FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2154385611> ?p ?o ?g. }

• W2154385611 endingPage "548" @default.
• W2154385611 startingPage "546" @default.
• W2154385611 abstract "HomeCirculation ResearchVol. 115, No. 6Finding the Missing Link Between the Unfolded Protein Response and O-GlcNAcylation in the Heart Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBFinding the Missing Link Between the Unfolded Protein Response and O-GlcNAcylation in the Heart Christopher C. Glembotski Christopher C. GlembotskiChristopher C. Glembotski From the Department of Biology, San Diego State University Heart Institute, CA. Search for more papers by this author Originally published29 Aug 2014https://doi.org/10.1161/CIRCRESAHA.114.304855Circulation Research. 2014;115:546–548X-box Binding Protein 1 Couples the Unfolded Protein Response to Hexosamine Biosynthetic Pathway Wang et al Cell. 2014;156:1179–1192.The endoplasmic reticulum (ER) stress–inducible transcription factor, x-box binding protein 1 (XBP1), which enhances protein glycosylation in the ER, was shown to also enhance protein glycosylation outside the ER, via a process called O-GlcNAcylation, which protected the heart from ischemia/reperfusion damage.O-GlcNAcylation is a reversible post-translational modification that takes place outside of the ER and affects the functions of target proteins. In cardiac myocytes, O-GlcNAcylation increases acutely in response to a variety of conditions, including hypoxia, ischemia, ischemia/reperfusion, and oxidative stress, during which O-GlcNAcylation is generally protective. However, chronic increases in O-GlcNAcylation during diseases, such as diabetes mellitus, exacerbate cardiac dysfunction and damage. In contrast to O-GlcNAcylation, N-linked glycosylation (N-glycosylation) of proteins occurs in the ER, is relatively permanent, and is required for folding and trafficking of proteins in the ER and Golgi. N-glycosylation can be impaired by many of the same stresses that affect O-GlcNAcylation in the heart. Impaired N-glycosylation causes ER stress, subsequent activation of the unfolded protein response (UPR), and activation of the transcription factor, XBP1, which induces genes that restore N-glycosylation in the ER and promote adaptation to ER stress. A recent study, published in the journal Cell, showed that XBP1 also enhances O-GlcNAcylation, which protects the heart from ischemia/reperfusion damage.1 Thus, in response to potentially damaging stress, XBP1 coordinates glycosylation inside and outside of the ER to confer protection.The study by Wang et al1 showed that XBP1 is the missing link between protein O-GlcNAcylation and the UPR (Figure [A]). In the heart, ischemia/reperfusion leads to ER stress, activation of the UPR and XBP1, which Wang et al determined to be a direct transcriptional activator of the gene encoding the rate-limiting step in the hexosamine biosynthetic pathway, which supplies the substrate required for O-GlcNAcylation, that is, uridine diphosphate N-acetylglucosamine (UDP-GlcNAc). These findings reveal previously unappreciated links among the UPR, hexosamine biosynthesis, and O-GlcNAcylation that may serve protective roles in several tissues other than the heart.Download figureDownload PowerPointFigure. A, x-box binding protein 1 (XBP1) is the missing link between the unfolded protein response (UPR) and O-GlcNAcylation. The contributions made by Wang et al are shown in blue. B, Proteins are glycosylated in different cell compartments. C, A key substrate for O-GlcNAcylation, which is used by the enzyme O-GlcNAc transferase (OGT), is uridine diphosphate N-acetyl glucosamine (UDP-GlcNAc). D, UDP-GlcNAc is generated by the hexose biosynthetic pathway (HBP). O-GlcNAc groups can be removed from proteins by O-GlcNAcase. The contributions made by Wang et al are shown in blue. ER indicates endoplasmic reticulum; and GFAT, glutamine:fructose amidotransferase.The UPR is a conserved intracellular signaling system that is activated in response to an imbalance in ER protein homeostasis