FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2071843318> ?p ?o ?g. }

• W2071843318 endingPage "30207" @default.
• W2071843318 startingPage "30204" @default.
• W2071843318 abstract "BNC1 is a mammalian neuronal cation channel in the novel DEG/ENaC ion channel family. BNC1 channels are transiently activated by extracellular protons and are constitutively activated by insertion of large residues, such as valine, in place of Gly-430; residue 430 is a site where analogous mutations in someCaenorhabditis elegans family members cause a swelling neurodegeneration. Mutation of Gly-430 to a small amino acid, cysteine, neither generated constitutive currents nor allowed modification of this residue by sulfhydryl-reactive methanethiosulfonate (MTS) compounds. However, when protons activated the channel, Cys-430 became accessible to extracellular MTS reagents, which modified Cys-430 to generate constitutive currents. Fluorescent MTS reagents also labeled Cys-430 in activated channels. These data indicate that protons induce a reversible conformational change that activates BNC1 thereby exposing residue 430 to the extracellular solution. Once Cys-430 is modified with a large chemical group, the channel is prevented from relaxing back to the inactive state. These results link ligand-dependent activation and activation by mutations that cause neurodegeneration. BNC1 is a mammalian neuronal cation channel in the novel DEG/ENaC ion channel family. BNC1 channels are transiently activated by extracellular protons and are constitutively activated by insertion of large residues, such as valine, in place of Gly-430; residue 430 is a site where analogous mutations in someCaenorhabditis elegans family members cause a swelling neurodegeneration. Mutation of Gly-430 to a small amino acid, cysteine, neither generated constitutive currents nor allowed modification of this residue by sulfhydryl-reactive methanethiosulfonate (MTS) compounds. However, when protons activated the channel, Cys-430 became accessible to extracellular MTS reagents, which modified Cys-430 to generate constitutive currents. Fluorescent MTS reagents also labeled Cys-430 in activated channels. These data indicate that protons induce a reversible conformational change that activates BNC1 thereby exposing residue 430 to the extracellular solution. Once Cys-430 is modified with a large chemical group, the channel is prevented from relaxing back to the inactive state. These results link ligand-dependent activation and activation by mutations that cause neurodegeneration. 4-morpholineethanesulfonic acid methanethiosulfonate 2-aminoethyl methanethiosulfonate hydrobromide (2-(trimethylammonium)ethyl) methanethiosulfonate bromide sodium 2-sulfonatoethyl methanethiosulfonate N-biotinylaminoethyl methanethiosulfonate. Proteins in the DEG/ENaC superfamily form multimeric cation channels that are blocked by amiloride (1Tavernarakis N. Driscoll M. Annu. Rev. Physiol. 1997; 59: 659-689Crossref PubMed Scopus (183) Google Scholar, 2Fyfe G.K. Quinn A. Canessa C.M. Semin. Nephrol. 1998; 18: 138-151PubMed Google Scholar, 3Corey D.P. Garcı́a-Añoveros J. Science. 1996; 273: 323-324Crossref PubMed Scopus (99) Google Scholar). Several neuronal members of this family require extracellular ligands to open the channel. For example, the FMRFamide-activated Na+ channel (FaNaCh) from neurons of the snail Helix aspersa requires application of neuropeptide to the extracellular surface for channel activation (4Lingueglia E. Champigny G. Lazdunski M. Barbry P. Nature. 1995; 378: 730-733Crossref PubMed Scopus (346) Google Scholar). Likewise, mammalian DEG/ENaC family members, BNC1 (also called MDEG and BNaC-l) (5Price M.P. Snyder P.M. Welsh M.J. J. Biol. Chem. 1996; 271: 7879-7882Abstract Full Text Full Text PDF PubMed Scopus (287) Google Scholar, 6Waldmann R. Champigny G. Voilley N. Lauritzen I. Lazdunski M. J. Biol. Chem. 1996; 271: 10433-10436Abstract Full Text Full Text PDF PubMed Scopus (276) Google Scholar, 7Garcı́a-Añoveros J. Derfler B. Neville-Golden J. Hyman B.T. Corey D.P. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 1459-1464Crossref PubMed Scopus (290) Google Scholar), BNaC-2 (also called ASIC) (7Garcı́a-Añoveros J. Derfler B. Neville-Golden J. Hyman B.T. Corey D.P. