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. 1998 Oct 15;17(20):5923–5932. doi: 10.1093/emboj/17.20.5923

Gelsolin and functionally similar actin-binding proteins are regulated by lysophosphatidic acid.

K Meerschaert 1, V De Corte 1, Y De Ville 1, J Vandekerckhove 1, J Gettemans 1
PMCID: PMC1170920  PMID: 9774337

Abstract

An extensive survey was carried out for compounds capable of regulating actin-binding proteins in a manner similar to phosphatidylinositol 4,5 bisphosphate (PI 4,5-P2). For this purpose we developed a sensitive assay involving release of radioactively phosphorylated actin from the fragminP-actin complex. We found that the structurally simplest lysophospholipid, lysophosphatidic acid (LPA), dissociated the complex between fragminP and actin, whereas other lysophospholipids or sphingosine-1-phosphate were inactive. Furthermore, LPA inhibited the F-actin severing activity of human gelsolin, purified from plasma or as recombinant protein, mouse adseverin and Physarum fragminP. Dissociation of actin-containing complexes by LPA analyzed by gelfiltration indicated that LPA is active as a monomer, in contrast to PI 4,5-P2. We further show that binding of LPA to these actin-regulatory proteins promotes their phosphorylation by pp60(c-src). A PI 4,5-P2-binding peptide counteracted the effects mediated by LPA, suggesting that LPA binds to the same target region in these actin-binding proteins. When both LPA and PI 4,5-P2 were used in combination we found that LPA reduced the threshold concentration at which PI 4,5-P2 was active. Significantly, LPA promoted the release of gelsolin from barbed actin filaments in octylglucoside-permeabilized human platelets. These results suggest that lysophosphatidic acid could act as an intracellular modulator of actin-binding proteins. Our findings can also explain agonist-induced changes in the actin cytoskeleton that are not mediated by polyphosphoinositides.

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Selected References

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  1. Ahmed S., Lee J., Kozma R., Best A., Monfries C., Lim L. A novel functional target for tumor-promoting phorbol esters and lysophosphatidic acid. The p21rac-GTPase activating protein n-chimaerin. J Biol Chem. 1993 May 25;268(15):10709–10712. [PubMed] [Google Scholar]
  2. An S., Dickens M. A., Bleu T., Hallmark O. G., Goetzl E. J. Molecular cloning of the human Edg2 protein and its identification as a functional cellular receptor for lysophosphatidic acid. Biochem Biophys Res Commun. 1997 Feb 24;231(3):619–622. doi: 10.1006/bbrc.1997.6150. [DOI] [PubMed] [Google Scholar]
  3. André E., Lottspeich F., Schleicher M., Noegel A. Severin, gelsolin, and villin share a homologous sequence in regions presumed to contain F-actin severing domains. J Biol Chem. 1988 Jan 15;263(2):722–727. [PubMed] [Google Scholar]
  4. Arcaro A. The small GTP-binding protein Rac promotes the dissociation of gelsolin from actin filaments in neutrophils. J Biol Chem. 1998 Jan 9;273(2):805–813. doi: 10.1074/jbc.273.2.805. [DOI] [PubMed] [Google Scholar]
  5. Ardlie N. G., Packham M. A., Mustard J. F. Adenosine diphosphate-induced platelet aggregation in suspensions of washed rabbit platelets. Br J Haematol. 1970 Jul;19(1):7–17. doi: 10.1111/j.1365-2141.1970.tb01596.x. [DOI] [PubMed] [Google Scholar]
