The role of reactive oxygen species and proinflammatory cytokines in type 1 diabetes pathogenesis

Abstract

Type 1 diabetes (T1D) is a T cell–mediated autoimmune disease characterized by the destruction of insulin‐secreting pancreatic β cells. In humans with T1D and in nonobese diabetic (NOD) mice (a murine model for human T1D), autoreactive T cells cause β‐cell destruction, as transfer or deletion of these cells induces or prevents disease, respectively. CD4 + and CD8 + T cells use distinct effector mechanisms and act at different stages throughout T1D to fuel pancreatic β‐cell destruction and disease pathogenesis. While these adaptive immune cells employ distinct mechanisms for β‐cell destruction, one central means for enhancing their autoreactivity is by the secretion of proinflammatory cytokines, such as IFN‐γ, TNF‐α, and IL‐1. In addition to their production by diabetogenic T cells, proinflammatory cytokines are induced by reactive oxygen species (ROS) via redox‐dependent signaling pathways. Highly reactive molecules, proinflammatory cytokines are produced upon lymphocyte infiltration into pancreatic islets and induce disease pathogenicity by directly killing β cells, which characteristically possess low levels of antioxidant defense enzymes. In addition to β‐cell destruction, proinflammatory cytokines are necessary for efficient adaptive immune maturation, and in the context of T1D they exacerbate autoimmunity by intensifying adaptive immune responses. The first half of this review discusses the mechanisms by which autoreactive T cells induce T1D pathogenesis and the importance of ROS for efficient adaptive immune activation, which, in the context of T1D, exacerbates autoimmunity. The second half provides a comprehensive and detailed analysis of (1) the mechanisms by which cytokines such as IL‐1 and IFN‐γ influence islet insulin secretion and apoptosis and (2) the key free radicals and transcription factors that control these processes.

Shown for reading. Its publisher allows quoting it, not republishing it.

References 195

1. 1.

   van Belle TL, Coppieters KT, von Herrath MG. Type 1 diabetes: etiology, immunology, and therapeutic strategies. Physiol. Rev. 2011;91:79-118.

   Not in our library10.1152/physrev.00003.2010

2. 2.

   Haskins K, et al. Oxidative stress in type 1 diabetes. Ann. N.Y. Acad. Sci. 2003;1005:43-54.

   Not in our library10.1196/annals.1288.006

3. 3.

   Curtsinger JM, et al. Inflammatory cytokines provide a third signal for activation of naive CD4+ and CD8+ T cells. J. Immunol. 1999;162:3256-3262.

   Not in our library

4. 4.

   Pape KA, et al. Inflammatory cytokines enhance the in vivo clonal expansion and differentiation of antigen-activated CD4+ T cells. J. Immunol. 1997;159:591-598.

   Not in our library

5. 5.

   Tse HM, Milton MJ, Piganelli JD. Mechanistic analysis of the immunomodulatory effects of a catalytic antioxidant on antigen-presenting cells: implication for their use in targeting oxidation-reduction reactions in innate immunity. Free Radic. Biol. Med. 2004;36:233-247.

   Not in our library10.1016/j.freeradbiomed.2003.10.029

6. 6.

   Patterson CC, et al. Trends in childhood type 1 diabetes incidence in Europe during 1989–2008: evidence of non-uniformity over time in rates of increase. Diabetologia. 2012;55:2142-2147.

   Not in our library10.1007/s00125-012-2571-8

7. 7.

   Patterson CC, et al. Incidence trends for childhood type 1 diabetes in Europe during 1989–2003 and predicted new cases 2005–20: a multicentre prospective registration study. Lancet. 2009;373:2027-2033.

   Not in our library10.1016/s0140-6736(09)60568-7

8. 8.

   Redondo MJ, et al. Concordance for islet autoimmunity among monozygotic twins. N. Engl. J. Med. 2008;359:2849-2850.

   Not in our library10.1056/nejmc0805398

9. 9.

   Banting FG, Best CH. The internal secretion of the pancreas. J. Lab. Clin. Med. 1922;7:465-480.

   Not in our library

10. 10.

    Willcox A, et al. Analysis of islet inflammation in human type 1 diabetes. Clin. Exp. Immunol. 2009;155:173-181.

    Not in our library10.1111/j.1365-2249.2008.03860.x

11. 11.

    Herold KC, et al. Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. N. Engl. J. Med. 2002;346:1692-1698.

    Not in our library10.1056/nejmoa012864

12. 12.

    Bougneres PF, et al. Factors associated with early remission of type I diabetes in children treated with cyclosporine. N. Engl. J. Med. 1988;318:663-670.

    Not in our library10.1056/nejm198803173181103

13. 13.

    Keymeulen B, et al. Four-year metabolic outcome of a randomised controlled CD3-antibody trial in recent-onset type 1 diabetic patients depends on their age and baseline residual beta cell mass. Diabetologia. 2010;53:614-623.

    Not in our library10.1007/s00125-009-1644-9

14. 14.

    Voltarelli JC, et al. Autologous nonmyeloablative hematopoietic stem cell transplantation in newly diagnosed type 1 diabetes mellitus. JAMA. 2007;297:1568-1576.

    Not in our library10.1001/jama.297.14.1568

15. 15.
    Cellular Islet Autoimmunity Associates with Clinical Outcome of Islet Cell Transplantation · 2008

    No notice
16. 16.

    Katz J, Benoist C, Mathis D. Major histocompatibility complex class I molecules are required for the development of insulitis in non-obese diabetic mice. Eur. J. Immunol. 1993;23:3358-3360.

    Not in our library10.1002/eji.1830231244

17. 17.

    Serreze DV, et al. Major histocompatibility complex class I-deficient NOD-B2m null mice are diabetes and insulitis resistant. Diabetes. 1994;43:505-509.

    Not in our library10.2337/diab.43.3.505

18. 18.