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 1459-1464Crossref PubMed Scopus (290) Google Scholar, 8Waldmann R. Champigny G. Bassilana F. Heurteaux C. Lazdunski M. Nature. 1997; 386: 173-177Crossref PubMed Scopus (1106) Google Scholar), and DRASIC (9Waldmann R. Bassilana F. de Weille J. Champigny G. Heurteaux C. Lazdunski M. J. Biol. Chem. 1997; 272: 20975-20978Abstract Full Text Full Text PDF PubMed Scopus (466) Google Scholar) require a reduced extracellular pH for activation (6Waldmann R. Champigny G. Voilley N. Lauritzen I. Lazdunski M. J. Biol. Chem. 1996; 271: 10433-10436Abstract Full Text Full Text PDF PubMed Scopus (276) Google Scholar, 8Waldmann R. Champigny G. Bassilana F. Heurteaux C. Lazdunski M. Nature. 1997; 386: 173-177Crossref PubMed Scopus (1106) Google Scholar, 9Waldmann R. Bassilana F. de Weille J. Champigny G. Heurteaux C. Lazdunski M. J. Biol. Chem. 1997; 272: 20975-20978Abstract Full Text Full Text PDF PubMed Scopus (466) Google Scholar). In addition, genetic studies suggest that three Caenorhabditis elegans family members (MEC-4, MEC-10, and UNC-105) require an interaction with extracellular collagen for normal activity (1Tavernarakis N. Driscoll M. Annu. Rev. Physiol. 1997; 59: 659-689Crossref PubMed Scopus (183) Google Scholar, 10Liu J. Schrank B. Waterston R.H. Science. 1996; 273: 361-364Crossref PubMed Scopus (130) Google Scholar,11Du H. Gu G. William C.M. Chalfie M. Neuron. 1996; 16: 183-194Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar). Activation by an extracellular ligand is consistent with an important neurosensory function for some members of this channel family. For example, proton sensitivity, coupled with expression in peripheral nociceptive neurons, suggests that BNC1, BNaC-2, and DRASIC may be involved in sensation of painful stimuli. Expression of BNC1 and BNaC2 in the central nervous system also suggests a potential role in synaptic transmission. Several C. elegans DEG/ENaC proteins (DEG-1, MEC-4, MEC-10, UNC-105, and UNC-8) may serve as mechanosensory channels because mutations disrupt touch sensation and coordinated movement (10Liu J. Schrank B. Waterston R.H. Science. 1996; 273: 361-364Crossref PubMed Scopus (130) Google Scholar, 12Chalfie M. Wolinsky E. Nature. 1990; 345: 410-416Crossref PubMed Scopus (256) Google Scholar, 13Driscoll M. Chalfie M. Nature. 1991; 349: 588-593Crossref PubMed Scopus (450) Google Scholar, 14Huang M. Chalfie M. Nature. 1994; 367: 467-470Crossref PubMed Scopus (342) Google Scholar, 15Tavernarakis N. Shreffler W. Wang S. Driscoll M. Neuron. 1997; 18: 107-119Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar). Despite the obvious importance for their function, it is not known how ligands activate these neuronal cation channels. However, a clue comes from the observation that several DEG/ENaC channels can be activated by a specific mutation. Studies of DEG-1, MEC-4, and MEC-10 in C. elegans showed that rare dominant mutations at a specific conserved site caused neurons expressing the mutant protein to swell and degenerate (12Chalfie M. Wolinsky E. Nature. 1990; 345: 410-416Crossref PubMed Scopus (256) Google Scholar, 13Driscoll M. Chalfie M. Nature. 1991; 349: 588-593Crossref PubMed Scopus (450) Google Scholar, 14Huang M. Chalfie M. Nature. 1994; 367: 467-470Crossref PubMed Scopus (342) Google Scholar). This swollen cellular phenotype suggested that the degeneration-causing, or “Deg” mutation caused persistent channel activation, thereby disrupting control of cell volume. Deg mutations affect a residue thought to lie just external to the second membrane-spanning sequence (M2) in or near the pore. The neurodegenerative phenotype required that Deg mutations substitute a Val or other large residue for the wild-type Ala residue, leading to the speculation that bulky side chains might interfere with the closing of a channel gate (1Tavernarakis N. Driscoll M. Annu. Rev. Physiol. 1997; 59: 659-689Crossref PubMed Scopus (183) Google Scholar). Subsequent electrophysiologic studies showed that analogous Deg mutations in BNC1 (6Waldmann R. Champigny G. Voilley N. Lauritzen I. Lazdunski M. J. Biol. Chem. 1996; 271: 10433-10436Abstract Full Text Full Text PDF PubMed Scopus (276) Google Scholar), the DrosophilaNa+ channel Ripped Pocket (16Adams C.M. Anderson M.G. Motto D.G. Price M.P. Johnson W.A. Welsh M.J. J. Cell Biol. 1998; 140: 143-152Crossref PubMed Scopus (205) Google Scholar), and UNC-105 (17Garcı́a-Añoveros J. Garcia J.A. Liu J.