beta P[1-40] channel. Because the Zn2+ chelator o-phenanthroline can reverse this blockade, we conclude that the underlying mechanism involves a direct interaction between the transition element Zn2+ and sites in the A beta P[1-40] channel pore. These properties of the A beta P[1-40] channel are rather similar to those observed in the artificial bilayer system. We also show here, by immunocytochemical confocal microscopy, that amyloid beta-protein molecules form deposits closely associated with the plasma membrane of a substantial fraction of the GnRH neurons. Taken together, these results suggest that the interactions between amyloid beta-protein and neuronal membranes also occur in vivo, lending further support to the idea that A beta P[1-40] channel formation might be a mechanism of amyloid beta-protein neurotoxicity. Images FIGURE 5 PMID:9199772

  4. Scanning mutagenesis of omega-atracotoxin-Hv1a reveals a spatially restricted epitope that confers selective activity against insect calcium channels.

    PubMed

    Tedford, Hugo W; Gilles, Nicolas; Ménez, André; Doering, Clinton J; Zamponi, Gerald W; King, Glenn F

    2004-10-15

    We constructed a complete panel of alanine mutants of the insect-specific calcium channel blocker omega-atracotoxin-Hv1a. Lethality assays using these mutant toxins identified three spatially contiguous residues, Pro10, Asn27, and Arg35, that are critical for insecticidal activity against flies (Musca domestica) and crickets (Acheta domestica). Competitive binding assays using radiolabeled omega-atracotoxin-Hv1a and neuronal membranes prepared from the heads of American cockroaches (Periplaneta americana) confirmed the importance of these three residues for binding of the toxin to target calcium channels presumably expressed in the insect membranes. At concentrations up to 10 microm, omega-atracotoxin-Hv1a had no effect on heterologously expressed rat Cav2.1, Cav2.2, and Cav1.2 calcium channels, consistent with the previously reported insect selectivity of the toxin. 30 microm omega-atracotoxin-Hv1a inhibited rat Cav currents by 10-34%, depending on the channel subtype, and this low level of inhibition was essentially unchanged when Asn27 and Arg35, which appears to be critical for interaction of the toxin with insect Cav channels, were both mutated to alanine. We propose that the spatially contiguous epitope formed by Pro10, Asn27, and Arg35 confers specific binding to insect Cav channels and is largely responsible for the remarkable phyletic selectivity of omega-atracotoxin-Hv1a. This epitope provides a structural template for rational design of chemical insecticides that selectively target insect Cav channels. PMID:15308644

  5. Quantification of Entanglement Entropies for Doubly Excited States in Helium

    NASA Astrophysics Data System (ADS)

    Lin, Chien-Hao; Ho, Yew Kam

    2015-05-01

    In this work, we study the quantum entanglement for doubly excited resonance states in helium by using highly correlated Hylleraas type functions to represent such states of the two-electron system. The doubly-excited resonance states are determined by calculation of density of resonance states under the framework of the stabilization method. The spatial (electron-electron orbital) entanglement measures for the low-lying doubly excited 2 s 2, 2 s3 s, and 2 p 2 1 S e states are carried out. Once a resonance state wave function is obtained, the linear entropy and von Neumann entropy for such a state are quantified using the Schmidt-Slater decomposition method. To check the consistence, linear entropy is also determined by solving analytically the needed four-electron (12-dimensional) integrals.

  6. A doubly cross-linked nano-adhesive for the reliable sealing of flexible microfluidic devices.

    PubMed

    You, Jae Bem; Min, Kyoung-Ik; Lee, Bora; Kim, Dong-Pyo; Im, Sung Gap

    2013-04-01

    Along with the expansion of microfluidics into many areas of applications such as sensors, microreactors and analytical tools, many other materials besides poly(dimethylsiloxane) (PDMS) have been suggested such as poly(imide) (PI) or poly(ethylene terephthalate) (PET). However, the sealing methods for these materials are not reliable in that many of the methods are specific to the substrate materials. Here, we report a novel robust doubly cross-linked nano-adhesive (DCNA) for bonding of various heterogeneous substrates. By depositing 200 nm of epoxy-containing polymer, poly(glycidyl methacrylate), via initiated chemical vapour deposition (iCVD) onto various substrates and cross-linking them with ethylenediamine, a strong adhesion was obtained between the substrates. This adhesive system was not only able to bond various difficult-to-bond substrates, such as PET or PI, but it could also preserve the complicated morphology of the surfaces owing to the thin nature of the DCNA system. The DCNA allowed fabrication of microfluidic devices using both rigid substrates, such as silicon wafer and glass, and flexible substrates, such as PDMS, PET and PI. The burst pressure of the devices sealed with DCNA exceeded 2.5 MPa, with a maximum burst pressure of 11.7 MPa. Furthermore, the adhesive system demonstrated an exceptional chemical and thermal resistance. The adhesion strength of the adhesive sandwiched between glass substrates remained the same even after a 10 day exposure to strong organic solvents such as toluene, acetone, and tetrahydrofuran (THF). Also, exposure to 200 °C for 15 h was not able to damage the adhesion strength. Using the high adhesive strength and flexibility of DCNA, flexible microfluidic devices that can be completely folded or rolled without any delamination during the operation were fabricated. The DCNA bonding is highly versatile in the sealing of microfluidic systems, and is compatible with a wide selection of materials, including flexible and

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

    PubMed Central

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

    2010-01-01

    Because of their prominent role in electro-excitability, voltage-gated sodium (NaV) channels have become the foremost important target of animal toxins. These toxins have developed the ability to discriminate between closely related NaV subtypes, making them powerful tools to study NaV 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 NaV currents in rat dorsal root ganglion neurons. To illuminate the underlying NaV subtype-selectivity pattern, we have assayed the effects of CgNa on a broad range of mammalian isoforms (NaV1.2–NaV1.8) expressed in Xenopus oocytes. This study demonstrates that CgNa selectively slows the fast inactivation of rNaV1.3/β1, mNaV1.6/β1 and, to a lesser extent, hNaV1.5/β1, while the other mammalian isoforms remain unaffected. Importantly, CgNa was also examined on the insect sodium channel DmNaV1/tipE, revealing a clear phyla-selectivity in the efficacious actions of the toxin. CgNa strongly inhibits the inactivation of the insect NaV 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 NaV channel subtypes. Moreover, further structural studies could provide important information on the molecular mechanism of NaV channel inactivation. PMID:21833172

  8. Comparison of Estradiol, Testosterone, Vitellogenin and Cathepsin Profiles Among Two-year-old Channel Catfish (Ictalurus punctatus) Females from Four Selectively Bred Strains

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Potential variation in reproductive performance as young broodfish among four selectively bred strains of channel catfish was evaluated by comparing profiles of plasma estradiol, testosterone, and vitellogenin, and activities of cathepsin D, L, and B in follicle-enclosed oocytes during vitellogenesi...

  9. Role of the central arginine R133 toward the ion selectivity of the phosphate specific channel OprP: effects of charge and solvation.

    PubMed

    Modi, Niraj; Bárcena-Uribarri, Iván; Bains, Manjeet; Benz, Roland; Hancock, Robert E W; Kleinekathöfer, Ulrich

    2013-08-20

    The outer membrane porin OprP of Pseudomonas aeruginosa forms a highly specific phosphate selective channel. This channel is responsible for the high-affinity uptake of phosphate ions into the periplasmic space of the bacteria. A detailed investigation of the structure-function relationship of OprP is inevitable to decipher the anion and phosphate selectivity of this porin in particular and to broaden the present understanding of the ion selectivity of different channels. To this end we investigated the role of the central arginine of OprP, R133, in terms of its effects in selectivity and ion transport properties of the pore. Electrophysiological bilayer measurements and free-energy molecular dynamics simulations were carried out to probe the transport of different ions through various R133 mutants. For these mutants, the change in phosphate binding specificity, ion conduction, and anion selectivity was determined and compared to previous molecular dynamic calculations and electrophysiological measurements with wild-type OprP. Molecular analysis revealed a rather particular role of arginine 133 and its charge, while at the same time this residue together with the network of other residues, namely, D94 and Y114, has the ability to dehydrate the permeating ion. These very specific features govern the ion selectivity of OprP. PMID:23875754

  10. 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.

  11. Structural Heterogeneity of Doubly-Charged Peptide b-Ions

    NASA Astrophysics Data System (ADS)

    Li, Xiaojuan; Huang, Yiqun; O'Connor, Peter B.; Lin, Cheng

    2011-02-01

    Performing collisionally activated dissociation (CAD) and electron capture dissociation (ECD) in tandem has shown great promise in providing comprehensive sequence information that was otherwise unobtainable by using either fragmentation method alone or in duet. However, the general applicability of this MS3 approach in peptide sequencing may be undermined by the formation of non-direct sequence ions, as sometimes observed under CAD, particularly when multiple stages of CAD are involved. In this study, varied-sized doubly-charged b-ions from three tachykinin peptides were investigated by ECD. Sequence scrambling was observed in ECD of all b-ions from neurokinin A (HKTDSFVGLM-NH2), suggesting the presence of N- and C-termini linked macro-cyclic conformers. On the contrary, none of the b-ions from eledoisin (pEPSKDAFIGLM-NH2) produced non-direct sequence ions under ECD, as it does not contain a free N-terminal amino group. ECD of several b-ions from Substance P (RPKPQQFFGLM-NH2) showed series of cm-Lys fragment ions which suggested that the macro-cyclic structure may also be formed by connecting the C-terminal carbonyl group and the ɛ-amino group of the lysine side chain. Theoretical investigation of selected Substance P b-ions revealed several low energy conformers, including both linear oxazolones and macro-ring structures, in corroboration with the experimental observation. This study showed that a b-ion may exist as a mixture of several forms, with their propensities influenced by its N-terminus, length, and certain side-chain groups. Further, the presence of several macro-cyclic structures may result in erroneous sequence assignment when the combined CAD and ECD methods are used in peptide sequencing.

  12. N-Terminally extended analogues of the K⁺ channel toxin from Stichodactyla helianthus as potent and selective blockers of the voltage-gated potassium channel Kv1.3.

    PubMed

    Chang, Shih C; Huq, Redwan; Chhabra, Sandeep; Beeton, Christine; Pennington, Michael W; Smith, Brian J; Norton, Raymond S

    2015-06-01

    The voltage-gated potassium channel Kv1.3 is an important target for the treatment of autoimmune diseases and asthma. Blockade of Kv1.3 by the sea anemone peptide K⁺-channel toxin from Stichodactyla helianthus (ShK) inhibits the proliferation of effector memory T lymphocytes and ameliorates autoimmune diseases in animal models. However, the lack of selectivity of ShK for Kv1.3 over the Kv1.1 subtype has driven a search for Kv1.3-selective analogues. In the present study, we describe N-terminally extended analogues of ShK that contain a negatively-charged Glu, designed to mimic the phosphonate adduct in earlier Kv1.3-selective analogues, and consist entirely of common protein amino acids. Molecular dynamics simulations indicated that a Trp residue at position [-3] of the tetrapeptide extension could form stable interactions with Pro377 of Kv1.3 and best discriminates between Kv1.3 and Kv1.1. This led to the development of ShK with an N-terminal Glu-Trp-Ser-Ser extension ([EWSS]ShK), which inhibits Kv1.3 with an IC₅₀ of 34 pm and is 158-fold selective for Kv1.3 over Kv1.1. In addition, [EWSS]ShK is more than 2900-fold more selective for Kv1.3 over Kv1.2 and KCa3.1 channels. As a highly Kv1.3-selective analogue of ShK based entirely on protein amino acids, which can be produced by recombinant expression, this peptide is a valuable addition to the complement of therapeutic candidates for the treatment of autoimmune diseases. PMID:25864722

  13. Cisapride, a selective serotonin 5-HT4-receptor agonist, inhibits voltage-dependent K(+) channels in rabbit coronary arterial smooth muscle cells.

    PubMed

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

    2016-09-23

    We investigated the effect of cisapride, a selective serotonin 5-HT4-receptor agonist, on voltage-dependent K(+) (Kv) channels using freshly isolated smooth muscle cells from the coronary arteries of rabbits. The amplitude of Kv currents was reduced by cisapride in a concentration-dependent manner, with an IC50 value of 6.77 ± 6.01 μM and a Hill coefficient of 0.51 ± 0.18. The application of cisapride shifted the steady-state inactivation curve toward a more negative potential, but had no significant effect on the steady-state activation curve. This suggested that cisapride inhibited the Kv channel in a closed state by changing the voltage sensitivity of Kv channels. The application of another selective serotonin 5-HT4-receptor agonist, prucalopride, did not affect the basal Kv current and did not alter the inhibitory effect of cisapride on Kv channels. From these results, we concluded that cisapride inhibited vascular Kv current in a concentration-dependent manner by shifting the steady-state inactivation curve, independent of its own function as a selective serotonin 5-HT4-receptor agonist. PMID:27569285

  14. Observation of doubly spin-polarized deuterium by electron-spin resonance

    SciTech Connect

    Shinkoda, I.; Reynolds, M.W.; Cline, R.W.; Hardy, W.N.

    1986-09-08

    We have studied spin-polarized deuterium, Darrow-down, in the temperature range 0.3 to 0.7 K in a field of 40 kG using electron-spin resonance at 114 GHz. The intrinsic rates for recombination of two D atoms to form D/sub 2/ on the surface of l-/sup 4/He have been measured for both the ortho and para channels. The two rates are approximately equal and when extrapolated to zero field are 1600 times greater than the rates for H/sub 2/ formation. Doubly spin-polarized deuterium, Darrow-downX, has been observed for the first time, with nuclear-spin purities >0.98 and sample lifetimes as long as 1 h.

  15. Observation of the Doubly Strange b Baryon {omega}{sub b}{sup -}

    SciTech Connect

    Abazov, V. M.; Alexeev, G. D.; Kharzheev, Y. M.; Komissarov, E. V.; Malyshev, V. L.; Merekov, Y. P.; Rozhdestvenski, A.; Tokmenin, V. V.; Vertogradov, L. S.; Vertogradova, Y.; Yatsunenko, Y. A.; Abbott, B.; Gutierrez, P.; Hossain, S.; Jain, S.; Rominsky, M.; Severini, H.; Skubic, P.; Strauss, M.; Abolins, M.

    2008-12-05

    We report the observation of the doubly strange b baryon {omega}{sub b}{sup -} in the decay channel {omega}{sub b}{sup -}{yields}J/{psi}{omega}{sup -}, with J/{psi}{yields}{mu}{sup +}{mu}{sup -} and {omega}{sup -}{yields}{lambda}K{sup -}{yields}(p{pi}{sup -})K{sup -}, in pp collisions at {radical}(s)=1.96 TeV. Using approximately 1.3 fb{sup -1} of data collected with the D0 detector at the Fermilab Tevatron Collider, we observe 17.8{+-}4.9(stat){+-}0.8(syst) {omega}{sub b}{sup -} signal events at a mass of 6.165{+-}0.010(stat){+-}0.013(syst) GeV. The significance of the observed signal is 5.4{sigma}, corresponding to a probability of 6.7x10{sup -8} of it arising from a background fluctuation.

  16. Co-expression of non-selective cation channels of the transient receptor potential canonical family in central aminergic neurones.

    PubMed

    Sergeeva, Olga A; Korotkova, Tatiana M; Scherer, Annette; Brown, Ritchie E; Haas, Helmut L

    2003-06-01

    The mammalian transient receptor potential canonical (TRPC) group of channels is a family of Ca2+-permeable cation channels that are activated following receptor-mediated stimulation of different isoforms of phospholipase C. In vitro TRPC proteins can form hetero- or homo-oligomeric channels. We performed single-cell RT-PCR analysis to reveal the co-expression of seven TRPC channels in identified rat aminergic neurones. All serotonergic neurones of the dorsal raphe (DR), the majority of histaminergic (tuberomamillary nucleus; TMN) and dopaminergic cells of the ventral tegmental area (VTA), as well as some GABAergic neurones from the VTA, expressed at least one variant of TRPC channels. No TRPC channel expression was found in the locus coeruleus. In raphe neurones TRPC6 and TRPC5 mRNAs occurred most frequently. In VTA and TMN co-expression of TRPC4 with TRPC5 and TRPC6 with TRPC7 was not found in individual neurones (in contrast to the whole-brain regions). Their co-expression in non-neuronal cells could not be excluded. The neonatal TRPC3 subunit was rarely seen. In DR, but not in the other nuclei studied, the expression of orexin receptors correlated with the expression of TRPC channels. We conclude that several TRPC channel populations exist in individual neurones and that their subunit co-expression pattern is region and cell-type specific. PMID:12787073

  17. 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...

  18. 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.

  19. 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.

  20. Caribbean maitotoxin elevates [Ca2+]i and activates non-selective cation channels in HIT-T15 cells

    PubMed Central

    Lu, Xin-Zhong; Deckey, Robert; Jiao, Guo-Liang; Ren, Hui-Feng; Li, Ming

    2013-01-01

    AIM: To investigate the cytotoxic mechanism of caribbean maitotoxin (MTX-C) in mammalian cells. METHODS: We used whole-cell patch-clamp techniques and fluorescence calcium imaging to determine the cellular toxic mechanisms of MTX-C in insulin secreting HIT-T15 cells, which is a system where the effects of MTX have been observed. HIT-T15 cells stably express L-type calcium current, making it a suitable model for this study. Using the fluorescence calcium indicator Indo-1 AM, we found that there is a profound increase in HIT-T15 intracellular free calcium 3 min after application of 200 nmol/L MTX-C. RESULTS: About 3 min after perfusion of MTX-C, a gradual increase in free calcium concentration was observed. This elevation was sustained throughout the entire recording period. Application of MTX-C did not elicit the L-type calcium current, but large cationic currents appeared after applying MTX-C to the extracellular solution. The current-voltage relationship of the cation current is approximately linear within the voltage range from -60 to 50 mV, but flattened at voltages at -80 and -100 mV. These results indicate that MTX-C induces a non-voltage activated, inward current under normal physiological conditions, which by itself or through a secondary mechanism results in a large amount of cationic influx. The biophysical mechanism of MTX-C is different to its isoform, pacific maitotoxin (MTX-P), when the extracellular calcium is removed. CONCLUSION: We conclude that MTX-C causes the opening of non-selective, non-voltage-activated ion channels, which elevates level of intracellular calcium concentration and leads to cellular toxicities. PMID:23772275

  1. A measurement of the top pair production cross-section in the dilepton channel using lepton plus track selection

    SciTech Connect

    Mills, Corrinne Elaine; /UC, Santa Barbara

    2007-06-01

    Using 1.1 fb{sup -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 {ge} 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 {yields} Wb {yields} {ell}{nu}b, 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 {yields} {ell}{nu}) = 10.8% and a top mass of m{sub t} = 175 GeV/c{sup 2}, the measured cross-section is {sigma}(p{bar p} {yields} 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{sub -0.9}{sup +0.7} pb and represents a significant improvement in precision over previous results using this selection.

