請用此 Handle URI 來引用此文件：
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/77018完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 張淑媛(Sui-Yuan Chang) | |
| dc.contributor.author | Han-Chieh Kao | en |
| dc.contributor.author | 高函潔 | zh_TW |
| dc.date.accessioned | 2021-07-10T21:43:31Z | - |
| dc.date.available | 2021-07-10T21:43:31Z | - |
| dc.date.copyright | 2020-09-10 | |
| dc.date.issued | 2020 | |
| dc.date.submitted | 2020-07-23 | |
| dc.identifier.citation | 1. Megan L. Shaw, P.P., Orthomyxoviridas. Fields virology. 2007. 2. Zheng, W. and Y.J. Tao, Structure and assembly of the influenza A virus ribonucleoprotein complex. FEBS Lett, 2013. 587(8): p. 1206-14. 3. Gamblin, S.J. and J.J. Skehel, Influenza hemagglutinin and neuraminidase membrane glycoproteins. J Biol Chem, 2010. 285(37): p. 28403-9. 4. Shtyrya, Y.A., L.V. Mochalova, and N.V. Bovin, Influenza virus neuraminidase: structure and function. Acta Naturae, 2009. 1(2): p. 26-32. 5. Bui, M., et al., Role of the influenza virus M1 protein in nuclear export of viral ribonucleoproteins. J Virol, 2000. 74(4): p. 1781-6. 6. Pielak, R.M. and J.J. Chou, Influenza M2 proton channels. Biochim Biophys Acta, 2011. 1808(2): p. 522-9. 7. Cady, S.D., et al., Structure and function of the influenza A M2 proton channel. Biochemistry, 2009. 48(31): p. 7356-64. 8. Lin, D., J. Lan, and Z. Zhang, Structure and function of the NS1 protein of influenza A virus. Acta Biochim Biophys Sin (Shanghai), 2007. 39(3): p. 155-62. 9. Hale, B.G., et al., The multifunctional NS1 protein of influenza A viruses. J Gen Virol, 2008. 89(Pt 10): p. 2359-2376. 10. O'Neill, R.E., J. Talon, and P. Palese, The influenza virus NEP (NS2 protein) mediates the nuclear export of viral ribonucleoproteins. EMBO J, 1998. 17(1): p. 288-96. 11. Neumann, G., M.T. Hughes, and Y. Kawaoka, Influenza A virus NS2 protein mediates vRNP nuclear export through NES-independent interaction with hCRM1. EMBO J, 2000. 19(24): p. 6751-8. 12. Fujiyoshi, Y., et al., Fine structure of influenza A virus observed by electron cryo-microscopy. EMBO J, 1994. 13(2): p. 318-26. 13. Calder, L.J., et al., Structural organization of a filamentous influenza A virus. Proc Natl Acad Sci U S A, 2010. 107(23): p. 10685-90. 14. Schroeder, C., et al., The influenza virus ion channel and maturation cofactor M2 is a cholesterol-binding protein. Eur Biophys J, 2005. 34(1): p. 52-66. 15. Hsu, M.T., et al., Genomic RNAs of influenza viruses are held in a circular conformation in virions and in infected cells by a terminal panhandle. Proc Natl Acad Sci U S A, 1987. 84(22): p. 8140-4. 16. Cheong, H.K., C. Cheong, and B.S. Choi, Secondary structure of the panhandle RNA of influenza virus A studied by NMR spectroscopy. Nucleic Acids Res, 1996. 24(21): p. 4197-201. 17. Hirst, G.K., Adsorption of Influenza Virus on Cells of the Respiratory Tract. J Exp Med, 1943. 78(2): p. 99-109. 18. Matlin, K.S., et al., Infectious entry pathway of influenza virus in a canine kidney cell line. J Cell Biol, 1981. 91(3 Pt 1): p. 601-13. 19. Matrosovich, M., G. Herrler, and H.D. Klenk, Sialic Acid Receptors of Viruses. Top Curr Chem, 2015. 