沙門氏菌感染是一門常見的人畜共通傳染性疾病，其主要感染途徑食媒性途徑進入人體，造成腸炎、腹瀉甚至引起傷寒熱。沙門氏菌能夠藉由多種毒力因子的表達去干擾宿主細胞的細胞骨架重組、自噬作用 (Autophagy) 和細胞凋亡 (Cell apoptosis) 等細胞訊息調節途徑而提升其致病性，並藉由自噬體 (Autophagosome) 存活於宿主細胞中，造成難以根治的沙門氏菌感染症 (Salmonellosis)。先前研究顯示，由人類與小鼠共同表達且被視為腫瘤抑制因子的含雙色胺酸功能區氧化還原酶 (WW domain-containing oxidoreductase, WWOX) 其所參與的細胞內訊息調節路徑與沙門氏菌所誘導的宿主細胞反應路徑多有重疊。因此，我們假設WWOX可能在沙門氏菌與宿主的相互作用中起作用，並設計實驗去探討WWOX在沙門氏菌感染宿主的過程中所扮演的角色。
在為期10天的沙門氏菌口腔感染小鼠模型中，Wwox異質型（Wwox +/-）與Wwox野生型（Wwox + / +）小鼠相比，其清除入侵沙門氏菌的能力較低，並伴隨較低的存活率。這樣的結果顯示，Wwox能夠協助宿主抵禦經由攝食感染的沙門氏菌。同樣地，在骨髓分化巨噬細胞 (Bone marrow derived macrophages, BMDMs) 的感染實驗中，與衍生自Wwox + / + BMDMs相比，衍生自Wwox +/-和Wwox-/-小鼠的BMDMs傾向於表現出較嚴重的感染程度，並伴隨著較高程度的自噬作用與較低程度的細胞凋亡傾向和細胞激素分泌。這些結果顯示，Wwox的確能夠協助宿主巨噬細胞抵禦沙門氏菌的感染。在為期3天的沙門氏菌口腔感染小鼠模型中，儘管感染後的Wwox + / + 和Wwox +/- 小鼠表現相似的體重變化和糞便與器官菌數計數，Wwox +/-相較於Wwox + / +小鼠在盲腸的細胞激素（MCP-1和IL-6）表現上卻有較低的傾向。這樣的結果亦反應於免疫細胞的表現上，感染後的Wwox +/-小鼠在盲腸B細胞、單核細胞和顆粒細胞的比率上亦較Wwox + / +小鼠低。這些結果顯示，Wwox可能能於細菌感染早期協助誘導宿主的免疫反應，並在感染後期減少沙門氏菌的入侵與感染所造成的器官組織損傷，而有助於提升小鼠感染後的存活率。
綜合上述，我們證明了WWOX可以協助宿主控制沙門氏菌的感染。這一發現有助於我們了解WWOX在沙門氏菌感染中的作用，從這項研究中所獲得的知識有助於開發針對細菌感染所使用的新型抗菌策略。

Salmonella infection is a common bacterial infection in both humans and animals. The main infection route of the bacteria is through oral ingestion, consequently causing intestinal inflammation, diarrhea and even typhoid fever. Salmonella exerts its pathogenicity through interfering with the cytoskeletal reorganization, autophagy and apoptosis pathways of host cells. Previous studies have shown that the WW domain-containing oxidoreductase (WWOX), which is known as a tumor suppressor in hosts, is involved in regulating the intracellular signaling pathways that are also involved in the host cell responses to Salmonella infection. Therefore, we hypothesized that WWOX may play a role in the Salmonella-host interaction.
In mice oral infection model, Wwox facilitated host animals to resist Salmonella infection, because Wwox heterogeneous type (Wwox+/-) mice showed decreased abilities to clear invading Salmonella and showed decreased survival rates than the Wwox wild-type (Wwox+/+) mice after Salmonella infection for 10 days. Consistently, in comparison with bone marrow derived macrophages (BMDMs) come from the wild type mice, BMDMs derived from Wwox+/- and Wwox-/- mice tend to show higher levels of infection, accompanied by higher levels of autophagy and lower levels of apoptosis and cytokine secretion. These findings suggest that Wwox contribute to host resistance against Salmonella infection. At 3 days post oral infection, Wwox+/- mice showed lower levels of cytokines (MCP-1 and IL-6) and lower amounts of immune cells (B cells, monocytes, and granulocytes) in the cecum than the wild-type mice, although both type of animals showed similar levels of fecal and organ bacterial burden and similar weight change. These results suggest that Wwox may contribute to immune response induction in the early stage of infection and subsequently reduced the invading bacteria burden and tissue damage in the later stage of the infection.