-D. Corey D.P. Neuron. 1998; 20: 1231-1241Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar) caused channel activation even in the absence of any ligand. To understand how DEG/ENaC channels are gated and how Deg mutations cause persistent channel activation, we studied BNC1, a proton-activated Na+channel expressed in human neurons (5Price M.P. Snyder P.M. Welsh M.J. J. Biol. Chem. 1996; 271: 7879-7882Abstract Full Text Full Text PDF PubMed Scopus (287) Google Scholar, 6Waldmann R. Champigny G. Voilley N. Lauritzen I. Lazdunski M. J. Biol. Chem. 1996; 271: 10433-10436Abstract Full Text Full Text PDF PubMed Scopus (276) Google Scholar, 18Lingueglia E. de Weille J.R. Bassilana F. Heurteaux C. Sakai H. Waldmann R. Lazdunski M. J. Biol. Chem. 1997; 272: 29778-29783Abstract Full Text Full Text PDF PubMed Scopus (430) Google Scholar). BNC1 mutants were constructed by single-stranded mutagenesis of BNC1 (5Price M.P. Snyder P.M. Welsh M.J. J. Biol. Chem. 1996; 271: 7879-7882Abstract Full Text Full Text PDF PubMed Scopus (287) Google Scholar) in pBluescript. The validity of constructs was confirmed by DNA sequencing. Constructs were cloned into pMT3 (19Swick A.G. Janicot M. Cheneval-Kastelic T. McLenithan J.C. Lane M.D. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 1812-1816Crossref PubMed Scopus (111) Google Scholar) for expression. cDNA constructs were expressed in defolliculated albino Xenopus laevis oocytes (Nasco, Fort Atkinson, WI) by nuclear injection of plasmid DNA at concentrations ranging from 5 to 10 ng/μl. Following injection, oocytes were incubated at 18 °C in modified Barth's solution. 12–24 h after injection, whole cell currents were measured using a two-electrode voltage clamp. During recording, oocytes were bathed in frog Ringer's solution (116 mm NaCl, 0.4 mm CaCl2, 1 mm MgCl2). pH 7.4 and pH 6 solutions were buffered with 5 mm HEPES; more acidic solutions were buffered with 5 mmMES.1 Membrane voltage was held at −60 mV. MTS compounds were from Toronto Research Biochemicals (Toronto, Ontario). MTS compounds and amiloride were added to the extracellular solution that bathed the oocyte. 3–5 h after DNA injection, oocytes were pre-treated at 25 °C with 1 mm MTSEA at pH 5 for 5 min and at pH 7.4 for 20 min. The pre-treatment was designed to modify cysteines on endogenous cell-surface proteins with a nonfluorescent compound; at this early time point, oocytes were not yet expressing channels. Oocytes were then incubated in modified Barth's solution at 18 °C for 12–18 h to allow for channel expression. Oocytes were next exposed for 1 min at 25 °C to 5 μm MTSEA-fluorescein in frog Ringer's solution, pH 7.4 or pH 5; each oocyte was treated five times. Between MTSEA-fluorescein treatments, oocytes were kept in frog Ringer's solution, pH 7.4, for 1 min. After the fifth treatment, oocytes were washed extensively in modified Barth's solution. Oocytes were visualized and relative fluorescence calculated using a laser scanning confocal microscope (Bio-Rad, MRC-600). Analysis was similar to that previously reported (20Mannuzzu L.M. Moronne M.M. Isacoff E.Y. Science. 1996; 271: 213-216Crossref PubMed Scopus (391) Google Scholar). When wild-type BNC1 is expressed in Xenopus oocytes, it generates only a very small basal Na+ current (5Price M.P. Snyder P.M. Welsh M.J. J. Biol. Chem. 1996; 271: 7879-7882Abstract Full Text Full Text PDF PubMed Scopus (287) Google Scholar). However, acidification of the extracellular solution produces a transient activation (21Bassilana F. Champigny G. Waldmann R. de Weille J.R. Heurteaux C. Lazdunski M. J. Biol. Chem. 1997; 272: 28819-28822Abstract Full Text Full Text PDF PubMed Scopus (194) Google Scholar). We first examined the effect of Deg mutations on basal channel activity at pH 7.4. In BNC1, the Deg residue is Gly-430. We found that channels containing Thr, Val, or Phe at position 430 generated large basal amiloride-sensitive currents (Fig. 1 A-D), consistent with a previous report (6Waldmann R. Champigny G. Voilley N. Lauritzen I. Lazdunski M. J. Biol. Chem. 1996; 271: 10433-10436Abstract Full Text Full Text PDF PubMed Scopus (276) Google Scholar). In contrast, when a Cys was incorporated at position 430, the basal current was small and not different from wild type. However, treatment with extracellular protons stimulated a large transient current (Fig. 1, E and F). This is consistent with the finding that in MEC-4, mutation of the Deg residue to Cys did not cause neurodegeneration (13Driscoll M. Chalfie M. Nature. 