  6. Arpin M., Pringault E., Finidori J., Garcia A., Jeltsch J. M., Vandekerckhove J., Louvard D. Sequence of human villin: a large duplicated domain homologous with other actin-severing proteins and a unique small carboxy-terminal domain related to villin specificity. J Cell Biol. 1988 Nov;107(5):1759–1766. doi: 10.1083/jcb.107.5.1759. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Barkalow K., Witke W., Kwiatkowski D. J., Hartwig J. H. Coordinated regulation of platelet actin filament barbed ends by gelsolin and capping protein. J Cell Biol. 1996 Jul;134(2):389–399. doi: 10.1083/jcb.134.2.389. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Bengtsson T., Rundquist I., Stendahl O., Wymann M. P., Andersson T. Increased breakdown of phosphatidylinositol 4,5-bisphosphate is not an initiating factor for actin assembly in human neutrophils. J Biol Chem. 1988 Nov 25;263(33):17385–17389. [PubMed] [Google Scholar]
  9. Benton A. M., Gerrard J. M., Michiel T., Kindom S. E. Are lysophosphatidic acids or phosphatidic acids involved in stimulus activation coupling in platelets? Blood. 1982 Sep;60(3):642–649. [PubMed] [Google Scholar]
  10. Bradford M. M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976 May 7;72:248–254. doi: 10.1016/0003-2697(76)90527-3. [DOI] [PubMed] [Google Scholar]
  11. Brenner S. L., Korn E. D. On the mechanism of actin monomer-polymer subunit exchange at steady state. J Biol Chem. 1983 Apr 25;258(8):5013–5020. [PubMed] [Google Scholar]
  12. Chellaiah M., Hruska K. Osteopontin stimulates gelsolin-associated phosphoinositide levels and phosphatidylinositol triphosphate-hydroxyl kinase. Mol Biol Cell. 1996 May;7(5):743–753. doi: 10.1091/mbc.7.5.743. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Chettibi S., Lawrence A. J., Stevenson R. D., Young J. D. Effect of lysophosphatidic acid on motility, polarisation and metabolic burst of human neutrophils. FEMS Immunol Med Microbiol. 1994 Mar;8(3):271–281. doi: 10.1111/j.1574-695X.1994.tb00452.x. [DOI] [PubMed] [Google Scholar]
  14. Cooper J. A., Bryan J., Schwab B., 3rd, Frieden C., Loftus D. J., Elson E. L. Microinjection of gelsolin into living cells. J Cell Biol. 1987 Mar;104(3):491–501. doi: 10.1083/jcb.104.3.491. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Cuvillier O., Rosenthal D. S., Smulson M. E., Spiegel S. Sphingosine 1-phosphate inhibits activation of caspases that cleave poly(ADP-ribose) polymerase and lamins during Fas- and ceramide-mediated apoptosis in Jurkat T lymphocytes. J Biol Chem. 1998 Jan 30;273(5):2910–2916. doi: 10.1074/jbc.273.5.2910. [DOI] [PubMed] [Google Scholar]
  16. Dadabay C. Y., Patton E., Cooper J. A., Pike L. J. Lack of correlation between changes in polyphosphoinositide levels and actin/gelsolin complexes in A431 cells treated with epidermal growth factor. J Cell Biol. 1991 Mar;112(6):1151–1156. doi: 10.1083/jcb.112.6.1151. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Das A. K., Hajra A. K. Critical micellar concentrations of palmitoyl dehydroxyacetone phosphate and 1-palmitoyl-rac-glycerol 3-phosphate. J Biol Chem. 1992 May 15;267(14):9731–9731. [PubMed] [Google Scholar]
  18. De Corte V., Gettemans J., Vandekerckhove J. Phosphatidylinositol 4,5-bisphosphate specifically stimulates PP60(c-src) catalyzed phosphorylation of gelsolin and related actin-binding proteins. FEBS Lett. 1997 Jan 20;401(2-3):191–196. doi: 10.1016/s0014-5793(96)01471-8. [DOI] [PubMed] [Google Scholar]
