1. Buonaguro FM, Tornesello ML, Buonaguro L. New adjuvants in evolving vaccine strategies. Expert opinion on biological therapy. 2011; 11(7): 827-32. https://doi.org/10.1517/14712598.2011.587802 2. Tritto E, Mosca F, De Gregorio E. Mechanism of action of licensed vaccine adjuvants. Vaccine. 2009 May; 27(25-26): 3331-34. doi:10.1016/j.vaccine.2009.01.084 3. Guy B. The perfect mix: recent progress in adjuvant research. Nat Rev Microbiol. 2007 Jul; 5(7): 505-17. doi:10.1038/nrmicro1681 4. Alving CR, Peachman KK, Rao M, Reed SG. Adjuvants for human vaccines. Curr Opin Immunol. 2012; 24(3): 310-15. doi:10.1016/j.coi.2012.03.008 5. Batista-Duharte A, Lindblad EB, Oviedo-Orta E. Progress in understanding adjuvant immunotoxicity mechanisms. Toxicol Lett. 2011 Jun;203(2):97-105. doi:10.1016/j.toxlet.2011.03.001 6. Reed SG, Orr MT, Fox CB. Key roles of adjuvants in modern vaccines. Nat Med. 2013 Dec; 19(12): 1597-608. doi:10.1038/nm.3409 7. Savelkoul HF, Ferro VA, Strioga MM, Schijns VE. Choice and Design of Adjuvants for Parenteral and Mucosal Vaccines. Vaccines (Basel). 2015 Mar; 3(1): 148-71. doi:10.3390/vaccines3010148 8. Fox CB, Baldwin SL, Duthie MS, Reed SG, Vedvick TS. Immunomodulatory and physical effects of oil composition in vaccine adjuvant emulsions. Vaccine. 2011 Nov; 29(51): 9563-72. doi:10.1016/j.vaccine.2011.08.089 9. Morel S, Didierlaurent A, Bourguignon P, Delhaye S, Baras B, Jacob V, et al. Adjuvant System AS03 containing -tocopherol modulates innate immune response and leads to improved adaptive immunity. Vaccine. 2011 Mar; 29(13): 2461-73. doi:10.1016/j.vaccine.2011.01.011 10. Mosca F, Tritto E, Muzzi A, Monaci E, Bagnoli F, Iavarone C, et al. Molecular and cellular signatures of human vaccine adjuvants. Proc Natl Acad Sci USA. 2008; 105(30): 10501-6. https://doi.org/10.1073/pnas.0804699105 11. Kool M, Fierens K, Lambrecht BN. Alum adjuvant: some of the tricks of the oldest adjuvant. J Med Microbiol. 2012 Jul; 61(Pt 7): 927-34. doi:10.1099/jmm.0.038943-0 12. Maughan CN, Preston SG, Williams GR. Particulate inorganic adjuvants: recent developments and future outlook. J Pharm Pharmacol. 2015 Mar; 67(3): 426-49. doi:10.1111/jphp.12352 13. Vogel FR, Powell MF. A compendium of vaccine adjuvants and excipients. Pharm Biotechnol. 1995; 6: 141-228. 14. Exley C. When an aluminium adjuvant is not an aluminium adjuvant used in human vaccination programmes. Vaccine. 2012 Mar; 30(12): 2042. doi:10.1016/j.vaccine.2011.10.042 15. Bleam WF, Pfeffer PE, Goldberg S, Taylor RW, Dudley R. A phosphorus-31 solid-state nuclear magnetic resonance study of phosphate adsorption at the boehmite/aqueous solution interface. Langmuir. 1991; 7(8): 1702-12. doi:10.1021/la00056a023 16. Lu F, Boutselis I, Borch RF, Hogenesch H. Control of antigen-binding to aluminum adjuvants and the immune response with a novel phosphonate linker. Vaccine. 2013 Sep; 31(40): 4362-67. doi:10.1016/j.vaccine.2013.07.019 17. Chang M, Shi Y, Nail SL, HogenEsch H, Adams SB, White JL, et al. Degree of antigen adsorption in the vaccine or interstitial fluid and its effect on the antibody response in rabbits. Vaccine. 2001 Apr; 19(20-22): 2884-89. 18. Gupta RK, Chang AC, Griffin P, Rivera R, Siber GR. In vivo distribution of radioactivity in mice after injection of biodegradable polymer microspheres containing 14C-labeled tetanus toxoid. Vaccine. 