  2. Quantifying the causal effects of 20mph zones on road casualties in London via doubly robust estimation.

    PubMed

    Li, Haojie; Graham, Daniel J

    2016-08-01

    This paper estimates the causal effect of 20mph zones on road casualties in London. Potential confounders in the key relationship of interest are included within outcome regression and propensity score models, and the models are then combined to form a doubly robust estimator. A total of 234 treated zones and 2844 potential control zones are included in the data sample. The propensity score model is used to select a viable control group which has common support in the covariate distributions. We compare the doubly robust estimates with those obtained using three other methods: inverse probability weighting, regression adjustment, and propensity score matching. The results indicate that 20mph zones have had a significant causal impact on road casualty reduction in both absolute and proportional terms. PMID:27173361

  3. 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. PMID:26235584

  4. D1-like dopamine receptors selectively block P/Q-type calcium channels to reduce glutamate release onto cholinergic basal forebrain neurones of immature rats

    PubMed Central

    Momiyama, Toshihiko; Fukazawa, Yugo

    2007-01-01

    Whole-cell patch-clamp recordings of non-NMDA glutamatergic EPSCs were made from identified cholinergic neurones in slices of basal forebrain (BF) of young rats (P13–P18), to investigate the subtypes of calcium channels involved in dopamine D1-like receptor-mediated presynaptic inhibition of the EPSCs. The BF cholinergic neurones were pre-labelled by intracerebroventricular injection of a fluorescent marker, Cy3-192IgG. A D1-like receptor agonist, SKF 81297 (30 μm) suppressed the EPSCs reversibly by about 30%, and this inhibition was reproducible. Calcium channel subtypes involved in the glutamatergic transmission were elucidated using selective Ca2+ channel blockers. The N-type Ca2+ channel blocker ω-conotoxin (ω-CgTX, 3 μm) suppressed the EPSCs by 57.5%, whereas the P/Q-type channel selective blocker ω-agatoxin-TK (ω-Aga-TK, 200 nm) suppressed the EPSCs by 68.9%. Simultaneous application of both blockers suppressed the EPSCs by 96.1%. The R-type Ca2+ channel blocker SNX-482 (300 nm) suppressed the EPSCs by 18.4%, whereas nifedipine, the L-type Ca2+ channel blocker (10 μm), had little effect. In the presence of ω-Aga-TK, SKF 81297, a dopamine D1-like receptor agonist, had no effect on the EPSCs. On the other hand, SKF 81297 could still inhibit the EPSCs in the presence of either ω-CgTX, SNX-482 or nifedipine. SKF 81297 had no further effect on the EPSCs when external Ca2+ concentration was raised to 7.2 mm in the presence of ω-Aga-TK, but could still inhibit the EPSCs in high Ca2+ solution after ω-CgTX application. Forskolin (FK, 10 μm), an activator of adenylyl cyclase pathway, suppressed the EPSCs, and the FK-induced effect was mostly blocked in the presence of ω-Aga-TK but not that of ω-CgTX. These results suggest that D1-like receptor activation selectively blocks P/Q-type calcium channels to reduce glutamate release onto BF cholinergic neurones. PMID:17234695

  5. Histidines, heart of the hydrogen ion channel from influenza A virus: Toward an understanding of conductance and proton selectivity

    NASA Astrophysics Data System (ADS)

    Hu, Jun; Fu, Riqiang; Nishimura, Katsuyuki; Zhang, Li; Zhou, Huan-Xiang; Busath, David D.; Vijayvergiya, Viksita; Cross, Timothy A.

    2006-05-01

    The heart of the H+ conductance mechanism in the homotetrameric M2 H+ channel from influenza A is a set of four histidine side chains. Here, we show that protonation of the third of these imidazoles coincides with acid activation of this transmembrane channel and that, at physiological pH, the channel is closed by two imidazole-imidazolium dimers, each sharing a low-barrier hydrogen bond. This unique construct succeeds in distributing a pair of charges over four rings and many atoms in a low dielectric environment to minimize charge repulsion. These dimers form with identical pKas of 8.2 ± 0.2, suggesting cooperative H+ binding and clearly illustrating high H+ affinity for this channel. The protonation behavior of the histidine side chains has been characterized by using solid-state NMR spectroscopy on the M2 transmembrane domain in fully hydrated lipid bilayers where the tetrameric backbone structure is known. Furthermore, electrophysiological measurements of multichannel and single-channel experiments confirm that these protein constructs are functional. M2 channel | proton channel | solid-state NMR | low-barrier hydrogen bond | histidine ionization constants

  6. Bumetanide Derivatives AqB007 and AqB011 Selectively Block the Aquaporin-1 Ion Channel Conductance and Slow Cancer Cell Migration.

    PubMed

    Kourghi, Mohamad; Pei, Jinxin V; De Ieso, Michael L; Flynn, Gary; Yool, Andrea J

    2016-01-01

    Aquaporins (AQPs) in the major intrinsic family of proteins mediate fluxes of water and other small solutes across cell membranes. AQP1 is a water channel, and under permissive conditions, a nonselective cation channel gated by cGMP. In addition to mediating fluid transport, AQP1 expression facilitates rapid cell migration in cell types including colon cancers and glioblastoma. Work here defines new pharmacological derivatives of bumetanide that selectively inhibit the ion channel, but not the water channel, activity of AQP1. Human AQP1 was analyzed in the Xenopus laevis oocyte expression system by two-electrode voltage clamp and optical osmotic swelling assays. The aquaporin ligand bumetanide derivative AqB011 was the most potent blocker of the AQP1 ion conductance (IC50 of 14 μM), with no effect on water channel activity (at up to 200 μM). The order of potency for inhibition of the ionic conductance was AqB011 > AqB007 > AqB006 ≥ AqB001. Migration of human colon cancer (HT29) cells was assessed with a wound-closure assay in the presence of a mitotic inhibitor. AqB011 and AqB007 significantly reduced migration rates of AQP1-positive HT29 cells without affecting viability. The order of potency for AQP1 ion channel block matched the order for inhibition of cell migration, as well as in silico modeling of the predicted order of energetically favored binding. Docking models suggest that AqB011 and AqB007 interact with the intracellular loop D domain, a region involved in AQP channel gating. Inhibition of AQP1 ionic conductance could be a useful adjunct therapeutic approach for reducing metastasis in cancers that upregulate AQP1 expression. PMID:26467039

  7. Selective inhibition of the K(ir)2 family of inward rectifier potassium channels by a small molecule probe: the discovery, SAR, and pharmacological characterization of ML133.

    PubMed

    Wang, Hao-Ran; Wu, Meng; Yu, Haibo; Long, Shunyou; Stevens, Amy; Engers, Darren W; Sackin, Henry; Daniels, J Scott; Dawson, Eric S; Hopkins, Corey R; Lindsley, Craig W; Li, Min; McManus, Owen B

    2011-08-19

    The K(ir) inward rectifying potassium channels have a broad tissue distribution and are implicated in a variety of functional roles. At least seven classes (K(ir)1-K(ir)7) of structurally related inward rectifier potassium channels are known, and there are no selective small molecule tools to study their function. In an effort to develop selective K(ir)2.1 inhibitors, we performed a high-throughput screen (HTS) of more than 300,000 small molecules within the MLPCN for modulators of K(ir)2.1 function. Here we report one potent K(ir)2.1 inhibitor, ML133, which inhibits K(ir)2.1 with an IC(50) of 1.8 μM at pH 7.4 and 290 nM at pH 8.5 but exhibits little selectivity against other members of Kir2.x family channels. However, ML133 has no effect on K(ir)1.1 (IC(50) > 300 μM) and displays weak activity for K(ir)4.1 (76 μM) and K(ir)7.1 (33 μM), making ML133 the most selective small molecule inhibitor of the K(ir) family reported to date. Because of the high homology within the K(ir)2 family-the channels share a common design of a pore region flanked by two transmembrane domains-identification of site(s) critical for isoform specificity would be an important basis for future development of more specific and potent K(ir) inhibitors. Using chimeric channels between K(ir)2.1 and K(ir)1.1 and site-directed mutagenesis, we have identified D172 and I176 within M2 segment of K(ir)2.1 as molecular determinants critical for the potency of ML133 mediated inhibition. Double mutation of the corresponding residues of K(ir)1.1 to those of K(ir)2.1 (N171D and C175I) transplants ML133 inhibition to K(ir)1.1. Together, the combination of a potent, K(ir)2 family selective inhibitor and identification of molecular determinants for the specificity provides both a tool and a model system to enable further mechanistic studies of modulation of K(ir)2 inward rectifier potassium channels. PMID:21615117

  8. Selective inhibition of the Kir2 family of inward rectifier potassium channels by a small molecule probe: the discovery, SAR and pharmacological characterization of ML133

    PubMed Central

    Wang, Hao-Ran; Wu, Meng; Yu, Haibo; Long, Shunyou; Stevens, Amy; Engers, Darren W.; Sackin, Henry; Daniels, J. Scott; Dawson, Eric S.; Hopkins, Corey R.; Lindsley, Craig W.; Li, Min; McManus, Owen B

    2011-01-01

    The Kir inward rectifying potassium channels have a broad tissue distribution and are implicated in a variety of functional roles. At least seven classes (Kir1 – Kir7) of structurally related inward rectifier potassium channels are known, and there are no selective small molecule tools to study their function. In an effort to develop selective Kir2.1 inhibitors, we performed a high-throughput screen (HTS) of more than 300,000 small molecules within the MLPCN for modulators of Kir2.1 function. Here we report one potent Kir2.1 inhibitor, ML133, which inhibits Kir2.1 with IC50 of 1.8 μM at pH 7.4 and 290 nM at pH 8.5, but exhibits little selectivity against other members of Kir2.x family channels. However, ML133 has no effect on Kir1.1 (IC50 > 300 μM), and displays weak activity for Kir4.1 (76 μM) and Kir7.1 (33 μM), making ML133 the most selective small molecule inhibitor of the Kir family reported to date. Due to the high homology within the Kir family, the channels share a common design of a pore region flanked by two transmembrane domains, identification of site(s) critical for isoform specificity would be an important basis for future development of more specific and potent Kir inhibitors. Using chimeric channels between Kir2.1 and Kir1.1 and site-directed mutagenesis, we have identified D172 and I176 within M2 segment of Kir2.1 as molecular determinants critical for the potency of ML133 mediated inhibition. Double mutation of the corresponding residues of Kir1.1 to those of Kir2.1 (N171D and C175I) transplants ML133 inhibition to Kir1.1. Together, the combination of a potent, Kir2 family selective inhibitor and identification of molecular determinants for the specificity provides both a tool and a model system to enable further mechanistic studies of modulation of Kir2 inward rectifier potassium channels. PMID:21615117

  9. The Earliest Ion Channels

    NASA Astrophysics Data System (ADS)

    Pohorille, A.; Wilson, M. A.; Wei, C.

    2009-12-01

    Supplying protocells with ions required assistance from channels spanning their membrane walls. The earliest channels were most likely short proteins that formed transmembrane helical bundles surrounding a water-filled pore. These simple aggregates were capable of transporting ions with efficiencies comparable to those of complex, contemporary ion channels. Channels with wide pores exhibited little ion selectivity but also imposed only modest constraints on amino acid sequences of channel-forming proteins. Channels with small pores could have been selective but also might have required a more precisely defined sequence of amino acids. In contrast to modern channels, their protocellular ancestors had only limited capabilities to regulate ion flux. It is postulated that subsequent evolution of ion channels progressed primarily to acquire precise regulation, and not high efficiency or selectivity. It is further proposed that channels and the surrounding membranes co-evolved.

  10. 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. PMID:25887396

  11. 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

  12. Antitumor and biological investigation of doubly cyclometalated ruthenium(ii) organometallics derived from benzimidazolyl derivatives.

    PubMed

    Elumalai, Palani; Jeong, Yong Joon; Park, Dae Won; Kim, Dong Hwan; Kim, Hyunuk; Kang, Se Chan; Chi, Ki-Whan

    2016-04-12

    In this study, we report the synthesis, anticancer and biological properties of three doubly cyclometalated phenylbenzimidazole derived ruthenium(ii) organometallics () and their corresponding three organic ligands. The structures of were fully characterized by various analytical techniques, and the meso stereoisomer of the doubly cyclometalated ruthenacycle was unambiguously confirmed by single crystal X-ray diffraction. The anticancer effects of the newly synthesized compounds were tested against selected human cancer cell lines AGS (gastric carcinoma), SK-hep-1 (hepatocellular carcinoma), and HCT-15 (colorectal carcinoma). The growth inhibitory effects of ruthenacycles on cancer cells were found to be considerably more effective against the abovementioned cancer cells than the reference drug oxaliplatin. Compound exhibited a more specific effect on the AGS cells. Gene-fishing and ELISA array were performed to analyze the target genes and cytokine secretion by . As a result, a significant reduction was observed in RPS21 by . Moreover, increased the secretion of cytokines such as IFNγ in macrophages and reduced the release of cytokines such as rantes and IGF-1. These results show that could be a very good anticancer drug through the regulation of the RPS21 gene and cytokines. PMID:26974823

  13. Identification of Selective Inhibitors of the Potassium Channel Kv1.1–1.2(3) by High-Throughput Virtual Screening and Automated Patch Clamp

    PubMed Central

    Wacker, Sören J; Jurkowski, Wiktor; Simmons, Katie J; Fishwick, Colin W G; Johnson, A Peter; Madge, David; Lindahl, Erik; Rolland, Jean-Francois; de Groot, Bert L

    2012-01-01

    Abstract Two voltage-dependent potassium channels, Kv1.1 (KCNA1) and Kv1.2 (KCNA2), are found to co-localize at the juxtaparanodal region of axons throughout the nervous system and are known to co-assemble in heteromultimeric channels, most likely in the form of the concatemer Kv1.1–1.2(3). Loss of the myelin sheath, as is observed in multiple sclerosis, uncovers the juxtaparanodal region of nodes of Ranvier in myelinated axons leading to potassium conductance, resulting in loss of nerve conduction. The selective blocking of these Kv channels is therefore a promising approach to restore nerve conduction and function. In the present study, we searched for novel inhibitors of Kv1.1–1.2(3) by combining a virtual screening protocol and electrophysiological measurements on a concatemer Kv1.1–1.2(3) stably expressed in Chinese hamster ovary K1 (CHO-K1) cells. The combined use of four popular virtual screening approaches (eHiTS, FlexX, Glide, and Autodock-Vina) led to the identification of several compounds as potential inhibitors of the Kv1.1–1.2(3) channel. From 89 electrophysiologically evaluated compounds, 14 novel compounds were found to inhibit the current carried by Kv1.1–1.2(3) channels by more than 80 % at 10 μM. Accordingly, the IC50 values calculated from concentration–response curve titrations ranged from 0.6 to 6 μM. Two of these compounds exhibited at least 30-fold higher potency in inhibition of Kv1.1–1.2(3) than they showed in inhibition of a set of cardiac ion channels (hERG, Nav1.5, and Cav1.2), resulting in a profile of selectivity and cardiac safety. The results presented herein provide a promising basis for the development of novel selective ion channel inhibitors, with a dramatically lower demand in terms of experimental time, effort, and cost than a sole high-throughput screening approach of large compound libraries. PMID:22473914

  14. Limited selection of sodium channel blocking toxin-producing bacteria from paralytic shellfish toxin-contaminated mussels (Aulacomya ater).

    PubMed

    Vásquez, Mónica; Grüttner, Carol; Möeller, Blanca; Moore, Edward R B

    2002-01-01

    Paralytic shellfish toxins (PSTs) are sodium channel blocking (SCB) toxins, produced by cyanobacteria, as well as by marine dinoflagellates and their associated bacteria, and cause serious health and economic concern worldwide. In a previous study, approximately 70% of the bacteria enriched from PST-contaminated shellfish tissue and isolated on marine agar medium were observed to produce SCB toxins. In the study reported here, the high percentage of cultivable toxigenic bacteria is demonstrated to be obtained through a marked selection on marine agar medium. The cultivable as well as the total bacterial diversity associated with PST-contaminated shellfish collected from the Magallanes region in the south of Chile has been analysed. Approximately 80% of bacterial isolates, analysed by restriction analysis of PCR amplified ribosomal DNA (i.e., ARDRA fingerprinting), were limited to only two genotypic OTUs (operational taxonomic unit). Sequence determination and analysis of the 16S rDNA from representative isolates of both OTUs established them to be closely related to species of the Psychrobacter genus of the gamma-subclass of the Proteobacteria. The total bacterial diversity in the shellfish was further analysed, using a cultivation-independent strategy of extraction of total DNA from contaminated tissue, PCR-amplification of bacterial 16S rRNA genes, cloning of the PCR products and analysis of the cloned 16S rDNA sequence types by fingerprinting and sequencing. Only 2% of the cloned sequence types corresponded to species of the Psychrobacter genus. The 16S rDNA sequence types detected clustered with species of the y-Proteobacteria subclass, the Cytophaga-Flexibacter-Bacteroides (CFB), the Fusobacteria and the Firmicutes phyla. The level of diversity observed within the libraries of cloned 16S rDNA was markedly greater than that observed among isolates obtained through marine agar enrichment cultures from the same shellfish tissue. Additionally the predominant

  15. Identification of (R)-N-(4-(4-methoxyphenyl)thiazol-2-yl)-1-tosylpiperidine-2-carboxamide, ML277, as a novel, potent and selective Kv7.1 (KCNQ1) potassium channel activator

    PubMed Central

    Mattmann, Margrith E.; Yu, Haibo; Lin, Zhihong; Xu, Kaiping; Huang, Xiaofang; Long, Shunyou; Wu, Meng; McManus, Owen B.; Engers, Darren W.; Le, Uyen M.; Li, Min; Lindsley, Craig W.; Hopkins, Corey R.

    2012-01-01

    A high-throughput screen utilizing a depolarization-triggered thallium influx through KCNQ1 channels was developed and used to screen the MLSMR collection of over 300,000 compounds. An iterative medicinal chemistry approach was initiated and from this effort, ML277 was identified as a potent activator of KCNQ1 channels (EC50 = 260 nM). ML277 was shown to be highly selective against other KCNQ channels (>100-fold selectivity versus KCNQ2 and KCNQ4) as well as against the distantly related hERG potassium channel. PMID:22910039

  16. Cd(2+) sensitivity and permeability of a low voltage-activated Ca(2+) channel with CatSper-like selectivity filter.

    PubMed

    Garza-López, Edgar; Chávez, Julio César; Santana-Calvo, Carmen; López-González, Ignacio; Nishigaki, Takuya

    2016-07-01

    CatSper is a sperm-specific Ca(2+) channel that plays an essential role in the male fertility. However, its biophysical properties have been poorly characterized mainly due to its deficient heterologous expression. As other voltage-gated Ca(2+) channels (CaVs), CatSper possesses a conserved Ca(2+)-selective filter motif ([T/S]x[D/E]xW) in the pore region. Interestingly, CatSper conserves four aspartic acids (DDDD) as the negatively charged residues in this motif while high voltage-activated CaVs have four glutamic acids (EEEE) and low voltage-activated CaVs possess two glutamic acids and two aspartic acids (EEDD). Previous studies based on site-directed mutagenesis of L- and T-type channels showed that the number of D seems to have a negative correlation with their cadmium (Cd(2+)) sensitivity. These results suggest that CatSper (DDDD) would have low sensitivity to Cd(2+). To explore Cd(2+)-sensitivity and -permeability of CatSper, we performed two types of experiments: 1) Electrophysiological analysis of heterologously expressed human CaV3.1 channel and three pore mutants (DEDD, EDDD and DDDD), 2) Cd(2+) imaging of human spermatozoa with FluoZin-1. Electrophysiological studies showed a significant increase in Cd(2+) and manganese (Mn(2+)) currents through the CaV3.1 mutants as well as a reduction in the inhibitory effect of Cd(2+) on the Ca(2+) current. In fluorescence imaging with human sperm, we observed an increase in Cd(2+) influx potentiated by progesterone, a potent activator of CatSper. These results support our hypothesis, namely that Cd(2+)-sensitivity and -permeability are related to the absolute number of D in the Ca(2+)-selective filter independently to the type of the Cav channels. PMID:27134080

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

    PubMed Central

    Bon, Robin S; Beech, David J

    2013-01-01

    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

  18. Histidines, heart of the hydrogen ion channel from influenza A virus: Toward an understanding of conductance and proton selectivity

    PubMed Central

    Hu, Jun; Fu, Riqiang; Nishimura, Katsuyuki; Zhang, Li; Zhou, Huan-Xiang; Busath, David D.; Vijayvergiya, Viksita; Cross, Timothy A.