    Sumida T, et al. Prevention of insulitis and diabetes in beta 2-microglobulin-deficient non-obese diabetic mice. Int. Immunol. 1994;6:1445-1449.

    Not in our library10.1093/intimm/6.9.1445

19. 19.

    Skowera A, et al. CTLs are targeted to kill beta cells in patients with type 1 diabetes through recognition of a glucose-regulated preproinsulin epitope. J. Clin. Invest. 2008;118:3390-3402.

    Not in our library10.1172/jci35449

20. 20.

    Willcox A, et al. Analysis of islet inflammation in human type 1 diabetes. Clin. Exp. Immunol. 2009;155:173-181.

    Not in our library10.1111/j.1365-2249.2008.03860.x

21. 21.

    Wong FS, et al. CD8 T cell clones from young nonobese diabetic (NOD) islets can transfer rapid onset of diabetes in NOD mice in the absence of CD4 cells. J. Exp. Med. 1996;183:67-76.

    Not in our library10.1084/jem.183.1.67

22. 22.

    DiLorenzo TP, et al. Major histocompatibility complex class I-restricted T cells are required for all but the end stages of diabetes development in nonobese diabetic mice and use a prevalent T cell receptor alpha chain gene rearrangement. Proc. Natl. Acad. Sci. USA. 1998;95:12538-12543.

    Not in our library10.1073/pnas.95.21.12538

23. 23.

    Nagata M, et al. Evidence for the role of CD8+ cytotoxic T cells in the destruction of pancreatic beta-cells in nonobese diabetic mice. J. Immunol. 1994;152:2042-2050.

    Not in our library

24. 24.

    Dudek NL, et al. Cytotoxic T-cells from T-cell receptor transgenic NOD8.3 mice destroy beta-cells via the perforin and Fas pathways. Diabetes. 2006;55:2412-2418.

    Not in our library10.2337/db06-0109

25. 25.

    Graser RT, et al. Identification of a CD8 T cell that can independently mediate autoimmune diabetes development in the complete absence of CD4 T cell helper functions. J. Immunol. 2000;164:3913-3918.

    Not in our library10.4049/jimmunol.164.7.3913

26. 26.

    Wong FS, et al. Activation of insulin-reactive CD8 T-cells for development of autoimmune diabetes. Diabetes. 2009;58:1156-1164.

    Not in our library10.2337/db08-0800

27. 27.

    Wang B, et al. The role of CD8+ T cells in the initiation of insulin-dependent diabetes mellitus. Eur. J. Immunol. 1996;26:1762-1769.

    Not in our library10.1002/eji.1830260815

28. 28.

    Podack ER, et al. Function of granule perforin and esterases in T cell-mediated reactions. Components required for delivery of molecules to target cells. Ann. N.Y. Acad. Sci. 1988;532:292-302.

    Not in our library10.1111/j.1749-6632.1988.tb36347.x

29. 29.

    Savinov AY, et al. Contribution of Fas to diabetes development. Proc. Natl. Acad. Sci. USA. 2003;100:628-632.

    Not in our library10.1073/pnas.0237359100

30. 30.

    Hamilton-Williams EE, et al. Beta cell MHC class I is a late requirement for diabetes. Proc. Natl. Acad. Sci. USA. 2003;100:6688-6693.

    Not in our library10.1073/pnas.1131954100

31. 31.

    Shizuru JA, et al. Immunotherapy of the nonobese diabetic mouse: treatment with an antibody to T-helper lymphocytes. Science. 1988;240:659-662.

    Not in our library10.1126/science.2966437

32. 32.

    Haskins K, et al. Pancreatic islet-specific T-cell clones from nonobese diabetic mice. Proc. Natl. Acad. Sci. USA. 1989;86:8000-8004.

    Not in our library10.1073/pnas.86.20.8000

33. 33.

    Katz JD, et al. Following a diabetogenic T cell from genesis through pathogenesis. Cell. 1993;74:1089-1100.

    Not in our library10.1016/0092-8674(93)90730-e

34. 34.

    Stadinski BD, et al. Chromogranin A is an autoantigen in type 1 diabetes. Nat. Immunol. 2010;11:225-231.

    Not in our library10.1038/ni.1844

35. 35.

    Christianson SW, Shultz LD, Leiter EH. Adoptive transfer of diabetes into immunodeficient NOD-scid/scid mice. Relative contributions of CD4+ and CD8+ T-cells from diabetic versus prediabetic NOD.NON-Thy-1a donors. Diabetes. 1993;42:44-55.

    Not in our library10.2337/diab.42.1.44

36. 36.

    Thivolet C, et al. CD8+ T cell homing to the pancreas in the nonobese diabetic mouse is CD4+ T cell-dependent. J. Immunol. 1991;146:85-88.

    Not in our library

37. 37.

    Yagi H, et al. Analysis of the roles of CD4+ and CD8+ T cells in autoimmune diabetes of NOD mice using transfer to NOD athymic nude mice. Eur. J. Immunol. 1992;22:2387-2393.

    Not in our library10.1002/eji.1830220931

38. 38.

    Varanasi V, et al. Cytotoxic mechanisms employed by mouse T cells to destroy pancreatic β-cells. Diabetes. 2012;61:2862-2870.

    Not in our library10.2337/db11-1784

39. 39.

    Thomas HE, et al. Beta cell apoptosis in diabetes. Apoptosis. 2009;14:1389-1404.

    Not in our library10.1007/s10495-009-0339-5

40. 40.

    Campbell IL, et al. Essential role for interferon-gamma and interleukin-6 in autoimmune insulin-dependent diabetes in NOD/Wehi mice. J. Clin. Invest. 1991;87:739-742.

    Not in our library10.1172/jci115055

41. 41.

    Nicoletti F, et al. The effects of a nonimmunogenic form of murine soluble interferon-gamma receptor on the development of autoimmune diabetes in the NOD mouse. Endocrinology. 1996;137:5567-5575.

    Not in our library10.1210/endo.137.12.8940385

42. 42.