  19. De Corte V., Gettemans J., Waelkens E., Vandekerckhove J. In vivo phosphorylation of actin in Physarum polycephalum. Study of the substrate specificity of the actin-fragmin kinase. Eur J Biochem. 1996 Nov 1;241(3):901–908. doi: 10.1111/j.1432-1033.1996.00901.x. [DOI] [PubMed] [Google Scholar]
  20. Eberle M., Traynor-Kaplan A. E., Sklar L. A., Norgauer J. Is there a relationship between phosphatidylinositol trisphosphate and F-actin polymerization in human neutrophils? J Biol Chem. 1990 Oct 5;265(28):16725–16728. [PubMed] [Google Scholar]
  21. Eichholtz T., Jalink K., Fahrenfort I., Moolenaar W. H. The bioactive phospholipid lysophosphatidic acid is released from activated platelets. Biochem J. 1993 May 1;291(Pt 3):677–680. doi: 10.1042/bj2910677. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Eichinger L., Bomblies L., Vandekerckhove J., Schleicher M., Gettemans J. A novel type of protein kinase phosphorylates actin in the actin-fragmin complex. EMBO J. 1996 Oct 15;15(20):5547–5556. [PMC free article] [PubMed] [Google Scholar]
  23. Fourcade O., Simon M. F., Viodé C., Rugani N., Leballe F., Ragab A., Fournié B., Sarda L., Chap H. Secretory phospholipase A2 generates the novel lipid mediator lysophosphatidic acid in membrane microvesicles shed from activated cells. Cell. 1995 Mar 24;80(6):919–927. doi: 10.1016/0092-8674(95)90295-3. [DOI] [PubMed] [Google Scholar]
  24. Fukami K., Takenawa T. Phosphatidic acid that accumulates in platelet-derived growth factor-stimulated Balb/c 3T3 cells is a potential mitogenic signal. J Biol Chem. 1992 Jun 5;267(16):10988–10993. [PubMed] [Google Scholar]
  25. Gettemans J., De Ville Y., Vandekerckhove J., Waelkens E. Physarum actin is phosphorylated as the actin-fragmin complex at residues Thr203 and Thr202 by a specific 80 kDa kinase. EMBO J. 1992 Sep;11(9):3185–3191. doi: 10.1002/j.1460-2075.1992.tb05395.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Gettemans J., De Ville Y., Vandekerckhove J., Waelkens E. Purification and partial amino acid sequence of the actin-fragmin kinase from Physarum polycephalum. Eur J Biochem. 1993 May 15;214(1):111–119. doi: 10.1111/j.1432-1033.1993.tb17902.x. [DOI] [PubMed] [Google Scholar]
  27. Gettemans J., De Ville Y., Waelkens E., Vandekerckhove J. The actin-binding properties of the Physarum actin-fragmin complex. Regulation by calcium, phospholipids, and phosphorylation. J Biol Chem. 1995 Feb 10;270(6):2644–2651. doi: 10.1074/jbc.270.6.2644. [DOI] [PubMed] [Google Scholar]
  28. Goldschmidt-Clermont P. J., Machesky L. M., Baldassare J. J., Pollard T. D. The actin-binding protein profilin binds to PIP2 and inhibits its hydrolysis by phospholipase C. Science. 1990 Mar 30;247(4950):1575–1578. doi: 10.1126/science.2157283. [DOI] [PubMed] [Google Scholar]
  29. Guo Z., Liliom K., Fischer D. J., Bathurst I. C., Tomei L. D., Kiefer M. C., Tigyi G. Molecular cloning of a high-affinity receptor for the growth factor-like lipid mediator lysophosphatidic acid from Xenopus oocytes. Proc Natl Acad Sci U S A. 1996 Dec 10;93(25):14367–14372. doi: 10.1073/pnas.93.25.14367. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Hartwig J. H., Bokoch G. M., Carpenter C. L., Janmey P. A., Taylor L. A., Toker A., Stossel T. P. Thrombin receptor ligation and activated Rac uncap actin filament barbed ends through phosphoinositide synthesis in permeabilized human platelets. Cell. 1995 Aug 25;82(4):643–653. doi: 10.1016/0092-8674(95)90036-5. [DOI] [PubMed] [Google Scholar]