1996 Oct; 14(15): 1412-16. 19. Hutchison S, Benson RA, Gibson VB, Pollock AH, Garside P, Brewer JM. Antigen depot is not required for alum adjuvanticity. FASEB J. 2012 Mar; 26(3): 1272-79. doi:10.1096/fj.11-184556 20. Munks MW, McKee AS, Macleod MK, Powell RL, Degen JL, Reisdorph NA, et al. Aluminum adjuvants elicit fibrin-dependent extracellular traps in vivo. Blood. 2010 Dec; 116(24): 5191-99. doi:10.1182/blood-2010-03-275529 21. Calabro S, Tortoli M, Baudner BC, Pacitto A, Cortese M, O'Hagan DT, et al. Vaccine adjuvants alum and MF59 induce rapid recruitment of neutrophils and monocytes that participate in antigen transport to draining lymph nodes. Vaccine. 2011 Feb; 29(9): 1812-23. doi:10.1016/j.vaccine.2010.12.090 22. McKee AS, Munks MW, MacLeod MK, Fleenor CJ, Van Rooijen N, Kappler JW, et al. Alum induces innate immune responses through macrophage and mast cell sensors, but these sensors are not required for alum to act as an adjuvant for specific immunity. J Immunol. 2009 Oct; 183(7): 4403-14. doi:10.4049/jimmunol.0900164 23. Mantovani A, Cassatella MA, Costantini C, Jaillon S. Neutrophils in the activation and regulation of innate and adaptive immunity. Nat Rev Immunol. 2011 Jul; 11(8): 519-31. doi:10.1038/nri3024 24. Wang HB, Weller PF. Pivotal advance: eosinophils mediate early alum adjuvant-elicited B cell priming and IgM production. J Leukoc Biol. 2008 Apr; 83(4): 817-21. doi:10.1189/jlb.0607392 25. Kuroda E, Ishii KJ, Uematsu S, Ohata K, Coban C, Akira S, et al. Silica crystals and aluminum salts regulate the production of prostaglandin in macrophages via NALP3 inflammasome-independent mechanisms. Immunity. 2011 Apr; 34(4): 514-26. doi:10.1016/j.immuni.2011.03.019 26. Brewer JM, Conacher M, Satoskar A, Bluethmann H, Alexander J. In interleukin-4-deficient mice, alum not only generates T helper 1 responses equivalent to freund's complete adjuvant, but continues to induce T helper 2 cytokine production. Eur J Immunol. 1996 Sep; 26(9): 2062-66. doi:10.1002/eji.1830260915 27. Tavassoli A, Haghparast A. [Inflammasomes and their role in diseases]. J Isfahan Med Sch. 2014; 32(304): 1668-89. [Article in Persian] 28. Agostini L, Martinon F, Burns K, McDermott MF, Hawkins PN, Tschopp J. NALP3 forms an IL-1beta-processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder. Immunity. 2004 Mar; 20(3):319-25. 29. Tschopp J, Schroder K. NLRP3 inflammasome activation: The convergence of multiple signalling pathways on ROS production? Nat Rev Immunol. 2010 Mar; 10(3): 210-5. doi:10.1038/nri2725 30. Lambrecht BN, Kool M, Willart MA, Hammad H. Mechanism of action of clinically approved adjuvants. Curr Opin Immunol. 2009 Feb; 21(1): 23-29. doi:10.1016/j.coi.2009.01.004 31. Huber M, Beuscher HU, Rohwer P, Kurrle R, Röllinghoff M, Lohoff M. Costimulation via TCR and IL-1 receptor reveals a novel IL-1-mediated autocrine pathway of Th2 cell proliferation. J Immunol. 1998; 160(9): 4242-47. 