367: p. 1-28. 20. Zhou, N.N., et al., Genetic reassortment of avian, swine, and human influenza A viruses in American pigs. J Virol, 1999. 73(10): p. 8851-6. 21. Lakadamyali, M., M.J. Rust, and X. Zhuang, Endocytosis of influenza viruses. Microbes Infect, 2004. 6(10): p. 929-36. 22. Sieczkarski, S.B. and G.R. Whittaker, Influenza virus can enter and infect cells in the absence of clathrin-mediated endocytosis. J Virol, 2002. 76(20): p. 10455-64. 23. Hamilton, B.S., G.R. Whittaker, and S. Daniel, Influenza virus-mediated membrane fusion: determinants of hemagglutinin fusogenic activity and experimental approaches for assessing virus fusion. Viruses, 2012. 4(7): p. 1144-68. 24. Gorlich, D., et al., Isolation of a protein that is essential for the first step of nuclear protein import. Cell, 1994. 79(5): p. 767-78. 25. Adam, E.J. and S.A. Adam, Identification of cytosolic factors required for nuclear location sequence-mediated binding to the nuclear envelope. J Cell Biol, 1994. 125(3): p. 547-55. 26. Gorlich, D., et al., A 41 amino acid motif in importin-alpha confers binding to importin-beta and hence transit into the nucleus. EMBO J, 1996. 15(8): p. 1810-7. 27. Mikulasova, A., E. Vareckova, and E. Fodor, Transcription and replication of the influenza a virus genome. Acta Virol, 2000. 44(5): p. 273-82. 28. Zheng, H., et al., Influenza A virus RNA polymerase has the ability to stutter at the polyadenylation site of a viral RNA template during RNA replication. J Virol, 1999. 73(6): p. 5240-3. 29. Paterson, D. and E. Fodor, Emerging roles for the influenza A virus nuclear export protein (NEP). PLoS Pathog, 2012. 8(12): p. e1003019. 30. Li, J., et al., Nucleocytoplasmic shuttling of influenza A virus proteins. Viruses, 2015. 7(5): p. 2668-82. 31. Rossman, J.S. and R.A. Lamb, Influenza virus assembly and budding. Virology, 2011. 411(2): p. 229-36. 32. Su, S., et al., Epidemiology, Evolution, and Recent Outbreaks of Avian Influenza Virus in China. J Virol, 2015. 89(17): p. 8671-6. 33. Uyeki, T.M., et al., Lack of evidence for human-to-human transmission of avian influenza A (H9N2) viruses in Hong Kong, China 1999. Emerg Infect Dis, 2002. 8(2): p. 154-9. 34. Kilbourne, E.D., Influenza pandemics of the 20th century. Emerg Infect Dis, 2006. 12(1): p. 9-14. 35. Jhung, M.A., et al., Epidemiology of 2009 pandemic influenza A (H1N1) in the United States. Clin Infect Dis, 2011. 52 Suppl 1: p. S13-26. 36. Smith, G.J., et al., Origins and evolutionary genomics of the 2009 swine-origin H1N1 influenza A epidemic. Nature, 2009. 459(7250): p. 1122-5. 37. Wu, Y., et al., Bat-derived influenza-like viruses H17N10 and H18N11. Trends Microbiol, 2014. 22(4): p. 183-91. 38. Klenk, H.D. and W. Garten, Host cell proteases controlling virus pathogenicity. Trends Microbiol, 1994. 2(2): p. 39-43. 39. Chen, J., et al., First genome report and analysis of chicken H7N9 influenza viruses with poly-basic amino acids insertion in the hemagglutinin cleavage site. Sci Rep, 2017. 7(1): p. 9972. 40. WHO, Summary of status of development and availability of avian influenza A(H7N9) candidate vaccine viruses and potency testing reagents. 