Glycoconjugate Journal

, Volume 25, Issue 5, pp 427–439

TLR-independent induction of human monocyte IL-1 by phosphoglycolipids from thermophilic bacteria

  • Feng-Ling Yang
  • Kuo-Feng Hua
  • Yu-Liang Yang
  • Wei Zou
  • Yen-Po Chen
  • Shu-Mei Liang
  • Hsien-Yeh Hsu
  • Shih-Hsiung Wu
Article

Abstract

The structures of phosphoglycolipids PGL1 and PGL2 from the thermophilic bacteria Meiothermus taiwanensis, Meiothermus ruber, Thermus thermophilus, and Thermus oshimai are determined recently (Yang et al. in J Lipid Res. 47:1823–1932, 2006). These bacteria belong to Gram-negative bacteria that do not contain lipopolysaccharide, but high amounts of phosphoglycolipids and glycoglycerolipids. Here we show that PGL1/PGL2 mixture (PGL1: PGL2 = 10:1 ~ 10:2) from M. taiwanensis and T. oshimai, but not T. thermophilus and M. ruber, up-regulate interleukin-1β (IL-1β) production in human THP-1 monocytes and blood-isolated primary monocytes. PGL2 was purified after phospholipase A2 hydrolysis of PGL1 in the PGL1/PGL2 mixture followed by column chromatography. PGL2 did not induce proIL-1 production, even, partially (35–40%) inhibited PGL1-mediated proIL-1 production, showing that PGL1 is the main inducer of proIL-1 production in PGL1/PGL2 mixture. The production of proIL-1 stimulated by phosphoglycolipids was strongly inhibited by specific PKC-α, MEK1/2, and JNK inhibitors, but not by p38-specific inhibitor. The intracellular calcium influx was involved in phosphoglycolipids-mediated proIL-1 production. Using blocking antibody and Toll-like receptor (TLR)-linked NF-κB luciferase assays, we found that the cellular receptor(s) for phosphoglycolipids on proIL-1 production was TLR-independent. Further, phosphoglycolipids isolated from T. thermophilus and M. ruber did not induce proIL-1 production, even though T. thermophilus possess more PGL1 than PGL2 (6:4). Specially, the fatty acid composition of phosphoglycolipids from both T. thermophilus and M. ruber consists of a low percentage of C15 (<10%) and a high percentage of C17 (>75%). It suggests, the C15 percentage of PGL may play a critical role in PGL-mediated proIL-1 induction.

Keywords

Phosphoglycolipids Thermophilic bacteria Immunomodulators 

References

  1. 1.
    Ray, P.H., White, D.C., Brock, T.D.: Effect of growth temperature on the lipid composition of Thermus aquaticus. J. Bacteriol. 108, 227–235 (1971)PubMedGoogle Scholar
  2. 2.
    Williams, R.A.D., Da Costa, M.S.: The genus Thermus and related microorganisms. In: Balows, A., Truper, H.G., Dworkin, M., Harder, W., Schleifer, K.-H. (eds.) The Prokaryotes, 2nd edn., pp 3745–3753. Springer, New York (1992)Google Scholar
  3. 3.
    Ferreira, A.M., Wait, R., Nobre, M.F., Da Costa, M.S.: Characterization of glycolipids from Meiothermus spp. Microbiology 145, 1191–1199 (1999)PubMedGoogle Scholar
  4. 4.
    Silva, Z., Borges, N., Martins, L.O., Wait, R., Da Costa, M.S., Santos, H.: Combined effect of the growth temperature and salinity of the medium of the accumulation of compatible solutes by Rhodothermus marinus and Rhodothermus obamensis. Extremophiles 3, 163–172 (1999)PubMedCrossRefGoogle Scholar
  5. 5.
    Forterre, P., Bouthier de la Tour, C., Philippe, H., Duguet, M.: Reverse gyrase from hyperthermophiles: probable transfer of a thermoadaptation trait from archaea to bacteria. Trends Genet. 16, 152–154 (2000)PubMedCrossRefGoogle Scholar
  6. 6.
    Lesley, S.A., Kuhn, P., Godzik, A., Deacon, A.M., Mathews, I., Kreusch, A., Spraggon, G., Klock, H.E., McMullan, D., Shin, T., et al.: Structural genomics of the Thermotoga maritima proteome implemented in a high-throughput structure determination pipeline. Proc. Natl. Acad. Sci. U. S. A. 99, 11664–11669 (2002)PubMedCrossRefGoogle Scholar
  7. 7.