    2006-01-01

    The heart of the H+ conductance mechanism in the homotetrameric M2 H+ channel from influenza A is a set of four histidine side chains. Here, we show that protonation of the third of these imidazoles coincides with acid activation of this transmembrane channel and that, at physiological pH, the channel is closed by two imidazole–imidazolium dimers, each sharing a low-barrier hydrogen bond. This unique construct succeeds in distributing a pair of charges over four rings and many atoms in a low dielectric environment to minimize charge repulsion. These dimers form with identical pKas of 8.2 ± 0.2, suggesting cooperative H+ binding and clearly illustrating high H+ affinity for this channel. The protonation behavior of the histidine side chains has been characterized by using solid-state NMR spectroscopy on the M2 transmembrane domain in fully hydrated lipid bilayers where the tetrameric backbone structure is known. Furthermore, electrophysiological measurements of multichannel and single-channel experiments confirm that these protein constructs are functional. PMID:16632600

  19. Tityus bahiensis toxin IV-5b selectively affects Na channel inactivation in chick dorsal root ganglion neurons.

    PubMed

    Trequattrini, C; Zamudio, F Z; Petris, A; Prestipino, G; Possani, L D; Franciolini, F

    1995-09-01

    A novel toxin was isolated from the venom of the Brazilian scorpion Tityus (T.) bahiensis. The N-terminal amino acid sequence of this toxin was shown to be 80% identical to the corresponding segment of T. serrulatus toxin IV-5. The new toxin was thus named toxin IV-5b. Toxin IV-5b was found to markedly slow inactivation of Na channel in dorsal root ganglion neurons from chick embryo. By contrast, Na channel activation was only negligibly delayed, and deactivation completely unaffected. Similarly unaffected by the toxin were K and Ca currents. The slowing effect of the toxin starts to appear at concentrations of c. 80 nM, and shows a KD of 143 nM. With a toxin concentration of 2.4 microM, the Na channel inactivation time constant was increased c. 3-fold with respect to the control. The slowing of inactivation was voltage dependent, and increased with depolarization. PMID:7553331

  20. Molecular analysis of a store-operated and 2-acetyl-sn-glycerol-sensitive non-selective cation channel. Heteromeric assembly of TRPC1-TRPC3.

    PubMed

    Liu, Xibao; Bandyopadhyay, Bidhan C; Singh, Brij B; Groschner, Klaus; Ambudkar, Indu S

    2005-06-01

    We have reported that internal Ca2+ store depletion in HSY cells stimulates a nonselective cation current which is distinct from I(CRAC) in RBL cells and TRPC1-dependent I(SOC) in HSG cells (Liu, X., Groschner, K., and Ambudkar, I. S. (2004) J. Membr. Biol. 200, 93-104). Here we have analyzed the molecular composition of this channel. Both thapsigargin (Tg) and 2-acetyl-sn-glycerol (OAG) stimulated similar non-selective cation currents and Ca2+ entry in HSY cells. The effects of Tg and OAG were not additive. HSY cells endogenously expressed TRPC1, TRPC3, and TRPC4 but not TRPC5 or TRPC6. Immunoprecipitation of TRPC1 pulled down TRPC3 but not TRPC4. Conversely, TRPC1 co-immunoprecipitated with TRPC3. Expression of antisense TRPC1 decreased (i) Tg- and OAG-stimulated currents and Ca2+ entry and (ii) the level of endogenous TRPC1 but not TRPC4. Antisense TRPC3 similarly reduced Ca2+ entry and endogenous TRPC3. Yeast two-hybrid analysis revealed an interaction between NTRPC1 and NTRPC3 (CTRPC1-CTRPC3, CTRPC3-CTRPC1, or CTRPC1-NTRPC3 did not interact), which was confirmed by glutathione S-transferase (GST) pull-down assays (GST-NTRPC3 pulled down TRPC1 and vice versa). Expression of NTRPC1 or NTRPC3 induced similar dominant suppression of Tg- and OAG-stimulated Ca2+ entry. NTRPC3 did not alter surface expression of TRPC1 or TRPC3 but disrupted TRPC1-TRPC3 association. In aggregate, our data demonstrate that TRPC1 and TRPC3 co-assemble, via N-terminal interactions, to form a heteromeric store-operated non-selective cation channel in HSY cells. Thus selective association between TRPCs generate distinct store-operated channels. Diversity of store-operated channels might be related to the physiology of the different cell types. PMID:15834157

  1. D2 dopamine receptor activation of potassium channels is selectively decoupled by Galpha-specific GoLoco motif peptides.

    PubMed

    Webb, Christina K; McCudden, Christopher R; Willard, Francis S; Kimple, Randall J; Siderovski, David P; Oxford, Gerry S

    2005-03-01

    The GoLoco motif is a short polypeptide sequence found in G-protein signaling regulators such as regulator of G-protein signaling proteins type 12 and 14 and activator of G-protein signaling protein type 3. A unique property of the GoLoco motifs from these three proteins is their preferential interaction with guanosine diphosphate (GDP)-bound Galpha(i1), Galpha(i3) and, sometimes, Galpha(i2) subunits over Galpha(o) subunits. This interaction prevents both spontaneous guanine nucleotide release and reassociation of Galpha(i)-GDP with Gbetagamma. We utilized this property of the GoLoco motif to examine dopamine (D2 and D3) and somatostatin receptor coupling to G-protein-regulated inwardly rectifying potassium (GIRK) channels in mouse AtT20 cells. GoLoco motif peptides had no effect on either basal channel activity or the initial responses to agonists, suggesting that the GoLoco motif cannot disrupt pre-formed G-protein heterotrimers. GoLoco motif peptides did, however, interfere with human D2((short)) receptor coupling to GIRK channels as demonstrated by the progressively diminished responses after repeated agonist application. This behavior is consistent with some form of compartmentalization of D2 receptors and GIRK channels such that Gbetagamma subunits, freed by local receptor activation and prevented from reforming a heterotrimeric complex, are not functionally constrained within the receptor-channel complex and thus are unable to exert a persistent activating effect. In contrast, GoLoco motif peptides had no effect on either D3 or somatostatin coupling to GIRK channels. Our results suggest that GoLoco motif-based peptides will be useful tools in examining the specificity of G-protein-coupled receptor-effector coupling. PMID:15748159

  2. Regulation of the desensitization and ion selectivity of ATP-gated P2X2 channels by phosphoinositides.

    PubMed

    Fujiwara, Yuichiro; Kubo, Yoshihiro

    2006-10-01

    Phosphoinositides (PIP(n)s) are known to regulate the activity of some ion channels. Here we determined that ATP-gated P2X(2) channels also are regulated by PIP(n)s, and investigated the structural background and the unique features of this regulation. We initially used two-electrode voltage clamp to analyse the electrophysiological properties of P2X(2) channels expressed in Xenopus oocytes, and observed that preincubation with wortmannin or LY294002, two PI3K inhibitors, accelerated channel desensitization. K365Q or K369Q mutation of the conserved, positively charged, amino acid residues in the proximal region of the cytoplasmic C-terminal domain also accelerated desensitization, whereas a K365R or K369R mutation did not. We observed that the permeability of the channel to N-methyl-d-glucamine (NMDG) transiently increased and then decreased after ATP application, and that the speed of the decrease was accelerated by K365Q or K369Q mutation or PI3K inhibition. Using GST-tagged recombinant proteins spanning the proximal C-terminal region, we then analysed their binding of the P2X(2) cytoplasmic domain to anionic lipids using PIP(n)s-coated nitrocellulose membranes. We found that the recombinant proteins that included the positively charged region bound to PIPs and PIP(2)s, and that this binding was eliminated by the K365Q and K369Q mutations. We also used a fluorescence assay to confirm that fusion proteins comprising the proximal C-terminal region of P2X(2) with EGFP expressed in COS-7 cells closely associated with the membrane. Taken together, these results show that membrane-bound PIP(n)s play a key role in maintaining channel activity and regulating pore dilation through electrostatic interaction with the proximal region of the P2X(2) cytoplasmic C-terminal domain. PMID:16857707

  3. 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

  4. 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.

  5. Doubly-charged ions in the planetary ionospheres: a review.

    PubMed

    Thissen, Roland; Witasse, Olivier; Dutuit, Odile; Wedlund, Cyril Simon; Gronoff, Guillaume; Lilensten, Jean

    2011-11-01

    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. PMID:21931881

  6. 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.

  7. Transient model of a doubly excited reluctance motor

    SciTech Connect

    Xu, L.; Liang, F.; Lipo, T.A. . Dept. of Electrical and Computer Engineering)

    1991-03-01

    A transient machine model of a doubly fed reluctance motor is derived by means of winding function and d-q transformation theory. The machine consists of a double wound stator having four and eight pole sets. The rotor is equipped with six poles. The machine, related to the Hunt motor, has a synchronous speed of a twelve pole machine. Comparison of simulated to tested results indicates that the higher harmonics in the motor inductances are important for predicting current waveform.

  8. 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

  9. Doubly sensitivity-enhanced 3D TOCSY-HSQC.

    PubMed

    Wijmenga, S S; van Mierlo, C P; Steensma, E

    1996-10-01

    Recently, strategies for double sensitivity enhancement in heteronuclear three-dimensional NMR experiments were introduced (Krishnamurthy, V.V. (1995) J. Magn. Reson., B106, 170-177; Sattler et al. (1995) J. Biomol. NMR, 6, 11-22; Sattler et al. (1995) J. Magn. Reson., B108, 235-242). Since a sensitivity enhancement of a factor 2(1/2) can be achieved for each indirect dimension, nD spectra can theoretically be enhanced up to a factor of 2(((n-1)/2)). We propose and analyze a doubly enhanced three-dimensional TOCSY-HSQC sequence. The application of the doubly enhanced three-dimensional {(15)N, (1)H} TOCSY-HSQC sequence is shown for uniformly (13)C-/(15)N- and (15)N-labeled samples of the relatively large Azotobacter vinelandii flavodoxin II (179 amino acids). The main factors that contribute to the final signal-to-noise enhancement have been systematically investigated. The sensitivity enhancement obtained for the doubly enhanced TOCSY-HSQC pulse sequence as compared to the standard (unenhanced) version is close to the theoretically expected factor of two. PMID:20686884

  10. 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.

  11. Making A Better Hybrid Catfish: Can Hybridization of Channel Catfish Selected for ESC Resistance Improve Disease Resistance?

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Improved production traits such as disease resistance and growth have long been realized from the hybridization of channel catfish (Ictalurus punctatus) female X and blue catfish (Ictalurus furcatus) male. Recent advances in hybrid embryo production technology to consistently produce higher number...

  12. Pharmaceutical Optimization of Peptide Toxins for Ion Channel Targets: Potent, Selective, and Long-Lived Antagonists of Kv1.3.

    PubMed

    Murray, Justin K; Qian, Yi-Xin; Liu, Benxian; Elliott, Robin; Aral, Jennifer; Park, Cynthia; Zhang, Xuxia; Stenkilsson, Michael; Salyers, Kevin; Rose, Mark; Li, Hongyan; Yu, Steven; Andrews, Kristin L; Colombero, Anne; Werner, Jonathan; Gaida, Kevin; Sickmier, E Allen; Miu, Peter; Itano, Andrea; McGivern, Joseph; Gegg, Colin V; Sullivan, John K; Miranda, Les P

    2015-09-10

    To realize the medicinal potential of peptide toxins, naturally occurring disulfide-rich peptides, as ion channel antagonists, more efficient pharmaceutical optimization technologies must be developed. Here, we show that the therapeutic properties of multiple cysteine toxin peptides can be rapidly and substantially improved by combining direct chemical strategies with high-throughput electrophysiology. We applied whole-molecule, brute-force, structure-activity analoging to ShK, a peptide toxin from the sea anemone Stichodactyla helianthus that inhibits the voltage-gated potassium ion channel Kv1.3, to effectively discover critical structural changes for 15× selectivity against the closely related neuronal ion channel Kv1.1. Subsequent site-specific polymer conjugation resulted in an exquisitely selective Kv1.3 antagonist (>1000× over Kv1.1) with picomolar functional activity in whole blood and a pharmacokinetic profile suitable for weekly administration in primates. The pharmacological potential of the optimized toxin peptide was demonstrated by potent and sustained inhibition of cytokine secretion from T cells, a therapeutic target for autoimmune diseases, in cynomolgus monkeys. PMID:26288216

  13. 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

  14. 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. PMID:23849427

  15. Dopamine D2-like receptors selectively block N-type Ca2+ channels to reduce GABA release onto rat striatal cholinergic interneurones

    PubMed Central

    Momiyama, Toshihiko; Koga, Eiko

    2001-01-01

    The modulatory roles of dopamine (DA) in inhibitory transmission onto striatal large cholinergic interneurones were investigated in rat brain slices using patch-clamp recording. Pharmacologically isolated GABAA receptor-mediated IPSCs were recorded by focal stimulation within the striatum. Bath application of DA reversibly suppressed the amplitude of evoked IPSCs in a concentration-dependent manner (IC50, 10.0 μm). A D2-like receptor agonist, quinpirole (3–30 μm), also suppressed the IPSCs, whereas a D1-like receptor agonist, SKF 81297, did not affect IPSCs. Sulpiride, a D2-like receptor antagonist, blocked the DA-induced suppression of IPSCs (apparent dissociation constant (KB), 0.36 μm), while a D1-like receptor antagonist, SCH 23390 (10 μm), had no effect. DA (30 μm) reduced the frequency of spontaneous miniature IPSCs (mIPSCs) without changing their amplitude distribution, suggesting that GABA release was inhibited, whereas the sensitivity of postsynaptic GABAA receptors was not affected. The effect of DA on the frequency of mIPSCs was diminished when extracellular Ca2+ was replaced by Mg2+ (5 mm), indicating that DA affected the Ca2+ entry into the presynaptic terminal. An N-type Ca2+ channel selective blocker, ω-conotoxin GVIA (ω-CgTX, 3 μm), suppressed IPSCs by 65.4%, whereas a P/Q-type Ca2+ channel selective blocker, ω-agatoxin IVA (ω-Aga-IVA, 200 nm), suppressed IPSCs by 78.4%. Simultaneous application of both blockers suppressed IPSCs by 95.9%. Assuming a 3rd power relationship between Ca2+ concentration and transmitter release, the contribution of N-, P/Q- and other types of Ca2+ channels to presynaptic Ca2+ entry is estimated to be, respectively, 29.8, 40.0 and 34.5% at this synapse. After the application of ω-CgTX, DA (30 μm) no longer affected IPSCs. In contrast, ω-Aga-IVA did not alter the level of suppression by DA, suggesting that the action of DA was selective for N-type Ca2+ channels. A G protein alkylating agent, N

  16. He photoionization dominated by doubly excited resonances

    SciTech Connect

    Chang, T.N.; Zhen, M.

    1993-05-01

    We present the theoretical He photoionization, cross sections from the ground and the {sup 1,3}S bound excited states using a B-spline based configuration-interaction procedure for continuum (CIC). The resonant structures associated with selected sp,2n{sup {plus_minus}} and 2pnd {sup 1,3}P autoionization series below the He{sup +} N=2 threshold will be expressed quantitatively in terms of their resonant energies, widths, and peak cross sections. Comparisons with earlier theoretical results and recent experimental measurement will be presented. The nonresonant spectra from the 1s2s {sup 1,3}S metastable states will also be reexamined.

  17. Reductions in Susceptibility of Channel Catfish (Ictalutus punctatus) to Enteric Septicemia of Catfish (ESC) Through Two Generations of Selection

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Improvement of disease resistance in aquaculture species through selective breeding has had some success. At the USDA-ARS Catfish Genetics Research Unit, Stoneville, MS, a multitrait selection index was utilized to select for growth, carcass yield, and resistance to enteric septicemia of catfish (...

  18. Synthetic Ciguatoxins Selectively Activate Nav1.8-derived Chimeric Sodium Channels Expressed in HEK293 Cells*

    PubMed Central

    Yamaoka, Kaoru; Inoue, Masayuki; Miyazaki, Keisuke; Hirama, Masahiro; Kondo, Chie; Kinoshita, Eiji; Miyoshi, Hiroshi; Seyama, Issei

    2009-01-01

    The synthetic ciguatoxin CTX3C has been shown to activate tetrodotoxin (TTX)-sensitive sodium channels (Nav1.2, Nav1.4, and Nav1.5) by accelerating activation kinetics and shifting the activation curve toward hyperpolarization (Yamaoka, K., Inoue, M., Miyahara, H., Miyazaki, K., and Hirama, M. (2004) Br. J. Pharmacol. 142, 879–889). In this study, we further explored the effects of CTX3C on the TTX-resistant sodium channel Nav1.8. TTX-resistant channels have been shown to be involved in transducing pain and related sensations (Akopian, A. N., Sivilotti, L., and Wood, J. N. (1996) Nature 379, 257–262). Thus, we hypothesized that ciguatoxin-induced activation of the Nav1.8 current would account for the neurological symptoms of ciguatera poisoning. We found that 0.1 μm CTX3C preferentially affected the activation process of the Nav1.8 channel compared with those of the Nav1.2 and Nav1.4 channels. Importantly, without stimulation, 0.1 μm CTX3C induced a large leakage current (IL). The conductance of the IL calculated relative to the maximum conductance (Gmax) was 10 times larger than that of Nav1.2 or Nav1.4. To determine the molecular domain of Nav1.8 responsible for conferring higher sensitivity to CTX3C, we made two chimeric constructs from Nav1.4 and Nav1.8. Chimeras containing the N-terminal half of Nav1.8 exhibited a large response similar to wild-type Nav1.8, indicating that the region conferring high sensitivity to ciguatoxin action is located in the D1 or D2 domains. PMID:19164297

  19. 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. PMID:16497878

  20. 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

  1. 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

  2. Photodissociation investigation of doubly charged ethanol clusters induced by inner-shell electron ionization.

    PubMed

    Tamenori, Y; Okada, K; Tabayashi, K; Hiraya, A; Gejo, T; Honma, K

    2011-05-28

    Fragmentation of doubly charged ethanol clusters [(C(2)H(5)OH)(n)] following the O 1s ionization has been investigated by means of the photoelectron-photoion-photoion coincidence (PEPIPICO) method. The dominant fission channel of (C(2)H(5)OH)(n)(2+) was the formation of protonated cluster ion pairs [H(C(2)H(5)OH)(l)(+)/H(C(2)H(5)OH)(m)(+)]. The fragmentation mechanisms of these ion pairs were discussed based on the analysis of the PEPIPICO contour shape. It was clarified that the prominent fragmentation channel was a secondary decay mechanism, where neutral evaporation occurs after charge separation. On the other hand, the formation of small fragment ions was suppressed, excluding the formation of certain specific fragments (H(3)O(+), C(2)H(5)(+)/COH(+), and C(2)H(4)OH(+)). The formation of small fragment ions was suppressed due to the cooling effect caused by the neutral evaporation and the decrease in the electrostatic repulsive force caused by charge separation. PMID:21639435

  3. Particle swarm optimization for discrete-time inverse optimal control of a doubly fed induction generator.

    PubMed

    Ruiz-Cruz, Riemann; Sanchez, Edgar N; Ornelas-Tellez, Fernando; Loukianov, Alexander G; Harley, Ronald G

    2013-12-01

    In this paper, the authors propose a particle swarm optimization (PSO) for a discrete-time inverse optimal control scheme of a doubly fed induction generator (DFIG). For the inverse optimal scheme, a control Lyapunov function (CLF) is proposed to obtain an inverse optimal control law in order to achieve trajectory tracking. A posteriori, it is established that this control law minimizes a meaningful cost function. The CLFs depend on matrix selection in order to achieve the control objectives; this matrix is determined by two mechanisms: initially, fixed parameters are proposed for this matrix by a trial-and-error method and then by using the PSO algorithm. The inverse optimal control scheme is illustrated via simulations for the DFIG, including the comparison between both mechanisms. PMID:24273145

  4. TRP channels.

    PubMed

    Benemei, Silvia; Patacchini, Riccardo; Trevisani, Marcello; Geppetti, Pierangelo

    2015-06-01

    Evidence is accumulating on the role of transient receptor potential (TRP) channels, namely TRPV1, TRPA1, TRPV4 and TRPM8, expressed by C- and Aδ-fibres primary sensory neurons, in cough mechanism. Selective stimuli for these channels have been proven to provoke and, more rarely, to inhibit cough. More importantly, cough threshold to TRP agonists is increased by proinflammatory conditions, known to favour cough. Off-target effects of various drugs, such as tiotropium or desflurane, seem to produce their protective or detrimental actions on airway irritation and cough via TRPV1 and TRPA1, respectively. Thus, TRPs appear to encode the process that initiates or potentiates cough, activated by exogenous irritants and endogenous proinflammatory mediators. More research on TRP channels may result in innovative cough medicines. PMID:25725213

  5. YM155, a selective survivin inhibitor, reverses chronic hypoxic pulmonary hypertension in rats via upregulating voltage-gated potassium channels.