32. Kool M, Soullié T, van Nimwegen M, Willart MA, Muskens F, Jung S, et al. Alum adjuvant boosts adaptive immunity by inducing uric acid and activating inflammatory dendritic cells. J Exp Med. 2008 Apr; 205(4): 869-82. doi:10.1084/jem.20071087 33. Marichal T, Ohata K, Bedoret D, Mesnil C, Sabatel C, Kobiyama K, et al. DNA released from dying host cells mediates aluminum adjuvant activity. Nat Med. 2011 Jul; 17(8): 996-1002. doi:10.1038/nm.2403 34. McKee AS, Burchill MA, Munks MW, Jin L, Kappler JW, Friedman RS, et al. Host DNA released in response to aluminum adjuvant enhances MHC class II-mediated antigen presentation and prolongs CD4 T-cell interactions with dendritic cells. Proc Natl Acad Sci U S A. 2013 Mar; 110(12): E1122-31. doi:10.1073/pnas.1300392110 35. Oleszycka E, Lavelle EC. Immunomodulatory properties of the vaccine adjuvant alum. Curr Opin Immunol. 2014 Jun; 28: 1-5. doi:10.1016/j.coi.2013.12.007 36. De Gregorio E, Caproni E, Ulmer JB. Vaccine adjuvants: mode of action. Front Immunol. 2013 Jul; 4: 214. doi:10.3389/fimmu.2013.00214 37. Hogenesch H. Mechanism of immunopotentiation and safety of aluminum adjuvants. Front Immunol. 2013 Jan; 3: 406. doi:10.3389/fimmu.2012.00406 38. Duthie MS, Windish HP, Fox CB, Reed SG. Use of defined TLR ligands as adjuvants within human vaccines. Immunol Rev. 2011 Jan; 239(1): 178-96. doi:10.1111/j.1600-065X.2010.00978.x 39. Yang C, Shi H, Zhou J, Liang Y, Xu H. CpG oligodeoxynucleotides are a potent adjuvant for an inactivated polio vaccine produced from Sabin strains of poliovirus. Vaccine. 2009 Nov; 27(47): 6558-63. doi:10.1016/j.vaccine.2009.08.047 40. Bourne N, Bravo FJ, Francotte M, Bernstein DI, Myers MG, Slaoui M, et al. Herpes simplex virus (HSV) type 2 glycoprotein D subunit vaccines and protection against genital HSV-1 or HSV-2 disease in guinea pigs. J Infect Dis. 2003 Feb; 187(4): 542-49. doi:10.1086/374002 41. Garçon N, Segal L, Tavares F, Van Mechelen M. The safety evaluation of adjuvants during vaccine development: the AS04 experience. Vaccine. 2011 Jun; 29(27): 4453-59. doi:10.1016/j.vaccine.2011.04.046 42. Clapp T, Siebert P, Chen D, Jones Braun L. Vaccines with aluminum-containing adjuvants: optimizing vaccine efficacy and thermal stability. J Pharm Sci. 2011 Feb; 100(2): 388-401. doi:10.1002/jps.22284 43. Relyveld EH. Preparation and use of calcium phosphate adsorbed vaccines. Dev Biol Stand. 1986; 65: 131-36. 44. Jones S, Asokanathan C, Kmiec D, Irvine J, Fleck R, Xing D, et al. Protein coated microcrystals formulated with model antigens and modified with calcium phosphate exhibit enhanced phagocytosis and immunogenicity. Vaccine. 2014; 32(33): 4234-42. doi:10.1016/j.vaccine.2013.09.061 45. Cho WS, Duffin R, Bradley M, Megson IL, Macnee W, Howie SE, et al. NiO and Co3O4 nanoparticles induce lung DTH-like responses and alveolar lipoproteinosis. Eur Respir J. 2012 Mar; 39(3): 546-57. doi:10.1183/09031936.00047111 46. O'Hagan DT. MF59 is a safe and potent vaccine adjuvant that enhances protection against influenza virus infection. Expert Rev Vaccines. 2007 Oct; 6(5): 699-710. doi:10.1586/14760584.6.5.699 47. Vogel FR, Caillet C, Kusters IC, Haensler J. Emulsion-based adjuvants for influenza vaccines. Expert Rev Vaccines. 2009 Apr; 8(4): 483-92. doi:10.1586/erv.09.5 48. Singh M, O'Hagan DT. Recent advances in veterinary vaccine adjuvants. Int J Parasitol. 2003 May; 33(5-6): 469-78. 49. Aucouturier J, Ganne V. Assessment of oil adjuvants in Newcastle disease vaccine. Proceedings of the 20th World Poultry Congress, Montreal, Canada, August; 2000. 