  31. Hecht J. H., Weiner J. A., Post S. R., Chun J. Ventricular zone gene-1 (vzg-1) encodes a lysophosphatidic acid receptor expressed in neurogenic regions of the developing cerebral cortex. J Cell Biol. 1996 Nov;135(4):1071–1083. doi: 10.1083/jcb.135.4.1071. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Jalink K., van Corven E. J., Moolenaar W. H. Lysophosphatidic acid, but not phosphatidic acid, is a potent Ca2(+)-mobilizing stimulus for fibroblasts. Evidence for an extracellular site of action. J Biol Chem. 1990 Jul 25;265(21):12232–12239. [PubMed] [Google Scholar]
  33. Janmey P. A., Iida K., Yin H. L., Stossel T. P. Polyphosphoinositide micelles and polyphosphoinositide-containing vesicles dissociate endogenous gelsolin-actin complexes and promote actin assembly from the fast-growing end of actin filaments blocked by gelsolin. J Biol Chem. 1987 Sep 5;262(25):12228–12236. [PubMed] [Google Scholar]
  34. Janmey P. A., Lamb J., Allen P. G., Matsudaira P. T. Phosphoinositide-binding peptides derived from the sequences of gelsolin and villin. J Biol Chem. 1992 Jun 15;267(17):11818–11823. [PubMed] [Google Scholar]
  35. Janmey P. A. Phosphoinositides and calcium as regulators of cellular actin assembly and disassembly. Annu Rev Physiol. 1994;56:169–191. doi: 10.1146/annurev.ph.56.030194.001125. [DOI] [PubMed] [Google Scholar]
  36. Janmey P. A., Stossel T. P. Modulation of gelsolin function by phosphatidylinositol 4,5-bisphosphate. Nature. 1987 Jan 22;325(6102):362–364. doi: 10.1038/325362a0. [DOI] [PubMed] [Google Scholar]
  37. Laemmli U. K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. doi: 10.1038/227680a0. [DOI] [PubMed] [Google Scholar]
  38. Lauener R., Shen Y., Duronio V., Salari H. Selective inhibition of phosphatidylinositol 3-kinase by phosphatidic acid and related lipids. Biochem Biophys Res Commun. 1995 Oct 4;215(1):8–14. doi: 10.1006/bbrc.1995.2427. [DOI] [PubMed] [Google Scholar]
  39. Lee M. J., Van Brocklyn J. R., Thangada S., Liu C. H., Hand A. R., Menzeleev R., Spiegel S., Hla T. Sphingosine-1-phosphate as a ligand for the G protein-coupled receptor EDG-1. Science. 1998 Mar 6;279(5356):1552–1555. doi: 10.1126/science.279.5356.1552. [DOI] [PubMed] [Google Scholar]
  40. Lin K. M., Wenegieme E., Lu P. J., Chen C. S., Yin H. L. Gelsolin binding to phosphatidylinositol 4,5-bisphosphate is modulated by calcium and pH. J Biol Chem. 1997 Aug 15;272(33):20443–20450. doi: 10.1074/jbc.272.33.20443. [DOI] [PubMed] [Google Scholar]
  41. Low M. G., Huang K. S. Phosphatidic acid, lysophosphatidic acid, and lipid A are inhibitors of glycosylphosphatidylinositol-specific phospholipase D. Specific inhibition of a phospholipase by product analogues? J Biol Chem. 1993 Apr 25;268(12):8480–8490. [PubMed] [Google Scholar]
  42. Lu P. J., Shieh W. R., Rhee S. G., Yin H. L., Chen C. S. Lipid products of phosphoinositide 3-kinase bind human profilin with high affinity. Biochemistry. 1996 Nov 5;35(44):14027–14034. doi: 10.1021/bi961878z. [DOI] [PubMed] [Google Scholar]
  43. Matsudaira P. T., Burgess D. R. SDS microslab linear gradient polyacrylamide gel electrophoresis. Anal Biochem. 1978 Jul 1;87(2):386–396. doi: 10.1016/0003-2697(78)90688-7. [DOI] [PubMed] [Google Scholar]