    PubMed

    Fan, Zaiwen; Liu, Bo; Zhang, Shuai; Liu, Huiguo; Li, Yang; Wang, Dong; Liu, Ying; Li, Jian; Wang, Ning; Liu, Yi; Zhang, Bo

    2015-01-01

    To test the hypothesis that chronic hypoxic pulmonary hypertension (CH-PH) is associated with increased survivin and decreased voltage-gated potassium (KV) channels expression in pulmonary arteries, rats were randomized as: normoxia (N); normoxia + YM155, survivin suppressor (NY); hypoxia (H); hypoxia + YM155 (HY). HY group had significantly reduced pulmonary arterial pressure, right ventricular weight and right ventricular hypertrophy compared with H group. Survivin mRNA and protein were detected in pulmonary arteries of rats with CH-PH, but not rats without CH-PH. YM155 downregulated survivin protein and mRNA. KV channel expression and activity were upregulated after YM155 treatment. Survivin may play a role in the pathogenesis of CH-PH. PMID:25856227

  6. 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.

  7. 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

  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

    2016-01-01

    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

  9. A Potent and Selective Peptide Blocker of the Kv1.3 Channel: Prediction from Free-Energy Simulations and Experimental Confirmation

    PubMed Central

    Rashid, M. Harunur; Heinzelmann, Germano; Huq, Redwan; Tajhya, Rajeev B.; Chang, Shih Chieh; Chhabra, Sandeep; Pennington, Michael W.; Beeton, Christine; Norton, Raymond S.; Kuyucak, Serdar

    2013-01-01

    The voltage-gated potassium channel Kv1.3 is a well-established target for treatment of autoimmune diseases. ShK peptide from a sea anemone is one of the most potent blockers of Kv1.3 but its application as a therapeutic agent for autoimmune diseases is limited by its lack of selectivity against other Kv channels, in particular Kv1.1. Accurate models of Kv1.x-ShK complexes suggest that specific charge mutations on ShK could considerably enhance its specificity for Kv1.3. Here we evaluate the K18A mutation on ShK, and calculate the change in binding free energy associated with this mutation using the path-independent free energy perturbation and thermodynamic integration methods, with a novel implementation that avoids convergence problems. To check the accuracy of the results, the binding free energy differences were also determined from path-dependent potential of mean force calculations. The two methods yield consistent results for the K18A mutation in ShK and predict a 2 kcal/mol gain in Kv1.3/Kv1.1 selectivity free energy relative to wild-type peptide. Functional assays confirm the predicted selectivity gain for ShK[K18A] and suggest that it will be a valuable lead in the development of therapeutics for autoimmune diseases. PMID:24244345

  10. Synthesis, structural characterization and selectively catalytic properties of metal-organic frameworks with nano-sized channels: A modular design strategy

    SciTech Connect

    Qiu Lingguang Gu Lina; Hu Gang; Zhang Lide

    2009-03-15

    Modular design method for designing and synthesizing microporous metal-organic frameworks (MOFs) with selective catalytical activity was described. MOFs with both nano-sized channels and potential catalytic activities could be obtained through self-assembly of a framework unit and a catalyst unit. By selecting hexaaquo metal complexes and the ligand BTC (BTC=1,3,5-benzenetricarboxylate) as framework-building blocks and using the metal complex [M(phen){sub 2}(H{sub 2}O){sub 2}]{sup 2+} (phen=1,10-phenanthroline) as a catalyst unit, a series of supramolecular MOFs 1-7 with three-dimensional nano-sized channels, i.e. [M{sup 1}(H{sub 2}O){sub 6}].[M{sup 2}(phen){sub 2}(H{sub 2}O){sub 2}]{sub 2}.2(BTC).xH{sub 2}O (M{sup 1}, M{sup 2}=Co(II), Ni(II), Cu(II), Zn(II), or Mn(II), phen=1,10-phenanthroline, BTC=1,3,5-benzenetricarboxylate, x=22-24), were synthesized through self-assembly, and their structures were characterized by IR, elemental analysis, and single-crystal X-ray diffraction. These supramolecular microporous MOFs showed significant size and shape selectivity in the catalyzed oxidation of phenols, which is due to catalytic reactions taking place in the channels of the framework. Design strategy, synthesis, and self-assembly mechanism for the construction of these porous MOFs were discussed. - Grapical abstract: A modular design strategy has been developed to synthesize microporous metal-organic frameworks with potential catalytic activity by self-assembly of the framework-building blocks and the catalyst unit.

  11. Gramicidin Channels: Versatile Tools

    NASA Astrophysics Data System (ADS)

    Andersen, Olaf S.; Koeppe, Roger E., II; Roux, Benoît

    Gramicidin channels are miniproteins in which two tryptophan-rich subunits associate by means of transbilayer dimerization to form the conducting channels. That is, in contrast to other ion channels, gramicidin channels do not open and close; they appear and disappear. Each subunit in the bilayer-spanning channel is tied to the bilayer/solution interface through hydrogen bonds that involve the indole NH groups as donors andwater or the phospholipid backbone as acceptors. The channel's permeability characteristics are well-defined: gramicidin channels are selective for monovalent cations, with no measurable permeability to anions or polyvalent cations; ions and water move through a pore whose wall is formed by the peptide backbone; and the single-channel conductance and cation selectivity vary when the amino acid sequence is varied, even though the permeating ions make no contact with the amino acid side chains. Given the plethora of available experimental information—for not only the wild-type channels but also for channels formed by amino acid-substituted gramicidin analogues—gramicidin channels continue to provide important insights into the microphysics of ion permeation through bilayer-spanning channels. For similar reasons, gramicidin channels constitute a system of choice for evaluating computational strategies for obtaining mechanistic insights into ion permeation through the more complex channels formed by integral membrane proteins.

  12. 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

    2016-08-01

    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. PMID:27158117

  13. Hydraulic and channel characteristics of selected streams in the Kantishna Hills area, Denali National Park and Preserve, Alaska, 1982-84

    USGS Publications Warehouse

    Van Maanen, J.L.; Solin, G.L.

    1988-01-01

    The Kantishna Hills area of the Denali National Park and Preserve contains extensive placer gold deposits. In order to develop plans for the management of this natural resource, and to assess the effects of placer mining on aquatic systems, documentation of the physical characteristics of the streams in the area is needed. Channel morphology, streamflow and streambed composition data were collected at 14 stream reaches in the Kantishna Hills area in September 1982 and in June, July, August , and September of 1983 and 1984. The reaches selected include locations of historical and current mining activity and locations which are undisturbed. The data indicate only minor differences in the physical properties of the streams in mined and unmined drainage basins. The composition of streambeds below mined areas tended to consist of finer sized particles and exhibited less variation in mean particle size than streambed in unmined basins. This may be due in part to the natural sorting of material in stream channels because mined areas, and thus study reaches below them, tended to be located relatively farther downstream (nearer the stream mouth) than were study reaches in basins where no mining has occurred. Changes in the physical properties of the streams which could be directly attributed to mining activity were noted at only one location, Rainy Creek near Kantishna, where the stream had been diverted from its natural channel by the construction of settling ponds. (Author 's abstract)

  14. Structural and dynamic basis of human cytochrome P450 7B1: a survey of substrate selectivity and major active site access channels.

    PubMed

    Cui, Ying-Lu; Zhang, Ji-Long; Zheng, Qing-Chuan; Niu, Rui-Juan; Xu, Yu; Zhang, Hong-Xing; Sun, Chia-Chung

    2013-01-01

    Cytochrome P450 (CYP) 7B1 is a steroid cytochrome P450 7α-hydroxylase that has been linked directly with bile salt synthesis and hereditary spastic paraplegia type 5 (SPG5). The enzyme provides the primary metabolic route for neurosteroids dehydroepiandrosterone (DHEA), cholesterol derivatives 25-hydroxycholesterol (25-HOChol), and other steroids such as 5α-androstane-3β,17β-diol (anediol), and 5α-androstene-3β,17β-diol (enediol). A series of investigations including homology modeling, molecular dynamics (MD), and automatic docking, combined with the results of previous experimental site-directed mutagenesis studies and access channels analysis, have identified the structural features relevant to the substrate selectivity of CYP7B1. The results clearly identify the dominant access channels and critical residues responsible for ligand binding. Both binding free energy analysis and total interaction energy analysis are consistent with the experimental conclusion that 25-HOChol is the best substrate. According to 20 ns MD simulations, the Phe cluster residues that lie above the active site, particularly Phe489, are proposed to merge the active site with the adjacent channel to the surface and accommodate substrate binding in a reasonable orientation. The investigation of CYP7B1-substrate binding modes provides detailed insights into the poorly understood structural features of human CYP7B1 at the atomic level, and will be valuable information for drug development and protein engineering. PMID:23180418

  15. Control of the Aquaporin-4 Channel Water Permeability by Structural Dynamics of Aromatic/Arginine Selectivity Filter Residues.

    PubMed

    Kitchen, Philip; Conner, Alex C

    2015-11-17

    The aquaporins (AQPs) make up a family of integral membrane proteins that control cellular water flow. Gating of the water channel by conformational changes induced by phosphorylation or protein-protein interactions is an established regulatory mechanism for AQPs. Recent in silico and crystallographic analyses of the structural biology of AQPs suggest that the rate of water flow can also be controlled by small movements of single-amino acid side chains lining the water pore. Here we use measurements of the membrane water permeability of mammalian cells expressing AQP4 mutants to provide the first in vitro evidence in support of this hypothesis. PMID:26512424

  16. A C-terminally amidated analogue of ShK is a potent and selective blocker of the voltage-gated potassium channel Kv1.3.

    PubMed

    Pennington, Michael W; Harunur Rashid, M; Tajhya, Rajeev B; Beeton, Christine; Kuyucak, Serdar; Norton, Raymond S

    2012-11-16

    ShK, a 35-residue peptide from a sea anemone, is a potent blocker of potassium channels. Here we describe a new ShK analogue with an additional C-terminus Lys residue and amide. ShK-K-amide is a potent blocker of Kv1.3 and, in contrast to ShK and ShK-amide, is selective for Kv1.3. To understand this selectivity, we created complexes of ShK-K-amide with Kv1.3 and Kv1.1 using docking and molecular dynamics simulations, then performed umbrella sampling simulations to construct the potential of mean force of the ligand and calculate the corresponding binding free energy for the most stable configuration. The results agree well with experimental data. PMID:23063513

  17. Doubly anchored nematic polymer brushes: Shear, field effects, and quasipiezoelectricity

    NASA Astrophysics Data System (ADS)

    Halperin, A.; Williams, D. R. M.

    1994-02-01

    The shear behavior of a doubly anchored brush of liquid-crystalline polymers immersed in a nematic solvent is investigated. In such a brush the grafted polymers bridge two plates. Remarkably, the Franck nematic elasticity in this system can dominate the shear modulus. In the presence of a field the system undergoes a Fréedericksz transition modified by the bridging polymers. In particular: (i) the polymeric elasticity affects the critical field Ec; (ii) the shear modulus vanishes as the field approaches Ec; and (iii) the nematic distortion couples to a shear strain. The system exhibits quasipiezoelectricity, which is nonlinear and is not associated with any inverse effect.

  18. Center mode of a doubly resonant optical periodic structure

    NASA Astrophysics Data System (ADS)

    Alagappan, G.; Png, C. E.

    2016-07-01

    An optical periodic structure with a single spatial resonance exhibits a stopband. When a second spatial resonance very close to the first one is added, the resulting doubly resonant structure exhibits a Gaussian enveloped, high quality factor transmission state right at the center of the original stopband. Using a slowly varying envelope approximation, we describe the optical characteristics of this transmission state analytically. The transmission state exists despite an optical structure of low refractive index contrast, and has potential applications in nano-optics, and photonics.

  19. 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.

  20. On the road to doubly-magic {sup 48}Ni

    SciTech Connect

    Blank, B.; Czajkowski, S.; Davi, F.; Del Moral, R.; Dufour, J. P.; Fleury, A.; Marchand, C.; Pravikoff, M. S.; Benlliure, J.; Boue, F.; Collatz, R.; Heinz, A.; Hellstroem, M.; Hu, Z.; Roeckl, E.; Shibata, M.; Suemmerer, K.; Lewitowicz, M.; Janas, Z.; Karny, M.

    1998-12-21

    A relativistic primary beam of {sup 58}Ni from the SIS synchrotron at GSI was used to produce proton-rich isotopes in the titanium-to-nickel region by projectile fragmention at the FRS. We report here on the first observation of the T{sub z}=-7/2 nuclei {sup 45}Fe and {sup 49}Ni. In addition, the new isotope {sup 42}Cr (T{sub z}=-3) was identified. This opens the route to the yet unobserved doubly-magic nucleus {sup 48}Ni.

  1. Conversion of the ion selectivity of the 5-HT(3a) receptor from cationic to anionic reveals a conserved feature of the ligand-gated ion channel superfamily.

    PubMed

    Gunthorpe, M J; Lummis, S C

    2001-06-15

    The 5-hydroxytryptamine(3) (5-HT(3)) receptor is a member of a superfamily of ligand-gated ion channels, which includes nicotinic acetylcholine, gamma-aminobutyric acid, and glycine receptors. The receptors are either cation or anion selective, leading to their distinctive involvement in either excitatory or inhibitory neurotransmission. Using a combination of site-directed mutagenesis and electrophysiological characterization of homomeric 5-HT(3A) receptors expressed in HEK293 cells, we have identified a set of mutations that convert the ion selectivity of the 5-HT(3A) receptor from cationic to anionic; these were substitution of V13'T in M2 together with neutralization of glutamate residues (E-1'A) and the adjacent insertion of a proline residue (P-1') in the M1-M2 loop. Mutant receptors showed significant chloride permeability (P(Cl)/P(Na) = 12.3, P(Na)/P(Cl) = 0.08), whereas WT receptors are predominantly permeable to sodium (P(Na)/P(Cl) > 20, P(Cl)/P(Na) < 0.05). Since the equivalent mutations have previously been shown to convert alpha7 nicotinic acetylcholine receptors from cationic to anionic (Galzi J.-L., Devillers-Thiery, A, Hussy, N., Bertrand, S. Changeux, J. P., and Bertrand, D. (1992) Nature 359, 500-505) and, recently, the converse mutations have allowed the construction of a cation selective glycine receptor (Keramidas, A., Moorhouse, A. J., French, C. R., Schofield, P. R., and Barry, P. H. (2000) Biophys. J. 78, 247-259), it appears that the determinants of ion selectivity represent a conserved feature of the ligand-gated ion channel superfamily. PMID:11439930

  2. Conversion of the ion selectivity of the 5-HT(3a) receptor from cationic to anionic reveals a conserved feature of the ligand-gated ion channel superfamily.

    PubMed

    Gunthorpe, M J; Lummis, S C

    2001-04-01

    The 5-hydroxytryptamine(3) (5-HT(3)) receptor is a member of a superfamily of ligand-gated ion channels, which includes nicotinic acetylcholine, gamma-aminobutyric acid, and glycine receptors. The receptors are either cation or anion selective, leading to their distinctive involvement in either excitatory or inhibitory neurotransmission. Using a combination of site-directed mutagenesis and electrophysiological characterization of homomeric 5-HT(3A) receptors expressed in HEK293 cells, we have identified a set of mutations that convert the ion selectivity of the 5-HT(3A) receptor from cationic to anionic; these were substitution of V13'T in M2 together with neutralization of glutamate residues (E-1'A) and the adjacent insertion of a proline residue (P-1') in the M1-M2 loop. Mutant receptors showed significant chloride permeability (P(Cl)/P(Na) = 12.3, P(Na)/P(Cl) = 0.08), whereas WT receptors are predominantly permeable to sodium (P(Na)/P(Cl) > 20, P(Cl)/P(Na) < 0.05). Since the equivalent mutations have previously been shown to convert alpha7 nicotinic acetylcholine receptors from cationic to anionic (Galzi J.-L., Devillers-Thiery, A, Hussy, N., Bertrand, S. Changeux, J. P., and Bertrand, D. (1992) Nature 359, 500-505) and, recently, the converse mutations have allowed the construction of a cation selective glycine receptor (Keramidas, A., Moorhouse, A. J., French, C. R., Schofield, P. R., and Barry, P. H. (2000) Biophys. J. 78, 247-259), it appears that the determinants of ion selectivity represent a conserved feature of the ligand-gated ion channel superfamily. PMID:11139582

  3. 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. PMID:25733897

  4. Pyroptosis is driven by non-selective gasdermin-D pore and its morphology is different from MLKL channel-mediated necroptosis.