50. Durando P, Icardi G, Ansaldi F. MF59-adjuvanted vaccine: a safe and useful tool to enhance and broaden protection against seasonal influenza viruses in subjects at risk. Expert Opin Biol Ther. 2010 Apr; 10(4): 639-51. doi:10.1517/14712591003724662 51. Dupuis M, Denis-Mize K, LaBarbara A, Peters W, Charo IF, McDonald DM, et al. Immunization with the adjuvant MF59 induces macrophage trafficking and apoptosis. Eur J Immunol. 2001 Oct; 31(10): 2910-18. doi:10.1002/1521-4141(2001010)31:10 52. Ellebedy AH, Lupfer C, Ghoneim HE, DeBeauchamp J, Kanneganti TD, Webby RJ. Inflammasome-independent role of the apoptosis-associated speck-like protein containing CARD (ASC) in the adjuvant effect of MF59. Proc Natl Acad Sci U S A. 2011 Feb; 108(7): 2927-32. doi:10.1073/pnas.1012455108 53. Seubert A, Calabro S, Santini L, Galli B, Genovese A, Valentini S, et al. Adjuvanticity of the oil-in-water emulsion MF59 is independent of Nlrp3 inflammasome but requires the adaptor protein MyD88. Proc Natl Acad Sci U S A. 2011 Jul; 108(27): 11169-74. doi:10.1073/pnas.1107941108 54. Vajdy M. Immunomodulatory properties of vitamins, flavonoids and plant oils and their potential as vaccine adjuvants and delivery systems. Expert Opin Biol Ther. 2011 Nov; 11(11): 1501-13. doi:10.1517/14712598.2011.623695 55. Shah RR, Brito LA, O’Hagan DT, Amiji MM. Emulsions as vaccine adjuvants. In: Foged C, Rades T, Perrie Y, Hook S. Subunit Vaccine Delivery. 1st. New York: Springer. 2015; pp: 59-76. 56. Coffman RL, Sher A, Seder RA. Vaccine adjuvants: putting innate immunity to work. Immunity. 2010 Oct; 33(4): 492-503. doi:10.1016/j.immuni.2010.10.002 57. Fox CB, Haensler J. An update on safety and immunogenicity of vaccines containing emulsion-based adjuvants. Expert Rev Vaccines. 2013 Jul; 12(7): 747-58. doi:10.1586/14760584.2013.811188 58. Li P, Wang F. Polysaccharides: Candidates of promising vaccine adjuvants. Drug Discov Ther. 2015 Apr; 9(2): 88-93. doi:10.5582/ddt.2015.01025 59. Agmon-Levin N, Hughes GR, Shoenfeld Y. The spectrum of ASIA: Autoimmune (Auto-inflammatory) Syndrome induced by Adjuvants. Lupus. 2012 Feb; 21(2): 118-20. doi:10.1177/0961203311429316 60. Bekerecioglu M, Onat AM, Tercan M, Buyukhatipoglu H, Karakok M, Isik D, et al. The association between silicone implants and both antibodies and autoimmune diseases. Clin Rheumatol. 2008 Feb; 27(2): 147-50. doi:10.1007/s10067-007-0659-1 61. Hida S, Miura NN, Adachi Y, Ohno N. Cell wall beta-glucan derived from Candida albicans acts as a trigger for autoimmune arthritis in SKG mice. Biol Pharm Bull. 2007 Aug; 30(8): 1589-92. 62. Yoshitomi H, Sakaguchi N, Kobayashi K, Brown GD, Tagami T, Sakihama T, et al. A role for fungal {beta}-glucans and their receptor Dectin-1 in the induction of autoimmune arthritis in genetically susceptible mice. J Exp Med. 2005 Mar; 201(6): 949-60. doi:10.1084/jem.20041758 63. Shakya AK, Nandakumar KS. Applications of polymeric adjuvants in studying autoimmune responses and vaccination against infectious diseases. J R Soc Interface. 2013 Feb; 10(79): 20120536. doi:10.1098/rsif.2012.0536 64. Petrovsky N. Sugar-based immune adjuvants for use in recombinant, viral vector, DNA and other styles of vaccines. In: Lukashevich IS, Shirwan H. Novel technologies for vaccine development. Chap 7. 1st ed. New York: Springer. 2014; pp: 179-200. 