In summary, we demonstrate that WWOX can facilitate host to control Salmonella infections. This finding helps us understand the role of WWOX in Salmonella infections. The knowledge derived from this study may facilitate the development of novel antimicrobial strategies to against bacterial infections.

1. Popoff, M.Y., J. Bockemuhl, and L.L. Gheesling, Supplement 2002 (no. 46) to the Kauffmann-White scheme. Res Microbiol, 2004. 155(7): p. 568-70.
2. D'Aoust, J.-Y., Salmonella and the international food trade. International Journal of Food Microbiology, 1994. 24(1): p. 11-31.
3. Crump, J.A., S.P. Luby, and E.D. Mintz, The global burden of typhoid fever. Bull World Health Organ, 2004. 82(5): p. 346-53.
4. Blaser, M.J. and L.S. Newman, A review of human salmonellosis: I. Infective dose. Rev Infect Dis, 1982. 4(6): p. 1096-106.
5. Chen, J., et al., Salmonella septic arthritis in systemic lupus erythematosus and other systemic diseases. Clinical rheumatology, 1998. 17(4): p. 282-287.
6. Jepson, M.A. and M.A. Clark, The role of M cells in Salmonella infection. Microbes Infect, 2001. 3(14-15): p. 1183-90.
7. Sansonetti, P., Host–pathogen interactions: the seduction of molecular cross talk. Gut, 2002. 50(suppl 3): p. iii2-iii8.
8. Van Der Heijden, J. and B.B. Finlay, Type III effector-mediated processes in Salmonella infection. Future microbiology, 2012. 7(6): p. 685-703.
9. Liu, Y., et al., Mechanisms of acid tolerance in bacteria and prospects in biotechnology and bioremediation. Biotechnol Adv, 2015. 33(7): p. 1484-92.
10. Malik Kale, P., et al., Salmonella–at home in the host cell. Frontiers in microbiology, 2011. 2: p. 125.
11. Ashida, H., M. Kim, and C. Sasakawa, Exploitation of the host ubiquitin system by human bacterial pathogens. Nature Reviews Microbiology, 2014. 12: p. 399.
12. Lamas, A., et al., A comprehensive review of non-enterica subspecies of Salmonella enterica. Microbiological research, 2018. 206: p. 60-73.
13. Zhang, S., et al., Molecular pathogenesis of Salmonella enterica serotype typhimurium-induced diarrhea. Infect Immun, 2003. 71(1): p. 1-12.
14. Hapfelmeier, S. and W.D. Hardt, A mouse model for S. typhimurium-induced enterocolitis. Trends Microbiol, 2005. 13(10): p. 497-503.
15. Watson, K.G. and D.W. Holden, Dynamics of growth and dissemination of Salmonella in vivo. Cell Microbiol, 2010. 12(10): p. 1389-97.
16. Barthel, M., et al., Pretreatment of mice with streptomycin provides a Salmonella enterica serovar Typhimurium colitis model that allows analysis of both pathogen and host. Infect Immun, 2003. 71(5): p. 2839-58.
17. Galan, J.E. and D. Zhou, Striking a balance: modulation of the actin cytoskeleton by Salmonella. Proc Natl Acad Sci U S A, 2000. 97(16): p. 8754-61.
18. Ribet, D. and P. Cossart, How bacterial pathogens colonize their hosts and invade deeper tissues. Microbes Infect, 2015. 17(3): p. 173-83.
19. Ramos-Morales, F., Impact of Salmonella enterica type III secretion system effectors on the eukaryotic host cell. ISRN Cell Biology, 2012. 2012.
20. Ohlson, M.B., et al., Structure and function of Salmonella SifA indicate that its interactions with SKIP, SseJ, and RhoA family GTPases induce endosomal tubulation. Cell Host Microbe, 2008. 4(5): p. 434-46.
21. Haraga, A., M.B. Ohlson, and S.I. Miller, Salmonellae interplay with host cells. Nat Rev Microbiol, 2008. 6(1): p. 53-66.
22. Steele-Mortimer, O., The Salmonella-containing vacuole: moving with the times. Curr Opin Microbiol, 2008. 11(1): p. 38-45.
23. Garcia-del Portillo, F., et al., Growth control in the Salmonella-containing vacuole. Curr Opin Microbiol, 2008. 11(1): p. 46-52.