    De Groot, A., Chapon, V., Servant, P., Chriten, R., Saux, M.F., Sommer, S., Heulin, T.: Deinococcus deserti sp. nov., a gamma-radiation-tolerant bacterium isolated from the Sahara desert. Inst. J. Sys. Evol. Microbiol. 55, 2441–2446 (2005)CrossRefGoogle Scholar
  8. 8.
    Yang, Y.L., Yang, F.L., Jao, S.C., Chen, M.Y., Tsay, S.S., Zou, W., Wu, S.H.: Structural elucidation of phosphoglycolipids from strains of the bacterial thermophiles Thermus and Meiothermus. J. Lipid Res. 47, 1823–1832 (2006)PubMedCrossRefGoogle Scholar
  9. 9.
    Dutronc, Y., Porcelli, S.A.: The CD1 family and T cell recognition of lipid antigens. Tissue Antigens 60, 337–353 (2002)PubMedCrossRefGoogle Scholar
  10. 10.
    Parekh, V.V., Wilson, M.T., Van Kaer, L.: iNKT-cell responses to glycolipids. Crit. Rev. Immunol. 25, 183–213 (2005)PubMedCrossRefGoogle Scholar
  11. 11.
    Krishnan, L., Dicaire, C., Patel, G.B., Sprott, G.D.: Archaeosome vaccine adjuvants induce strong humoral, cell-mediated and memory responses: comparison to conventional liposomes and alum. Infect. Immun. 68, 54–63 (2000)PubMedCrossRefGoogle Scholar
  12. 12.
    Kinjo, Y., Wu, D., Kim, G., Xing, G.-W., Poles, M.A., Ho, D.D., Kawahara, K., Wong, C.-H., Kronenberg, M.: Recognition of bacterial glycosphingolipids by natural killer T cells. Nature 434, 520–525 (2005)PubMedCrossRefGoogle Scholar
  13. 13.
    Kinjo, Y., Tupin, E., Wu, D., Fujio, M., Garcia-Navarro, R., Benhnia, M.R.-E.-I., Zajonc, D.M., Ben-Menachem, G., Ainge, G.D., Painter, G.F., Khurana, A., Hoebe, K., Behar, S.M., Beutler, B., Wilson, I.A., Tsuji, M., Sellati, T.J., Wong, C.-H., Kronenberg, M.: Natural killer T cells recognize diacylglycerol antigens from pathogenic bacteria. Nature Immun. 7, 978–986 (2006)PubMedCrossRefGoogle Scholar
  14. 14.
    Stetson, D.B., Mohrs, M., Reinhardt, R.L., Baron, J.L., Wang, Z.E., Gapin, L., Kronenberg, M., Locksley, R.M.: Constitutive cytokine mRNAs mark natural killer (NK) and NK T cells poised for rapid effector function. J. Exp. Med. 198, 1069–1076 (2003)PubMedCrossRefGoogle Scholar
  15. 15.
    Bruno, A., Rossi, C., Marcolongo, G., Di Lena, A., Venzo, A., Berrie, C.P., Corda, D.: Selective in vivo anti-inflammatory action of the galactolipid monogalactosyl-diacylglycerol. Eur. J. Pharmacol. 524, 159–168 (2005)PubMedCrossRefGoogle Scholar
  16. 16.
    Phoebe, C.H., Jr., Combie, J., Albert, F.G., Van Tran, K., Cabrera, J., Correira, H.J., Guo, Y., Lindermuth, J., Rauert, N., Galbraith, W., Selitrennikoff, C.P.: Extremophilic organisms as an unexplored source of antifungal compounds. J. Antibiot. (Tokyo) 54, 56–65 (2001)PubMedGoogle Scholar
  17. 17.
    Anderson, R., Huang, Y.: Fatty acids are precursors of alkylamines in Deinococcus radiodurans. J. Bacteriol. 174, 7168–7173 (1992)PubMedGoogle Scholar
  18. 18.
    Cerretti, D.P., Kozlosky, C.J., Mosley, B., Nelson, N., Van Ness, K., Greenstreet, T.A., March, C.J., Kronheim, S.R., Druck, T., Cannizzaro, L.A., Huebner, K., Black, R.A.: Molecular cloning of the interleukin-1β converting enzyme. Science 256, 97–100 (1992)PubMedCrossRefGoogle Scholar
  19. 19.