    PubMed

    Chen, Xin; He, Wan-Ting; Hu, Lichen; Li, Jingxian; Fang, Yuan; Wang, Xin; Xu, Xiaozheng; Wang, Zhuo; Huang, Kai; Han, Jiahuai

    2016-09-01

    Necroptosis and pyroptosis are two forms of programmed cell death with a common feature of plasma membrane rupture. Here we studied the morphology and mechanism of pyroptosis in comparison with necroptosis. Different from necroptosis, pyroptosis undergoes membrane blebbing and produces apoptotic body-like cell protrusions (termed pyroptotic bodies) prior to plasma membrane rupture. The rupture in necroptosis is explosion-like, whereas in pyroptosis it leads to flattening of cells. It is known that the execution of necroptosis is mediated by mixed lineage kinase domain-like (MLKL) oligomers in the plasma membrane, whereas gasdermin-D (GSDMD) mediates pyroptosis after its cleavage by caspase-1 or caspase-11. We show that N-terminal fragment of GSDMD (GSDMD-N) generated by caspase cleavage also forms oligomer and migrates to the plasma membrane to kill cells. Both MLKL and GSDMD-N are lipophilic and the N-terminal sequences of both proteins are important for their oligomerization and plasma membrane translocation. Unlike MLKL which forms channels on the plasma membrane that induces influx of selected ions which osmotically swell the cells to burst, GSDMD-N forms non-selective pores and does not rely on increased osmolarity to disrupt cells. Our study reveals the pore-forming activity of GSDMD and channel-forming activity of MLKL determine different ways of plasma membrane rupture in pyroptosis and necroptosis. PMID:27573174

  5. 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).

  6. Engineering potent and selective analogues of GpTx-1, a tarantula venom peptide antagonist of the Na(V)1.7 sodium channel.

    PubMed

    Murray, Justin K; Ligutti, Joseph; Liu, Dong; Zou, Anruo; Poppe, Leszek; Li, Hongyan; Andrews, Kristin L; Moyer, Bryan D; McDonough, Stefan I; Favreau, Philippe; Stöcklin, Reto; Miranda, Les P

    2015-03-12

    NaV1.7 is a voltage-gated sodium ion channel implicated by human genetic evidence as a therapeutic target for the treatment of pain. Screening fractionated venom from the tarantula Grammostola porteri led to the identification of a 34-residue peptide, termed GpTx-1, with potent activity on NaV1.7 (IC50 = 10 nM) and promising selectivity against key NaV subtypes (20× and 1000× over NaV1.4 and NaV1.5, respectively). NMR structural analysis of the chemically synthesized three disulfide peptide was consistent with an inhibitory cystine knot motif. Alanine scanning of GpTx-1 revealed that residues Trp(29), Lys(31), and Phe(34) near the C-terminus are critical for potent NaV1.7 antagonist activity. Substitution of Ala for Phe at position 5 conferred 300-fold selectivity against NaV1.4. A structure-guided campaign afforded additive improvements in potency and NaV subtype selectivity, culminating in the design of [Ala5,Phe6,Leu26,Arg28]GpTx-1 with a NaV1.7 IC50 value of 1.6 nM and >1000× selectivity against NaV1.4 and NaV1.5. PMID:25658507

  7. 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

  8. Validation of doubly labeled water method using a ruminant

    SciTech Connect

    Fancy, S.G.; Blanchard, J.M.; Holleman, D.F.; Kokjer, K.J.; White, R.G.

    1986-07-01

    CO/sub 2/ production (CDP, ml CO/sub 2/ . g-1 . h-1) by captive caribou and reindeer (Rangifer tarandus) was measured using the doubly labeled water method (/sup 3/H/sub 2/O and H2(18)O) and compared with CO/sub 2/ expiration rates (VCO/sub 2/), adjusted for CO/sub 2/ losses in CH4 and urine, as determined by open-circuit respirometry. CDP calculated from samples of blood or urine from a reindeer in winter was 1-3% higher than the adjusted VCO/sub 2/. Differences between values derived by the two methods of 5-20% were found in summer trials with caribou. None of these differences were statistically significant (P greater than 0.05). Differences in summer could in part be explained by the net deposition of /sup 3/H, 18O, and unlabeled CO/sub 2/ in antlers and other growing tissues. Total body water volumes calculated from /sup 3/H/sub 2/O dilution were up to 15% higher than those calculated from H/sub 2/(18)O dilution. The doubly labeled water method appears to be a reasonably accurate method for measuring CDP by caribou and reindeer in winter when growth rates are low, but the method may overestimate CDP by rapidly growing and/or fattening animals.

  9. 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.

  10. Wave packet dynamics in doubly excited states of He

    NASA Astrophysics Data System (ADS)

    Feist, Johannes; Nagele, Stefan; Persson, Emil; Burgdörfer, Joachim; Schneider, Barry

    2007-06-01

    We have developed a method for the ab initio simulation of the interaction of ultrashort laser pulses with helium atoms. We expand the two-electron Schr"odinger equation in coupled spherical harmonics and perform direct time integration utilizing either the Arnoldi-Lanczos or the Leapfrog method. The spatial discretization is performed in an FEDVR basis [1]. This allows for a numerically accurate description while possessing desirable computational features, e.g. a block-diagonal form of the kinetic energy matrix. We will present results on electron-electron correlation and wave packet dynamics in He. By using a suitable combination of attosecond XUV/EUV pulses, we prepare a wave packet in the doubly excited states of helium. The motion of this wave packet can be observed by using a probe pulse to induce ionization. We aim for a detailed understanding of the process by a careful study of the ionized electrons, e.g. by investigating doubly differential momentum spectra. [enumi] *B. I. Schneider and L. A. Collins. J. Non-Cryst. Solids 351, 1551.

  11. 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.

  12. 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.

  13. 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

  14. 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. PMID:26861708

  15. Channel architecture in maltoporin: dominance studies with lamB mutations influencing maltodextrin binding provide evidence for independent selectivity filters in each subunit.

    PubMed Central

    Ferenci, T; Lee, K S

    1989-01-01

    Maltoporin trimers constitute maltodextrin-selective channels in the outer membrane of Escherichia coli. To study the organization of the maltodextrin-binding site within trimers, dominance studies were undertaken with maltoporin variants of altered binding affinity. It has been established that amino acid substitutions at three dispersed regions of the maltoporin sequence (at residues 8, 82, and 360) resulted specifically in maltodextrin-binding defects and loss of maltodextrin channel selectivity; a substitution at residue 118 increased both binding affinity and maltodextrin transport. Strains heterodiploid for lamB were constructed in which these substitutions were encoded by chromosomal and plasmid-borne genes, and the relative level of maltoporin expression from these genes was estimated. Binding assays with bacteria forming maltoporin heterotrimers were performed in order to test for complementation between binding-negative alleles, negative dominance of negative over wild-type alleles, and possible dominance of negatives over the high-affinity allele. Double mutants with mutations affecting residues 8 and 118, 82 and 118, and 118 and 360 were constructed in vitro, and the dominance properties of the mutations in cis were also tested. There was no complementation between negatives and no negative dominance in heterotrimers. The high-affinity mutation was dominant over negatives in trans but not in cis. The affinity of binding sites in heterotrimer populations was characteristic of the high-affinity allele present and uninfluenced by the negative allele. These results are consistent with the presence of three discrete binding sites in a maltoporin trimer and suggest that the selectivity filter for maltodextrins is not at the interface between the three subunits. PMID:2521623

  16. Study of the doubly and singly Cabibbo suppressed decays D+ --> K+ pi- pi+ and D(s)+ --> K+ pi- pi+ in the FOCUS experiment

    SciTech Connect

    Edera, Laura

    2005-01-01

    This thesis illustrates a complete study of the doubly and singly Cabibbo suppressed decays D{sup +} and D{sub s}{sup +} {yields} K{sup +} {pi}{sup -}{pi}{sup +}. Data for this analysis have been collected by the fixed-target high-energy photoproduction experiment FOCUS at Fermilab. The authors have selected the D{sup +} and D{sub s}{sup +} samples with cuts to obtain a sufficiently high statistics, a good signal to noise ratio and, at the same time, eliminate possible contaminations from the more copious and favored decays. The D{sup +} yield consists of 189 {+-} 24 events, with a signal to noise ratio {approx} 1; the D{sub s}{sup +} yield is 567 {+-} 31 and the signal to noise ratio is {approx} 2.5. The authors have measured {Lambda}(D{sup +} {yields} K{sup +}{pi}{sup -}{pi}{sup +})/{Lambda}(D{sup +} {yields} K{sup -}{pi}{sup +}{pi}{sup +}) = 0.0065 {+-} 0.0008 {+-} 0.004 and {Lambda}(D{sub s}{sup +} {yields} K{sup +}{pi}{sup -}{pi}{sup +})/{Lambda}(D{sub s}{sup +} {yields} K{sup +}K{sup -}{pi}{sup +}) = 0.127 {+-} 0.007 {+-} 0.014, improving the previous determinations of a factor of 2 and 5, respectively. The author has also performed a Dalitz plot analysis for both decays. The amplitude analysis for D{sub s}{sup +} {yields} K{sup +}{pi}{sup -}{pi}{sup +} represents the first available measurement for this channel.

  17. 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 ¯]^{'}. PMID:26430989

  18. 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.

  19. Quasi-collinear tunable acousto-optic paratellurite crystal filters for wavelength division multiplexing and optical channel selection

    SciTech Connect

    Molchanov, V Ya; Makarov, O Yu; Voloshinov, V B

    2009-04-30

    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 {lambda} {approx_equal} 1550 nm are considered. (light modulation)

  20. 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

  1. Quenching of the 2pnd Po1 doubly excited states of helium by a dc electric field

    NASA Astrophysics Data System (ADS)

    Bučar, K.; Žitnik, M.; Mihelič, A.; Penent, F.; Lablanquie, P.; Palaudoux, J.; Andrić, L.; Braune, M.; Püttner, R.

    2014-07-01

    The fluorescence yield quenching of low-lying doubly excited 2pnd Po1 states is observed to depend strongly on a dc electric field strength and its orientation with respect to the polarization of the incoming photon beam. The reduction of the yield accompanied by the lifetime shortening is attributed to the Stark mixing with the neighboring 2sns Se1 states, which redirects the 2pnd Po1 decay to the prompt autoionization channel. For n ≥4, the lifetimes decrease from several hundred picoseconds down to several tens of picoseconds when an electric field in the kV/cm range is applied parallel to the photon probe polarization. Practically no lifetime change is observed for polarization perpendicular to the electric field direction. The results of the complex-scaling calculations are in a good agreement with the experimental data.

  2. Selective localization of /sup 3/H-nitrendipine recognition sites and voltage-sensitive Ca/sup 2 +/ channels in nerve cell bodies of caudate nuclei

    SciTech Connect

    Sanna, E.; Wright, A.G. Jr.; Hanbauer, I.

    1986-03-05

    /sup 3/H-Nitrendipine, a Ca/sup 2 +/ channel antagonist, binds with high affinity to recognition sites on neuronal membranes and may serve as biochemical marker for Ca/sup 2 +/ channels. Seven days after injection of kainic acid into the caudate nucleus the number of specific binding sites for /sup 3/H-nitrendipine decreases from 240 +/- 19 fmol/mg prot (contralateral) to 38 +/- 3 fmol/mg prot (ipsilateral), while the affinity for /sup 3/H-nitrendipine remains unchanged (K/sub D/=2.0 x 10/sup -10/M). Selective destruction of serotonergic or dopaminergic nerve terminals in caudate nucleus fails to alter the number of /sup 3/H-nitrendipine binding sites. The accumulation of /sup 45/Ca/sup 2 +/ was measured in slices prepared from intact of kainic acid-lesioned caudate nuclei. In intact slices the /sup 45/Ca/sup 2 +/ uptake is maximally increased (5-fold) in presence of 10/sup -5/M veratridine. The veratridine-elicited increase of /sup 45/Ca/sup 2 +/ uptake is attenuated by the addition of 10/sup -6/M tetrodotoxin in the incubation medium. In kainic acid-lesioned striatal slices the basal and veratridine-elicited increment of /sup 45/Ca/sup 2 +/ uptake are almost abolished. The present data provide evidence that in caudate nucleus /sup 3/H-nitrendipine binding sites and voltage-dependent Ca/sup 2 +/ channels are located in intrinsic neutrons but not in nerve terminals emanating from other brain areas.

  3. 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

  4. 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.

  5. 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. PMID:15601082

  6. Tetrahydroisoquinoline-Derived Urea and 2,5-Diketopiperazine Derivatives as Selective Antagonists of the Transient Receptor Potential Melastatin 8 (TRPM8) Channel Receptor and Antiprostate Cancer Agents.

    PubMed

    De Petrocellis, Luciano; Arroyo, Francisco J; Orlando, Pierangelo; Schiano Moriello, Aniello; Vitale, Rosa Maria; Amodeo, Pietro; Sánchez, Aránzazu; Roncero, Cesáreo; Bianchini, Giulia; Martín, M Antonia; López-Alvarado, Pilar; Menéndez, J Carlos

    2016-06-23

    Tetrahydroisoquinoline derivatives containing embedded urea functions were identified as selective TRPM8 channel receptor antagonists. Structure-activity relationships were investigated, with the following conclusions: (a) The urea function and the tetrahydroisoquinoline system are necessary for activity. (b) Bis(1-aryl-6,7dimethoxy-1,2,3,4-tetrahydroisoquinolyl)ureas are more active than compounds containing one tetrahydroisoquinoline ring and than an open phenetylamine ureide. (c) Trans compounds are more active than their cis isomers. (d) Aryl substituents are better than alkyls at the isoquinoline C-1 position. (e) Electron-withdrawing substituents lead to higher activities. The most potent compound is the 4-F derivative, with IC50 in the 10(-8) M range and selectivities around 1000:1 for most other TRP receptors. Selected compounds were found to be active in reducing the growth of LNCaP prostate cancer cells. TRPM8 inhibition reduces proliferation in the tumor cells tested but not in nontumor prostate cells, suggesting that the activity against prostate cancer is linked to TRPM8 inhibition. PMID:27232526

  7. 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

  8. 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

    2016-01-01

    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

  9. Selected cysteine point mutations confer mercurial sensitivity to the mercurial-insensitive water channel MIWC/AQP-4.

    PubMed

    Shi, L B; Verkman, A S

    1996-01-16

    The mercurial-insensitive water channel (MIWC or AQP-4) is a 30-32 kDA integral membrane protein expressed widely in fluid-transporting epithelia [Hasegawa et al. (1994) J. Biol. Chem. 269, 5497-5500]. To investigate the mercurial insensitivity and key residues involved in MIWC-mediated water transport, amino acids just proximal to the conserved NPA motifs (residues 69-74 and 187-190) were mutated individually to cysteine. Complementary RNAs were expressed in Xenopus oocytes for assay of osmotic water permeability (Pf) and HgCl2 inhibition dose-response. Oocytes expressing the cysteine mutants were highly water permeable, with Pf values (24-33 x 10(-3) cm/s) not different from that of wild-type (WT) MIWC. Pf was reversibly inhibited by HgCl2 in mutants S70C, G71C, G72C, H73C, and S189C but insensitive to HgCl2 in the other mutants. K1/2 values for 50% inhibition of Pf by HgCl2 were as follows (in millimolar): 0.40 (S70C), 0.36 (G71C), 0.14 (G72C), 0.45 (H73C), 0.24 (S189C), and > 1 for WT MIWC and the other mutants. To test the hypothesis that these residues are near the MIWC aqueous pore, residues 72 and 188 were mutated individually to the larger amino acid tryptophan. Pf in oocytes expressing mutants G72W or A188W (1.3-1.4 x 10(-3) cm/s) was not greater than that in water-injected oocytes even though these proteins were expressed at the oocyte plasma membrane as shown by quantitative immunofluorescence. Coinjection of cRNAs encoding WT MIWC and G72W or A188W indicated a dominant negative effect; Pf (x 10(-3) cm/s) was 22 (0.25 ng of WT), 10 (0.25 ng of WT + 0.25 ng of G72W), and 12 (0.25 ng of WT + 0.25 ng of A188W). Taken together, these results suggest the MIWC is mercurial-insensitive because of absence of a cysteine residue near the NPA motifs and that residues 70-73 and 189 are located at or near the MIWC aqueous pore. In contrast to previous data for the channel-forming integral protein of 28kDa (CHIP28), the finding of a dominant negative phenotype for

  10. 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.

  11. 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.

  12. A highly selective ratiometric visual and red-emitting fluorescent dual-channel probe for imaging fluoride anions in living cells.

    PubMed

    Zhu, Baocun; Kan, He; Liu, Jingkai; Liu, Hanqing; Wei, Qin; Du, Bin

    2014-02-15

    Recently, growing attention has been paid to the accurate determination of fluoride anion (F(-)) in the environment and living systems for its toxicity and biological function investigation. In this paper, we developed a ratiometric visual and red-emitting fluorescent dual-channel probe (1) employed Si-O bond as a highly selective recognition receptor for imaging F(-) in living cells. Probe 1 possesses a potential internal charge transfer (ICT) structure, and displays a large (158 nm) red-shifted absorption spectrum and the color changes from yellow to blue upon addition of F(-) in the aqueous solution. In addition, probe 1 can be used to detect F(-) quantitatively by the ratiometric absorption and turn-on fluorescence spectroscopy methods with excellent sensitivity. Finally, the results of its application to bioimaging of F(-) in living cells show that probe 1 would be of great benefit to biomedical researchers for investigating the effects of fluoride in biological systems. PMID:24080208

  13. 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.

  14. Optomechanical Enhancement of Doubly Resonant 2D Optical Nonlinearity.

    PubMed

    Yi, Fei; Ren, Mingliang; Reed, Jason C; Zhu, Hai; Hou, Jiechang; Naylor, Carl H; Johnson, A T Charlie; Agarwal, Ritesh; Cubukcu, Ertugrul

    2016-03-01

    Emerging two-dimensional semiconductor materials possess a giant second order nonlinear response due to excitonic effects while the monolayer thickness of such active materials limits their use in practical nonlinear devices. Here, we report 3300 times optomechanical enhancement of second harmonic generation from a MoS2 monolayer in a doubly resonant on-chip optical cavity. We achieve this by engineering the nonlinear light-matter interaction in a microelectro-mechanical system enabled optical frequency doubling device based on an electrostatically tunable Fabry-Perot microresonator. Our versatile optomechanical approach will pave the way for next generation efficient on-chip tunable light sources, sensors, and systems based on molecularly thin materials. PMID:26854706

  15. Doubly robust estimation of the local average treatment effect curve

    PubMed Central

    Ogburn, Elizabeth L.; Rotnitzky, Andrea; Robins, James M.

    2014-01-01

    Summary We consider estimation of the causal effect of a binary treatment on an outcome, conditionally on covariates, from observational studies or natural experiments in which there is a binary instrument for treatment. We describe a doubly robust, locally efficient estimator of the parameters indexing a model for the local average treatment effect conditionally on covariates V when randomization of the instrument is only true conditionally on a high dimensional vector of covariates X, possibly bigger than V. We discuss the surprising result that inference is identical to inference for the parameters of a model for an additive treatment effect on the treated conditionally on V that assumes no treatment–instrument interaction. We illustrate our methods with the estimation of the local average effect of participating in 401(k) retirement programs on savings by using data from the US Census Bureau's 1991 Survey of Income and Program Participation. PMID:25663814

  16. 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.

  17. 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.

  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. Time-resolved doubly bent crystal x-ray spectrometer

    SciTech Connect

    Hockaday, M.P.; Wilke, M.D.; Blake, R.L.; Vaninetti, J.; Gray, N.T.; Nedrow, P.T.

    1988-08-01

    X-ray spectroscopy is an essential tool in high-temperature plasma research. We describe a time-resolved x-ray spectrometer suitable for measuring spectra in harsh environments common to many very high-energy density laboratory plasma sources. The spectrometer consisted of a doubly curved Si(111) crystal diffraction element, a WL-1201 (ZnO:Ga) phosphor, a coherent fiber-optic array, and two visible streak cameras. The spectrometer design described here has a minimum time resolution of 1.3 ns with 2.8-eV spectral resolution over a 200-eV-wide bandpass in the 6--7-keV region of the spectrum. Complete system spectral throughput calibrations were done at the Cornell High Energy Synchrotron (CHESS). Details of the design and calibration results are presented.