24. Beuzón, C.R., et al., Salmonella maintains the integrity of its intracellular vacuole through the action of SifA. The EMBO journal, 2000. 19(13): p. 3235-3249.
25. Brumell, J.H., et al., SifA permits survival and replication of Salmonella typhimurium in murine macrophages. Cellular microbiology, 2001. 3(2): p. 75-84.
26. Ganesan, R., et al., Salmonella Typhimurium disrupts Sirt1/AMPK checkpoint control of mTOR to impair autophagy. PLoS pathogens, 2017. 13(2): p. e1006227.
27. Owen, K.A., et al., Activation of focal adhesion kinase by Salmonella suppresses autophagy via an Akt/mTOR signaling pathway and promotes bacterial survival in macrophages. PLoS pathogens, 2014. 10(6): p. e1004159.
28. Casanova, J.E., Bacterial Autophagy: Offense and Defense at the Host-Pathogen Interface. Cell Mol Gastroenterol Hepatol, 2017. 4(2): p. 237-243.
29. Wang, L., et al., Autophagy and Ubiquitination in Salmonella Infection and the Related Inflammatory Responses. Frontiers in Cellular and Infection Microbiology, 2018. 8(78).
30. Collier-Hyams, L.S., et al., Cutting edge: Salmonella AvrA effector inhibits the key proinflammatory, anti-apoptotic NF-kappa B pathway. J Immunol, 2002. 169(6): p. 2846-50.
31. Jones, R.M., et al., Salmonella AvrA Coordinates Suppression of Host Immune and Apoptotic Defenses via JNK Pathway Blockade. Cell Host Microbe, 2008. 3(4): p. 233-44.
32. Wu, H., R.M. Jones, and A.S. Neish, The Salmonella effector AvrA mediates bacterial intracellular survival during infection in vivo. Cell Microbiol, 2012. 14(1): p. 28-39.
33. Wu, S., et al., Salmonella typhimurium infection increases p53 acetylation in intestinal epithelial cells. American Journal of Physiology-Gastrointestinal and Liver Physiology, 2010. 298(5): p. G784-G794.
34. Knodler, L.A., B.B. Finlay, and O. Steele-Mortimer, The Salmonella effector protein SopB protects epithelial cells from apoptosis by sustained activation of Akt. J Biol Chem, 2005. 280(10): p. 9058-64.
35. Brennan, M.A. and B.T. Cookson, Salmonella induces macrophage death by caspase-1-dependent necrosis. Mol Microbiol, 2000. 38(1): p. 31-40.
36. Fink, S.L. and B.T. Cookson, Apoptosis, pyroptosis, and necrosis: mechanistic description of dead and dying eukaryotic cells. Infect Immun, 2005. 73(4): p. 1907-16.
37. Hersh, D., et al., The <em>Salmonella</em> invasin SipB induces macrophage apoptosis by binding to caspase-1. Proceedings of the National Academy of Sciences, 1999. 96(5): p. 2396-2401.
38. Miao, E.A., et al., Cytoplasmic flagellin activates caspase-1 and secretion of interleukin 1beta via Ipaf. Nat Immunol, 2006. 7(6): p. 569-75.
39. Miao, E.A., et al., Innate immune detection of the type III secretion apparatus through the NLRC4 inflammasome. Proc Natl Acad Sci U S A, 2010. 107(7): p. 3076-80.
40. Monack, D.M., C.S. Detweiler, and S. Falkow, Salmonella pathogenicity island 2-dependent macrophage death is mediated in part by the host cysteine protease caspase-1. Cell Microbiol, 2001. 3(12): p. 825-37.
41. Rytkönen, A., et al., SseL, a Salmonella deubiquitinase required for macrophage killing and virulence. Proceedings of the National Academy of Sciences, 2007. 104(9): p. 3502-3507.
42. Ganz, T., Defensins: antimicrobial peptides of innate immunity. Nature reviews immunology, 2003. 3(9): p. 710.
43. Brogden, K.A., Antimicrobial peptides: pore formers or metabolic inhibitors in bacteria? Nature reviews microbiology, 2005. 3(3): p. 238.
44. Broz, P., M.B. Ohlson, and D.M. Monack, Innate immune response to Salmonella typhimurium, a model enteric pathogen. Gut Microbes, 2012. 3(2): p. 62-70.
45. Martin, T.R. and C.W. Frevert, Innate immunity in the lungs. Proceedings of the American Thoracic Society, 2005. 2(5): p. 403-411.