    Thornberry, N.A., Bull, H.G., Calaycay, J.R., Chapman, K.T., Howard, A.D., Kostura, M.J., Miller, D.K., Molineaux, S.M., Weidner, J.R., Aunins, J., et al.: A novel heterodimeric cysteine protease is required for interleukin-1β processing in monocytes. Nature 356, 768–774 (1992)PubMedCrossRefGoogle Scholar
  20. 20.
    Dinarello, C.A.: Interleukin-1. Cytokine Growth Factor Rev. 8, 253–265 (1997)PubMedCrossRefGoogle Scholar
  21. 21.
    Schumann, R.R., Belka, C., Reuter, D., Lamping, N., Kirschning, C.J., Weber, J.R., Pfeil, D.: Lipopolysaccharide activates caspase-1 (interleukin-1-converting) in cultured monocytic and endothelial cells. Blood 91, 577–584 (1998)PubMedGoogle Scholar
  22. 22.
    Loppnow, H., Werdan, K., Reuter, G., Flad, H.D.: The interleukin-1 and interleukin-1 converting enzyme families in cardiovascular system. Eur. Cytokine. Netw. 9, 675–680 (1998)PubMedGoogle Scholar
  23. 23.
    Li, X., Commane, M., Jiang, Z., Stark, G.R.: IL-1-induced NFκB and c-Jun N-terminal kinase (JNK) activation diverge at IL-1 receptor-associated kinase (IRAK). Proc. Natl. Acad. Sci. U. S. A. 98, 4461–4465 (2001)PubMedCrossRefGoogle Scholar
  24. 24.
    Loppnow, H., Libby, P.: Proliferating or interleukin 1-activated human vascular smooth muscle cells secrete copious interleukin 6. J. Clin. Invest. 85, 731–738 (1990)PubMedCrossRefGoogle Scholar
  25. 25.
    Beales, I.L.: Effect of Interlukin-1 on proliferation of gastric epithelial cells in culture. BMC Gastroenterology 2, 7 (2002)PubMedCrossRefGoogle Scholar
  26. 26.
    Xaus, J., Comalada, M., Valledor, A.F., Lloberas, J., Lopez-Soriano, F., Argiles, J.M., Yang, J., Hooper, W.C., Phillips, D.J., Talkington, D.F.: Interleukin-1beta responses to Mycoplasma pneumoniae infection are cell-type specific. Microb. Pathog. 34, 17–25 (2003)CrossRefGoogle Scholar
  27. 27.
    Pearson, G., Robinson, F., Beers Gibson, T., Xu, B.E., Karandikar, M., Berman, K., Cobb, M.H.: Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocr. Rev. 22, 153–183 (2001)PubMedCrossRefGoogle Scholar
  28. 28.
    Raingeaud, J., Gupta, S., Rogers, J.S., Dickens, M., Han, J., Ulevitch, R.J., Davis, R.J.: Pro-inflammatory cytokines and environmental stress cause p38 mitogen-activated protein kinase activation by dual phosphorylation on tyrosine and threonine. J. Biol. Chem. 270, 7420–7426 (1995)PubMedCrossRefGoogle Scholar
  29. 29.
    Scherle, P.A., Jones, E.A., Favata, M.F., Daulerio, A.J., Covington, M.B., Nurnberg, S.A., Magolda, R.L., Tracks, J.M.: Inhibition of MAP kinase kinase prevents cytokine and prostaglandin E2 production in lipopolysaccharide-stimulated monocytes. J. Immunol. 161, 5681–5686 (1998)PubMedGoogle Scholar
  30. 30.
    Carter, A.B., Monick, M., Hunninghake, G.W.: Both Erk and p38 kinases are necessary for cytokine gene transcription. Am. J. Respir. Cell. Mol. Biol. 20, 751–758 (1999)PubMedGoogle Scholar
  31. 31.
    Binétruy, B., Smeal, T., Karin, M.: Ha-Ras augments c-Jun activity and stimulates phosphorylation of its activation domain. Nature 351, 122–127 (1991)PubMedCrossRefGoogle Scholar
  32. 32.
    Devary, Y., Gottlieb, R.A., Lau, L.F., Karin, M.: Rapid and preferential activation of the c-jun gene during the mammalian UV response. Mol. Cell. Biol. 11, 2804–2811 (1991)PubMedGoogle Scholar
  33. 33.