    Sarvetnick N, et al. Loss of pancreatic islet tolerance induced by beta-cell expression of interferon-gamma. Nature. 1990;346:844-847.

    Not in our library10.1038/346844a0

43. 43.

    Hultgren B, et al. Genetic absence of gamma-interferon delays but does not prevent diabetes in NOD mice. Diabetes. 1996;45:812-817.

    Not in our library10.2337/diab.45.6.812

44. 44.

    Kanagawa O, et al. Protection of nonobese diabetic mice from diabetes by gene(s) closely linked to IFN-gamma receptor loci. J. Immunol. 2000;164:3919-3923.

    Not in our library10.4049/jimmunol.164.7.3919

45. 45.

    Serreze DV, et al. Interferon-gamma receptor signaling is dispensable in the development of autoimmune type 1 diabetes in NOD mice. Diabetes. 2000;49:2007-2011.

    Not in our library10.2337/diabetes.49.12.2007

46. 46.

    Campbell IL, et al. Intercellular adhesion molecule 1 is induced on isolated endocrine islet cells by cytokines but not by reovirus infection. Proc. Natl. Acad. Sci. USA. 1989;86:4282-4286.

    Not in our library10.1073/pnas.86.11.4282

47. 47.

    Yagi N, et al. Expression of intercellular adhesion molecule 1 on pancreatic beta-cells accelerates beta-cell destruction by cytotoxic T-cells in murine autoimmune diabetes. Diabetes. 1995;44:744-752.

    Not in our library10.2337/diab.44.7.744

48. 48.

    Zhang F, et al. Inhibition of TNF-alpha induced ICAM-1, VCAM-1 and E-selectin expression by selenium. Atherosclerosis. 2002;161:381-386.

    Not in our library10.1016/s0021-9150(01)00672-4

49. 49.

    Campbell IL, et al. Regulation of MHC protein expression in pancreatic beta-cells by interferon-gamma and tumor necrosis factor-alpha. Mol. Endocrinol. 1988;2:101-107.

    Not in our library10.1210/mend-2-2-101

50. 50.

    David-Watine B, Israel A, Kourilsky P. The regulation and expression of MHC class I genes. Immunol. Today. 1990;11:286-292.

    Not in our library10.1016/0167-5699(90)90114-o

51. 51.

    Stephens LA, et al. Tumor necrosis factor-alpha-activated cell death pathways in NIT-1 insulinoma cells and primary pancreatic beta cells. Endocrinology. 1999;140:3219-3227.

    Not in our library10.1210/endo.140.7.6873

52. 52.

    Santamaria P. Effector lymphocytes in islet cell autoimmunity. Rev. Endocr. Metab. Disord. 2003;4:271-280.

    Not in our library10.1023/a:1025156413404

53. 53.

    Cantor J, Haskins K. Recruitment and activation of macrophages by pathogenic CD4 T cells in type 1 diabetes: evidence for involvement of CCR8 and CCL1. J. Immunol. 2007;179:5760-5767.

    Not in our library10.4049/jimmunol.179.9.5760

54. 54.

    Lam GY, Huang J, Brumell JH. The many roles of NOX2 NADPH oxidase-derived ROS in immunity. Semin. Immunopathol. 2010;32:415-430.

    Not in our library10.1007/s00281-010-0221-0

55. 55.

    Dinauer MC, Orkin SH. Chronic granulomatous disease. Annu. Rev. Med. 1992;43:117-124.

    Not in our library10.1146/annurev.me.43.020192.001001

56. 56.

    Matute JD, et al. A new genetic subgroup of chronic granulomatous disease with autosomal recessive mutations in p40 phox and selective defects in neutrophil NADPH oxidase activity. Blood. 2009;114:3309-3315.

    Not in our library10.1182/blood-2009-07-231498

57. 57.

    Afonso V, et al. Reactive oxygen species and superoxide dismutases: role in joint diseases. Joint Bone Spine. 2007;74:324-329.

    Not in our library10.1016/j.jbspin.2007.02.002

58. 58.

    Weissmann G. Pathogenesis of rheumatoid arthritis. J. Clin. Rheumatol. 2004;10:S26-S31.

    Not in our library10.1097/01.rhu.0000130687.75646.44

59. 59.

    Gilgun-Sherki Y, Melamed E, Offen D. The role of oxidative stress in the pathogenesis of multiple sclerosis: the need for effective antioxidant therapy. J. Neurol. 2004;251:261-268.

    Not in our library10.1007/s00415-004-0348-9

60. 60.

    Mirshafiey A, Mohsenzadegan M. Antioxidant therapy in multiple sclerosis. Immunopharmacol. Immunotoxicol. 2009;31:13-29.

    Not in our library10.1080/08923970802331943

61. 61.

    Roessner A, et al. Oxidative stress in ulcerative colitis-associated carcinogenesis. Pathol. Res. Pract. 2008;204:511-524.

    Not in our library10.1016/j.prp.2008.04.011

62. 62.

    Harrison D, et al. Role of oxidative stress in atherosclerosis. Am. J. Cardiol. 2003;91:7A-11A.

    Not in our library10.1016/s0002-9149(02)03144-2

63. 63.

    Bonifacio E, et al. Islet autoantibody markers in IDDM: risk assessment strategies yielding high sensitivity. Diabetologia. 1995;38:816-822.

    Not in our library10.1007/s001250050358

64. 64.

    Khan MW, et al. Characterization of hydroxyl radical modified GAD65: a potential autoantigen in type 1 diabetes. Autoimmunity. 2009;42:150-158.

    Not in our library10.1080/08916930802468276

65. 65.
    Detection of autoantibodies against reactive oxygen species modified glutamic acid decarboxylase-65 in type 1 diabetes associated complications · 2011

    Not checked
66. 66.

    Babior BM, Kipnes RS, Curnutte JT. Biological defense mechanisms. The production by leukocytes of superoxide, a potential bactericidal agent. J. Clin. Invest. 1973;52:741-744.

