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• W2057365364 abstract "In the short history of the field of metalloprotease-disintegrin proteins, several fascinating and remarkably different paths of inquiry have converged on the discovery of new members of this protein family. About eight years ago, purification of a potent anticoagulant toxin and high-affinity integrin ligand from snake venom yielded the first sequence of a soluble disintegrin protein (8Huang T.F. Holt J.C. Kirby E.P. Niewiarowski S. Biochemistry. 1989; 28: 661-666Crossref PubMed Scopus (142) Google Scholar). A few years later, purification and cloning of the heterodimeric sperm protein fertilin, which had previously been implicated in sperm–egg fusion, revealed that both subunits are membrane-anchored metalloprotease-disintegrins (see5Blobel C.P. Wolfsberg T.G. Turck C.W. Myles D.G. Primakoff P. White J.M. Nature. 1992; 356: 248-252Crossref PubMed Scopus (604) Google Scholar, 15Wolfsberg T.G. White J.M. Dev. Biol. 1996; 180: 389-401Crossref PubMed Scopus (215) Google Scholar; and references therein). Subsequently, the metalloprotease-disintegrin meltrin α was linked to the process of muscle fusion in C2C12 myoblasts (16Yagami-Hiromasa T. Sato T. Kurisaki T. Kamijo K. Nabeshima Y. Fujisawa-Sehara A. Nature. 1995; 377: 652-656Crossref PubMed Scopus (432) Google Scholar). In Drosophila, two elegant genetic searches revealed that the metalloprotease-disintegrin Kuzbanian (KUZ) plays a role in promoting and inhibiting the neural cell fate at different stages of neurogenesis (12Rooke J. Pan D. Xu T. Rubin G.M. Science. 1996; 273: 1227-1230Crossref PubMed Scopus (293) Google Scholar) and in axonal extension (6Fambrough D. Pan D. Rubin G.M. Goodman C.S. Proc. Natl. Acad. Sci. USA. 1996; 93: 13233-13238Crossref PubMed Scopus (152) Google Scholar). Finally, metalloprotease-disintegrins are involved in cleaving at least two highly relevant substrates: the proinflammatory membrane–anchored cytokine tumor necrosis factor α (TNFα), which is released from the plasma membrane by the TNFα convertase (TACE; 3Black R. Rauch C.T. Kozlosky C.J. Peschon J.J. Slack J.L. Wolfson M.F. Castner B.J. Stocking K.L. Reddy P. Srinivasan S. et al.Nature. 1997; 385: 729-733Crossref PubMed Scopus (2555) Google Scholar, 9Moss M.L. Jin S.-L.C. Milla M.E. Burkhart W. Cartner H.L. Chen W.-J. Clay W.C. Didsbury J.R. Hassler D. Hoffman C.R. et al.Nature. 1997; 385: 733-736Crossref PubMed Scopus (1408) Google Scholar), and Drosophila Notch, which apparently is cleaved by KUZ as part of a pathway that mediates lateral inhibition of the neuronal cell fate (11Pan D. Rubin G.M. Cell. 1997; 90: 271-280Abstract Full Text Full Text PDF PubMed Scopus (345) Google Scholar). Metalloprotease-disintegrins are a family of membrane-anchored glycoproteins that are comprised of several distinct protein modules, including a pro- and metalloprotease domain, disintegrin domain, cysteine-rich region, and an EGF repeat (see Figure 1). The two most commonly used acronyms for members of this protein family reflect this unique domain structure: ADAM stands for isintegrin nd etalloprotease, and MDC, which will be used here, stands for etalloprotease/isintegrin/ysteine-rich protein. This minireview will focus mainly on the biochemical and functional concepts that have emerged from studies of the disintegrin domain and metalloprotease domain of different MDC proteins, and will highlight some of the questions that are now raised about the function of this intriguing protein family (for a comprehensive review and background references, see15Wolfsberg T.G. White J.M. Dev. Biol. 1996; 180: 389-401Crossref PubMed Scopus (215) Google Scholar). Most of the initial functional studies of membrane anchored metalloprotease-disintegrins centered on the potential role of the disintegrin domain in cell–cell