2020. 41. Nguyen-Van-Tam, J.S., et al., Outbreak of low pathogenicity H7N3 avian influenza in UK, including associated case of human conjunctivitis. Euro Surveill, 2006. 11(5): p. E060504 2. 42. Tweed, S.A., et al., Human illness from avian influenza H7N3, British Columbia. Emerg Infect Dis, 2004. 10(12): p. 2196-9. 43. Kurtz, J., R.J. Manvell, and J. Banks, Avian influenza virus isolated from a woman with conjunctivitis. Lancet, 1996. 348(9031): p. 901-2. 44. Fouchier, R.A., et al., Avian influenza A virus (H7N7) associated with human conjunctivitis and a fatal case of acute respiratory distress syndrome. Proc Natl Acad Sci U S A, 2004. 101(5): p. 1356-61. 45. Gao, R., et al., Human infection with a novel avian-origin influenza A (H7N9) virus. N Engl J Med, 2013. 368(20): p. 1888-97. 46. Wang, X., et al., Epidemiology of avian influenza A H7N9 virus in human beings across five epidemics in mainland China, 2013-17: an epidemiological study of laboratory-confirmed case series. Lancet Infect Dis, 2017. 17(8): p. 822-832. 47. Tang, J., et al., Highly pathogenic avian influenza H7N9 viruses with reduced susceptibility to neuraminidase inhibitors showed comparable replication capacity to their sensitive counterparts. Virology Journal, 2019. 16(1): p. 87. 48. Yang, L., et al., Genesis and Spread of Newly Emerged Highly Pathogenic H7N9 Avian Viruses in Mainland China. J Virol, 2017. 91(23). 49. Hay, A.J., et al., The molecular basis of the specific anti-influenza action of amantadine. EMBO J, 1985. 4(11): p. 3021-4. 50. Monto, A.S., The role of antivirals in the control of influenza. Vaccine, 2003. 21(16): p. 1796-800. 51. von Itzstein, M., et al., A study of the active site of influenza virus sialidase: an approach to the rational design of novel anti-influenza drugs. J Med Chem, 1996. 39(2): p. 388-91. 52. Hurt, A.C., et al., Oseltamivir resistance and the H274Y neuraminidase mutation in seasonal, pandemic and highly pathogenic influenza viruses. Drugs, 2009. 69(18): p. 2523-31. 53. Taniguchi, K., et al., Inhibition of avian-origin influenza A(H7N9) virus by the novel cap-dependent endonuclease inhibitor baloxavir marboxil. Sci Rep, 2019. 9(1): p. 3466. 54. Kiso, M., et al., Treatment of Highly Pathogenic H7N9 Virus-Infected Mice with Baloxavir Marboxil. Viruses, 2019. 11(11). 55. Marjuki, H., et al., Characterization of drug-resistant influenza A(H7N9) variants isolated from an oseltamivir-treated patient in Taiwan. J Infect Dis, 2015. 211(2): p. 249-57. 56. Tang, J., et al., Highly pathogenic avian influenza H7N9 viruses with reduced susceptibility to neuraminidase inhibitors showed comparable replication capacity to their sensitive counterparts. Virol J, 2019. 16(1): p. 87. 57. Hai, R., et al., Influenza A(H7N9) virus gains neuraminidase inhibitor resistance without loss of in vivo virulence or transmissibility. Nat Commun, 2013. 4: p. 2854. 58. Gerhard, W., et al., Role of the B-cell response in recovery of mice from primary influenza virus infection. Immunol Rev, 1997. 159: p. 95-103. 