    Not in our library10.1172/jci107236

67. 67.

    Lander HM, et al. Redox regulation of cell signalling. Nature. 1996;381:380-381.

    Not in our library10.1038/381380a0

68. 68.

    Curtsinger JM, Lins DC, Mescher MF. Signal 3 determines tolerance versus full activation of naive CD8 T cells: dissociating proliferation and development of effector function. J. Exp. Med. 2003;197:1141-1151.

    Not in our library10.1084/jem.20021910

69. 69.

    Janeway CA. A trip through my life with an immunological theme. Annu. Rev. Immunol. 2002;20:1-28.

    Not in our library10.1146/annurev.immunol.20.080801.102422

70. 70.

    Janeway CA, Bottomly K. Signals and signs for lymphocyte responses. Cell. 1994;76:275-285.

    Not in our library10.1016/0092-8674(94)90335-2

71. 71.

    Janeway CA, Medzhitov R. Innate immune recognition. Annu. Rev. Immunol. 2002;20:197-216.

    Not in our library10.1146/annurev.immunol.20.083001.084359

72. 72.

    Medzhitov R, Janeway C. Innate immunity. N. Engl. J. Med. 2000;343:338-344.

    Not in our library10.1056/nejm200008033430506

73. 73.

    Sklavos MM, Tse HM, Piganelli JD. Redox modulation inhibits CD8 T cell effector function. Free Radic. Biol. Med. 2008;45:1477-1486.

    Not in our library10.1016/j.freeradbiomed.2008.08.023

74. 74.

    Tse HM, et al. Disruption of innate-mediated proinflammatory cytokine and reactive oxygen species third signal leads to antigen-specific hyporesponsiveness. J. Immunol. 2007;178:908-917.

    Not in our library10.4049/jimmunol.178.2.908

75. 75.

    Kay TW, et al. The beta cell in autoimmune diabetes: many mechanisms and pathways of loss. Trends Endocrinol. Metab. 2000;11:11-15.

    Not in our library10.1016/s1043-2760(99)00210-6

76. 76.

    Jackson SH, et al. T cells express a phagocyte-type NADPH oxidase that is activated after T cell receptor stimulation. Nat. Immunol. 2004;5:818-827.

    Not in our library10.1038/ni1096

77. 77.

    Chan AC, Desai DM, Weiss A. The role of protein tyrosine kinases and protein tyrosine phosphatases in T cell antigen receptor signal transduction. Annu. Rev. Immunol. 1994;12:555-592.

    Not in our library10.1146/annurev.iy.12.040194.003011

78. 78.

    Lenschow DJ, Walunas TL, Bluestone JA. CD28/B7 system of T cell costimulation. Annu. Rev. Immunol. 1996;14:233-258.

    Not in our library10.1146/annurev.immunol.14.1.233

79. 79.

    Mescher MF, et al. Signals required for programming effector and memory development by CD8+ T cells. Immunol. Rev. 2006;211:81-92.

    Not in our library10.1111/j.0105-2896.2006.00382.x

80. 80.

    Curtsinger JM, Mescher MF. Inflammatory cytokines as a third signal for T cell activation. Curr. Opin. Immunol. 2010;22:333-340.

    Not in our library10.1016/j.coi.2010.02.013

81. 81.

    Curtsinger JM, et al. Type I IFNs provide a third signal to CD8 T cells to stimulate clonal expansion and differentiation. J. Immunol. 2005;174:4465-4469.

    Not in our library10.4049/jimmunol.174.8.4465

82. 82.

    Ben-Sasson SZ, et al. IL-1 acts directly on CD4 T cells to enhance their antigen-driven expansion and differentiation. Proc. Natl. Acad. Sci. USA. 2009;106:7119-7124.

    Not in our library10.1073/pnas.0902745106

83. 83.

    Agarwal P, et al. Gene regulation and chromatin remodeling by IL-12 and type I IFN in programming for CD8 T cell effector function and memory. J. Immunol. 2009;183:1695-1704.

    Not in our library10.4049/jimmunol.0900592

84. 84.

    Seleme MC, et al. Dysregulated TLR3-dependent signaling and innate immune activation in superoxide-deficient macrophages from nonobese diabetic mice. Free Radic. Biol. Med. 2012;52:2047-2056.

    Not in our library10.1016/j.freeradbiomed.2012.01.027

85. 85.

    Tse HM, et al. NADPH oxidase deficiency regulates Th lineage commitment and modulates autoimmunity. J. Immunol. 2010;185:5247-5258.

    Not in our library10.4049/jimmunol.1001472

86. 86.

    Van Parijs L, et al. Role of interleukin 12 and costimulators in T cell anergy in vivo. J. Exp. Med. 1997;186:1119-1128.

    Not in our library10.1084/jem.186.7.1119

87. 87.

    Thomas HE, et al. IL-1 receptor deficiency slows progression to diabetes in the NOD mouse. Diabetes. 2004;53:113-121.

    Not in our library10.2337/diabetes.53.1.113

88. 88.

    Hultqvist M, et al. Lack of reactive oxygen species breaks T cell tolerance to collagen type II and allows development of arthritis in mice. J. Immunol. 2007;179:1431-1437.

    Not in our library10.4049/jimmunol.179.3.1431

89. 89.

    Hultqvist M, et al. Enhanced autoimmunity, arthritis, and encephalomyelitis in mice with a reduced oxidative burst due to a mutation in the Ncf1 gene. Proc. Natl. Acad. Sci. USA. 2004;101:12646-12651.

    Not in our library10.1073/pnas.0403831101

90. 90.

    Matsuki T, et al. Abnormal T cell activation caused by the imbalance of the IL-1/IL-1R antagonist system is responsible for the development of experimental autoimmune encephalomyelitis. Int. Immunol. 2006;18:399-407.

    Not in our library10.1093/intimm/dxh379

91. 91.