1991; 349: 588-593Crossref PubMed Scopus (450) Google Scholar). Because Thr, Val, and Phe are larger than Gly or Cys, these results suggested that large amino acids at the Deg position activate BNC1 in the absence of a proton stimulus. Because a Cys at the Deg position may have been too small to activate BNC1, we tested the hypothesis that BNC1-Cys-430 might be activated if its side chain was chemically modified to attach a larger group. To test this, we used water-soluble sulfhydryl-reactive MTS compounds. When we applied MTSEA (100 μm) to the extracellular solution at pH 7.4, it did not activate BNC1-G430C, nor did it alter subsequent activation by protons (Fig. 2 A). We also tested three other MTS compounds, (2-(trimethylammonium)ethyl) methanethiosulfonate bromide (MTSET), sodium 2-sulfonatoethyl methanethiosulfonate (MTSES), and N-biotinylaminoethyl methanethiosulfonate (MTSEA-biotin), and found that they also failed to activate BNC1-G430C at pH 7.4 (Fig. 3 A-C). These results suggested that MTS compounds did not modify Cys-430, perhaps because the residue was not accessible to the extracellular solution under basal conditions at pH 7.4.Figure 3Modification of BNC1-G430C by MTS compounds. At times indicated by bars, 300 μm MTSET (ET), 5 mm MTSES (ES), 300 μm MTS-biotin (biotin), 1 mmamiloride, or pH 5 solution was applied to extracellular surface. Total number of experiments was, two (ET), four (ES), and four (biotin). Membrane voltage was −60 mV.View Large Image Figure ViewerDownload Hi-res image Download (PPT) To test the hypothesis that Cys-430 might become accessible once the channel is open, we simultaneously applied both protons (extracellular pH 5, to open the channel) and MTSEA (to modify Cys-430). This generated a large noninactivating current (Fig. 2 B) that persisted even after MTSEA and protons were removed. The current showed a cation selectivity and amiloride sensitivity similar to that of BNC1-G430V (Fig. 2, C and D). The effect of MTSEA at pH 5 was likely due to covalent modification of Cys-430 because the effect was irreversible, and because MTSEA did not stimulate BNC1-G430V or the wild-type channel under basal or activated conditions (not shown). Persistent activation of the channel after covalent modification of Cys-430 is consistent with the constitutive currents observed when Gly-430 is mutated to a larger residue (Fig. 1). The ability of MTSEA to modify Cys-430 at an acidic pH cannot be explained by a change in the protonation state of Cys-430, because MTS compounds react much more slowly with protonated cysteine side chains (22Roberts D.D. Lewis S.D. Ballou D.P. Olson S.T. Shafer J.A. Biochemistry. 1986; 25: 5595-5601Crossref PubMed Scopus (198) Google Scholar). Rather, the acidic pH altered the channel conformation, activating the channel and exposing Cys-430 to extracellular MTSEA. MTSEA is a relatively small, cationic compound. To examine size and charge constraints for access to Cys-430, we tested slightly larger cationic (MTSET) and anionic (MTSES) compounds, as well as a much larger compound consisting of MTSEA linked to biotin. Like MTSEA, each of these compounds irreversibly activated BNC1-G430C, but only when the channel was activated by protons (Fig. 3, A-C). The MTS compounds did not appear to modify Cys-430 in the basal state because a drop in pH did not produce sustained activation after pretreatment with MTS. Moreover, application of MTS alone did not prevent subsequent activation by MTS when pH was reduced. We noticed that in some experiments a single application of an MTS compound with protons did not produce a maximal effect on current. For example, as shown in Fig. 3 C, repeated proton activation of BNC1-G430C in the presence of MTSES progressively increased current. This suggested that accessibility of Cys-430 might be limited to the time the channel was open, and once the channel had inactivated, Cys-430 was no longer accessible to MTS reagents. To test this further, we slowed the rate of