59. Brandenburg, B., et al., Mechanisms of hemagglutinin targeted influenza virus neutralization. PLoS One, 2013. 8(12): p. e80034. 60. Kallewaard, N.L., et al., Structure and Function Analysis of an Antibody Recognizing All Influenza A Subtypes. Cell, 2016. 166(3): p. 596-608. 61. Chen, Z., et al., Human monoclonal antibodies targeting the haemagglutinin glycoprotein can neutralize H7N9 influenza virus. Nature Communications, 2015. 6. 62. Ito, M., et al., Characterization of Mouse Monoclonal Antibodies Against the HA of A(H7N9) Influenza Virus. Viruses-Basel, 2019. 11(2). 63. Tan, G.S., et al., Broadly-Reactive Neutralizing and Non-neutralizing Antibodies Directed against the H7 Influenza Virus Hemagglutinin Reveal Divergent Mechanisms of Protection. Plos Pathogens, 2016. 12(4). 64. Kymab, Deep mining of Kymab's antibody repertoire. https://www.kymab.com/technology/intelliselect/. 65. Stadlbauer, D., et al., Cross-reactive mouse monoclonal antibodies raised against the hemagglutinin of A/Shanghai/1/2013 (H7N9) protect against novel H7 virus isolates in the mouse model. Emerging Microbes Infections, 2018. 7. 66. Chen, C., et al., Broad neutralizing activity of a human monoclonal antibody against H7N9 strains from 2013 to 2017. Emerg Microbes Infect, 2018. 7(1): p. 179. 67. Huang, K.A., et al., Structure-function analysis of neutralizing antibodies to H7N9 influenza from naturally infected humans. Nat Microbiol, 2019. 4(2): p. 306-315. 68. Yasuhara, A., et al., Isolation and Characterization of Human Monoclonal Antibodies That Recognize the Influenza A(H1N1)pdm09 Virus Hemagglutinin Receptor-Binding Site and Rarely Yield Escape Mutant Viruses. Front Microbiol, 2018. 9: p. 2660. 69. Wu, J., et al., Influenza H5/H7 Virus Vaccination in Poultry and Reduction of Zoonotic Infections, Guangdong Province, China, 2017-18. Emerg Infect Dis, 2019. 25(1): p. 116-118. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/77018 | - |
| dc.description.abstract | 2013年於中國爆發的A型流感病毒H7N9由禽鳥類流感病毒重組生成，至今引起了五波大流行。在2017年的第五波爆發中出現了高致病性的病毒，死亡率高達50%。臨床上常用神經胺酸酶(neuraminidase, NA)抑制劑來治療流感病毒感染，但在高致病性的H7N9病毒中，發現了許多抗神經胺酸酶抑制劑的抗藥性突變，如NA上R292K的突變，因此必須研發新型的治療方式。針對流感病毒顆粒表面血球凝集蛋白(hemagglutinin, HA)的抗體，被認為可以抑制病毒進入宿主細胞的步驟，達到中和病毒感染力的效果。本篇研究目的為針對十支可中和2013 H7N9病毒的治療性抗體進行功能以及結合位點的探討。我們依據抗體的重鏈及輕鏈序列將抗體分成五組：A組包含CL-163099, CL-163110；B組包含CL-163084, CL-163118, CL-163121；C組包含CL-163095, CL-163098；D組包含CL-163109, CL-163219，E組為CL-163117。首先以微量中和試驗(Micro-neutralization test)初步測試十支抗體對於2013H7N9的中和力，IC50 範圍在0.1-0.3 μg/mL。另外也以免疫螢光染色(Immunofluorescence assay)的方式確認抗體可以結合2013H7N9的HA。接著針對抗體廣效性進行測試，發現十支抗體皆可結合2017H7N9, H7N3, H7N7的HA，也可中和2017年高致病性的H7N9重組病毒。進一步以溶菌斑減少中和試驗，確認在感染細胞前加入抗體，或是感染後才加入抗體，抗H7抗體皆可有效抑制病毒複製。為了找出抗體的結合位點，我們將抗體CL-163099與病毒共培養，A組第一代(抗體濃度60 ng/mL)在感染後48小時，病毒大量生成，第二代培養我們將抗體量提升至50 μg/mL，病毒仍能生長，我們將突變病毒的HA定序，發現病毒帶有G151E突變。而在B組，我們在第一代時看到了A156A/V突變，第二代(1 μg/mL)有R149K及A156V，並在第三代(5 μg/mL)及第四代(20 μg/mL)都帶有這兩個突變點，而在第五代我們將抗體量提升至50 μg/mL，病毒出現了del151-153+A156V突變。在HA的結構上，我們發現突變點集中在Antigenic site A 及Receptor binding site 140 loop上，這可能就是CL-163099的結合位。我們以定位點突變試驗合成帶有突變的HA，以免疫螢光染色及流式細胞儀測試是否會影響十支抗體的結合力。A組、B組及E組的抗體對於帶有R149K的HA失去結合力；帶有G151E的HA只有B組的三隻抗體可以結合；只有A組的抗體失去帶有A156V的HA的結合力；只有CL-163098仍可結合帶有兩個突變點R149K+A156V的HA；而所有抗體都無法結合上帶有del151-153或是del151+153+A156V的HA。