    Kassiotis G, Kranidioti K, Kollias G. Defective CD4T cell priming and resistance to experimental autoimmune encephalomyelitis in TNF-deficient mice due to innate immune hypo-responsiveness. J. Neuroimmunol. 2001;119:239-247.

    Not in our library10.1016/s0165-5728(01)00403-9

92. 92.

    Nakae S, et al. IL-1 enhances T cell-dependent antibody production through induction of CD40 ligand and OX40 on T cells. J. Immunol. 2001;167:90-97.

    Not in our library10.4049/jimmunol.167.1.90

93. 93.

    Piganelli JD, et al. A Metalloporphyrin-based superoxide dismutase mimic inhibits adoptive transfer of autoimmune diabetes by a diabetogenic T-cell clone. Diabetes. 2002;51:347-355.

    Not in our library10.2337/diabetes.51.2.347

94. 94.

    Thayer TC, et al. Superoxide production by macrophages and T cells is critical for the induction of autoreactivity and type 1 diabetes. Diabetes. 2011;60:2144-2151.

    Not in our library10.2337/db10-1222

95. 95.

    George-Chandy A, et al. Th17 development and autoimmune arthritis in the absence of reactive oxygen species. J. Immunol. 2008;38:1118-1126.

    Not in our library10.1002/eji.200737348

96. 96.

    Efimova O, Szankasi P, Kelley TW. Ncf1 (p47phox) is essential for direct regulatory T cell mediated suppression of CD4+ effector T cells. PLoS One. 2011;6:e16013.

    Not in our library10.1371/journal.pone.0016013

97. 97.

    Kraaij MD, et al. Induction of regulatory T cells by macrophages is dependent on production of reactive oxygen species. Proc. Natl. Acad. Sci. USA. 2010;107:17686-17691.

    Not in our library10.1073/pnas.1012016107

98. 98.

    Mathews CE, et al. Mechanisms underlying resistance of pancreatic islets from ALR/Lt mice to cytokine-induced destruction. J. Immunol. 2005;175:1248-1256.

    Not in our library10.4049/jimmunol.175.2.1248

99. 99.

    Chen J, et al. Role of increased ROS dissipation in prevention of T1D. Ann. N.Y. Acad. Sci. 2008;1150:157-166.

    Not in our library10.1196/annals.1447.045

100. 100.
     Unusual resistance of ALR/Lt mouse β cells to autoimmune destruction: Role for β cell-expressed resistance determinants · 2001

     Not checked
101. 101.

     Mathews CE, et al. Genetic analysis of resistance to Type-1 Diabetes in ALR/Lt mice, a NOD-related strain with defenses against autoimmune-mediated diabetogenic stress. Immunogenetics. 2003;55:491-496.

     Not in our library10.1007/s00251-003-0603-8

102. 102.

     Mathews CE, et al. mt-Nd2 Allele of the ALR/Lt mouse confers resistance against both chemically induced and autoimmune diabetes. Diabetologia. 2005;48:261-267.

     Not in our library10.1007/s00125-004-1644-8

103. 103.

     Mathews CE, et al. Genetic control of neutrophil superoxide production in diabetes-resistant ALR/Lt mice. Free Radic. Biol. Med. 2002;32:744-751.

     Not in our library10.1016/s0891-5849(02)00747-5

104. 104.

     Mandrup-Poulsen T, et al. Cytokines cause functional and structural damage to isolated islets of Langerhans. Allergy. 1985;40:424-429.

     Not in our library10.1111/j.1398-9995.1985.tb02681.x

105. 105.

     Bendtzen K, et al. Cytotoxicity of human pI 7 interleukin-1 for pancreatic islets of Langerhans. Science. 1986;232:1545-1547.

     Not in our library10.1126/science.3086977

106. 106.

     Mandrup-Poulsen T, et al. Affinity-purified human interleukin I is cytotoxic to isolated islets of Langerhans. Diabetologia. 1986;29:63-67.

     Not in our library10.1007/bf02427283

107. 107.

     Lacy PE. The intraislet macrophage and type I diabetes. Mount Sinai J. Med. 1994;61:170-174.

     Not in our library

108. 108.

     Nerup J, et al. Mechanisms of pancreatic beta-cell destruction in type I diabetes. Diabetes Care. 1988;11(Suppl 1):16-23.

     Not in our library

109. 109.

     Comens PG, et al. Interleukin 1 is potent modulator of insulin secretion from isolated rat islets of Langerhans. Diabetes. 1987;36:963-970.

     Not in our library10.2337/diab.36.8.963

110. 110.

     Hughes JH, et al. Interleukin 1 inhibits insulin secretion from isolated rat pancreatic islets by a process that requires gene transcription and mRNA translation. J. Clin. Invest. 1990;86:856-863.

     Not in our library10.1172/jci114785

111. 111.

     Spinas GA, et al. Low concentrations of interleukin-1 stimulate and high concentrations inhibit insulin release from isolated rat islets of Langerhans. Acta Endocrinologica. 1986;113:551-558.

     Not in our library10.1530/acta.0.1130551

112. 112.

     Lacy PE, Finke EH. Activation of intraislet lymphoid cells causes destruction of islet cells. Am. J. Pathol. 1991;138:1183-1190.

     Not in our library

113. 113.

     Corbett JA, et al. Interleukin 1 beta induces the formation of nitric oxide by beta-cells purified from rodent islets of Langerhans. Evidence for the beta-cell as a source and site of action of nitric oxide. J. Clin. Invest. 1992;90:2384-2391.

     Not in our library10.1172/jci116129

114. 114.

     Eizirik DL. Interleukin-1 induced impairment in pancreatic islet oxidative metabolism of glucose is potentiated by tumor necrosis factor. Acta Endocrinologica. 1988;119:321-325.

     Not in our library10.1530/acta.0.1190321

115. 115.

     Scarim AL, Heitmeier MR, Corbett JA. Irreversible inhibition of metabolic function and islet destruction after a 36-hour exposure to interleukin-1beta. Endocrinology. 1997;138:5301-5307.