interactions. The reasons for this focus were simple: (i) both subunits of fertilin on mature and fertilization-competent sperm lack a metalloprotease domain, and (ii) the smallest functional snake venom disintegrins consist only of a disintegrin domain (see Figure 1). Many short snake venom disintegrins contain the integrin ligand sequence RGD in a hairpin loop structure, which is a favorable conformation for high affinity binding to the platelet integrin αIIbβ3. Because all but one of the presently known MDC proteins do not contain an RGD sequence in their disintegrin domain, the sequence found in lieu of the snake venom RGD in MDC proteins has been proposed to act as an integrin binding sequence (5Blobel C.P. Wolfsberg T.G. Turck C.W. Myles D.G. Primakoff P. White J.M. Nature. 1992; 356: 248-252Crossref PubMed Scopus (604) Google Scholar, 15Wolfsberg T.G. White J.M. Dev. Biol. 1996; 180: 389-401Crossref PubMed Scopus (215) Google Scholar). The first support for this hypothesis came from a study in which a peptide corresponding to the predicted binding sequence of guinea pig fertilin β was shown to inhibit fertilization in a concentration-dependent manner, whereas a scrambled control peptide did not (10Myles D.G. Kimmel L.H. Blobel C.P. White J.M. Primakoff P. Proc. Natl. Acad. Sci. USA. 1994; 91: 4195-4198Crossref PubMed Scopus (230) Google Scholar). These results were later reproduced in mice, suggesting that fertilin β might indeed be involved in fertilization by binding to a receptor on the egg (reviewed by15Wolfsberg T.G. White J.M. Dev. Biol. 1996; 180: 389-401Crossref PubMed Scopus (215) Google Scholar). Two recent studies, one in mice (17Yuan R. Primakoff P. Myles D.G. J. Cell Biol. 1997; 137: 105-112Crossref PubMed Scopus (195) Google Scholar) and the second in Xenopus laevis (13Shilling F.M. Krätzschmar J. Cai H. Weskamp G. Gayko U. Leibow J. Myles D.G. Nuccitelli R. Blobel C.P. Dev. Biol. 1997; 186: 155-164Crossref PubMed Scopus (67) Google Scholar), go on to show that peptides designed to mimic the predicted integrin binding sequence of other MDC proteins besides fertilin β can also inhibit fertilization, suggesting that more than one MDC protein might be involved in fertilization. As an independent approach toward testing the function of MDC proteins in fertilization17Yuan R. Primakoff P. Myles D.G. J. Cell Biol. 1997; 137: 105-112Crossref PubMed Scopus (195) Google Scholar raised polyclonal anti-peptide antibodies against the predicted integrin binding sequence of the mouse sperm MDC proteins fertilin β and cyritestin. Antibodies against both proteins can inhibit fertilization and bind to sperm in indirect immunofluorescence experiments, thus providing the first clear evidence that the predicted binding sequence of an MDC protein is exposed and accessible on the cell surface. Although a direct interaction of a metalloprotease-disintegrin protein with an integrin remains to be shown, the combined peptide and antibody inhibition data support the hypothesis that the disintegrin domain of MDC proteins plays a role in cell–cell interactions, most likely by binding to an integrin. Integrins are expressed on mouse eggs, and since antibodies against the α6β1 integrin block fertilization in mice (1Almeida E.A.C. Huovila A.-P.J. Sutherland A.E. Stephens L.E. Calarco P.G. Shaw L.M. Mercurio A.M. Sonnenberg A. Primakoff P. Myles D.G. White J.M. Cell. 1995; 81: 1095-1104Abstract Full Text PDF PubMed Scopus (465) Google Scholar), this integrin is a candidate receptor for one or more sperm surface MDC proteins. Further research is needed to establish which sperm MDC protein(s) can bind to the α6β1 integrin, whether additional egg integrins are involved in fertilization by binding to MDC proteins or to ligands, and further what role the disintegrin domain of MDC proteins plays in somatic cell–cell