46. Mogensen, T.H., Pathogen Recognition and Inflammatory Signaling in Innate Immune Defenses. Clinical Microbiology Reviews, 2009. 22(2): p. 240-273.
47. Miao, E.A., et al., Caspase-1-induced pyroptosis is an innate immune effector mechanism against intracellular bacteria. Nat Immunol, 2010. 11(12): p. 1136-42.
48. Thiennimitr, P., S.E. Winter, and A.J. Baumler, Salmonella, the host and its microbiota. Curr Opin Microbiol, 2012. 15(1): p. 108-14.
49. Voedisch, S., et al., Mesenteric Lymph Nodes Confine Dendritic Cell-Mediated Dissemination of Salmonella enterica Serovar Typhimurium and Limit Systemic Disease in Mice. Infection and Immunity, 2009. 77(8): p. 3170-3180.
50. Tobar, J.A., et al., Virulent Salmonella enterica Serovar Typhimurium Evades Adaptive Immunity by Preventing Dendritic Cells from Activating T Cells. Infection and Immunity, 2006. 74(11): p. 6438-6448.
51. Kalupahana, R.S., et al., Activation of murine dendritic cells and macrophages induced by Salmonella enterica serovar Typhimurium. Immunology, 2005. 115(4): p. 462-72.
52. Delamarre, L., et al., Differential lysosomal proteolysis in antigen-presenting cells determines antigen fate. Science, 2005. 307(5715): p. 1630-4.
53. Pietila, T.E., et al., Activation, cytokine production, and intracellular survival of bacteria in Salmonella-infected human monocyte-derived macrophages and dendritic cells. J Leukoc Biol, 2005. 78(4): p. 909-20.
54. Lo, W.F., et al., T cell responses to Gram-negative intracellular bacterial pathogens: a role for CD8+ T cells in immunity to Salmonella infection and the involvement of MHC class Ib molecules. J Immunol, 1999. 162(9): p. 5398-406.
55. Janeway, C.A., et al., Immunobiology: the immune system in health and disease. Vol. 7. 1996: Current Biology London.
56. Chesnut, R.W. and H.M. Grey, Studies on the capacity of B cells to serve as antigen-presenting cells. J Immunol, 1981. 126(3): p. 1075-9.
57. Mastroeni, P., et al., Igh-6(-/-) (B-cell-deficient) mice fail to mount solid acquired resistance to oral challenge with virulent Salmonella enterica serovar typhimurium and show impaired Th1 T-cell responses to Salmonella antigens. Infect Immun, 2000. 68(1): p. 46-53.
58. Mizuno, Y., et al., Th1 and Th1‐inducing cytokines in Salmonella infection. Clinical & Experimental Immunology, 2003. 131(1): p. 111-117.
59. Kak, G., M. Raza, and B.K. Tiwari, Interferon-gamma (IFN-gamma): Exploring its implications in infectious diseases. Biomol Concepts, 2018. 9(1): p. 64-79.
60. Casadevall, A., Antibody-mediated protection against intracellular pathogens. Trends in microbiology, 1998. 6(3): p. 102-107.
61. Ravindran, R. and S.J. McSorley, Tracking the dynamics of T‐cell activation in response to Salmonella infection. Immunology, 2005. 114(4): p. 450-458.
62. Chan, K.L., et al., Replication stress induces sister-chromatid bridging at fragile site loci in mitosis. Nature cell biology, 2009. 11(6): p. 753.
63. Salah, Z., R. Aqeilan, and K. Huebner, WWOX gene and gene product: tumor suppression through specific protein interactions. Future Oncology, 2010. 6(2): p. 249-259.
64. Aqeilan, R.I., et al., Targeted deletion of Wwox reveals a tumor suppressor function. Proceedings of the National Academy of Sciences, 2007. 104(10): p. 3949-3954.
65. Aqeilan, R.I., et al., Inactivation of the Wwox gene accelerates forestomach tumor progression in vivo. Cancer research, 2007. 67(12): p. 5606-5610.
66. Aqeilan, R.I., et al., The WWOX tumor suppressor is essential for postnatal survival and normal bone metabolism. Journal of Biological Chemistry, 2008. 283(31): p. 21629-21639.
67. Chang, N.S., et al., WW domain-containing oxidoreductase: a candidate tumor suppressor. Trends Mol Med, 2007. 13(1): p. 12-22.