inactivation by reducing the temperature from 23° to 10 °C (Fig. 4 B). Of note, the kinetics of inactivation were complex, perhaps consistent with the multimeric nature of the channel. Importantly, when inactivation was slowed and the duration of channel activity increased, a single application of protons with MTSET produced a greater sustained increase in current (Fig. 4, A and C). These results suggest that Cys-430 is accessible to MTS compounds only during the time that the channel is open. To confirm this and to directly label the channels, we examined the accessibility of Cys-430 to labeling by MTS-4-fluorescein, a fluorescent MTS reagent. As with the other MTS reagents, MTS-4-fluorescein irreversibly activated BNC1-G430C at pH 5 (Fig. 5 A). After labeling, confocal microscopy showed patchy areas of cell-surface fluorescence (Fig. 5, B and E) that may suggest organization and localization by association with cytosolic or membrane structures. In contrast, uninjected oocytes or oocytes expressing wild-type BNC1 had only a small amount of diffuse background fluorescence (Fig. 5, C and E). In addition, oocytes expressing BNC1-G430C that were labeled at pH 7.4 had only a small amount of diffuse fluorescence (Fig. 5, D and E), indicating that labeling required activation by protons. These results are consistent with the electrophysiologic data showing that Cys-430 was accessible to MTS compounds only when the channel was activated. In addition, the ability to selectively modify open channels with a fluorescent MTS reagent provides a novel reporter of the cell surface localization and functional status of these channels. These data indicate that protons induce a reversible conformational change to activate BNC1 and expose the Deg residue. Fig. 6 shows a schematic of a potential mechanism suggested by the results; we model BNC1 activation as a synchronous rotation of channel subunits based on studies of another ligand-gated channel, the nicotinic acetylcholine receptor (23Unwin N. Nature. 1995; 373: 37-43Crossref PubMed Scopus (902) Google Scholar). In this model, protons bind a regulatory site to reversibly rotate the channel subunits. The rotation would have two effects. It would reversibly open the pore to allow current flow. As a consequence, it would also move residue 430 from a buried position to one facing the extracellular environment where it can be irreversibly modified by MTS compounds. Modification of residue 430 with a bulky side chain would sterically hinder rotation of the subunits back to a closed state that buries residue 430. Thus, following modification, the channel would be locked in an open state. This model can also explain the finding that introduction of large amino acids at the Deg position constitutively activates several DEG/ENaC channels (12Chalfie M. Wolinsky E. Nature. 1990; 345: 410-416Crossref PubMed Scopus (256) Google Scholar, 13Driscoll M. Chalfie M. Nature. 1991; 349: 588-593Crossref PubMed Scopus (450) Google Scholar, 14Huang M. Chalfie M. Nature. 1994; 367: 467-470Crossref PubMed Scopus (342) Google Scholar) and causes a swelling degeneration in C. elegans neurons; large side chains at residue 430 prevent the conformational changes required for the channel to close. We thank Dan Bucher, Dawn Melssen, Ellen Tarr, and Theresa Mayhew for excellent assistance. We especially appreciate the discussions and help of Joseph Cotten, John Rogers, and Tom Moninger. We thank the University of Iowa DNA Core Facility for assistance with sequencing and oligonucleotide synthesis." @default.
• W2071843318 created "2016-06-24" @default.
• W2071843318 creator A5016363572 @default.
• W2071843318 creator A5019875978 @default.
• W2071843318 creator A5037321572 @default.
• W2071843318 creator A5071352303 @default.
• W2071843318 date "1998-11-01" @default.
• W2071843318 modified "2023-10-18" @default.
• W2071843318 title "Protons Activate Brain Na+ Channel 1 by Inducing a Conformational Change That Exposes a Residue Associated with Neurodegeneration" @default.
• W2071843318 cites W1974642350 @default.
• W2071843318 cites W1978823643 @default.
• W2071843318 cites W1982816670 @default.
• W2071843318 cites W1983153703 @default.
• W2071843318 cites W1994929421 @default.
• W2071843318 cites W1998564418 @default.
• W2071843318 cites W2005865069 @default.