or ER proteostasis.2 Conditions that impair protein folding in the ER, such as the lack of oxygen and nutrients in the ischemic heart, result in ER stress, which can lead to an imbalance in proteostasis because of the accumulation of potentially toxic misfolded proteins. One of the major ER stress signaling pathways is mediated by the ER-transmembrane protein, inositol-requiring protein-1. By way of mRNA splicing, inositol-requiring protein-1 converts the XBP1 mRNA from a transcript that encodes a protein that does not have transcriptional activity, XBP1 unspliced, to a transcript that encodes a form of XBP1 that is a potent transcription factor, XBP1 spliced (XBP1s). XBP1s-responsive genes encode proteins that, among other things, augment ER protein folding in various ways, including restoration and fortification of protein glycosylation in the ER lumen.Protein glycosylation is a widespread post-translational modification that has substantial impact on the function of the heart. It can take place in the ER lumen, as well as in the cytosol, mitochondria, and nucleus (Figure [B]).3 The O-linked protein glycosylation that takes place outside the ER is responsible for the post-translational modification of >1000 different proteins. O-linked glycosylation involves the post-translational addition of the monosaccharide, GlcNAc, to a serine or threonine in target proteins. In contrast to N-linked glycosylation, there is no known consensus sequence on target proteins that are modified by O-linked glycosylation outside the ER. O-linked glycosylation in the cytosol, nucleus, and mitochondria, also called O-GlcNAcylation, is mediated by O-GlcNAc transferase, which uses UDP-GlcNAc as the glycosyl donor (Figure [C]). N-glycosylation and O-GlcNAcylation share the intermediate, UDP-GlcNAc, which is generated from glucose by the hexosamine biosynthetic pathway (Figure [D]). The rate-limiting step in UDP-GlcNAc formation is the conversion of fructose-6-phosphate to glucosamine-6-phosphate by the enzyme, glutamine:fructose amidotransferase (GFAT).Before the study by Wang et al, it had been shown that ischemia could activate the UPR and XBP1 in cultured cardiac myocytes and in infarcted mouse hearts, and that XBP1 served a protective role under these conditions (Figure [A]).4 Moreover, it had been shown that ischemia/reperfusion can increase protein O-GlcNAcylation in cultured cardiac myocytes and in the mouse heart, in vivo, and that O-GlcNAcylation protected the heart from ischemia/reperfusion damage.5 However, the link between the UPR and O-GlcNAcylation remained unknown (Figure [A], black box). In pursuit of finding this missing link, Wang et al observed that, in the mouse heart, ischemia/reperfusion activated ER stress, XBP1, O-GlcNAcylation and GFAT1, as well as several other enzymes in the hexosamine biosynthetic pathway. They then postulated that enzymes responsible for hexosamine biosynthesis, in particular, GFAT1, which catalyzes the rate-limiting reaction, might be transcriptionally controlled by XBP1s. This was a critical insight that led to the discovery of the missing link. A most insightful leap was when Wang et al went on to show that the promoter-proximal 5′-flanking region of the GFAT1 gene has sequence through which XBP1s enhanced GFAT1 transcription in cardiac myocytes. Moreover, using combinations of XBP1 gain and loss of function in the heart, in vivo, and in cultured cardiac myocytes, coupled with GFAT1 gain- and loss-of-function maneuvers, Wang et al provided clear mechanistic evidence supporting the hypothesis that XBP1s is the missing link between the UPR and protein O-GlcNAcylation. Moreover, they provided evidence supporting the idea that XBP1s-mediated increases in O-GlcNAcylation can protect the heart from ischemia/reperfusion damage demonstrated by a reduction in infarct size.A few questions arise from the study by Wang et al, one of which concerns the other isoform of GFAT, GFAT2, which is considered to be the major isoform of GFAT in the heart.6 Other studies have