     Not in our library10.1210/endo.138.12.5583

116. 116.

     Lightfoot YL, Chen J, Mathews CE. Role of the mitochondria in immune-mediated apoptotic death of the human pancreatic beta cell line betaLox5. PLoS One. 2011;6:e20617.

     Not in our library10.1371/journal.pone.0020617

117. 117.

     Lightfoot YL, Chen J, Mathews CE. Immune-mediated β-cell death in type 1 diabetes: lessons from human β-cell lines. Eur. J. Clin. Invest. 2012;42:1244-1251.

     Not in our library10.1111/j.1365-2362.2012.02711.x

118. 118.

     Hibbs JB. Synthesis of nitric oxide from L-arginine: a recently discovered pathway induced by cytokines with antitumour and antimicrobial activity. Res. Immunol. 1991;142.

     Not in our library10.1016/0923-2494(91)90103-p

119. 119.

     Ignarro LJ. Signal transduction mechanisms involving nitric oxide. Biochem. Pharmacol. 1991;41:485-490.

     Not in our library10.1016/0006-2952(91)90618-f

120. 120.

     Moncada S, Palmer RM, Higgs EA. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol. Rev. 1991;43:109-142.

     Not in our library

121. 121.

     Nathan CF, Hibbs JB. Role of nitric oxide synthesis in macrophage antimicrobial activity. Curr. Opin. Immunol. 1991;3:65-70.

     Not in our library10.1016/0952-7915(91)90079-g

122. 122.

     Snyder SH, Bredt DS. Nitric oxide as a neuronal messenger. Trends Pharmacol. Sci. 1991;12:125-128.

     Not in our library10.1016/0165-6147(91)90526-x

123. 123.

     Southern C, Schulster D, Green IC. Inhibition of insulin secretion by interleukin-1 beta and tumour necrosis factor-alpha via an L-arginine-dependent nitric oxide generating mechanism. FEBS Lett. 1990;276:42-44.

     Not in our library10.1016/0014-5793(90)80502-a

124. 124.

     Corbett JA, et al. Interleukin-1 beta-induced formation of EPR-detectable iron-nitrosyl complexes in islets of Langerhans. Role of nitric oxide in interleukin- 1 beta-induced inhibition of insulin secretion. J. Biol. Chem. 1991;266:21351-21354.

     Not in our library

125. 125.

     Welsh N, et al. Interleukin-1 beta-induced nitric oxide production in isolated rat pancreatic islets requires gene transcription and may lead to inhibition of the Krebs cycle enzyme aconitase. Endocrinology. 1991;129:3167-3173.

     Not in our library10.1210/endo-129-6-3167

126. 126.

     Pollock JS, et al. Nitric oxide synthase isozymes antibodies. Histochem. J. 1995;27:738-744.

     Not in our library

127. 127.

     Corbett JA, et al. Nitric oxide and cyclic GMP formation induced by interleukin 1 beta in islets of Langerhans. Evidence for an effector role of nitric oxide in islet dysfunction. Biochem. J. 1992;287(Pt 1):229-235.

     Not in our library10.1042/bj2870229

128. 128.

     Jitrapakdee S, et al. Regulation of insulin secretion: role of mitochondrial signalling. Diabetologia. 2010;53:1019-1032.

     Not in our library10.1007/s00125-010-1685-0

129. 129.

     Koster JC, et al. Targeted overactivity of beta cell K(ATP) channels induces profound neonatal diabetes. Cell. 2000;100:645-654.

     Not in our library10.1016/s0092-8674(00)80701-1

130. 130.

     Corbett JA, McDaniel ML. Intraislet release of interleukin 1 inhibits beta cell function by inducing beta cell expression of inducible nitric oxide synthase. J. Exp. Med. 1995;181:559-568.

     Not in our library10.1084/jem.181.2.559

131. 131.

     Cetkovic-Cvrlje M, Eizirik DL. TNF-alpha and IFN-gamma potentiate the deleterious effects of IL-1 beta on mouse pancreatic islets mainly via generation of nitric oxide. Cytokine. 1994;6:399-406.

     Not in our library10.1016/1043-4666(94)90064-7

132. 132.

     Gysemans CA, et al. Dual role of interferon-gamma signalling pathway in sensitivity of pancreatic beta cells to immune destruction. Diabetologia. 2001;44:567-574.

     Not in our library10.1007/s001250051662

133. 133.

     Heitmeier MR, Corbett JA, Ignarro LJ. Cytotoxic role of nitric oxide in diabetes. Nitric Oxide Biology and Pathobiology. 2000;785-810.

     Not in our library

134. 134.

     Heitmeier MR, Scarim AL, Corbett JA. Interferon-gamma increases the sensitivity of islets of Langerhans for inducible nitric-oxide synthase expression induced by interleukin 1. J. Biol. Chem. 1997;272:13697-13704.

     Not in our library10.1074/jbc.272.21.13697

135. 135.

     Corbett JA, et al. Nitric oxide mediates cytokine-induced inhibition of insulin secretion by human islets of Langerhans. Proc. Natl. Acad. Sci. USA. 1993;90:1731-1735.

     Not in our library10.1073/pnas.90.5.1731

136. 136.

     Eizirik DL, et al. The harmony of the spheres: inducible nitric oxide synthase and related genes in pancreatic beta cells. Diabetologia. 1996;39:875-890.

     Not in our library10.1007/bf00403906

137. 137.

     Arnush M, et al. IL-1 produced and released endogenously within human islets inhibits beta cell function. J. Clin. Invest. 1998;102:516-526.

     Not in our library10.1172/jci844

138. 138.

     Arnush M, et al. Potential role of resident islet macrophage activation in the initiation of autoimmune diabetes. J. Immunol. 1998;160:2684-2691.

     Not in our library

139. 139.