interactions. In contrast to mature fertilin, where the metalloprotease domains have been removed during sperm maturation, most MDC proteins actually have a membrane-anchored metalloprotease and disintegrin domain. Only some MDC proteins have a metalloprotease domain with a catalytic site consensus sequence (HEXXH), indicating catalytic activity, whereas others do not, and are therefore not expected to be catalytically active. Two major breakthroughs have now linked the metalloprotease activity of different MDC proteins to critical physiological functions. The first was the report that TACE, which was independently identified by two groups, is an MDC protein (3Black R. Rauch C.T. Kozlosky C.J. Peschon J.J. Slack J.L. Wolfson M.F. Castner B.J. Stocking K.L. Reddy P. Srinivasan S. et al.Nature. 1997; 385: 729-733Crossref PubMed Scopus (2555) Google Scholar, 9Moss M.L. Jin S.-L.C. Milla M.E. Burkhart W. Cartner H.L. Chen W.-J. Clay W.C. Didsbury J.R. Hassler D. Hoffman C.R. et al.Nature. 1997; 385: 733-736Crossref PubMed Scopus (1408) Google Scholar). The second is that Drosophila KUZ apparently is responsible for a cleavage in the extracellular domain of Notch, which can explain how KUZ functions in lateral inhibition (11Pan D. Rubin G.M. Cell. 1997; 90: 271-280Abstract Full Text Full Text PDF PubMed Scopus (345) Google Scholar; see below). Interest in TACE has been fueled in part by the desire to block the release of the membrane-anchored proinflammatory cytokine TNFα from the plasma membrane with protease inhibitors, which might be useful to treat human diseases such as rheumathoid arthritis, cachexia, and Crohn's disease. Both 9Moss M.L. Jin S.-L.C. Milla M.E. Burkhart W. Cartner H.L. Chen W.-J. Clay W.C. Didsbury J.R. Hassler D. Hoffman C.R. et al.Nature. 1997; 385: 733-736Crossref PubMed Scopus (1408) Google Scholar and 3Black R. Rauch C.T. Kozlosky C.J. Peschon J.J. Slack J.L. Wolfson M.F. Castner B.J. Stocking K.L. Reddy P. Srinivasan S. et al.Nature. 1997; 385: 729-733Crossref PubMed Scopus (2555) Google Scholar used a peptide cleavage assay and a TNFα conversion assay to monitor purification of TACE, and ultimately cloned the same metalloprotease-disintegrin gene. To confirm the identity of the cloned gene9Moss M.L. Jin S.-L.C. Milla M.E. Burkhart W. Cartner H.L. Chen W.-J. Clay W.C. Didsbury J.R. Hassler D. Hoffman C.R. et al.Nature. 1997; 385: 733-736Crossref PubMed Scopus (1408) Google Scholar demonstrated that the expressed metalloprotease was able to process a TNFα peptide correctly and had a comparable protease inhibitor spectrum and specificity constants as the native enzyme. 3Black R. Rauch C.T. Kozlosky C.J. Peschon J.J. Slack J.L. Wolfson M.F. Castner B.J. Stocking K.L. Reddy P. Srinivasan S. et al.Nature. 1997; 385: 729-733Crossref PubMed Scopus (2555) Google Scholar generated chimeric mice with an embryonic stem cell line that was homozygous for a mutant mouse TACE and showed that mutant T cells, isolated with a cell sorter, lacked the metalloprotease activity that releases TNFα. It should be noted that only the exon carrying the catalytic site was deleted in the TACE mutant stem cell line. This will clearly abolish the metalloprotease activity of TACE but may also result in the expression of a mutant protein that could conceivably function as a dominant negative, or have other epigenetic effects. Nonetheless, the independent isolation of the same protein as the TNFα-converting metalloprotease by two different groups, and the controls for specificity outlined above, provide very compelling evidence that TACE is indeed the protease that processes TNFα. These findings immediately raise the intriguing question of whether other MDC proteins besides TACE are involved in protein ectodomain shedding. Currently a number of proteins are known to be released from the plasma membrane by yet-to-be-identified membrane-anchored metalloproteases. These proteins include cytokines such as the kit-ligand, TGFα, Fas-ligand, cytokine receptors such as the IL-6 receptor and the NGF receptor, as well as adhesion proteins such as L-selectin, and the β amyloid precursor protein (see2Arribas J. Coodly L. Vollmer P. Kishimoto T.K. Rose-John S. Massagué J. J. Biol. Chem. 1996; 271: 11376-11382Crossref PubMed Scopus (357) Google Scholar, 3Black R. Rauch C.T. Kozlosky C.J. Peschon J.J. Slack J.L. Wolfson M.F. Castner B.J. Stocking K.L. Reddy P. Srinivasan S. et al.Nature. 