shown that it is GFAT2, and not GFAT1 that is regulated in the heart by pressure overload or exercise.7–9 This leads to the question of whether GFAT2 could be regulated by XBP1s? There is a sequence at −273 to −265 in the mouse GFAT2 promoter (TCACGTCT), which is close to the sequence and location of the XBP1s binding site that Wang et al found at −276 of the mouse GFAT1 promoter (CCACGTCA). Both elements have the core ACGT sequence, which was previously shown to be required for XBP1s binding.10 Thus, as with GFAT1, XBP1s might bind to the GFAT2 promoter and increase GFAT2 transcription. Wang et al briefly investigated whether GFAT2 might also be regulated by XBP1, but found that, in contrast to GFAT1, GFAT2 expression was not increased by XBP1. These results are consistent with a previous study, which showed that GFAT1, but not GFAT2, was induced by XBP1s.11 Thus, although a putative XBP1s binding site exists in GFAT2, it seems that, in contrast to GFAT1, GFAT2 does not serve as an XBP1 target.Another question that arises is how does O-GlcNAcylation protect the heart from ischemia/reperfusion damage? Answering this question will require knowledge of the proteins that are O-GlcNAcylated, as well as an understanding of how O-GlcNAcylation alters their functions. Recently, the identities of many O-GlcNAcylated cardiac proteins were identified, but just how O-GlcNAcylation affects their functions remains to be determined.12Is O-GlcNAcylation always cardioprotective? Although O-GlcNAcylation protects the heart from ischemia/reperfusion damage, in other settings, including the diabetic heart, O-GlcNAcylation seems to contribute to cardiac dysfunction.13 Driven mostly by elevated glucose and the resulting increase in flux through the hexosamine biosynthesis, O-GlcNAcylation of several proteins increases in the diabetic heart. For example, Ca2+/calmodulin-dependent kinase II is O-GlcNAcylated in the diabetic heart, which leads to a hyperactivation of calmodulin-dependent kinase II, increased phosphorylation of the ryanodine receptor. Ryanodine receptor phosphorylation by calmodulin-dependent kinase II results in increased calcium leaks from the sarcoplasmic reticulum, which contributes to the arrhythmia observed in diabetic cardiomyopathy.14What roles does O-GlcNAcylation play in other cardiac pathologies? O-GlcNAcylation is increased in mouse models of pathological cardiac hypertrophy and heart failure. In hypertrophy, nuclear factor of activated T-cells (NFAT) activation, which is a key driver of hypertrophic growth, is inhibited by blocking O-GlcNAcylation.15 Moreover, NFAT is O-GlcNAcylated, leading to speculation that cardiac hypertrophy is evoked, at least partly, by the direct O-GlcNAcylation of NFAT.16 In a mouse model of heart failure induced by myocardial infarction, O-GlcNAcylation increased during heart failure.17 In this study, cardiac-specific deletion of OGA decreased O-GlcNAcylation, increased infarct size, and decreased survival, suggesting that O-GlcNAcylation is protective in this model of heart disease.In summary, O-GlcNAcylation has major effects in the healthy and diseased heart. However, unlike protein phosphorylation, which governs the structure and function of a wide spectrum of hundreds of protein kinase substrates, O-GlcNAcylation addition and removal require only 2 enzymes; thus, the molecular mechanisms regulating the extent and determining the targets of O-GlcNAcylation must be different than those that regulate protein phosphorylation. The study by Wang et al has contributed significantly to our understanding of how O-GlcNAcylation can be regulated by the UPR and the transcription factor, XBP1, and that XBP1 protects the heart from ischemia/reperfusion damage, partly by increasing O-GlcNAcylation. As a result of their study, XBP1 is now also recognized for its roles as a regulator of O-glycosylation outside of the ER. These findings suggest that, by coordinating N- and O-glycosylation, XBP1 plays a pivotal role in most glycosylation events and, thus, potentially