接著我們製造了帶有突變點的重組病毒，測試其生長速度，分別帶有R149K、G151E及A156V的重組病毒生長曲線較平緩，低於野生株。帶有R149K+A156V的重組病毒於感染後24小時的病毒量高於野生株，帶有del151-153及del151-153+A156V的重組病毒於感染後0小時至36小時的病毒量都高於野生株，並於感染後36小時達複製高峰。最後測試了帶有突變的重組病毒是否影響抗體的中和效果，以50 ng/mL的濃度進行實驗，十支抗體可接近100%的抑制野生株的重組病毒。對於帶有突變點的重組病毒，前述實驗測定會影響結合力者，大部分皆失去或降低中和力。本篇研究所探討之十支抗H7抗體，可廣效結合2013H7N9, 2017H7N9, H7N3及H7N7，並且對於2013H7N9及2017H7N9有良好的中和效果。另外也透過突變病毒篩選，找到可掙脫抗體的突變點，並製造帶有突變的HA及重組病毒，以反向驗證不同的突變點對於不同組別抗體的影響。經過序列分析，發現此組抗體結合位在H7病毒具有高度保留性，顯示抗體結合處為H7病毒重要的抗原位，也因此我們的抗體可以有很好的中和效果，預期對於大部分的H7病毒都可以有保護力。 | zh_TW |
| dc.description.abstract | Novel ressortant influenza A virus H7N9, first detected in China in 2013, has caused five waves of outbreaks in human. Highly pathogenic avian influenza (HPAI) H7N9 with a multibasic cleavage site has been detected in the fifth wave and caused about 50% morality in infected patients. Neuraminidase inhibitors have been used to treat influenza virus infection but resistant virus has been reported, including HPAI H7N9. Therefore, it is nesseray to develop new strategy for H7N9 treatment. Among these neutralizing antibodies against influenza HA have been reported to block virus entry, fusion, or relase. In this study, function of ten anti-H7 antibodies have been characterized and the epitopes of anti-H7 antibodies have been determined. According to genetic features, we classified the ten anti-H7 antibodies into 5 groups, with Group A (CL-163099 and CL-163110), Group B (CL-163084, CL-163118, CL-163121), Group C (CL-163095, CL-163098), Group D (CL-163109, CL-163219), and Group E (CL-163117). Neutralizing activity of anti-H7 antibodies determined by micro neutralization test were in the range between 0.1-0.3 μg/mL. Anti-H7 antibodies can recognize 2013H7N9 HA, 2017H7N9 HA, H7N3 HA, and H7N7 HA. HPAI r2017H7N9 virus could be neutralized by anti-H7 antibodies. To determine the epitopes of these anti-H7 antibodies, escape mutants were selected by co-culture of virus and antibodies (CL-163099). Different mutants were observed in the duplicated experiments. G151E was detected in line I-A, while A156V, R149K+A156V were detected in line I-B. Del151-153+A156V were observed in the 5th passage with 50 μg/mL of CL-163099. To confirm whether the amino acid substitutions contribute to escape from anti-H7 antibodies, site-directed mutagenesis was performed in 2013H7N9-HA. Immunofluorescence assay and flow cytometry were performed to determine antibody binding ability. Group A, B, and E antibodies lost binding ability to 2013H7-HA with R149K mutation. Only Group B antibodies could bind 2013H7-HA with G151E mutation. A156V substitution weakly reduced the binding ability of Group A antibody. Only CL-163098 could bind 2013H7-HA with R149K+A156V. All antibodies can not recognize 2013H7-HA with del151-153 or del151-153+A156V. Furthermore, recombinant viruses with various mutations have been genetrated. The virus replication titers of rH7N9-R149K, rH7N9-G151E, rH7N9-A156V were lower than those of wt-rH7N9. The virus titer of rH7N9-R149K+A156V at 24 hours post infection (hpi), rH7N9-del151-153 at 36 hpi