1997; 385: 729-733Crossref PubMed Scopus (2555) Google Scholar, 7Hooper N.M. Karran E.H. Turner A.J. Biochem. J. 1997; 321: 265-279Crossref PubMed Scopus (552) Google Scholar, 9Moss M.L. Jin S.-L.C. Milla M.E. Burkhart W. Cartner H.L. Chen W.-J. Clay W.C. Didsbury J.R. Hassler D. Hoffman C.R. et al.Nature. 1997; 385: 733-736Crossref PubMed Scopus (1408) Google Scholar; and references therein). In a remarkable experiment that shows just how prevalent protein ectodomain shedding is2Arribas J. Coodly L. Vollmer P. Kishimoto T.K. Rose-John S. Massagué J. J. Biol. Chem. 1996; 271: 11376-11382Crossref PubMed Scopus (357) Google Scholar have demonstrated that metalloprotease activities on CHO cells release a number of cell surface proteins ranging from 30 to 200 kDa when they are stimulated with PMA. Arribas et al. have also isolated two mutant CHO cell lines that have a general defect in this PMA-triggered protein ectodomain shedding, but no other detectable defects, such as in protein secretion or maturation of membrane proteins, or in PKC-dependent phosphorylation. Cell fusions between the two mutant cell lines do not rescue the shedding defect, whereas fusion of each cell line with wild-type cells does, leading the authors to hypothesize that the defect is in a factor that is required for protein ectodomain shedding in general. Based on the identification of TACE, membrane- anchored MDC proteins with a metalloprotease consensus sequence are the best candidate proteins for the role of protein ectodomain sheddases. While the defect of the mutant cell lines is currently not clear, it is intriguing to consider what the nature of this factor might be. Two possibilities are a protease that is necessary to activate protein ectodomain sheddases or a protein which is in a pathway that regulates the activity of these metalloproteases. Several MDC proteins contain cytoplasmic signaling motifs such as PKC phosphorylation sites and SH3 ligand domains (14Weskamp G. Krätzschmar J.R. Reid M. Blobel C.P. J. Cell Biol. 1996; 132: 717-726Crossref PubMed Scopus (181) Google Scholar, 15Wolfsberg T.G. White J.M. Dev. Biol. 1996; 180: 389-401Crossref PubMed Scopus (215) Google Scholar) and could therefore conceivably be activated by PKC or other means of inside-out regulation. Why are such functionally distinct protein modules as a metalloprotease domain and a disintegrin domain combined in MDC proteins? With respect to the metalloprotease functions, one possibility is that the disintegrin domain might be used to target the metalloprotease to another cell in trans via an integrin (see Figure 1). Alternatively, the disintegrin domain, or other protein domains such as the EGF repeat or cysteine-rich region, might be used to increase the efficiency of the protease by binding the substrate directly or indirectly in cis or in trans. It is also possible that removal of the metalloprotease domain may be used to regulate the function of the disintegrin domain, as suggested by two independent studies. In sperm fertilin β, removal of the noncatalytic metalloprotease-domain during sperm maturation correlates with the acquisition of fertilization competence and exposes an epitope that is recognized by a function-blocking monoclonal antibody. For meltrin α, which plays a role in muscle fusion, overexpression of a truncated form of the protein lacking the metalloprotease domain leads to an increase in muscle fusion, whereas overexpression of the full-length protein leads to a decrease in the observed fusion (16Yagami-Hiromasa T. Sato T. Kurisaki T. Kamijo K. Nabeshima Y. Fujisawa-Sehara A. Nature. 