regulates the functions of a vast number of proteins. Further underscoring the potentially beneficial functions of XBP1 on an organismal level was a study that appeared in the same issue of Cell as the article by Wang et al, which demonstrated that XBP1-mediated increases in hexosamine biosynthesis in Caenorhabditis elegans extended lifespan.18 Taken together, these paradigm-shifting studies significantly expand our understanding of the UPR, and specifically, XBP1 as central regulators of life and death decisions in cells.AcknowledgmentsI thank Drs Joseph Hill, Heinrich Taegtmeyer, Richard N. Sifers, and Shirin Doroudgar for critical reading of the article and for insightful discussions.Sources of FundingThis work was supported by National Institutes of Health, HL-075573, HL-085577, and HL104535.DisclosuresNone.FootnotesThe opinions expressed in this Commentary are not necessarily those of the editors or of the American Heart Association.Commentaries serve as a forum in which experts highlight and discuss articles (published here and elsewhere) that the editors of Circulation Research feel are of particular significance to cardiovascular medicine.Commentaries are edited by Aruni Bhatnagar & Ali J. Marian.Correspondence to Christopher C. Glembotski, PhD, Department of Biology, San Diego State University Heart Institute, San Diego, CA 92182. E-mail [email protected]References1. Wang ZV, Deng Y, Gao N, et al. Spliced X-box binding protein 1 couples the unfolded protein response to hexosamine biosynthetic pathway.Cell. 2014; 156:1179–1192.CrossrefMedlineGoogle Scholar2. Walter P, Ron D. The unfolded protein response: from stress pathway to homeostatic regulation.Science. 2011; 334:1081–1086.CrossrefMedlineGoogle Scholar3. Ngoh GA, Facundo HT, Zafir A, Jones SP. O-GlcNAc signaling in the cardiovascular system.Circ Res. 2010; 107:171–185.LinkGoogle Scholar4. Thuerauf DJ, Marcinko M, Gude N, Rubio M, Sussman MA, Glembotski CC. Activation of the unfolded protein response in infarcted mouse heart and hypoxic cultured cardiac myocytes.Circ Res. 2006; 99:275–282.LinkGoogle Scholar5. Ngoh GA, Watson LJ, Facundo HT, Jones SP. Augmented O-GlcNAc signaling attenuates oxidative stress and calcium overload in cardiomyocytes.Amino Acids. 2011; 40:895–911.CrossrefMedlineGoogle Scholar6. Oki T, Yamazaki K, Kuromitsu J, Okada M, Tanaka I. cDNA cloning and mapping of a novel subtype of glutamine:fructose-6-phosphate amidotransferase (GFAT2) in human and mouse.Genomics. 1999; 57:227–234.CrossrefMedlineGoogle Scholar7. Lunde IG, Aronsen JM, Kvaløy H, Qvigstad E, Sjaastad I, Tønnessen T, Christensen G, Grønning-Wang LM, Carlson CR. Cardiac O-GlcNAc signaling is increased in hypertrophy and heart failure.Physiol Genomics. 2012; 44:162–172.CrossrefMedlineGoogle Scholar8. Young ME, Yan J, Razeghi P, Cooksey RC, Guthrie PH, Stepkowski SM, McClain DA, Tian R, Taegtmeyer H. Proposed regulation of gene expression by glucose in rodent heart.Gene Regul Syst Bio. 2007; 1:251–262.MedlineGoogle Scholar9. Belke DD. Swim-exercised mice show a decreased level of protein O-GlcNAcylation and expression of O-GlcNAc transferase in heart.J Appl Physiol (1985). 2011; 111:157–162.CrossrefMedlineGoogle Scholar10. Kanemoto S, Kondo S, Ogata M, Murakami T, Urano F, Imaizumi K. XBP1 activates the transcription of its target genes via an ACGT core sequence under ER stress.Biochem Biophys Res Commun. 2005; 331:1146–1153.CrossrefMedlineGoogle Scholar11. Acosta-Alvear D, Zhou Y, Blais A, Tsikitis M, Lents NH, Arias C, Lennon CJ, Kluger Y, Dynlacht BD. XBP1 controls diverse cell type- and condition-specific transcriptional regulatory networks.Mol Cell. 2007; 27:53–66.CrossrefMedlineGoogle Scholar12. Zachara NE. The roles of O-linked β-N-acetylglucosamine in cardiovascular physiology and disease.Am J Physiol Heart Circ Physiol. 2012; 302:H1905–H1918.CrossrefMedlineGoogle Scholar13. Fricovsky ES, Suarez J, Ihm SH, Scott BT, Suarez-Ramirez JA, Banerjee I, Torres-Gonzalez M, Wang H, Ellrott I, Maya-Ramos L, Villarreal F, Dillmann WH. Excess protein O-GlcNAcylation and the progression of diabetic cardiomyopathy.Am J Physiol Regul Integr Comp Physiol. 