  20. Time-resolved doubly bent crystal x-ray spectrometer

    SciTech Connect

    Hockaday, M.P.; Wilke, M.D.; Blake, R.L.; Vaninetti, J.; Gray, N.T.; Nedrow, P.T.

    1988-01-01

    X-ray spectroscopy is an essential tool in high temperature plasma research. We describe a time-resolved x-ray spectrometer suitable for measuring spectra in harsh environments common to many very high energy density laboratory plasma sources. The spectrometer consisted of a doubly curved Si(111) crystal diffraction element, a WL-1201 (ZnO:Ga) phosphor, a coherent fiber optic array, and two visible streak cameras. The spectrometer design described here has a minimum time resolution of 1.3 ns with 2.8 eV spectral resolution over a 200 eV wide bandpass in the 6-7 keV region of the spectrum. Complete system spectral throughput calibrations were done at the Cornell High Energy Synchrotron (CHESS). Details of the design and calibration results are presented. 5 refs., 5 figs.

  1. Possibility of synthesizing a doubly magic superheavy nucleus

    SciTech Connect

    Aritomo, Y.

    2007-02-15

    The possibility of synthesizing a doubly magic superheavy nucleus, {sup 298}114{sub 184}, is investigated on the basis of fluctuation-dissipation dynamics. In order to synthesize this nucleus, we must generate more neutron-rich compound nuclei because of the neutron emissions from excited compound nuclei. The compound nucleus {sup 304}114 has two advantages to achieving a high survival probability. First, because of low neutron separation energy and rapid cooling, the shell correction energy recovers quickly. Secondly, owing to neutron emissions, the neutron number in the nucleus approaches that of the double closed shell and the nucleus attains a large fission barrier. Because of these two effects, the survival probability of {sup 304}114 does not decrease until the excitation energy E{sup *}=50 MeV. These properties lead to a rather high evaporation residue cross section.

  2. 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.

  3. Doubly magic nucleus (108)(270)Hs162.

    PubMed

    Dvorak, J; Brüchle, W; Chelnokov, M; Dressler, R; Düllmann, Ch E; Eberhardt, K; Gorshkov, V; Jäger, E; Krücken, R; Kuznetsov, A; Nagame, Y; Nebel, F; Novackova, Z; Qin, Z; Schädel, M; Schausten, B; Schimpf, E; Semchenkov, A; Thörle, P; Türler, A; Wegrzecki, M; Wierczinski, B; Yakushev, A; Yeremin, A

    2006-12-15

    Theoretical calculations predict 270Hs (Z=108, N=162) to be a doubly magic deformed nucleus, decaying mainly by alpha-particle emission. In this work, based on a rapid chemical isolation of Hs isotopes produced in the 26Mg+248Cm reaction, we observed 15 genetically linked nuclear decay chains. Four chains were attributed to the new nuclide 270Hs, which decays by alpha-particle emission with Qalpha=9.02+/-0.03 MeV to 266Sg which undergoes spontaneous fission with a half-life of 444(-148)(+444) ms. A production cross section of about 3 pb was measured for 270Hs. Thus, 270Hs is the first nucleus for which experimental nuclear decay properties have become available for comparison with theoretical predictions of the N=162 shell stability. PMID:17280272

  4. Doubly charged Higgs from e- γ scattering in the 3-3-1 Model

    NASA Astrophysics Data System (ADS)

    Cieza Montalvo, J. E.; Ramírez Ulloa, G. H.; Tonasse, M. D.

    2012-11-01

    We studied the production and signatures of doubly charged Higgs bosons in the process γe -→ H -- E +, where E + is a heavy lepton, at the e - e + International Linear Collider (ILC) and CERN Linear Collider (CLIC). The intermediate photons are given by the Weizsäcker-Williams and laser-backscattering distributions. We found that significant signatures are obtained by bremsstrahlung and backward Compton scattering of laser. A clear signal can be obtained for doubly charged Higgs bosons, doubly charged gauge bosons and heavy leptons.

  5. 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.

  6. 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

  7. Ab initio approach to effective single-particle energies in doubly closed shell nuclei

    NASA Astrophysics Data System (ADS)

    Duguet, T.; Hagen, G.

    2012-03-01

    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.

  8. MicroRNAs as a Selective Channel of Communication between Competing RNAs: a Steady-State Theory

    PubMed Central

    Figliuzzi, Matteo; Marinari, Enzo; De Martino, Andrea

    2013-01-01

    It has recently been suggested that the competition for a finite pool of microRNAs (miRNA) gives rise to effective interactions among their common targets (competing endogenous RNAs or ceRNAs) that could prove to be crucial for posttranscriptional regulation. We have studied a minimal model of posttranscriptional regulation where the emergence and the nature of such interactions can be characterized in detail at steady state. Sensitivity analysis shows that binding free energies and repression mechanisms are the key ingredients for the cross-talk between ceRNAs to arise. Interactions emerge in specific ranges of repression values, can be symmetrical (one ceRNA influences another and vice versa) or asymmetrical (one ceRNA influences another but not the reverse), and may be highly selective, while possibly limited by noise. In addition, we show that nontrivial correlations among ceRNAs can emerge in experimental readouts due to transcriptional fluctuations even in the absence of miRNA-mediated cross-talk. PMID:23473503

  9. MicroRNAs as a Selective Channel of Communication between Competing RNAs: a Steady-State Theory

    NASA Astrophysics Data System (ADS)

    Figliuzzi, Matteo; Marinari, Enzo; De Martino, Andrea

    2013-03-01

    It has recently been suggested that the competition for a finite pool of microRNAs (miRNA) gives rise to effective interactions among their common targets (competing endogenous RNAs or ceRNAs) that could prove to be crucial for post-transcriptional regulation (PTR). We have studied a minimal model of PTR where the emergence and the nature of such interactions can be characterized in detail at steady state. Sensitivity analysis shows that binding free energies and repression mechanisms are the key ingredients for the cross-talk between ceRNAs to arise. Interactions emerge in specific ranges of repression values, can be symmetrical (one ceRNA influences another and vice-versa) or asymmetrical (one ceRNA influences another but not the reverse) and may be highly selective, while possibly limited by noise. In addition, we show that non-trivial correlations among ceRNAs can emerge in experimental readouts due to transcriptional fluctuations even in absence of miRNA-mediated cross-talk.

  10. Distinct transport selectivity of two structural subclasses of the nodulin-like intrinsic protein family of plant aquaglyceroporin channels.

    PubMed

    Wallace, Ian S; Roberts, Daniel M

    2005-12-27

    Major intrinsic proteins (MIPs) are a diverse class of integral membrane proteins that facilitate the transport of water and some small solutes across cellular membranes. X-ray structures of MIPs indicate that a tetrad of residues (the ar/R region) form a narrow pore constriction that constitutes the selectivity filter. In comparison with mammalian and microbial species, plants have a greater number and diversity of MIPs with greater than 30 genes encoding four phylogenetic subfamilies with eight different classes of ar/R sequences. The nodulin 26-like intrinsic protein (NIP) subfamily in Arabidopsis can be subdivided into two ar/R subgroups: the NIP subgroup I, which resembles the archetype of the family, soybean nodulin 26, and the NIP subgroup II, which is represented by the Arabidopsis protein AtNIP6;1. These two NIPs differ principally by the substitution of a conserved alanine (NIP subgroup II) for a conserved tryptophan (NIP subgroup I) in the helix 2 position (H2) of the ar/R filter. A comparison of the water and solute tranport properties of the two proteins was performed by expression in Xenopus laevis oocytes. Nodulin 26 is an aquaglyceroporin with a modest osmotic water permeability (P(f)) and the ability to transport uncharged solutes such as glycerol and formamide. In constrast, AtNIP6;1 showed no measurable water permeability but transported glycerol, formamide, as well as larger solutes that were impermeable to nodulin 26. By site-directed mutagenesis, we show that the H2 position is the crucial determinant that confers these transport behaviors. A comparison of the NIPs and tonoplast-intrinsic proteins (TIP) shows that the H2 residue can predict the transport profile for water and glycerol with histidine found in TIP-like aquaporins, tryptophan found in aquaglyceroporins (NIP I), and alanine found in water-impermeable glyceroporins (AtNIP6;1). PMID:16363796

  11. 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.

  12. 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.

  13. Search for doubly charged Higgs bosons in like-sign dilepton final states at √s¯= 7 TeV with the ATLAS detector

    DOE PAGESBeta

    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

  14. 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.

  15. 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

  16. Discovery of Four Doubly Imaged Quasar Lenses from the Sloan Digital Sky Survey

    NASA Astrophysics Data System (ADS)

    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 zs = 2.165, the lens redshift zl = 0.381, and the image separation θ = 1.''034, SDSS J1128+2402 with zs = 1.608 and θ = 0.''844, SDSS J1405+0959 with zs = 1.810, zl ≈ 0.66, and θ = 1.''978, and SDSS J1515+1511 with zs = 2.054, zl = 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.

  17. 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.

  18. 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

  19. 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 Oregon prompted a study of the vertical distribution of selected trace metals and organic compounds in bottom sediments. These data are needed to evaluate the effects of dredging and disposal operations. Elutriation testing of bottom material indicated chemical concentrations as large as 900 ug/L for barium, 6,500 ug/L for manganese, and 14 ug/L for nickel. The amount of oxygen present during elutriation testing of reduced bottom material was shown to have a negligble effect on manganese elutriate-test concentrations, but it did affect barium and iron concentrations. Sediment-associated organochlorine compounds detected in bottom-sediment core samples were as large as 0.1 ug/kg (micrograms/kilogram) for aldrin, 2.0 ug/kg for chlordane, 27 ug/kg for DDD, 5.0 ug/kg for DDE, 0.2 ug/kg for DDT, 0.2 ug/kg for dieldrin, 37 ug/kg for PCB 's 1.0 ug/kg for PCN 's and 1.0 ug/kg for heptachlor epoxide. Concentrations of cadmium, lead, and zinc in selected cores were found to exceed those of local basalts. Concentrations of cadmium, lead, and zinc were as large as 3.6 ug/g, 26 ug/g, and 210 ug/g respectively. Bottom-sediment concentrations of cadmium , chromium, copper, iron, and zinc associated with the less-than-100-micrometer size fraction are larger than those associated with the greater-than-100-micrometer fraction. (USGS)

  20. Effects of the selective KACh channel blocker NTC-801 on atrial fibrillation in a canine model of atrial tachypacing: comparison with class Ic and III drugs.

    PubMed

    Yamamoto, Wataru; Hashimoto, Norio; Matsuura, Junji; Machida, Taiichi; Ogino, Yasuhiro; Kobayashi, Tsunefumi; Yamanaka, Yoshihiro; Ishiwata, Norihisa; Yamashita, Toru; Tanimoto, Kojiro; Miyoshi, Shunichiro; Fukuda, Keiichi; Nakaya, Haruaki; Ogawa, Satoshi

    2014-05-01

    The present study examines the effects of NTC-801, a highly selective acetylcholine (ACh) receptor-activated potassium (KACh) channel blocker, on atrial fibrillation (AF) in a canine model with electrical remodeling. An experimental substrate for AF was created in dogs via left atrial (LA) tachypacing (400 bpm, 3-5 weeks). NTC-801, dofetilide, and flecainide were intravenously infused for 15 minutes, and the effects on AF inducibility, atrial effective refractory period (ERP), and atrial conduction velocity were examined. The effect of NTC-801 on AF termination was also evaluated. Atrial ERP was shortened and AF inducibility was increased after LA tachypacing. NTC-801 (0.3-3 µg·kg⁻¹·min⁻¹) prolonged atrial ERP irrespective of stimulation frequency and dose-dependently decreased AF inducibility. Dofetilide (5.3 µg·kg⁻¹·min⁻¹) and flecainide (0.13 mg·kg⁻¹·min⁻¹) did not significantly inhibit AF inducibility and minimally affected atrial ERP. Flecainide decreased atrial conduction velocity, whereas NTC-801 and dofetilide did not. NTC-801 (0.1 mg/kg) converted AF to normal sinus rhythm. In summary, NTC-801 exerted more effective antiarrhythmic effects than dofetilide and flecainide in a canine LA-tachypacing AF model. The antiarrhythmic activity of NTC-801 was probably due to prolonging atrial ERP independently of stimulation frequency. These results suggest that NTC-801 could prevent AF more effectively in the setting of atrial electrical remodeling. PMID:24805146

  1. Pharmacophore mapping based inhibitor selection and molecular interaction studies for identification of potential drugs on calcium activated potassium channel blockers, tamulotoxin

    PubMed Central

    Kumar, R. Barani; Suresh, M. Xavier

    2013-01-01

    Background: Tamulotoxin (TmTx) from Buthus tamulus was found to be a highly venomous toxin which accelerates the neurotransmitter release that directly affects the cardiovascular tissues and the respiratory system leading to death. TmTx from red Indian scorpion is a crucial inhibitor for Ca2+ activated K+ channel in humans. Objective: The study is aimed at the identification of potential inhibitors of TmTx through pharmacophore based inhibitor screening and understanding the molecular level interactions. Materials and Method: The potential inhibitors for TmTx were identified using pharmacophore model based descriptor information present in existing drugs with the analysis of pharmacokinetic properties. The compounds with good ADMET (Absorption, Distribution, Metabolism, Excretion and Toxicity) descriptors were subjected to molecular interaction studies. The stability of bound toxin-inhibitor complex was studied using molecular dynamics simulation over a period of one nanosecond. Results: From a dataset of 3406 compounds, few compounds were selected as potential inhibitors based on the generated best pharmacophore models, pharmacokinetic analysis, molecular docking and molecular dynamics studies. Conclusion: In conclusion, two compounds containing better inhibition properties against TmTx are suggested to be better lead molecules for drug development in future and this study will help us to explore more inhibitors from natural origin against tamulotoxin. PMID:23772102

  2. 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.

  3. New advanced control methods for doubly salient permanent magnet motor

    SciTech Connect

    Blaabjerg, F.; Christensen, L.; Rasmussen, P.O.; Oestergaard, L.; Pedersen, P.

    1995-12-31

    High performance and high efficiency in adjustable speed drives are needed and new motor constructions are world wide investigated and analyzed. This paper deals with advanced control of a recently developed Doubly Salient Permanent Magnet (DSPM) motor. The construction of the DSPM motor is shown and a dynamical model of the motor is used for simulations. As supply to the DSPM motor, a power converter with a split capacitor is used to reduce the number of devices, and a basic control method for this converter is explained. This control method will cause an unequal voltage distribution across the capacitors because the motor is asymmetrical and a decrease in efficiency and a poorer dynamic performance are the results. To minimize the problems with the unequal load of the capacitors in the converter, a new charge control strategy is developed. The efficiency of the motor can also be improved by using a power minimizing scheme based on changing the turn-on and turn-off angles of the current. The two different strategies are implemented in an adjustable-speed drive, and it is concluded that both control strategies improve the performance of the drive.

  4. Doubly robust methods for handling confounding by cluster.

    PubMed

    Zetterqvist, Johan; Vansteelandt, Stijn; Pawitan, Yudi; Sjölander, Arvid

    2016-04-01

    In clustered designs such as family studies, the exposure-outcome association is usually confounded by both cluster-constant and cluster-varying confounders. The influence of cluster-constant confounders can be eliminated by studying the exposure-outcome association within (conditional on) clusters, but additional regression modeling is usually required to control for observed cluster-varying confounders. A problem is that the working regression model may be misspecified, in which case the estimated within-cluster association may be biased. To reduce sensitivity to model misspecification we propose to augment the standard working model for the outcome with an auxiliary working model for the exposure. We derive a doubly robust conditional generalized estimating equation (DRCGEE) estimator for the within-cluster association. This estimator combines the two models in such a way that it is consistent if either model is correct, not necessarily both. Thus, the DRCGEE estimator gives the researcher two chances instead of only one to make valid inference on the within-cluster association. We have implemented the estimator in an R package and we use it to examine the association between smoking during pregnancy and cognitive abilities in offspring, in a sample of siblings. PMID:26508769

  5. 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

    2016-09-01

    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. PMID:27608997

  6. Analysis of thickness modes of contoured doubly rotated, quartz resonators.

    PubMed

    EerNisse, E P

    2001-09-01

    It is the intent of this work to provide a working resource for calculating all three mode families of a doubly rotated, contoured quartz resonator. It is shown that the theoretical development of Stevens and Tiersten [1] can be used for this purpose. Their approach uses a transformation of the mechanical displacement vector to the eigenvector triad of the pure thickness solution. The solution methodology here reorganizes the transformation matrix Q in their formulation to calculate the other two mode families. Calculations compare well with experimental results for the three mode families of an SC-cut crystal and an FC-cut crystal and with published calculations for the SBTC-cut mode family with major displacement along the x3 blank axis. The key constants for the SC-cut are presented for workers to use in the future. In addition, the equations of motion and boundary conditions are derived for the two additional mode families using assumptions parallel to those used by Stevens and Tiersten [1]. Calculations with these equations are presented for completeness to support the present conclusions by showing the equivalence of either simply reorganizing the Q matrix or using separate equations for each of the three mode families. PMID:11570760

  7. RFI channels

    NASA Technical Reports Server (NTRS)

    Mceliece, R. J.

    1980-01-01

    A class of channel models is presented which exhibit varying burst error severity much like channels encountered in practice. An information-theoretic analysis of these channel models is made, and conclusions are drawn that may aid in the design of coded communication systems for realistic noisy channels.

  8. Biophysics of CNG Ion Channels

    NASA Astrophysics Data System (ADS)

    Barry, Peter H.; Qu, Wei; Moorhouse, Andrew J.

    Cyclic nucleotide-gated (CNG) ion channels are cation-selective, opened by intracellular cyclic nucleotides like cAMP and cGMP, and present in many different neurons and non-neuronal cells. This chapter will concentrate primarily on the biophysical aspects of retinal and olfactory CNG channels, with special reference to ion permeation and selectivity and their underlying molecular basis, and will include a brief overview of the physiological function of CNG channels in both olfaction and phototransduction. We will review the subunit composition and molecular structure of the CNG channel and its similarity to the closely related potassium channels, and will also briefly outline the currently accepted molecular basis underlying activation of the channel and the location of the channel `gate'. We will then outline some general methodologies for investigating ion permeation and selectivity, before reviewing the ion permeation and selectivity properties of native and recombinant CNG channels. We will discuss divalent ion permeation through the channel and the mechanism of channel block by divalent ions. The chapter will conclude by discussing the results of recent experiments to investigate the molecular determinants of cation-anion selectivity in the channel.

  9. Solid phase synthesis, NMR structure determination of α-KTx3.8, its in silico docking to Kv1.x potassium channels, and electrophysiological analysis provide insights into toxin-channel selectivity.