  44. Meyer zu Heringdorf D., Lass H., Alemany R., Laser K. T., Neumann E., Zhang C., Schmidt M., Rauen U., Jakobs K. H., van Koppen C. J. Sphingosine kinase-mediated Ca2+ signalling by G-protein-coupled receptors. EMBO J. 1998 May 15;17(10):2830–2837. doi: 10.1093/emboj/17.10.2830. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Moolenaar W. H., Kranenburg O., Postma F. R., Zondag G. C. Lysophosphatidic acid: G-protein signalling and cellular responses. Curr Opin Cell Biol. 1997 Apr;9(2):168–173. doi: 10.1016/s0955-0674(97)80059-2. [DOI] [PubMed] [Google Scholar]
  46. Moolenaar W. H. Lysophosphatidic acid, a multifunctional phospholipid messenger. J Biol Chem. 1995 Jun 2;270(22):12949–12952. doi: 10.1074/jbc.270.22.12949. [DOI] [PubMed] [Google Scholar]
  47. Olivera A., Spiegel S. Sphingosine-1-phosphate as second messenger in cell proliferation induced by PDGF and FCS mitogens. Nature. 1993 Oct 7;365(6446):557–560. doi: 10.1038/365557a0. [DOI] [PubMed] [Google Scholar]
  48. Peppelenbosch M. P., Tertoolen L. G., den Hertog J., de Laat S. W. Epidermal growth factor activates calcium channels by phospholipase A2/5-lipoxygenase-mediated leukotriene C4 production. Cell. 1992 Apr 17;69(2):295–303. doi: 10.1016/0092-8674(92)90410-e. [DOI] [PubMed] [Google Scholar]
  49. Rani C. S., Wang F., Fuior E., Berger A., Wu J., Sturgill T. W., Beitner-Johnson D., LeRoith D., Varticovski L., Spiegel S. Divergence in signal transduction pathways of platelet-derived growth factor (PDGF) and epidermal growth factor (EGF) receptors. Involvement of sphingosine 1-phosphate in PDGF but not EGF signaling. J Biol Chem. 1997 Apr 18;272(16):10777–10783. doi: 10.1074/jbc.272.16.10777. [DOI] [PubMed] [Google Scholar]
  50. Robbens J., Louahed J., De Pestel K., Van Colen I., Ampe C., Vandekerckhove J., Renauld J. C. Murine adseverin (D5), a novel member of the gelsolin family, and murine adseverin are induced by interleukin-9 in T-helper lymphocytes. Mol Cell Biol. 1998 Aug;18(8):4589–4596. doi: 10.1128/mcb.18.8.4589. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Sando J. J., Chertihin O. I. Activation of protein kinase C by lysophosphatidic acid: dependence on composition of phospholipid vesicles. Biochem J. 1996 Jul 15;317(Pt 2):583–588. doi: 10.1042/bj3170583. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Singh S. S., Chauhan A., Murakami N., Chauhan V. P. Profilin and gelsolin stimulate phosphatidylinositol 3-kinase activity. Biochemistry. 1996 Dec 24;35(51):16544–16549. doi: 10.1021/bi9609634. [DOI] [PubMed] [Google Scholar]
  53. Spudich J. A., Watt S. The regulation of rabbit skeletal muscle contraction. I. Biochemical studies of the interaction of the tropomyosin-troponin complex with actin and the proteolytic fragments of myosin. J Biol Chem. 1971 Aug 10;246(15):4866–4871. [PubMed] [Google Scholar]
  54. Stossel T. P. On the crawling of animal cells. Science. 1993 May 21;260(5111):1086–1094. doi: 10.1126/science.8493552. [DOI] [PubMed] [Google Scholar]
  55. Svetlov S., Nigam S. Evidence for the presence of specific high affinity cytosolic binding sites for platelet-activating factor in human neutrophils. Biochem Biophys Res Commun. 1993 Jan 15;190(1):162–166. doi: 10.1006/bbrc.1993.1025. [DOI] [PubMed] [Google Scholar]