65. Huang MH, Huang CY, Lien SP, Siao SY, Chou AH, Chen HW, et al. Development of multi-phase emulsions based on bioresorbable polymers and oily adjuvant. Pharm Res. 2009 Aug; 26(8): 1856-62. doi:10.1007/s11095-009-9898-y 66. Nishiyama A, Tsuji S, Yamashita M, Henriksen RA, Myrvik QN, Shibata Y. Phagocytosis of N-acetyl-D-glucosamine particles, a Th1 adjuvant, by RAW 264.7 cells results in MAPK activation and TNF-alpha, but not IL-10, production. Cell Immunol. 2006 Feb; 239(2): 103-12. doi:10.1016/j.cellimm.2006.04.003 67. Rawal N, Rajagopalan R, Salvi VP. Stringent regulation of complement lectin pathway C3/C5 convertase by C4b-binding protein (C4BP). Mol Immunol. 2009 Sep; 46(15): 2902-10. doi:10.1016/j.molimm.2009.07.006 68. Dong SF, Chen JM, Zhang W, Sun SH, Wang J, Gu JX, et al. Specific immune response to HBsAg is enhanced by beta-glucan oligosaccharide containing an alpha-(1→ 3)-linked bond and biased towards M2/Th2. International immunopharmacology. 2007; 7(6): 725-33. https://doi.org/10.1016/j.intimp.2007.01.004 69. Haghparast A, Zakeri A, Ebrahimian M, Ramezani M. Targeting pattern recognition receptors (PRRs) in nano-adjuvants: current perspectives. Current Bionanotechnology. 2016; 2(1): 47-59. doi:10.2174/2213529402666160601125159 70. De Geest BG, Willart MA, Hammad H, Lambrecht BN, Pollard C, Bogaert P, et al. Polymeric multilayer capsule-mediated vaccination induces protective immunity against cancer and viral infection. ACS Nano. 2012 Mar; 6(3): 2136-49. doi:10.1021/nn205099c 71. Maisonneuve C, Bertholet S, Philpott DJ, De Gregorio E. Unleashing the potential of NOD- and Toll-like agonists as vaccine adjuvants. Proc Natl Acad Sci U S A. 2014 Aug; 111(34): 12294-99. doi:10.1073/pnas.1400478111 72. Haghparast A, Heidari Kharaji M, Malvandi AM. Down-regulation of CD14 transcripts in human glioblastoma cell line U87 MG. Iran J Immunol. 2011 Jun; 8(2): 111-19. doi:IJIv8i2A7 73. Tabatabaeizadeh SE, Haghparast A. [Improving the effectiveness of adjuvants: Targeting innate immune receptors with a special focus on toll-like receptor agonists]. J Isfahan Med Sch. 2013; 30(214): 1986-2009. [Article in Persian] 74. Zakeri A, Borji H, Haghparast A. Interaction between helminths and toll-like receptors: possibilities and potentials for asthma therapy. Int Rev Immunol. 2016 May; 35(3): 219-48. doi:10.3109/08830185.2015.1096936 75. Medzhitov R.Recognition of microorganisms and activation of the immune response. Nature. 2007 Oct; 449(7164): 819-26. doi:10.1038/nature06246 76. Magalhaes JG, Rubino SJ, Travassos LH, Le Bourhis L, Duan W, Sellge G, et al. Nucleotide oligomerization domain-containing proteins instruct T cell helper type 2 immunity through stromal activation. Proc Natl Acad Sci U S A. 2011 Sep; 108(36): 14896-901. doi:10.1073/pnas.1015063108 77. Kharaji MH, Haghparast A. Simultaneous detection of pattern recognition receptors (PRRs) in human peripheral blood mononuclear cells (PBMC) by touchdown PCR. World Applied Sciences Journal. 2010; 9(5): 479-83. 78. Gupta SK, Deb R, Dey S, Chellappa MM. Toll-like receptor-based adjuvants: enhancing the immune response to vaccines against infectious diseases of chicken. Expert Rev Vaccines. 2014 Jul; 13(7): 909-25. doi:10.1586/14760584.2014.920236 79. Bode C, Zhao G, Steinhagen F, Kinjo T, Klinman DM. CpG DNA as a vaccine adjuvant. Expert Rev Vaccines. 