    PubMed

    Kohl, Bastian; Rothenberg, Ina; Ali, Syed Abid; Alam, Mehtab; Seebohm, Guiscard; Kalbacher, Hubert; Voelter, Wolfgang; Stoll, Raphael

    2015-07-01

    Animal venoms, such as those from scorpions, are a potent source for new pharmacological substances. In this study we have determined the structure of the α-KTx3.8 (named as Bs6) scorpion toxin by multidimensional (1)H homonuclear NMR spectroscopy and investigated its function by molecular dynamics (MD) simulations and electrophysiological measurements. Bs6 is a potent inhibitor of the Kv1.3 channel which plays an important role during the activation and proliferation of memory T-cells (TEM), which play an important role in autoimmune diseases. Therefore, it could be an interesting target for treatment of autoimmune diseases. In this study, Bs6 was synthesised by solid phase synthesis and its three-dimensional (3D) structure has been determined. To gain a deeper insight into the interaction of Bs6 with different potassium channels like hKv1.1 and hKv1.3, the protein-protein complex was modelled based on known toxin-channel structures and tested for stability in MD simulations using GROMACS. The toxin-channel interaction was further analysed by electrophysiological measurements of different potassium channels like hKv1.3 and hKv7.1. As potassium channel inhibitors could play an important role to overcome autoimmune diseases like multiple sclerosis and type-1 diabetes mellitus, our data contributes to the understanding of the molecular mechanism of action and will ultimately help to develop new potent inhibitors in future. PMID:25953725

  10. 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.

  11. 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.

  12. 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

  13. 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. PMID:20886370

  14. Inactivation and Anion Selectivity of Volume-regulated Anion Channels (VRACs) Depend on C-terminal Residues of the First Extracellular Loop.

    PubMed

    Ullrich, Florian; Reincke, S Momsen; Voss, Felizia K; Stauber, Tobias; Jentsch, Thomas J

    2016-08-12

    Canonical volume-regulated anion channels (VRACs) are crucial for cell volume regulation and have many other important roles, including tumor drug resistance and release of neurotransmitters. Although VRAC-mediated swelling-activated chloride currents (ICl,vol) have been studied for decades, exploration of the structure-function relationship of VRAC has become possible only after the recent discovery that VRACs are formed by differently composed heteromers of LRRC8 proteins. Inactivation of ICl,vol at positive potentials, a typical hallmark of VRACs, strongly varies between native cell types. Exploiting the large differences in inactivation between different LRRC8 heteromers, we now used chimeras assembled from isoforms LRRC8C and LRRC8E to uncover a highly conserved extracellular region preceding the second LRRC8 transmembrane domain as a major determinant of ICl,vol inactivation. Point mutations identified two amino acids (Lys-98 and Asp-100 in LRRC8A and equivalent residues in LRRC8C and -E), which upon charge reversal strongly altered the kinetics and voltage dependence of inactivation. Importantly, charge reversal at the first position also reduced the iodide > chloride permeability of ICl,vol This change in selectivity was stronger when both the obligatory LRRC8A subunit and the other co-expressed isoform (LRR8C or -E) carried such mutations. Hence, the C-terminal part of the first extracellular loop not only determines VRAC inactivation but might also participate in forming its outer pore. Inactivation of VRACs may involve a closure of the extracellular mouth of the permeation pathway. PMID:27325695

  15. Comparison of doubly labeled water with respirometry at low- and high-activity levels

    SciTech Connect

    Westerterp, K.R.; Brouns, F.; Saris, W.H.; ten Hoor, F.

    1988-07-01

    In previous studies the doubly labeled water method for measuring energy expenditure in free-living humans has been validated against respirometry under sedentary conditions. In the present investigation, energy expenditure is measured simultaneously with doubly labeled water and respirometry at low- and high-activity levels. Over 6 days, five subjects were measured doing mainly sedentary activities like desk work; their average daily metabolic rate was 1.40 +/- 0.09 (SD) times sleeping metabolic rate. Four subjects were measured twice over 3.5 days, including 2 days with heavy bicycle ergometer work, resulting in an average daily metabolic rate of 2.61 +/- 0.25 (SD) times sleeping metabolic rate. At the low-activity level, energy expenditures from the doubly labeled water method were on the average 1.4 +/- 3.9% (SD) larger than those from respirometry. At the high-activity level, the doubly labeled water method yielded values that were 1.0 +/- 7.0% (SD) lower than those from respirometry. Results demonstrate the utility of the doubly labeled water method for the determination of energy expenditure in the range of activity levels in daily life.

  16. The Doubly Labeled Water Method for Measuring Human Energy Expenditure: Adaptations for Spaceflight

    NASA Technical Reports Server (NTRS)

    Schulz, Leslie O.

    1991-01-01

    It is essential to determine human energy requirements in space, and the doubly labeled water method has been identified as the most appropriate means of indirect calorimetry to meet this need. The method employs naturally occurring, stable isotopes of hydrogen (H-2, deuterium) and oxygen (O-18) which, after dosing, mix with body water. The deuterium is lost from the body as water while the O-18 is eliminated as both water and CO2. The difference between the two isotope elimination rates is therefore a measure of CO2 production and hence energy expenditure. Spaceflight will present a unique challenge to the application of the doubly labeled water method. Specifically, interpretation of doubly labeled water results assumes that the natural abundance or 'background' levels of the isotopes remain constant during the measurement interval. To address this issue, an equilibration model will be developed in an ongoing ground-based study. As energy requirements of women matched to counterparts in the Astronauts Corps are being determined by doubly labeled water, the baseline isotope concentration will be changed by consumption of 'simulated Shuttle water' which is artificially enriched. One group of subjects will be equilibrated on simulated Shuttle water prior to energy determinations by doubly labeled water while the others will consume simulated Shuttle water after dosing. This process will allow us to derive a prediction equation to mathematically model the effect of changing background isotope concentrations.

  17. Three-loop neutrino mass model with doubly charged particles from isodoublets

    NASA Astrophysics Data System (ADS)

    Okada, Hiroshi; Yagyu, Kei

    2016-01-01

    We propose a new type of a three-loop induced neutrino mass model with dark matter candidates which are required for the neutrino mass generation. The smallness of neutrino masses can be naturally explained without introducing super heavy particles, namely, much heavier than a TeV scale and quite small couplings as compared to the gauge couplings. We find that as a bonus, the anomaly of the muon anomalous magnetic moment can simultaneously be explained by loop effects of new particles. In our model, there are doubly charged scalar bosons and leptons from isospin doublet fields which give characteristic collider signatures. In particular, the doubly charged scalar bosons can decay into the same-sign dilepton with its chirality of both right-handed or left- and right-handed. This can be a smoking gun signature to identify our model and be useful to distinguish other models with doubly charged scalar bosons at collider experiments.

  18. Channel Change in 2007 at Selected Sites on the Marias River, Montana, Following a 2006 High-Flow Release from Tiber Dam

    USGS Publications Warehouse

    Auble, Gregor T.; Bowen, Zachary H.

    2009-01-01

    In June 2006, an opportunistic high-flow release was made from Tiber Dam on the Marias River in Montana to investigate possible alternatives for partially restoring the river's natural flow pattern and variability. At two sites along the river, we measured channel geometry in 2006 before and after the high-flow release to evaluate channel change and alteration of physical habitat. Here we provide data from a resurvey of those sites, conducted in August 2007.

  19. Model of the anisotropic behavior of doubly oriented and non-oriented materials using coenergy: Application to a large generator

    SciTech Connect

    Mekhiche, M.; Pera, T.; Marechal, Y.

    1995-05-01

    The anisotropic and nonlinear behavior of doubly oriented and non-oriented sheets are modeled using the coenergy density. These models have been implemented in a finite element computation. A large generator has been modeled and the advantages of doubly oriented sheets compared to the conventional non-oriented ones are shown.

  20. Dynamic stability of a doubly quantized vortex in a three-dimensional condensate

    NASA Astrophysics Data System (ADS)

    Lundh, Emil; Nilsen, Halvor M.

    2006-12-01

    The Bogoliubov equations are solved for a three-dimensional Bose-Einstein condensate containing a doubly quantized vortex, trapped in a harmonic potential. Complex frequencies, signifying dynamical instability, are found for certain ranges of parameter values. The existence of alternating windows of stability and instability, respectively, is explained qualitatively and quantitatively using variational calculus and direct numerical solutions. It is seen that the windows of stability disappear in the limit of a cigar-shaped condensate, which is consistent with recent experimental results on the lifetime of a doubly quantized vortex in that regime.

  1. Dynamic stability of a doubly quantized vortex in a three-dimensional condensate

    SciTech Connect

    Lundh, Emil; Nilsen, Halvor M.

    2006-12-15

    The Bogoliubov equations are solved for a three-dimensional Bose-Einstein condensate containing a doubly quantized vortex, trapped in a harmonic potential. Complex frequencies, signifying dynamical instability, are found for certain ranges of parameter values. The existence of alternating windows of stability and instability, respectively, is explained qualitatively and quantitatively using variational calculus and direct numerical solutions. It is seen that the windows of stability disappear in the limit of a cigar-shaped condensate, which is consistent with recent experimental results on the lifetime of a doubly quantized vortex in that regime.

  2. Doubly Connected V-States for the Generalized Surface Quasi-Geostrophic Equations

    NASA Astrophysics Data System (ADS)

    de la Hoz, Francisco; Hassainia, Zineb; Hmidi, Taoufik

    2016-06-01

    In this paper, we prove the existence of doubly connected V-states for the generalized SQG equations with α ∈]0, 1[. They can be described by countable branches bifurcating from the annulus at some explicit "eigenvalues" related to Bessel functions of the first kind. Contrary to Euler equations Hmidi et al. (Doubly connected V-states for the planar Euler equations, arXiv:1409.7096, 2015), we find V-states rotating with positive and negative angular velocities. At the end of the paper we discuss some numerical experiments concerning the limiting V-states.

  3. The Doubly Labeled Water Method Produces Highly Reproducible Longitudinal Results in Nutrition Studies12

    PubMed Central

    Wong, William W.; Roberts, Susan B.; Racette, Susan B.; Das, Sai Krupa; Redman, Leanne M.; Rochon, James; Bhapkar, Manjushri V.; Clarke, Lucinda L.; Kraus, William E.

    2014-01-01

    The doubly labeled water (DLW) method is considered the reference method for the measurement of energy expenditure under free-living conditions. However, the reproducibility of the DLW method in longitudinal studies is not well documented. This study was designed to evaluate the longitudinal reproducibility of the DLW method using 2 protocols developed and implemented in a multicenter clinical trial—the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE). To document the longitudinal reproducibility of the DLW method, 2 protocols, 1 based on repeated analysis of dose dilutions over the course of the clinical trial (dose-dilution protocol) and 1 based on repeated but blinded analysis of randomly selected DLW studies (test-retest protocol), were carried out. The dose-dilution protocol showed that the theoretical fractional turnover rates for 2H and 18O and the difference between the 2 fractional turnover rates were reproducible to within 1% and 5%, respectively, over 4.5 y. The Bland-Altman pair-wise comparisons of the results generated from 50 test-retest DLW studies showed that the fractional turnover rates and isotope dilution spaces for 2H and 18O, and total energy expenditure, were highly reproducible over 2.4 y. Our results show that the DLW method is reproducible in longitudinal studies and confirm the validity of this method to measure energy expenditure, define energy intake prescriptions, and monitor adherence and body composition changes over the period of 2.5–4.4 y. The 2 protocols can be adopted by other laboratories to document the longitudinal reproducibility of their measurements to ensure the long-term outcomes of interest are meaningful biologically. This trial was registered at clinicaltrials.gov as NCT00427193. PMID:24523488

  4. Ion channel regulation by phosphoinositides analyzed with VSPs—PI(4,5)P2 affinity, phosphoinositide selectivity, and PI(4,5)P2 pool accessibility

    PubMed Central

    Rjasanow, Alexandra; Leitner, Michael G.; Thallmair, Veronika; Halaszovich, Christian R.; Oliver, Dominik

    2015-01-01

    The activity of many proteins depends on the phosphoinositide (PI) content of the membrane. E.g., dynamic changes of the concentration of PI(4,5)P2 are cellular signals that regulate ion channels. The susceptibility of a channel to such dynamics depends on its affinity for PI(4,5)P2. Yet, measuring affinities for endogenous PIs has not been possible directly, but has relied largely on the response to soluble analogs, which may not quantitatively reflect binding to native lipids. Voltage-sensitive phosphatases (VSPs) turn over PI(4,5)P2 to PI(4)P when activated by depolarization. In combination with voltage-clamp electrophysiology VSPs are useful tools for rapid and reversible depletion of PI(4,5)P2. Because cellular PI(4,5)P2 is resynthesized rapidly, steady state PI(4,5)P2 changes with the degree of VSP activation and thus depends on membrane potential. Here we show that titration of endogenous PI(4,5)P2 with Ci-VSP allows for the quantification of relative PI(4,5)P2 affinities of ion channels. The sensitivity of inward rectifier and voltage-gated K+ channels to Ci-VSP allowed for comparison of PI(4,5)P2 affinities within and across channel subfamilies and detected changes of affinity in mutant channels. The results also reveal that VSPs are useful only for PI effectors with high binding specificity among PI isoforms, because PI(4,5)P2 depletion occurs at constant overall PI level. Thus, Kir6.2, a channel activated by PI(4,5)P2 and PI(4)P was insensitive to VSP. Surprisingly, despite comparable PI(4,5)P2 affinity as determined by Ci-VSP, the Kv7 and Kir channel families strongly differed in their sensitivity to receptor-mediated depletion of PI(4,5)P2. While Kv7 members were highly sensitive to activation of PLC by Gq-coupled receptors, Kir channels were insensitive even when PI(4,5)P2 affinity was lowered by mutation. We hypothesize that different channels may be associated with distinct pools of PI(4,5)P2 that differ in their accessibility to PLC and VSPs. PMID

  5. NOAA OTEC CWP (National Oceanic and Atmospheric Administration Ocean Thermal Energy Conversion Cold Water Pipe) at-sea test. Volume 3, part 1: Tabulation of the power spectra for selected channels

    NASA Astrophysics Data System (ADS)

    1983-11-01

    Data collected during the Ocean Thermal Energy Conversion (OTEC) Cold Water Pipe At-Sea Test was analyzed. Data presented included: (1)sensor factors and off sets and the data processing algorithms used to convert the recorded sensor measurements from electrical units to engineering units; (2) plots of the power spectra estimates obtained from a fast Fourier transform (FFT) analysis of selected channels; (3) plots of selected sensor measurements as a function of time; and (4) plots of bending strain along the pipe. The mean, root-mean-square (RMS) maximum, and minimum values at each depth are shown in each plot.

  6. An overview of historical channel adjustment and selected hydraulic values in the Lower Sabine and Lower Brazos River Basins, Texas and Louisiana

    USGS Publications Warehouse

    Heitmuller, Franklin T.; Greene, Lauren E.; John D. Gordon, John D.

    2010-01-01

    The Sabine and Brazos are alluvial rivers; alluvial rivers are dynamic systems that adjust their geometry in response to changes in streamflow (discharge) and sediment load. In fluvial geomorphology, the term 'channel adjustment' refers to river channel changes in three geometric dimensions: (1) channel slope (profile); (2) the outline or shape, such as meandering or braided, projected on a horizontal plane (planform); and (3) cross-sectional form (shape). The primary objective of the study was to investigate how the channel morphology of these rivers has changed in response to reservoirs and other anthropogenic disturbances that have altered streamflow and sediment load. The results of this study are expected to aid ecological assessments in the lower Sabine River and lower Brazos River Basins for the Texas Instream Flow Program. Starting in the 1920s, several dams have been constructed on the Sabine and Brazos Rivers and their tributaries, and numerous bridges have been built and sometimes replaced multiple times, which have changed the natural flow regime and reduced or altered sediment loads downstream. Changes in channel geometry over time can reduce channel conveyance and thus streamflow, which can have adverse ecological effects. Channel attributes including cross-section form, channel slope, and planform change were evaluated to learn how each river's morphology changed over many years in response to natural and anthropogenic disturbances. Climate has large influence on the hydrologic regimes of the lower Sabine and lower Brazos River Basins. Equally important as climate in controlling the hydrologic regime of the two river systems are numerous reservoirs that regulate downstream flow releases. The hydrologic regimes of the two rivers and their tributaries reflect the combined influences of climate, flow regulation, and drainage area. Historical and contemporary cross-sectional channel geometries at 15 streamflow-gaging stations in the lower Sabine and

  7. Effect of electric fields on the decay branching ratio of {sup 1}P{sup e} doubly excited states in helium measured by time-resolved fluorescence

    SciTech Connect

    Zitnik, Matjaz; Mihelic, A.; Bucar, K.; Penent, F.; Lablanquie, P.; Richter, R.; Alagia, M.; Stranges, S.

    2006-11-15

    We have measured the lifetimes of {sup 1}P{sup e} (n=9-12) doubly excited states in static electric fields (1-6 kV/cm) by observing the decay of the fluorescence signal as a function of time. The effects of the field on these helium states below the second ionization threshold are twofold: their excitation becomes possible due to the Stark mixing with the optically allowed {sup 1}P{sup o} series, and their lifetime is strongly modified by the opening of the autoionization channel, not accessible in zero field. Although the electric field represents only a tiny perturbation of the atomic potential, a substantial shortening of the lifetimes below 100 ps is observed. This is the simplest quantum system where the ratio of autoionization to fluorescence decay probability can be effectively controlled by an electric field of moderate strength.

  8. Measuring doubly 13C-substituted ethane by mass spectrometry

    NASA Astrophysics Data System (ADS)

    Clog, M.; Ling, C.; Eiler, J. M.

    2012-12-01

    Ethane (C2H6) is present in non-negligible amounts in most natural gas reservoirs and is used to produce ethylene for petrochemical industries. It is one of the by-products of lipid metabolism and is the arguably simplest molecule that can manifest multiple 13C substitutions. There are several plausible controls on the relative abundances of 13C2H6 in natural gases: thermodynamically controlled homogeneous isotope exchange reactions analogous to those behind carbonate clumped isotope thermometry; inheritance from larger biomolecules that under thermal degradation to produce natural gas; mixing of natural gases that differ markedly in bulk isotopic composition; or combinations of these and/or other, less expected fractionations. There is little basis for predicting which of these will dominate in natural samples. Here, we focus on an analytical techniques that will provide the avenue for exploring these phenomena. The method is based on high-resolution gas source isotope ratio mass spectrometry, using the Thermo 253-Ultra (a new prototype mass spectrometer). This instrument achieves the mass resolution (M/Δ M) up to 27,000, permitting separation of the isobaric interferences of potential contaminants and isotopologues of an analtye or its fragments which share a cardinal mass. We present techniques to analyze several isotopologues of molecular and fragment ions of C2H6. The critical isobaric separations for our purposes include: discrimination of 13C2H6 from 13C12CDH5 at mass 32 and separation of the 13CH3 fragment from 12CH4 at mass 16, both requiring at least a mass resolution of 20000 to make an adequate measurement. Other obvious interferences are either cleanly separated (e.g., O2, O) or accounted for by peak-stripping (CH3OH on mass 32 and NH2 on mass 16). We focus on a set of measurements which constrain: the doubly-substituted isotopologue, 13C2H6, and the 13CH3/12CH3 ratio of the methyl fragment, which constrains the bulk δ 13C. Similar methods can be

  9. Production of doubly heavy-flavored hadrons at e+e- colliders

    NASA Astrophysics Data System (ADS)

    Zheng, Xu-Chang; Chang, Chao-Hsi; Pan, Zan

    2016-02-01

    Production of the doubly heavy-flavored hadrons (Bc meson, doubly heavy baryons Ξc c , Ξb c , Ξb b , their excited states, and antiparticles of them as well) at e+e- colliders is investigated under two different approaches: LO (leading-order QCD complete calculation) and LL (leading-logarithm fragmentation calculation). The results for the production obtained by the LO and LL approaches, including the angle distributions of the produced hadrons with unpolarized and polarized incoming beams, the behaviors on the energy fraction of the produced doubly heavy-flavored hadron, and comparisons of results between the two approaches, are presented in tables and figures. Thus, characteristics of the production and uncertainties of the approaches are shown precisely, and it is concluded that only if the colliders run at the energies around the Z pole (which may be called the Z factories) and the luminosity of the colliders is as high as possible is the study of the doubly heavy-flavored hadrons completely accessible.