     Corbett JA, et al. A 1-hour pulse with IL-1 beta induces formation of nitric oxide and inhibits insulin secretion by rat islets of Langerhans: evidence for a tyrosine kinase signaling mechanism. FASEB J. 1993;7:369-374.

     Not in our library10.1096/fasebj.7.2.8440413

140. 140.

     Corbett JA, McDaniel ML. Reversibility of interleukin-1 beta-induced islet destruction and dysfunction by the inhibition of nitric oxide synthase. Biochem. J. 1994;299:719-724.

     Not in our library10.1042/bj2990719

141. 141.

     Hughes KJ, et al. Repair of nitric oxide-damaged DNA in beta-cells requires JNK-dependent GADD45alpha expression. J. Biol. Chem. 2009;284:27402-27408.

     Not in our library10.1074/jbc.m109.046912

142. 142.

     Rosales AL, et al. Repair of cytokine-induced DNA damage in cultured rat islets of Langerhans. Free Radic. Res. 2004;38:665-674.

     Not in our library10.1080/10715760410001697609

143. 143.

     Hughes KJ, et al. Nitric oxides mediates a shift from early necrosis to late apoptosis in cytokine-treated beta-cells that is associated with irreversible DNA damage. Am. J. Physiol. Endocrinol. Metabol. 2009;297:E1187-E1196.

     Not in our library10.1152/ajpendo.00214.2009

144. 144.

     Delaney CA, et al. Cytokines induce deoxyribonucleic acid strand breaks and apoptosis in human pancreatic islet cells. Endocrinology. 1997;138:2610-2614.

     Not in our library10.1210/endo.138.6.5204

145. 145.

     Eizirik DL, Pavlovic D. Is there a role for nitric oxide in beta-cell dysfunction and damage in IDDM. Diabetes Metab. Rev. 1997;13:293-307.

     Not in our library10.1002/(sici)1099-0895(199712)13:4<293::aid-dmr195>3.0.co;2-4

146. 146.

     Eizirik DL, et al. Major species differences between humans and rodents in the susceptibility to pancreatic beta-cell injury. Proc. Natl. Acad. Sci. USA. 1994;91:9253-9256.

     Not in our library10.1073/pnas.91.20.9253

147. 147.

     Eizirik DL, et al. Cytokines suppress human islet function irrespective of their effects on nitric oxide generation. J. Clin. Invest. 1994;93:1968-1974.

     Not in our library10.1172/jci117188

148. 148.

     Welsh N, et al. Differences in the expression of heat-shock proteins and antioxidant enzymes between human and rodent pancreatic islets: implications for the pathogenesis of insulin-dependent diabetes mellitus. Mol. Med. 1995;1:806-820.

     Not in our library

149. 149.

     Burkart V, et al. Natural resistance of human beta cells toward nitric oxide is mediated by heat shock protein 70. J. Biol. Chem. 2000;275:19521-19528.

     Not in our library10.1074/jbc.m002265200

150. 150.

     Scarim AL, Heitmeier MR, Corbett JA. Heat shock inhibits cytokine-induced nitric oxide synthase expression by rat and human islets. Endocrinology. 1998;139:5050-5057.

     Not in our library10.1210/endo.139.12.6366

151. 151.

     Weber SM, Scarim AL, Corbett JA. Inhibition of IFN-gamma -induced STAT1 activation by 15- deoxy-Delta 12,14-prostaglandin J2. Am. J. Physiol. Endocrinol. Metabol. 2003;284:E883-E891.

     Not in our library10.1152/ajpendo.00515.2002

152. 152.

     Weber SM, et al. PPARgamma ligands induce ER stress in pancreatic beta-cells: ER stress activation results in attenuation of cytokine signaling. Am. J. Physiol. Endocrinol. Metabol. 2004;287:E1171-E1177.

     Not in our library10.1152/ajpendo.00331.2004

153. 153.
     Interleukin-1 Stimulates β-Cell Necrosis and Release of the Immunological Adjuvant HMGB1 · 2005

     No notice
154. 154.

     Cnop M, et al. Mechanisms of pancreatic beta-cell death in type 1 and type 2 diabetes: many differences, few similarities. Diabetes. 2005;54(Suppl 2):S97-S107.

     Not in our library10.2337/diabetes.54.suppl_2.s97

155. 155.

     Eizirik DL, Mandrup-Poulsen T. A choice of death—the signal-transduction of immune-mediated beta-cell apoptosis. Diabetologia. 2001;44:2115-2133.

     Not in our library10.1007/s001250100021

156. 156.

     Gurzov EN, Eizirik DL. Bcl-2 proteins in diabetes: mitochondrial pathways of beta-cell death and dysfunction. Trends Cell Biol. 2011;21:424-431.

     Not in our library10.1016/j.tcb.2011.03.001

157. 157.

     Mandrup-Poulsen T. beta-cell apoptosis: stimuli and signaling. [Review] [63 refs]. Diabetes. 2001;50:S58-S63.

     Not in our library10.2337/diabetes.50.2007.s58

158. 158.

     McKenzie MD, et al. Glucose induces pancreatic islet cell apoptosis that requires the BH3-only proteins Bim and Puma and multi-BH domain protein Bax. Diabetes. 2010;59:644-652.

     Not in our library10.2337/db09-1151

159. 159.

     Thomas HE, Kay TW. Intracellular pathways of pancreatic beta-cell apoptosis in type 1 diabetes. Diabetes Metab. Res. Rev. 2011;27:790-796.

     Not in our library10.1002/dmrr.1253

160. 160.

     Cunha DA, et al. Death protein 5 and p53-upregulated modulator of apoptosis mediate the endoplasmic reticulum stress-mitochondrial dialog triggering lipotoxic rodent and human β-cell apoptosis. Diabetes. 2012;61:2763-2775.

     Not in our library10.2337/db12-0123

161. 161.

     Lee H, et al. Endoplasmic reticulum stress-induced JNK activation is a critical event leading to mitochondria-mediated cell death caused by beta-lapachone treatment. PLoS One. 2011;6:e21533.