    Pombo, C.M., Bonventre, J.V., Avruch, J., Woodgett, J.R., Kyriakis, J.M., Force, T.: The stress-activated protein kinases are major c-Jun amino-terminal kinases activated by ischemia and reperfusion. J. Biol. Chem. 269, 26546–26551 (1994)PubMedGoogle Scholar
  34. 34.
    Hambleton, J., Weinstein, S.L., Lem, L., DeFranco, A.L.: Activation of c-Jun N-terminal kinase in bacterial lipopolysaccharide-stimulated macrophages. Proc. Natl. Acad. Sci. U. S. A. 93, 2774–2778 (1996)PubMedCrossRefGoogle Scholar
  35. 35.
    Derijard, B., Hibi, M., Wu, I.H., Barrett, T., Su, B., Deng, T., Karin, M., Davis, R.J.: JNK1: a protein kinase stimulated by UV light and Ha-Has that binds and phosphorylates the c-Jun activation domain. Cell 76, 1025–1037 (1994)PubMedCrossRefGoogle Scholar
  36. 36.
    Kallunki, T., Su, B., Tsigelny, I., Sluss, H.K., Derijard, B., Moore, G., Davis, R., Karin, M.: JNK2 contains a specificity-determining region responsible for efficient c-Jun binding and phosphorylation. Genes Dev. 8, 2996–3007 (1994)PubMedCrossRefGoogle Scholar
  37. 37.
    Reimann, T., Buscher, D., Hipskind, R.A., Krautwald, S., Lohmann-Matthes, M.L., Baccarini, M.: Lipopolysaccharide induces activation of the Raf-1/MAP kinase pathway. A putative role for Raf-1 in the induction of the IL-1 beta and TNF-alpha genes. J. Immunol. 153, 5740–5749 (1994)PubMedGoogle Scholar
  38. 38.
    Bennett, B.L., Sasaki, D.T., Murray, B.W., O’Leary, E.C., Sakata, S.T., Xu, W., Leisten, J.C., Motiwala, A., Pierce, S., Satoh, Y., Bhagwat, S.S., Manning, A.M., Anderson, D.W.: SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase. Proc. Natl. Acad. Sci. U. S. A. 98, 13681–13686 (2001)PubMedCrossRefGoogle Scholar
  39. 39.
    Han, J., Lee, J.D., Bibbs, L., Ulevitch, R.J.: A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells. Science 265, 808–811 (1994)PubMedCrossRefGoogle Scholar
  40. 40.
    Lee, J.C., Laydon, J.T., McDonnell, P.C., Gallagher, T.F., Kumar, S., Green, D., McNulty, D., Blumenthal, M.J., Heys, J.R., Landvatter, S.W., Strickler, J.E., McLaughlin, M.M., Siemens, I.R., Fisher, S.M., Livi, G.P., White, J.R., Adams, J.L., Young, P.R.: A protein kinase involved in the regulation of inflammatory cytokine biosynthesis. Nature 372, 739–746 (1994)PubMedCrossRefGoogle Scholar
  41. 41.
    Geng, Y., Valbracht, J., Lotz, M.: Selective activation of the mitogen-activated protein kinase subgroups c-Jun NH2 terminal kinase and p38 by IL-1 and TNF in human articular chondrocytes. J. Clin. Invest. 98, 2425–2430 (1996)PubMedCrossRefGoogle Scholar
  42. 42.
    Chen, M.Y., Lin, G.H., Lin, Y.T., Tsay, S.S.: Meiothermus taiwanensis sp. nov., a novel filamentous, thermophilic species isolated in Taiwan. Int. J. Sys. Evol. Microbiol. 52, 1647–1654 (2002)CrossRefGoogle Scholar
  43. 43.
    Lu, T.L., Chen, C.S., Yang, F.L., Fung, J.M., Chen, M.Y., Tsay, S.S., Li, J., Zou, W., Wu, S.H.: Structure of a major glycolipid from Thermus oshimai NTU-063. Carbohydr. Research. 339, 2593–2598 (2004)CrossRefGoogle Scholar
  44. 44.
    Hsu, H.Y., Wen, M.H.: Lipopolysaccharide-mediated reactive oxygen species and signal transduction in the regulation of interleukin-1 gene expression. J. Biol. Chem. 277, 22131–22139 (2002)PubMedCrossRefGoogle Scholar
  45. 45.