  10. Measurement of doubly differential electron distributions induced by atomic collisions: Apparatus and related instrumental effects

    NASA Astrophysics Data System (ADS)

    Bernardi, G.; Suárez, S.; Fregenal, D.; Focke, P.; Meckbach, W.

    1996-05-01

    We describe the experimental setup at Centro Atómico Bariloche for the measurement of doubly differential electron distributions, in energy and angle of emission, induced by atomic collisions. We present detailed information about the performance of the equipment including a discussion of instrumental effects that could have affected the measured spectra.

  11. Periodic orbits in the doubly synchronous binary asteroid systems and their applications in space missions

    NASA Astrophysics Data System (ADS)

    Shang, Haibin; Wu, Xiaoyu; Cui, Pingyuan

    2015-01-01

    This paper investigates the periodic motion of a particle in the doubly synchronous binary asteroid systems. Two typical doubly synchronous systems, 809 Lundia and 3169 Ostro, are discussed in detail. Under the Roche figure assumption, the two bodies of doubly synchronous system can be modeled as two triaxial ellipsoids. The Ivory's theorem is used to derive the gravitational potential of the system. Then, a global numerical method, which combines grid searching and differential correction, is developed for systematically searching periodic orbits in the doubly synchronous systems. A total of 30 and 28 families of periodic orbits around Lundia and Ostro are found, respectively. Furthermore, on the basis of the analysis of morphology, stabilities and invariant manifolds, the potential applications of these periodic orbit families are studied. Several quasi-circular orbit families with low instability index are found to be suitable for the observation of the two typical binary systems. The invariant manifolds of some periodic orbits near the equilibrium points can provide the fuel-free trajectories to achieve the ballistic landing to the surface of the asteroids and transfer between the binary asteroids.

  12. Production of doubly charmed baryons at energy {radical}s=10.58 GeV

    SciTech Connect

    Kiselev, V.V.; Likhoded, A.K.; Shevlyagin, M.V.

    1995-06-01

    The cross section for the production of doubly charmed baryons at a B-factory is estimated on the basis of perturbative QCD calculations of the cross sections for cc-diquark production and of the quark-hadron duality. 14 refs., 2 figs.

  13. The doubly labeled water method produces highly reproducible longitudinal results in nutrition studies

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The doubly labeled water (DLW) method is considered the reference method for the measurement of energy expenditure under free-living conditions. However, the reproducibility of the DLW method in longitudinal studies is not well documented. This study was designed to evaluate the longitudinal reprodu...

  14. A tristable [2]rotaxane that is doubly gated by foldamer and azobenzene kinetic barriers.

    PubMed

    Wang, Wei-Kun; Xu, Zi-Yue; Zhang, Yun-Chang; Wang, Hui; Zhang, Dan-Wei; Liu, Yi; Li, Zhan-Ting

    2016-06-14

    A hydrogen bonded foldamer unit and an azobenzene unit have been incorporated into the linear component of a tristable [2]rotaxane to give rise to a doubly gated switching system tuned by the folding-defolding of the foldamer unit and the photo-initiated trans-cis isomerization of the azobenzene unit. PMID:27203526

  15. In vitro evaluation of the antimicrobial agent AquaFrin(TM) as a bactericide and selective algicide for use in channel catfish (Ictalurus punctatus) aquaculture

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Producers of pond-raised channel catfish in the southeastern United States can experience huge economic losses due to the bacterial diseases enteric septicemia of catfish (ESC) and columnaris and to the presence of the certain odor-producing cyanobacteria in production ponds that result in “off-flav...

  16. Differential contribution of the NR1- and NR2A-subunits to the selectivity filter of recombinant NMDA receptor channels.

    PubMed Central

    Wollmuth, L P; Kuner, T; Seeburg, P H; Sakmann, B

    1996-01-01

    1. The molecular determinants for the narrow constriction of recombinant N-methyl-D-aspartate (NMDA) receptor channels composed of wild-type and mutant NR1- and NR2A-subunits were studied in Xenopus oocytes. 2. The relative permeability of differently sized organic cations was used as an indicator of the size of the narrow constriction. From measured reversal potentials under bi-ionic conditions with K+ as the reference solution, permeability ratios were calculated with the Lewis equation. 3. For wild-type NMDA receptor channels, five organic cations showed clear reversal potentials, with permeability ratios (PX/PK): ammonium, 1.28; methylammonium, 0.48; dimethylammonium (DMA), 0.20; diethylammonium, 0.07; and dimethylethanol-ammonium, 0.02. 4. Mutation of the N-site asparagine (N) to glutamine (Q) at homologous positions in either NR1 (position 598) or NR2A (position 595) increased the permeability of DMA relative to wild-type channels about equally. However, for larger sized organic cations, the NR1(N598Q) mutation had stronger effects on increasing their permeability whereas the NR2A(N595Q) mutation was without effect. These changes in organic cation permeability suggest that the NR1(N598Q) mutation increases the pore size while the NR2A(N595Q) mutation does not. 5. Channels in which the NR1 N-site asparagine was replaced by the smaller glycine (G), NR1(N598G)-NR2A, showed the largest increase in pore size of all sites examined in either subunit. In contrast, in the NR2A-subunit the same N-site substitution to glycine produced only small effects on pore size. 6. For the NR2A-subunit, an asparagine residue (position 596) on the C-terminal side of the N-site, when mutated to larger or smaller sized amino acids, produced large, volume-specific effects on pore size. The mutant channel NR1-NR2A(N596G) had the largest increase in pore size of all sites examined in the NR2A-subunit. In contrast, mutation of the homologous position in the NR1-subunit had no effect on

  17. Roughness characteristics of natural channels

    USGS Publications Warehouse

    Barnes, Harry Hawthorne

    1967-01-01

    Color photographs and descriptive data are presented for 50 stream channels for which roughness coefficients have been determined. All hydraulic computations involving flow in open channels require an evaluation of the roughness characteristics of the channel. In the absence of a satisfactory quantitative procedure this evaluation remains chiefly an art. The ability to evaluate roughness coefficients must be developed through experience. One means of gaining this experience is by examining and becoming acquainted with the appearance of some typical channels whose roughness coefficients are known. The photographs and data contained in this report represent a wide range of channel conditions. Familiarity with the appearance, geometry, and roughness characteristics of these channels will improve the engineer's ability to select roughness coefficients for other channels .

  18. Message passing with queues and channels

    SciTech Connect

    Dozsa, Gabor J; Heidelberger, Philip; Kumar, Sameer; Ratterman, Joseph D; Steinmacher-Burow, Burkhard; Wisniewski, Robert W

    2013-09-24

    In an embodiment, a send thread receives an identifier that identifies a destination node and a pointer to data. The send thread creates a first send request in response to the receipt of the identifier and the data pointer. The send thread selects a selected channel from among a plurality of channels. The selected channel comprises a selected hand-off queue and an identification of a selected message unit. Each of the channels identifies a different message unit. The selected hand-off queue is randomly accessible. If the selected hand-off queue contains an available entry, the send thread adds the first send request to the selected hand-off queue. If the selected hand-off queue does not contain an available entry, the send thread removes a second send request from the selected hand-off queue and sends the second send request to the selected message unit.

  19. Exotic physics: search for doubly-charged higgs bosons decaying to dileptons in p anti-p collisions at s**(1/2) = 1.96 tev

    SciTech Connect

    Acosta, D.; CDF Collaboration

    2004-11-15

    The authors present the results of a search for doubly-charged Higgs bosons (H{sup {+-}}{sup {+-}}) decaying to dileptons (ll') using {approx} 240 pb{sup -1} of p{bar p} collision data collected by the CDF II experiment at the Fermilab Tevatron. In the search region, given by same-sign ll' mass m{sub ll'} > 80 GeV/c{sup 2} (100 GeV/c{sup 2} for ee channel), they observe no evidence for H{sup {+-}}{sup {+-}} production. They set limits on {sigma}(p{bar p} {yields} H{sup ++}H{sup --} {yields} l{sup +}l'{sup +}l{sup -}l'{sup -}) as a function of the mass of the H{sup {+-}}{sup {+-}} and the chirality of its couplings. Assuming exclusive same-sign dilepton decays, they derive lower mass limits on H{sub L}{sup {+-}}{sup {+-}} of 133 GeV/c{sup 2}, 136 GeV/c{sup 2}, and 115 GeV/c{sup 2} in the ee, {mu}{mu}, and e{mu} channels, respectively, and a lower mass limit of 113 GeV/c{sup 2} on H{sub R}{sup {+-}}{sup {+-}} in the {mu}{mu} channel, all at the 95% confidence level.

  20. The novel isoxazoline ectoparasiticide fluralaner: selective inhibition of arthropod γ-aminobutyric acid- and L-glutamate-gated chloride channels and insecticidal/acaricidal activity.

    PubMed

    Gassel, Michael; Wolf, Christian; Noack, Sandra; Williams, Heike; Ilg, Thomas

    2014-02-01

    Isoxazolines are a novel class of parasiticides that are potent inhibitors of γ-aminobutyric acid (GABA)-gated chloride channels (GABACls) and L-glutamate-gated chloride channels (GluCls). In this study, the effects of the isoxazoline drug fluralaner on insect and acarid GABACl (RDL) and GluCl and its parasiticidal potency were investigated. We report the identification and cDNA cloning of Rhipicephalus (R.) microplus RDL and GluCl genes, and their functional expression in Xenopus laevis oocytes. The generation of six clonal HEK293 cell lines expressing Rhipicephalus microplus RDL and GluCl, Ctenocephalides felis RDL-A285 and RDL-S285, as well as Drosophila melanogaster RDLCl-A302 and RDL-S302, combined with the development of a membrane potential fluorescence dye assay allowed the comparison of ion channel inhibition by fluralaner with that of established insecticides addressing RDL and GluCl as targets. In these assays fluralaner was several orders of magnitude more potent than picrotoxinin and dieldrin, and performed 5-236 fold better than fipronil on the arthropod RDLs, while a rat GABACl remained unaffected. Comparative studies showed that R. microplus RDL is 52-fold more sensitive than R. microplus GluCl to fluralaner inhibition, confirming that the GABA-gated chloride channel is the primary target of this new parasiticide. In agreement with the superior RDL on-target activity, fluralaner outperformed dieldrin and fipronil in insecticidal screens on cat fleas (Ctenocephalides felis), yellow fever mosquito larvae (Aedes aegypti) and sheep blowfly larvae (Lucilia cuprina), as well as in acaricidal screens on cattle tick (R. microplus) adult females, brown dog tick (Rhipicephalus sanguineus) adult females and Ornithodoros moubata nymphs. These findings highlight the potential of fluralaner as a novel ectoparasiticide. PMID:24365472

  1. Evaluation of an in vitro cell assay to select attenuated bacterial mutants of Aeromonas hydrophila and Edwardsiella tarda to channel catfish

    Technology Transfer Automated Retrieval System (TEKTRAN)

    To evaluate the feasibility of using an in vitro cell assay to select attenuated bacterial mutants. Using catfish gill cells G1B, the feasibility of using an in vitro assay instead of in vivo virulence assay using live fish to select attenuated bacterial mutants was evaluated in this study. Pearson ...

  2. Channel catfish

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This book chapter provides a comprehensive overview of channel catfish aquaculture. Sections include fish biology; commercial culture; culture facilities; production practices; water quality management; nutrition, feeding and feed formulation; infectious diseases; harvesting and processing; and the...

  3. Biophysics of BK Channel Gating.

    PubMed

    Pantazis, A; Olcese, R

    2016-01-01

    BK channels are universal regulators of cell excitability, given their exceptional unitary conductance selective for K(+), joint activation mechanism by membrane depolarization and intracellular [Ca(2+)] elevation, and broad expression pattern. In this chapter, we discuss the structural basis and operational principles of their activation, or gating, by membrane potential and calcium. We also discuss how the two activation mechanisms interact to culminate in channel opening. As members of the voltage-gated potassium channel superfamily, BK channels are discussed in the context of archetypal family members, in terms of similarities that help us understand their function, but also seminal structural and biophysical differences that confer unique functional properties. PMID:27238260

  4. Effects of a 2006 High-Flow Release from Tiber Dam on Channel Morphology at Selected Sites on the Marias River, Montana

    USGS Publications Warehouse

    Auble, Gregor T.; Bowen, Zachary H.

    2008-01-01

    In June 2006, an opportunistic high-flow release was made from Tiber Dam on the Marias River in Mont., to investigate possible alternatives for partially restoring the river's natural flow pattern and variability. At two sites along the river, we measured channel geometry before and after the high-flow release to evaluate channel change and alteration of physical habitat. Streamflow downstream from Tiber Dam has been stabilized by reduction of high flows and augmentation of low flows. This has produced flood-control benefits as well as some possible adverse environmental effects downstream from the dam. The 2006 high-flow release resulted in a downstream hydrograph with high flows of above-average magnitude in the post-dam flow regime of the Marias River. Timing of the peak and the declining limb of the release hydrograph were very similar to a historical, unregulated hydrograph of the Marias River. Furthermore, the high flow produced many of the qualitative elements of ecologically important physical processes that can be diminished or lost due to flow stabilization downstream from a dam. Typically dry back channels were occupied by flowing water. Islands were inundated, resulting in vegetation removal and sediment accretion that produced new disturbance patches of bare, moist substrate. Cut banks were eroded, and large woody debris was added to the river and redistributed. Flood-plain surfaces were inundated, producing substantial increases in wetted perimeter and spatially distinctive patterns of deposition associated with natural levee formation. The scale of the 2006 high flow - in terms of peak magnitude and the lateral extent of bottomland influenced by inundation or lateral channel movement - was roughly an order of magnitude smaller than the scale of an infrequent high flow in the pre-dam regime. Overall extent and composition of riparian vegetation will continue to change under a scaled-down, post-dam flow regime. For example, the importance of the non

  5. Relativistic description of pair production of doubly heavy baryons in e{sup +}e{sup −} annihilation

    SciTech Connect

    Martynenko, A. P.; Trunin, A. M.

    2015-05-15

    Relativistic corrections in the pair production of S-wave doubly heavy diquarks in electron-positron annihilation were calculated on the basis of perturbative QCD and the quark model. The relativistic corrections to the wave functions for quark bound states were taken into account with the aid of the Breit potential in QCD. Relativistic effects change substantially the nonrelativistic cross sections for pair diquark production. The yield of pairs of (ccq) doubly heavy baryons at B factories was estimated.

  6. Doubly Heavy Baryons, Heavy Quark-DiQuark Symmetry and NRQCD

    SciTech Connect

    Sean Fleming; Thomas Mehen

    2005-09-27

    In the heavy quark limit, properties of heavy mesons and doubly heavy baryons are related by heavy quark-diquark symmetry. This problem is reanalyzed in the framework of Non-Relativistic QCD (NRQCD). We introduce a novel method for deriving Potential NRQCD (pNRQCD) Lagrangians for composite fields from vNRQCD, which contains quarks and antiquarks as explicit degrees of freedom and maintains manifest power counting in the velocity via a label formalism. A Hubbard-Stratonovich transformation is used to eliminate four quark interactions in vNRQCD and then quarks and antiquarks are integrated out to get effective Lagrangians for composite fields. This method is used to rederive Lagrangians for the Q\\bar Q and QQ sectors of pNRQCD and give a correct derivation of the O(1/m_Q) prediction for the hyperfine splitting of doubly heavy baryons.

  7. Synthesis of γ-Phosphate-Labeled and Doubly Labeled Adenosine Triphosphate Analogs.

    PubMed

    Hacker, Stephan M; Welter, Moritz; Marx, Andreas

    2015-01-01

    This unit describes the synthesis of γ-phosphate-labeled and doubly labeled adenosine triphosphate (ATP) analogs and their characterization using the phosphodiesterase I from Crotalus adamanteus (snake venom phosphodiesterase; SVPD). In the key step of the synthesis, ATP or an ATP analog, bearing a linker containing a trifluoroacetamide group attached to the nucleoside, are modified with an azide-containing linker at the terminal phosphate using an alkylation reaction. Subsequently, different labels are introduced to the linkers by transformation of one functional group to an amine and coupling to an N-hydroxysuccinimide ester. Specifically, the Staudinger reaction of the azide is employed as a straightforward means to obtain an amine in the presence of various labels. Furthermore, the fluorescence characteristics of a fluorogenic, doubly labeled ATP analog are investigated following enzymatic cleavage by SVPD. PMID:25754889

  8. Advantages of doubly polished thin sections for the study of microfossils in volcanic rock

    PubMed Central

    Ivarsson, M

    2006-01-01

    Doubly polished thin sections, originally prepared for fluid inclusion studies, present great advantages in the study of microfossils in volcanic rocks. Better visibility and light conditions, variation in thickness of the thin sections and the possibility to combine fluid inclusion studies with microfossil studies lead to a wide range of advantages over ordinary thin sections. This includes the study of morphology, internal microstructures, colonies, association with the substrate that microfossils are attached to and geological and environmental context in which the microfossil once lived. When meeting the criteria of microfossil recognition the advantages of doubly polished thin sections are substantial and can be crucial in distinguishing between biogenic microfossils and abiotically formed abiomorphs. PMID:16759373

  9. Doubly fed induction generator wind turbines with fuzzy controller: a survey.

    PubMed

    Sathiyanarayanan, J S; Kumar, A Senthil

    2014-01-01

    Wind energy is one of the extraordinary sources of renewable energy due to its clean character and free availability. With the increasing wind power penetration, the wind farms are directly influencing the power systems. The majority of wind farms are using variable speed wind turbines equipped with doubly fed induction generators (DFIG) due to their advantages over other wind turbine generators (WTGs). Therefore, the analysis of wind power dynamics with the DFIG wind turbines has become a very important research issue, especially during transient faults. This paper presents fuzzy logic control of doubly fed induction generator (DFIG) wind turbine in a sample power system. Fuzzy logic controller is applied to rotor side converter for active power control and voltage regulation of wind turbine. PMID:25028677

  10. Doubly degenerate entanglement spectrum and entanglement plateau in the S=1 bond-alternating chain

    NASA Astrophysics Data System (ADS)

    Deng, Xiao-Yan; Dou, Jun-Ya; Liu, Guang-Hua

    2015-12-01

    Quantum entanglement, entanglement spectrum, magnetization, and ground-state energy of the S=1 bond-alternating antiferromagnetic Heisenberg chain under magnetic field are investigated by the infinite time-evolving block decimation (iTEBD) method. Bipartite entanglement and entanglement spectrum are found to be capable of describing all the quantum phase transitions (QPTs). A rich ground-state phase diagram, which comprises of five different phases, i.e., a singlet-dimer phase, a Haldane phase, a Tomonaga-Luttinger liquid (TLL) phase, a 1/2 plateau phase, and a saturated ferromagnetic phase, is determined. It is interesting that, with the appearance of magnetization plateaus, entanglement plateaus are observed simultaneously. In the Haldane phase, doubly degenerate entanglement spectra on both even and odd bonds are observed. However, in the 1/2 plateau phase, only the entanglement spectra on the even bonds are found to be doubly degenerated.

  11. Autoionizing