and rH7N9-del151-153+A156V at 36 hpi were all higher than those of wt-rH7N9. The ability of these antibodies to neutralize mutant virus was determined by plaque reduction assay. Those HA mutations reduced antibodies binding ability were confirmed to reduce antibodies neutralizing ability. In summary, we developed ten anti-H7 antibodies with great neutralizing ability against 2013H7N9 and 2017H7N9. We also did epitope mapping of these anti-H7 antibodies. Anti-H7 antibodies recognized critical and highly conserved regions of HA in H7 viruses. | en |
| dc.description.provenance | Made available in DSpace on 2021-07-10T21:43:31Z (GMT). No. of bitstreams: 1 U0001-2207202016325100.pdf: 5497275 bytes, checksum: ce3dd73360af6c74d99250324f9efcdb (MD5) Previous issue date: 2020 | en |
| dc.description.tableofcontents | 謝辭 2 摘要 3 Abstract 5 目錄 8 圖目錄 11 表目錄 13 第一章 緒論 14 1.1流感病毒 14 1.1.1流感病毒的結構 14 1.1.2流感病毒的複製 15 1.2流感病毒的流行病學及世界大流行 17 1.3 流感病毒H7與H7N9的生成及演化 18 1.4 A型流感病毒的抗病毒治療方法 20 1.4.1 A型流感病毒的治療 20 1.4.2 H7N9的抗藥性問題 21 1.4.3 流感病毒中和性抗體 22 1.4.4 研究動機及目的 23 第二章 材料及方法 24 2.1 材料 24 2.1.1 細胞 24 2.1.2 流感病毒株 24 2.1.3 細胞培養液及試劑 24 2.1.4 抗體 25 2.1.5 商業化套組 26 2.1.6 質體 26 2.1.7 引子 27 2.1.8 勝任細胞(Competent Cell) 27 2.1.9 細菌培養系統 27 2.1.10 限制酶 27 2.2 方法 28 2.2.1 細胞培養 28 2.2.2 病毒培養 28 2.2.3 溶菌斑試驗 29 2.2.4 病毒核酸萃取 29 2.2.5 反轉錄聚合酶鏈鎖反應 30 2.2.6 核酸膠體純化 30 2.2.7 熱衝擊轉型 (Heat- Shock Transfoemation) 30 2.2.8 細菌質體萃取 31 2.2.9 百分之五十組織培養感染劑量(TCID50) 31 2.2.10 微量中和試驗 32 2.2.11 轉染 (Transfection) 33 2.2.12 免疫螢光染色 33 2.2.13 溶菌斑減少中和試驗 (Plaque reduction neutralization assay) 34 2.2.14 定位突變試驗 (Site-directed mutagenesis) 34 2.2.15 重組病毒生成 34 2.2.16 病毒生長曲線測定 35 2.2.17 以流式細胞儀定量抗體結合率 35 2.2.18 單步驟即時定量聚合酶連鎖反應(One-step real-time PCR) 36 第三章 實驗結果 37 3.1抗體的生成與初步篩選 37 3.2廣效結合力的測試 38 3.3中和機制的探討 39 3.4可掙脫抗體的突變病毒篩選 40 3.5突變點對抗體結合力的影響 43 3.6重組病毒的生成與生長測試 44 3.7突變點對抗體中和力的影響 46 第四章 實驗討論 48 圖表 53 附錄 89 參考文獻 90 | |
| dc.language.iso | zh-TW | |
| dc.subject | 流感病毒 | zh_TW |
| dc.subject | H7 流感病毒 | zh_TW |
| dc.subject | H7N9 | zh_TW |
| dc.subject | 中和性抗體 | zh_TW |
| dc.subject | 血球凝集素突變點 | zh_TW |
| dc.subject | Influenza virus | en |
| dc.subject | Hemagglutinin mutation | en |
| dc.subject | Neutralizing antibody | en |
| dc.subject | H7 viruses | en |
| dc.subject | H7N9 | en |
| dc.title | 探討針對A型流感H7病毒之治療性單株抗體 | zh_TW |
| dc.title | Characterization of Therapeutic Monoclonal Antibodies Against H7 influenza A viruses | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 108-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 高全良(Chuan-Liang Kao),李君男(Chun-Nan Lee),劉麗鶯(Li-Ying Liu) | |
| dc.subject.keyword | 流感病毒,H7 流感病毒,H7N9,中和性抗體,血球凝集素突變點, | zh_TW |
| dc.subject.keyword | Influenza virus,H7 viruses,H7N9,Neutralizing antibody,Hemagglutinin mutation, | en |
| dc.relation.page | 96 | |
| dc.identifier.doi | 10.6342/NTU202001744 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2020-07-24 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 醫學檢驗暨生物技術學研究所 | zh_TW |
| 顯示於系所單位： | 醫學檢驗暨生物技術學系 | |
文件中的檔案：
| 檔案 | 大小 | 格式 | |
|---|---|---|---|
| U0001-2207202016325100.pdf 未授權公開取用 | 5.37 MB | Adobe PDF |
系統中的文件，除了特別指名其著作權條款之外，均受到著作權保護，並且保留所有的權利。