1995; 377: 652-656Crossref PubMed Scopus (432) Google Scholar). Since only a small percentage of the detectable meltrin α lacks the metalloprotease domain in C2C12 mouse myoblasts, one interesting possibility is that only this small pool of processed protein may promote muscle cell binding and fusion. MDC proteins have been proposed to mediate cell–cell fusion directly (see15Wolfsberg T.G. White J.M. Dev. Biol. 1996; 180: 389-401Crossref PubMed Scopus (215) Google Scholar, for details), although it should be noted that the studies that point toward a role of fertilin and meltrin α in membrane fusion can also be explained by simply invoking a critical binding step via the disintegrin domain that is a prerequisite for fusion to occur. The concepts of targeting the metalloprotease domain via the disintegrin domain and modulation of the disintegrin domain function by removal of the metalloprotease domain illustrate two of several conceivable means of MDC protein regulation that are not necessarily mutually exclusive. Different MDC proteins may employ these protein modules in different ways, and any particular protein might also have distinct functions depending on the stage of development, the tissue, or even the subcellular localization that it is expressed in. The Drosophila metalloprotease-disintegrin KUZ, which is currently the only MDC protein for which a mutant phenotype has been reported, is required in the early embryo for neural inhibition, and is later involved in eye development, neural-promoting and -inhibiting processes (12Rooke J. Pan D. Xu T. Rubin G.M. Science. 1996; 273: 1227-1230Crossref PubMed Scopus (293) Google Scholar), and axon extension (6Fambrough D. Pan D. Rubin G.M. Goodman C.S. Proc. Natl. Acad. Sci. USA. 1996; 93: 13233-13238Crossref PubMed Scopus (152) Google Scholar). A fascinating indication for a potentially distinct mechanism of the neural promoting and inhibiting activity mediated by KUZ is described by 12Rooke J. Pan D. Xu T. Rubin G.M. Science. 1996; 273: 1227-1230Crossref PubMed Scopus (293) Google Scholar. In the cuticle of adult mosaic Drosophila, clusters of sensory bristles appear at the boundary of kuz− and wildtype cells instead of the single sensory bristle that normally develops, whereas no sensory bristles are found in the interior of a mutant cell patch. Apparently a non-cell-autonomous neural-promoting signal can be supplied to the mutant cells by adjacent wildtype cells, and not by kuz− cells. Yet once kuz− cells have adopted a neural fate, they are unable to laterally inhibit the neural fate of other mutant cells, resulting in the formation of additional bristles only at the boundary of the mutant cell patch. 11Pan D. Rubin G.M. Cell. 1997; 90: 271-280Abstract Full Text Full Text PDF PubMed Scopus (345) Google Scholar have now provided strong genetic and biochemical evidence that the lateral inhibition mediated by KUZ involves a specific cleavage event in the extracellular domain of the transmembrane receptor Notch. Cleavage of Notch receptors in the extracellular domain appears to be an evolutionarily conserved feature, and the subcellular location of human Notch2 processing has been narrowed down to the trans-Golgi network (4Blaumueller C.M. Qi H. Zagouras P. Artavanis-Tsakonas S. Cell. 1997; 90: 281-291Abstract Full Text Full Text PDF PubMed Scopus (474) Google Scholar). Processing of the full-length ∼300 kDa human Notch2 yields a 110 kDa fragment containing the transmembrane domain and cytoplasmic tail, and a disulfide-linked 180 kDa