68. Macias, M.J., et al., Structure of the WW domain of a kinase-associated protein complexed with a proline-rich peptide. Nature, 1996. 382(6592): p. 646-649.
69. Lusk, C.P., G. Blobel, and M.C. King, Highway to the inner nuclear membrane: rules for the road. Nature Reviews Molecular Cell Biology, 2007. 8(5): p. 414-420.
70. Salah, Z., R. Aqeilan, and K. Huebner, WWOX gene and gene product: tumor suppression through specific protein interactions. Future Oncol, 2010. 6(2): p. 249-59.
71. Huang, S.-S., et al., Role of WW domain-containing oxidoreductase WWOX in driving T cell acute lymphoblastic leukemia maturation. Journal of Biological Chemistry, 2016. 291(33): p. 17319-17331.
72. Chang, N.-S., et al., WOX1 is essential for tumor necrosis factor-, UV light-, staurosporine-, and p53-mediated cell death, and its tyrosine 33-phosphorylated form binds and stabilizes serine 46-phosphorylated p53. Journal of Biological Chemistry, 2005. 280(52): p. 43100-43108.
73. Mahajan, N.P., et al., Activated tyrosine kinase Ack1 promotes prostate tumorigenesis: role of Ack1 in polyubiquitination of tumor suppressor Wwox. Cancer research, 2005. 65(22): p. 10514-10523.
74. Roberts, R.E. and M.B. Hallett, Neutrophil cell shape change: mechanism and signalling during cell spreading and phagocytosis. International journal of molecular sciences, 2019. 20(6): p. 1383.
75. Ivetic, A. and A.J. Ridley, Ezrin/radixin/moesin proteins and Rho GTPase signalling in leucocytes. Immunology, 2004. 112(2): p. 165-176.
76. Patel, S. and B.A. McCormick, Mucosal inflammatory response to Salmonella typhimurium infection. Frontiers in immunology, 2014. 5: p. 311.
77. Jin, C., et al., PKA-mediated protein phosphorylation regulates ezrin-WWOX interaction. Biochem Biophys Res Commun, 2006. 341(3): p. 784-91.
78. Pimenta, F.J., et al., Characterization of the tumor suppressor gene WWOX in primary human oral squamous cell carcinomas. International journal of cancer, 2006. 118(5): p. 1154-1158.
79. Genestier, L., et al., Mechanisms of action of methotrexate. Immunopharmacology, 2000. 47(2-3): p. 247.
80. Tsai, C., et al., WWOX suppresses autophagy for inducing apoptosis in methotrexate-treated human squamous cell carcinoma. Cell death & disease, 2013. 4(9): p. e792.
81. Nunez, M.I., J. Ludes-Meyers, and C.M. Aldaz, WWOX protein expression in normal human tissues. Journal of molecular histology, 2006. 37(3-4): p. 115-125.
82. Ludes-Meyers, J.H., et al., Generation and characterization of mice carrying a conditional allele of the Wwox tumor suppressor gene. PLoS One, 2009. 4(11): p. e7775.
83. Aqeilan, R.I., et al., Functional association between Wwox tumor suppressor protein and p73, a p53 homolog. Proceedings of the National Academy of Sciences, 2004. 101(13): p. 4401-4406.
84. Chang, N.-S., J. Doherty, and A. Ensign, JNK1 physically interacts with WW domain-containing oxidoreductase (WOX1) and inhibits WOX1-mediated apoptosis. Journal of Biological Chemistry, 2003. 278(11): p. 9195-9202.
85. McBride, K.M., et al., Wwox Deletion in Mouse B Cells Leads to Genomic Instability, Neoplastic Transformation, and Monoclonal Gammopathies. Front Oncol, 2019. 9: p. 517.
86. Uhlen, M., et al., Proteomics. Tissue-based map of the human proteome. Science, 2015. 347(6220): p. 1260419.
87. Del Mare, S., Z. Salah, and R.I. Aqeilan, WWOX: its genomics, partners, and functions. Journal of cellular biochemistry, 2009. 108(4): p. 737-745.
88. Yan, J., et al., Helicobacter pylori infection promotes methylation of WWOX gene in human gastric cancer. Biochem Biophys Res Commun, 2011. 408(1): p. 99-102.
89. Liu, P., N.A. Jenkins, and N.G. Copeland, A highly efficient recombineering-based method for generating conditional knockout mutations. Genome Res, 2003. 13(3): p. 476-84.