    Chuang, T.S., Lee, J., Kline, L., Mathison, J.C., Ulevitch, R.J.: Toll-like receptor 9 mediates CpG-DNA signaling. J. Leukoc. Biol. 71, 538–544 (2002)PubMedGoogle Scholar
  46. 46.
    Kuo, C.C., Lin, W.T., Liang, C.M., Liang, S.M.: Class I and III phosphatidylinositol 3’-kinase play distinct roles in TLR signaling pathway. J. Immunol. 176, 5943–5949 (2006)PubMedGoogle Scholar
  47. 47.
    Muzio, M., Natoli, G., Saccani, S., Levrero, M., Mantovani, A.: The human toll signaling pathway: divergence of nuclear factor kappaB and JNK/SAPK activation upstream of tumor necrosis factor receptor-association factor 6 (TRAF6). J. Exp. Med. 187, 2097–2101 (1998)PubMedCrossRefGoogle Scholar
  48. 48.
    Pask-Hughes, R.A., Shaw, N.: Glycolipids from some extreme thermophilic bacteria belonging to the genus Thermus. J. Bacteriol. 149, 54–58 (1982)PubMedGoogle Scholar
  49. 49.
    Silipo, A., Molinaro, A., de Castro, C., Ferrara, R., Romano, I., Nicolaus, B., Lanzetta, R., Parrilli, M.: Structural analysis of a novel polysaccharide of the lipopolysaccharide-deficient extremophile gram-negative bacterium Thermus thermophilus HB8. Eur. J. Org. Chem. 24, 5047–5054 (2004)CrossRefGoogle Scholar
  50. 50.
    Dobson, P.R., Skjodt, H., Plested, C.P., Short, A.D., Virdee, K., Russell, R.G., Brown, B.L.: Interleukin-1 stimulates diglyceride accumulation in the absence of protein kinase C activation. Regul. Pept. 29, 109–116 (1990)PubMedCrossRefGoogle Scholar
  51. 51.
    Brooks, J.W., Mizel, S.B.: Interleukin-1 and signal transduction. Eur. Cytokine. Netw. 5, 547–561 (1994)PubMedGoogle Scholar
  52. 52.
    Beales, I., Calam, J.: Stimulation of IL-8 production in human gastric epithelial cells by Helicobacter pylori, IL-1b and TNF-a requires tyrosine kinase activity, but not protein kinase C. Cytokine 9, 514–520 (1997)PubMedCrossRefGoogle Scholar
  53. 53.
    Beales, I., Calam, J.: lnterleukin-1b and tumor nexcrosis factor-a inhibit acid secretion in cultured rabbit parietal cells by multiple pathways. Gut 42, 227–234 (1998)PubMedCrossRefGoogle Scholar
  54. 54.
    Beales, I.L., Calam, J.: Inhibition of carbachol stimulated acid secretion by interleukin 1beta in rabbit parietal cells requires protein kinase C. Gut 48, 782–789 (2001)PubMedCrossRefGoogle Scholar
  55. 55.
    Chiodoni, C., Stoppacciaro, A., Sangaletti, S., Gri, G., Cappetti, B., Koezuka, Y., Colombo, M.P.: Different requirements for α-galactosylceramide and recombinant IL-12 antitumor activity in the treatment of C-26 colon carcinoma hepatic metastases. Eur. J. Immunol. 31, 3101–3110 (2001)PubMedCrossRefGoogle Scholar
  56. 56.
    Antonopoulou, S., Nomikos, T., Oilonomou, A., Kyriacou, A., Andriotis, M., Fragopoulou, E., Pantazidou, A.: Characterization of bioactive glycolipids from Scytonema julianum (cyanobacteria). Comp. Biochem. Physiol., Part B. 140, 219–231 (2005)CrossRefGoogle Scholar
  57. 57.
    Hiromatsu, K., Dascher, C.C., Sugita, M., Gingrich-Baker, C., Behar, S.M., LeClair, K.P., et al.: Characterization of guinea-pig group 1 CD1 proteins. Immunol. 106, 159–172 (2002)CrossRefGoogle Scholar
  58. 58.
    Buwitt-Beckmann, U., Heine, H., Wiesmüller, K.H., Jung, G., Brock, R., Ulmer, A.J.: Lipopeptide structure determines TLR2 dependent cell activation level. FEBS J. 272, 6354–6364 (2005)PubMedCrossRefGoogle Scholar
  59. 59.