2012; 303:R689–R699.CrossrefMedlineGoogle Scholar14. Erickson JR, Pereira L, Wang L, Han G, Ferguson A, Dao K, Copeland RJ, Despa F, Hart GW, Ripplinger CM, Bers DM. Diabetic hyperglycaemia activates CaMKII and arrhythmias by O-linked glycosylation.Nature. 2013; 502:372–376.CrossrefMedlineGoogle Scholar15. Facundo HT, Brainard RE, Watson LJ, Ngoh GA, Hamid T, Prabhu SD, Jones SP. O-GlcNAc signaling is essential for NFAT-mediated transcriptional reprogramming during cardiomyocyte hypertrophy.Am J Physiol Heart Circ Physiol. 2012; 302:H2122–H2130.CrossrefMedlineGoogle Scholar16. Dassanayaka S, Jones SP. O-GlcNAc and the cardiovascular system.Pharmacol Ther. 2014; 142:62–71.CrossrefMedlineGoogle Scholar17. Watson LJ, Facundo HT, Ngoh GA, Ameen M, Brainard RE, Lemma KM, Long BW, Prabhu SD, Xuan YT, Jones SP. O-linked β-N-acetylglucosamine transferase is indispensable in the failing heart.Proc Natl Acad Sci USA. 2010; 107:17797–17802.CrossrefMedlineGoogle Scholar18. Denzel MS, Storm NJ, Gutschmidt A, Baddi R, Hinze Y, Jarosch E, Sommer T, Hoppe T, Antebi A. Hexosamine pathway metabolites enhance protein quality control and prolong life.Cell. 2014; 156:1167–1178.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Laviada-Molina H, Leal-Berumen I, Rodriguez-Ayala E and Bastarrachea R (2020) Working Hypothesis for Glucose Metabolism and SARS-CoV-2 Replication: Interplay Between the Hexosamine Pathway and Interferon RF5 Triggering Hyperinflammation. Role of BCG Vaccine?, Frontiers in Endocrinology, 10.3389/fendo.2020.00514, 11 Arrieta A, Blackwood E, Stauffer W, Santo Domingo M, Bilal A, Thuerauf D, Pentoney A, Aivati C, Sarakki A, Doroudgar S and Glembotski C (2020) Mesencephalic astrocyte–derived neurotrophic factor is an ER-resident chaperone that protects against reductive stress in the heart, Journal of Biological Chemistry, 10.1074/jbc.RA120.013345, 295:22, (7566-7583), Online publication date: 1-May-2020. Yan B, Wang H, Tan Y and Fu W microRNAs in Cardiovascular Disease: Small Molecules but Big Roles, Current Topics in Medicinal Chemistry, 10.2174/1568026619666190808160241, 19:21, (1918-1947) Zhang G, Wang X, Gillette T, Deng Y and Wang Z Unfolded Protein Response as a Therapeutic Target in Cardiovascular Disease, Current Topics in Medicinal Chemistry, 10.2174/1568026619666190521093049, 19:21, (1902-1917) Bi X, Zhang G, Wang X, Nguyen C, May H, Li X, Al-Hashimi A, Austin R, Gillette T, Fu G, Wang Z and Hill J (2018) Endoplasmic Reticulum Chaperone GRP78 Protects Heart From Ischemia/Reperfusion Injury Through Akt Activation, Circulation Research, 122:11, (1545-1554), Online publication date: 25-May-2018. Liu M and Dudley S (2015) Role for the Unfolded Protein Response in Heart Disease and Cardiac Arrhythmias, International Journal of Molecular Sciences, 10.3390/ijms17010052, 17:1, (52) Altamirano F, Wang Z and Hill J (2015) Cardioprotection in ischaemia-reperfusion injury: novel mechanisms and clinical translation, The Journal of Physiology, 10.1113/JP270953, 593:17, (3773-3788), Online publication date: 1-Sep-2015. Wang Z and Hill J (2015) Protein Quality Control and Metabolism: Bidirectional Control in the Heart, Cell Metabolism, 10.1016/j.cmet.2015.01.016, 21:2, (215-226), Online publication date: 1-Feb-2015. August 29, 2014Vol 115, Issue 6 Advertisement Article InformationMetrics © 2014 American Heart Association, Inc.https://doi.org/10.1161/CIRCRESAHA.114.304855PMID: 25170091 Originally publishedAugust 29, 2014 PDF download Advertisement" @default.
• W2154385611 created "2016-06-24" @default.
• W2154385611 creator A5048050187 @default.
• W2154385611 date "2014-08-29" @default.
• W2154385611 modified "2023-09-30" @default.
• W2154385611 title "Finding the Missing Link Between the Unfolded Protein Response and O-GlcNAcylation in the Heart" @default.
• W2154385611 cites W1975959667 @default.
• W2154385611 cites W1977603207 @default.
• W2154385611 cites W1981515291 @default.