90. Chang, J.Y., et al., Trafficking protein particle complex 6A delta (TRAPPC6ADelta) is an extracellular plaque-forming protein in the brain. Oncotarget, 2015. 6(6): p. 3578-89.
91. Stanley, E.R., et al., The biology and action of colony stimulating factor-1. Stem Cells, 1994. 12 Suppl 1: p. 15-24; discussion 25.
92. Trouplin, V., et al., Bone marrow-derived macrophage production. J Vis Exp, 2013(81): p. e50966.
93. Borowitz, M., et al., Clinical applications of flow cytometry: Quality assurance and immunophenotyping of lymphocytes; approved guideline. 1998: NCCLS.
94. Milano, F., et al., Expression pattern of immune suppressive cytokines and growth factors in oesophageal adenocarcinoma reveal a tumour immune escape-promoting microenvironment. Scand J Immunol, 2008. 68(6): p. 616-23.
95. Collins, T.J., ImageJ for microscopy. Biotechniques, 2007. 43(S1): p. S25-S30.
96. Bode, C., S. Bhoopathy, and I.J. Hidalgo. Using Lentiviral Vector-Based shRNA to silence the expression and function of ABC Transporter (s) in Caco-2 Cells. in DRUG METABOLISM REVIEWS. 2011. INFORMA HEALTHCARE TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND.
97. Napier, B.A. and D.M. Monack, Creating a RAW264. 7 CRISPR-Cas9 Genome Wide Library. Bio-protocol, 2017. 7(10).
98. Fang, F.C., Antimicrobial reactive oxygen and nitrogen species: concepts and controversies. Nature Reviews Microbiology, 2004. 2(10): p. 820-832.
99. Liu, W., et al., Activation of TGF-β-activated kinase 1 (TAK1) restricts Salmonella Typhimurium growth by inducing AMPK activation and autophagy. Cell death & disease, 2018. 9(5): p. 570.
100. Napier, B.A., et al., Complement pathway amplifies caspase-11–dependent cell death and endotoxin-induced sepsis severity. Journal of Experimental Medicine, 2016. 213(11): p. 2365-2382.
101. Hammill, A.K., J.W. Uhr, and R.H. Scheuermann, Annexin V staining due to loss of membrane asymmetry can be reversible and precede commitment to apoptotic death. Experimental cell research, 1999. 251(1): p. 16-21.
102. Carr, M.W., et al., Monocyte chemoattractant protein 1 acts as a T-lymphocyte chemoattractant. Proceedings of the National Academy of Sciences, 1994. 91(9): p. 3652-3656.
103. Xu, L.L., et al., Human recombinant monocyte chemotactic protein and other C‐C chemokines bind and induce directional migration of dendritic cells in vitro. Journal of leukocyte biology, 1996. 60(3): p. 365-371.
104. Lee, M., Lippincott’s Illustrated Reviews: Immunology. Seoul: shinilbooks, 2008: p. 195-9.
105. Zaki, M.H., et al., Salmonella exploits NLRP12-dependent innate immune signaling to suppress host defenses during infection. Proceedings of the National Academy of Sciences, 2014. 111(1): p. 385-390.
106. Barthel, M., et al., Pretreatment of mice with streptomycin provides a Salmonella enterica serovar Typhimurium colitis model that allows analysis of both pathogen and host. Infection and immunity, 2003. 71(5): p. 2839-2858.
107. Johansson, M.E., H. Sjövall, and G.C. Hansson, The gastrointestinal mucus system in health and disease. Nature reviews Gastroenterology & hepatology, 2013. 10(6): p. 352.
108. Ugrinovic, S., et al., Characterization and development of T-Cell immune responses in B-cell-deficient (Igh-6(-/-)) mice with Salmonella enterica serovar Typhimurium infection. Infect Immun, 2003. 71(12): p. 6808-19.
109. Hsu, P.D., et al., DNA targeting specificity of RNA-guided Cas9 nucleases. Nature Biotechnology, 2013. 31: p. 827.
110. Liu, F., Y. Song, and D. Liu, Hydrodynamics-based transfection in animals by systemic administration of plasmid DNA. Gene therapy, 1999. 6(7): p. 1258.
111. Xia, X.G., et al., An enhanced U6 promoter for synthesis of short hairpin RNA. Nucleic Acids Research, 2003. 31(17): p. e100-e100.
112. Adra, C.N., P.H. Boer, and M.W. McBurney, Cloning and expression of the mouse pgk-1 gene and the nucleotide sequence of its promoter. Gene, 1987. 60(1): p. 65-74.