• W2071843318 cites W2009199141 @default.
• W2071843318 cites W2014853483 @default.
• W2071843318 cites W2029305793 @default.
• W2071843318 cites W2044120209 @default.
• W2071843318 cites W2081317765 @default.
• W2071843318 cites W2081556250 @default.
• W2071843318 cites W2081784613 @default.
• W2071843318 cites W2084845518 @default.
• W2071843318 cites W2085673468 @default.
• W2071843318 cites W2085862993 @default.
• W2071843318 cites W2091719660 @default.
• W2071843318 cites W2098588948 @default.
• W2071843318 cites W2119336577 @default.
• W2071843318 cites W2155624357 @default.
• W2071843318 cites W2159220779 @default.
• W2071843318 doi "https://doi.org/10.1074/jbc.273.46.30204" @default.
• W2071843318 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/9804777" @default.
• W2071843318 hasPublicationYear "1998" @default.
• W2071843318 type Work @default.
• W2071843318 sameAs 2071843318 @default.
• W2071843318 citedByCount "70" @default.
• W2071843318 countsByYear W20718433182012 @default.
• W2071843318 countsByYear W20718433182013 @default.
• W2071843318 countsByYear W20718433182014 @default.
• W2071843318 countsByYear W20718433182015 @default.
• W2071843318 countsByYear W20718433182016 @default.
• W2071843318 countsByYear W20718433182017 @default.
• W2071843318 countsByYear W20718433182022 @default.
• W2071843318 crossrefType "journal-article" @default.
• W2071843318 hasAuthorship W2071843318A5016363572 @default.
• W2071843318 hasAuthorship W2071843318A5019875978 @default.
• W2071843318 hasAuthorship W2071843318A5037321572 @default.
• W2071843318 hasAuthorship W2071843318A5071352303 @default.
• W2071843318 hasBestOaLocation W20718433181 @default.
• W2071843318 hasConcept C12554922 @default.
• W2071843318 hasConcept C126322002 @default.
• W2071843318 hasConcept C15744967 @default.
• W2071843318 hasConcept C169760540 @default.
• W2071843318 hasConcept C185592680 @default.
• W2071843318 hasConcept C2776925932 @default.
• W2071843318 hasConcept C2777339483 @default.
• W2071843318 hasConcept C2779134260 @default.
• W2071843318 hasConcept C2781338088 @default.
• W2071843318 hasConcept C55493867 @default.
• W2071843318 hasConcept C71924100 @default.
• W2071843318 hasConcept C86803240 @default.
• W2071843318 hasConceptScore W2071843318C12554922 @default.
• W2071843318 hasConceptScore W2071843318C126322002 @default.
• W2071843318 hasConceptScore W2071843318C15744967 @default.
• W2071843318 hasConceptScore W2071843318C169760540 @default.
• W2071843318 hasConceptScore W2071843318C185592680 @default.
• W2071843318 hasConceptScore W2071843318C2776925932 @default.
• W2071843318 hasConceptScore W2071843318C2777339483 @default.
• W2071843318 hasConceptScore W2071843318C2779134260 @default.
• W2071843318 hasConceptScore W2071843318C2781338088 @default.
• W2071843318 hasConceptScore W2071843318C55493867 @default.
• W2071843318 hasConceptScore W2071843318C71924100 @default.
• W2071843318 hasConceptScore W2071843318C86803240 @default.
• W2071843318 hasIssue "46" @default.
• W2071843318 hasLocation W20718433181 @default.
• W2071843318 hasOpenAccess W2071843318 @default.
• W2071843318 hasPrimaryLocation W20718433181 @default.
• W2071843318 hasRelatedWork W1536551662 @default.
• W2071843318 hasRelatedWork W1974297080 @default.
• W2071843318 hasRelatedWork W1995797290 @default.
• W2071843318 hasRelatedWork W2111495287 @default.
• W2071843318 hasRelatedWork W2179205971 @default.
• W2071843318 hasRelatedWork W2487609709 @default.
• W2071843318 hasRelatedWork W2517534055 @default.
• W2071843318 hasRelatedWork W2600384234 @default.
• W2071843318 hasRelatedWork W2969353500 @default.
• W2071843318 hasRelatedWork W3125725193 @default.
• W2071843318 hasVolume "273" @default.
• W2071843318 isParatext "false" @default.
• W2071843318 isRetracted "false" @default.
• W2071843318 magId "2071843318" @default.
• W2071843318 workType "article" @default.