fragment that most likely corresponds to the extracellular domain. Cell surface labeling experiments indicate that only cleaved but not full-length Notch2 emerges on the cell surface. The cleaved 110 kDa membrane-anchored fragment of human Notch2 resembles the ∼100 kDa processed form of Drosophila Notch. Since the ∼100 kDa form of Notch is not detectable in kuz− embryos11Pan D. Rubin G.M. Cell. 1997; 90: 271-280Abstract Full Text Full Text PDF PubMed Scopus (345) Google Scholar propose that KUZ mediates the extracellular cleavage of Notch and that this cleavage is necessary for Notch to mediate lateral inhibition. Taken together, the two papers support a model where KUZ or its mammalian homolog MDC/ADAM10 is responsible for maturation and functional activation of Notch receptors in the secretory pathway (4Blaumueller C.M. Qi H. Zagouras P. Artavanis-Tsakonas S. Cell. 1997; 90: 281-291Abstract Full Text Full Text PDF PubMed Scopus (474) Google Scholar, 11Pan D. Rubin G.M. Cell. 1997; 90: 271-280Abstract Full Text Full Text PDF PubMed Scopus (345) Google Scholar). It should be noted that the extracellular domain cleavage of Notch discussed here is distinct from a putative cytoplasmic cleavage that might allow the cytoplasmic domain to enter the nucleus (4Blaumueller C.M. Qi H. Zagouras P. Artavanis-Tsakonas S. Cell. 1997; 90: 281-291Abstract Full Text Full Text PDF PubMed Scopus (474) Google Scholar). If the processing of Notch receptors is evolutionarily conserved, then one might expect the Notch processing protease to be functionally conserved as well. Indeed11Pan D. Rubin G.M. Cell. 1997; 90: 271-280Abstract Full Text Full Text PDF PubMed Scopus (345) Google Scholar show that expression of a mouse dominant negative KUZ lacking the metalloprotease domain (KUZDN) in both Drosophila and Xenopus laevis results in an increased number of neurogenic cells, presumably due to a lack of lateral inhibition. Furthermore, expression of a Drosophila KUZDN in Drosophila neurons mimics the defect in axon extension reported by 6Fambrough D. Pan D. Rubin G.M. Goodman C.S. Proc. Natl. Acad. Sci. USA. 1996; 93: 13233-13238Crossref PubMed Scopus (152) Google Scholar, confirming the idea that the metalloprotease domain of KUZ, as opposed to other domains, is responsible for axon extension. The substrates of KUZ during axonal extension have not been identified but could be different from Notch, such as matrix proteins or cytokines. In conclusion, it is clear that metalloprotease-disintegrins are involved in a remarkably diverse set of tasks, ranging from a role in fertilization and muscle fusion, TNFα release from the plasma membrane, intracellular cleavage and activation of Notch, and other essential functions in Drosophila development. The nature of these diverse tasks further suggests that MDC proteins may function at different subcellular locations, such as on the cell surface (fertilin, TACE?), or intracellularly in the secretory pathway (KUZ?). It seems likely that the proteins discussed here, and the more than 20 family members of presently unknown function, which have been found in organisms ranging from C. elegans to mammals (references can be found in15Wolfsberg T.G. White J.M. Dev. Biol. 1996; 180: 389-401Crossref PubMed Scopus (215) Google Scholar) will unveil further exciting secrets. Due to an increasing interest in MDC proteins, a better understanding should soon begin to emerge about the mechanism of MDC protein function, of the specific functions of different family members in development and disease, and of the interactions with other proteins that govern MDC protein activity." @default.
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• W2057365364 title "Metalloprotease-Disintegrins: Links to Cell Adhesion and Cleavage of TNFα and Notch" @default.
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