  56. T'Jampens D., Meerschaert K., Constantin B., Bailey J., Cook L. J., De Corte V., De Mol H., Goethals M., Van Damme J., Vandekerckhove J. Molecular cloning, over-expression, developmental regulation and immunolocalization of fragminP, a gelsolin-related actin-binding protein from Physarum polycephalum plasmodia. J Cell Sci. 1997 May;110(Pt 10):1215–1226. doi: 10.1242/jcs.110.10.1215. [DOI] [PubMed] [Google Scholar]
  57. Toker A., Cantley L. C. Signalling through the lipid products of phosphoinositide-3-OH kinase. Nature. 1997 Jun 12;387(6634):673–676. doi: 10.1038/42648. [DOI] [PubMed] [Google Scholar]
  58. Towbin H., Staehelin T., Gordon J. Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. Proc Natl Acad Sci U S A. 1979 Sep;76(9):4350–4354. doi: 10.1073/pnas.76.9.4350. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Tsai M. H., Hall A., Stacey D. W. Inhibition by phospholipids of the interaction between R-ras, rho, and their GTPase-activating proteins. Mol Cell Biol. 1989 Nov;9(11):5260–5264. doi: 10.1128/mcb.9.11.5260. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Van Brocklyn J. R., Lee M. J., Menzeleev R., Olivera A., Edsall L., Cuvillier O., Thomas D. M., Coopman P. J., Thangada S., Liu C. H. Dual actions of sphingosine-1-phosphate: extracellular through the Gi-coupled receptor Edg-1 and intracellular to regulate proliferation and survival. J Cell Biol. 1998 Jul 13;142(1):229–240. doi: 10.1083/jcb.142.1.229. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Wang F., Nobes C. D., Hall A., Spiegel S. Sphingosine 1-phosphate stimulates rho-mediated tyrosine phosphorylation of focal adhesion kinase and paxillin in Swiss 3T3 fibroblasts. Biochem J. 1997 Jun 1;324(Pt 2):481–488. doi: 10.1042/bj3240481. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Watson S. P., McConnell R. T., Lapetina E. G. Decanoyl lysophosphatidic acid induces platelet aggregation through an extracellular action. Evidence against a second messenger role for lysophosphatidic acid. Biochem J. 1985 Nov 15;232(1):61–66. doi: 10.1042/bj2320061. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Yamamura S., Sadahira Y., Ruan F., Hakomori S., Igarashi Y. Sphingosine-1-phosphate inhibits actin nucleation and pseudopodium formation to control cell motility of mouse melanoma cells. FEBS Lett. 1996 Mar 11;382(1-2):193–197. doi: 10.1016/0014-5793(96)00175-5. [DOI] [PubMed] [Google Scholar]
  64. Yatomi Y., Yamamura S., Ruan F., Igarashi Y. Sphingosine 1-phosphate induces platelet activation through an extracellular action and shares a platelet surface receptor with lysophosphatidic acid. J Biol Chem. 1997 Feb 21;272(8):5291–5297. doi: 10.1074/jbc.272.8.5291. [DOI] [PubMed] [Google Scholar]
  65. Yu F. X., Johnston P. A., Südhof T. C., Yin H. L. gCap39, a calcium ion- and polyphosphoinositide-regulated actin capping protein. Science. 1990 Dec 7;250(4986):1413–1415. doi: 10.1126/science.2255912. [DOI] [PubMed] [Google Scholar]
  66. Yu F. X., Sun H. Q., Janmey P. A., Yin H. L. Identification of a polyphosphoinositide-binding sequence in an actin monomer-binding domain of gelsolin. J Biol Chem. 1992 Jul 25;267(21):14616–14621. [PubMed] [Google Scholar]
  67. Zhang H., Desai N. N., Olivera A., Seki T., Brooker G., Spiegel S. Sphingosine-1-phosphate, a novel lipid, involved in cellular proliferation. J Cell Biol. 1991 Jul;114(1):155–167. doi: 10.1083/jcb.114.1.155. [DOI] [PMC free article] [PubMed] [Google Scholar]

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