2011 Apr; 10(4): 499-511. doi:10.1586/erv.10.174 80. O'Neill LA. Signal transduction pathways activated by the IL-1 receptor/toll-like receptor superfamily. Curr Top Microbiol Immunol. 2002; 270: 47-61. 81. Brightbill HD, Modlin RL. Toll-like receptors: molecular mechanisms of the mammalian immune response. Immunology. 2000; 101(1): 1-10. doi:10.1046/j.1365-2567.2000.00093.x 82. Cook DN, Pisetsky DS, Schwartz DA. Toll-like receptors in the pathogenesis of human disease. Nat Immunol. 2004 Oct; 5(10): 975-9. doi:10.1038/ni1116 83. Suzuki N, Suzuki S, Yeh WC. IRAK-4 as the central TIR signaling mediator in innate immunity. Trends Immunol. 2002 Oct; 23(10): 503-6. 84. Pasare C, Medzhitov R. Toll-like receptors: linking innate and adaptive immunity. Microbes Infect. 2004 Dec; 6(15): 1382-87. doi:10.1016/j.micinf.2004.08.018 85. Gupta SK, Singh LV, Chellappa MM, Dey S. Toll-like receptor ligands and their combinations as adjuvants-current research and its relevance in chickens. World's Poultry Science Journal. 2015; 71(1): 95-110. https://doi.org/10.1017/S0043933915000094 86. Spickler AR, Roth JA. Adjuvants in veterinary vaccines: modes of action and adverse effects. J Vet Intern Med. 2003 May-Jun; 17(3): 273-81. 87. Prater MR, Johnson VJ, Germolec DR, Luster MI, Holladay SD. Maternal treatment with a high dose of CPG ODN during gestation alters fetal craniofacial and distal limb development in c57bl/6 mice. Vaccine. 2006; 24(3): 263-71. https://doi.org/10.1016/j.vaccine.2005.07.105 88. Burstein HJ. Cognitive side-effects of adjuvant treatments. Breast. 2007 Dec; 16(Suppl 2): S166-68. doi:10.1016/j.breast.2007.07.027 89. Heegaard PM, Dedieu L, Johnson N, Le Potier MF, Mockey M, Mutinelli F, et al. Adjuvants and delivery systems in veterinary vaccinology: current state and future developments. Arch Virol. 2011 Feb; 156(2): 183-202. doi:10.1007/s00705-010-0863-1 90. Gupta RK, Relyveld EH, Lindblad EB, Bizzini B, Ben-Efraim S, Gupta CK. Adjuvants--a balance between toxicity and adjuvanticity. Vaccine. 1993; 11(3): 293-306. 91. Sun HX, Xie Y, Ye YP. ISCOMs and ISCOMATRIX. Vaccine. 2009 Jul; 27(33): 4388-401. doi:10.1016/j.vaccine.2009.05.032 92. Sokolovska A, Hem SL, HogenEsch H. Activation of dendritic cells and induction of CD4(+) T cell differentiation by aluminum-containing adjuvants. Vaccine. 2007 Jun; 25(23): 4575-85. doi:10.1016/j.vaccine.2007.03.045 93. Shaw CA, Li D, Tomljenovic L. Are there negative CNS impacts of aluminum adjuvants used in vaccines and immunotherapy? Immunotherapy. 2014; 6(10): 1055-71. doi:10.2217/imt.14.81 94. Tomljenovic L, Shaw CA. Aluminum vaccine adjuvants: are they safe? Curr Med Chem. 2011; 18(17): 2630-37. 95. Campbell A, Becaria A, Lahiri DK, Sharman K, Bondy SC. Chronic exposure to aluminum in drinking water increases inflammatory parameters selectively in the brain. J Neurosci Res. 2004 Feb; 75(4): 565-72. doi:10.1002/jnr.10877 96. Walton JR. Functional impairment in aged rats chronically exposed to human range dietary aluminum equivalents. Neurotoxicology. 2009 Mar; 30(2): 182-93. doi:10.1016/j.neuro.2008.11.012 97. Nohynek H, Jokinen J, Partinen M, Vaarala O, Kirjavainen T, Sundman J, et al. AS03 adjuvanted AH1N1 vaccine associated with an abrupt increase in the incidence of childhood narcolepsy in Finland. PLoS One. 2012; 7(3): e33536. doi:10.1371/journal.pone.0033536
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