    Buwitt-Beckmann, U., Heine, H., Wiesmüller, K.H., Jung, G., Brock, R., Akira, S., Ulmer, A.J.: TLR1- and TLR6-independent recognition of bacterial lipopeptides. J. Biol. Chem. 281, 9049–9057 (2006)PubMedGoogle Scholar
  60. 60.
    Morr, M., Takeuchi, O., Akira, S., Simon, M.M., Mühlradt, P.F.:Differential recognition of structural details of bacterial lipopeptides by toll-like receptors. Eur. J. Immunol. 32, 3337–3347 (2002)PubMedGoogle Scholar
  61. 61.
    Kawahara, K., Moll, H., Knirel, Y.L., Seydel, U., Zahringer, U.: Structural analysis of two glycosphingolipids from the lipopolysaccharide-lacking bacterium Sphingomonas capsulata. Eur. J. Biochem. 267, 1837–1846 (2000)PubMedCrossRefGoogle Scholar
  62. 62.
    Gray, J.G., Chandra, G., Clay, W.C., Stinnett, S.W., Haneline, S.A., Lorenz, J.J., Patel, I.R., Wisely, G.B., Furdon, P.J., Taylor, J.D., et al.: A CRE/ATF-like site in the upstream regulatory sequence of the human interleukin 1 beta gene is necessary for the induction in U937 and THP-1 monocytic cell lines. Mol. Cell. Biol. 13, 6678–6689 (1993)PubMedGoogle Scholar
  63. 63.
    Geppert, T.D., Whitehurst, C.E., Thompson, P., Beutler, B.: Lipopolysaccharide signals activation of tumor necrosis factor biosynthesis through the ras/raf-1/MEK/ MAPK pathway. Mol. Med. 1, 93–103 (1994)PubMedGoogle Scholar
  64. 64.
    Rousset, M., Cens, T., Van Mau, N., Charnet, P.: Ca2+-dependent interaction of BAPTA with phospholipids. FEBS Letters 576, 41–45 (2004)PubMedCrossRefGoogle Scholar
  65. 65.
    Darveau, R.P.: Lipid A diversity and the innate host response to bacterial infection. Curr. Opin. Microbiol. 1, 36–42 (1998)PubMedCrossRefGoogle Scholar
  66. 66.
    Dubois, M.J., Vincent, J.L.: Clinically-oriented therapies in sepsis: a review. J. Endotoxin. Res. 6, 463–469 (2000)PubMedGoogle Scholar
  67. 67.
    Proctor, R.A., Will, J.A., Burhop, K.E., Raetz, C.R.H.: Protection of mice against lethal endotoxemia by a lipid A precursor. Infect. Immun. 52, 905–907 (1986)PubMedGoogle Scholar
  68. 68.
    Christ, W.J., Asano, O., Robidoux, A.L., Perez, M., Wang, Y., Dubuc, G.R., Gavin, W.E., Hawkins, L.D., McGuinness, P.D., Mullarkey, M.A., et al.: E5531, a pure endotoxin antagonist of high potency. Science 268, 80–83 (1995)PubMedCrossRefGoogle Scholar
  69. 69.
    Arend, W.P., Malyak, M., Guthridge, C.J., Gabay, C.: Interleukin-1 receptor antagonist; role in biology. Annu. Rev. Immunol. 16, 27–55 (1998)PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Feng-Ling Yang
    • 1
  • Kuo-Feng Hua
    • 2
  • Yu-Liang Yang
    • 1
  • Wei Zou
    • 3
  • Yen-Po Chen
    • 4
  • Shu-Mei Liang
    • 4
  • Hsien-Yeh Hsu
    • 2
    • 5
  • Shih-Hsiung Wu
    • 1
  1. 1.Institute of Biological ChemistryAcademia SinicaTaipeiTaiwan
  2. 2.Department of Biotechnology and Laboratory Science in MedicineNational Yang-Ming UniversityTaipeiTaiwan
  3. 3.Institute for Biological SciencesNational Research Council of CanadaOttawaCanada
  4. 4.Agricultural Biotechnology Research CenterAcademia SinicaTaipeiTaiwan
  5. 5.Department of Education and ResearchTaipei City HospitalTaipeiTaiwan

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