• W2154385611 cites W2027655677 @default.
• W2154385611 cites W2028240468 @default.
• W2154385611 cites W2062383366 @default.
• W2154385611 cites W2067056774 @default.
• W2154385611 cites W2076651708 @default.
• W2154385611 cites W2078330387 @default.
• W2154385611 cites W2081098379 @default.
• W2154385611 cites W2083418232 @default.
• W2154385611 cites W2094005996 @default.
• W2154385611 cites W2101290341 @default.
• W2154385611 cites W2103296967 @default.
• W2154385611 cites W2109229232 @default.
• W2154385611 cites W2115088504 @default.
• W2154385611 cites W2150191367 @default.
• W2154385611 doi "https://doi.org/10.1161/circresaha.114.304855" @default.
• W2154385611 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/4153403" @default.
• W2154385611 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/25170091" @default.
• W2154385611 hasPublicationYear "2014" @default.
• W2154385611 type Work @default.
• W2154385611 sameAs 2154385611 @default.
• W2154385611 citedByCount "10" @default.
• W2154385611 countsByYear W21543856112015 @default.
• W2154385611 countsByYear W21543856112018 @default.
• W2154385611 countsByYear W21543856112019 @default.
• W2154385611 countsByYear W21543856112020 @default.
• W2154385611 countsByYear W21543856112022 @default.
• W2154385611 crossrefType "journal-article" @default.
• W2154385611 hasAuthorship W2154385611A5048050187 @default.
• W2154385611 hasBestOaLocation W21543856111 @default.
• W2154385611 hasConcept C126322002 @default.
• W2154385611 hasConcept C134018914 @default.
• W2154385611 hasConcept C139447449 @default.
• W2154385611 hasConcept C158617107 @default.
• W2154385611 hasConcept C164705383 @default.
• W2154385611 hasConcept C185592680 @default.
• W2154385611 hasConcept C2778753846 @default.
• W2154385611 hasConcept C31258907 @default.
• W2154385611 hasConcept C41008148 @default.
• W2154385611 hasConcept C71924100 @default.
• W2154385611 hasConcept C86803240 @default.
• W2154385611 hasConcept C95444343 @default.
• W2154385611 hasConceptScore W2154385611C126322002 @default.
• W2154385611 hasConceptScore W2154385611C134018914 @default.
• W2154385611 hasConceptScore W2154385611C139447449 @default.
• W2154385611 hasConceptScore W2154385611C158617107 @default.
• W2154385611 hasConceptScore W2154385611C164705383 @default.
• W2154385611 hasConceptScore W2154385611C185592680 @default.
• W2154385611 hasConceptScore W2154385611C2778753846 @default.
• W2154385611 hasConceptScore W2154385611C31258907 @default.
• W2154385611 hasConceptScore W2154385611C41008148 @default.
• W2154385611 hasConceptScore W2154385611C71924100 @default.
• W2154385611 hasConceptScore W2154385611C86803240 @default.
• W2154385611 hasConceptScore W2154385611C95444343 @default.
• W2154385611 hasIssue "6" @default.
• W2154385611 hasLocation W21543856111 @default.
• W2154385611 hasLocation W21543856112 @default.
• W2154385611 hasLocation W21543856113 @default.
• W2154385611 hasLocation W21543856114 @default.
• W2154385611 hasOpenAccess W2154385611 @default.
• W2154385611 hasPrimaryLocation W21543856111 @default.
• W2154385611 hasRelatedWork W1998895168 @default.
• W2154385611 hasRelatedWork W2003338675 @default.
• W2154385611 hasRelatedWork W2072667779 @default.
• W2154385611 hasRelatedWork W2081690197 @default.
• W2154385611 hasRelatedWork W2748952813 @default.
• W2154385611 hasRelatedWork W2894384976 @default.
• W2154385611 hasRelatedWork W3034337622 @default.
• W2154385611 hasRelatedWork W3142122528 @default.
• W2154385611 hasRelatedWork W4220756668 @default.
• W2154385611 hasRelatedWork W4311514635 @default.
• W2154385611 hasVolume "115" @default.
• W2154385611 isParatext "false" @default.
• W2154385611 isRetracted "false" @default.
• W2154385611 magId "2154385611" @default.
• W2154385611 workType "article" @default.