     Not in our library10.1371/journal.pone.0021533

162. 162.

     Wang Q, et al. IL-1beta caused pancreatic beta-cells apoptosis is mediated in part by endoplasmic reticulum stress via the induction of endoplasmic reticulum Ca2+ release through the c-Jun N-terminal kinase pathway. Mol. Cell Biochem. 2009;324:183-190.

     Not in our library10.1007/s11010-008-9997-9

163. 163.

     Akerfeldt MC, et al. Cytokine-induced beta-cell death is independent of endoplasmic reticulum stress signaling. Diabetes. 2008;57:3034-3044.

     Not in our library10.2337/db07-1802

164. 164.

     Chambers KT, et al. The role of nitric oxide and the unfolded protein response in cytokine-induced beta-cell death. Diabetes. 2008;57:124-132.

     Not in our library10.2337/db07-0944

165. 165.

     Collier JJ, et al. Pro- and antiapoptotic proteins regulate apoptosis but do not protect against cytokine-mediated cytotoxicity in rat islets and beta-cell lines. Diabetes. 2006;55:1398-1406.

     Not in our library10.2337/db05-1000

166. 166.

     Cunningham JM, Green IC. Cytokines, nitric oxide and insulin secreting cells. Growth Regulation. 1994;4:173-180.

     Not in our library

167. 167.

     Collier JJ, et al. Pancreatic beta-cell death in response to pro-inflammatory cytokines is distinct from genuine apoptosis. PLoS One. 2011;6:e22485.

     Not in our library10.1371/journal.pone.0022485

168. 168.

     Scaffidi P, Misteli T, Bianchi ME. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature. 2002;418:191-195.

     Not in our library10.1038/nature00858

169. 169.

     Zong WX, et al. Alkylating DNA damage stimulates a regulated form of necrotic cell death. Genes Dev. 2004;18:1272-1282.

     Not in our library10.1101/gad.1199904

170. 170.

     Adeghate E, Parvez SH. Nitric oxide and neuronal and pancreatic beta cell death. Toxicology. 2000;153:143-156.

     Not in our library10.1016/s0300-483x(00)00310-3

171. 171.

     Hohmeier HE, et al. Inflammatory mechanisms in diabetes: lessons from the beta-cell. Int. J. Obesity Relat. Metabol. Disorders. 2003;27(Suppl 3)):S12-S16.

     Not in our library10.1038/sj.ijo.0802493

172. 172.

     Rabinovitch A. An update on cytokines in the pathogenesis of insulin-dependent diabetes mellitus. Diabetes Metab. Rev. 1998;14:129-151.

     Not in our library10.1002/(sici)1099-0895(199806)14:2<129::aid-dmr208>3.0.co;2-v

173. 173.

     Szabadkai G, Duchen MR. Mitochondria mediated cell death in diabetes. Apoptosis. 2009;14:1405-1423.

     Not in our library10.1007/s10495-009-0363-5

174. 174.

     Liu D, et al. Cytokines induce apoptosis in beta-cells isolated from mice lacking the inducible isoform of nitric oxide synthase (iNOS-/-). Diabetes. 2000;49:1116-1122.

     Not in our library10.2337/diabetes.49.7.1116

175. 175.

     Takamura T, et al. Transgenic mice overexpressing type 2 nitric-oxide synthase in pancreatic beta cells develop insulin-dependent diabetes without insulitis. J. Biol. Chem. 1998;273:2493-2496.

     Not in our library10.1074/jbc.273.5.2493

176. 176.

     Meares G, et al. AMP-activated protein kinase attenuates nitric oxide–induced beta-cell death. J. Biol. Chem. 2009;285:3191-3200.

     Not in our library10.1074/jbc.m109.047365

177. 177.

     Zong WX, Thompson CB. Necrotic death as a cell fate. Genes. Dev. 2006;20:1-15.

     Not in our library10.1101/gad.1376506

178. 178.

     Hughes K, et al. Repair of nitric oxide-damaged DNA in beta-cells requires JNK-dependent GADD45alpha expression. J. Biol. Chem. 2009;284:27402-27408.

     Not in our library10.1074/jbc.m109.046912

179. 179.

     Kim YM, Talanian RV, Billiar TR. Nitric oxide inhibits apoptosis by preventing increases in caspase-3-like activity via two distinct mechanisms. J. Biol. Chem. 1997;272:31138-31148.

     Not in our library10.1074/jbc.272.49.31138

180. 180.

     Rossig L, et al. Nitric oxide inhibits caspase-3 by S-nitrosation in vivo. J. Biol. Chem. 1999;274:6823-6826.

     Not in our library10.1074/jbc.274.11.6823

181. 181.

     Abdelli S, et al. The c-Jun N-terminal kinase JNK participates in cytokine- and isolation stress-induced rat pancreatic islet apoptosis. Diabetologia. 2007;50:1660-1669.

     Not in our library10.1007/s00125-007-0704-2

182. 182.

     Gurzov EN, et al. Signaling by IL-1beta+IFN-gamma and ER stress converge on DP5/Hrk activation: a novel mechanism for pancreatic beta-cell apoptosis. Cell Death Differentiation. 2009;16:1539-1550.

     Not in our library10.1038/cdd.2009.99

183. 183.

     Larsen L, et al. Extracellular signal-regulated kinase is essential for interleukin-1-induced and nuclear factor kappaB-mediated gene expression in insulin-producing INS-1E cells. Diabetologia. 2005;48:2582-2590.

     Not in our library10.1007/s00125-005-0039-9

184. 184.

     Scarim AL, et al. Role for c-Jun N-terminal kinase in beta-cell recovery from nitric oxide-mediated damage. Endocrinology. 2003;144:3415-3422.

     Not in our library10.1210/en.2002-0112

185. 185.

     Smith ML, Seo YR. p53 regulation of DNA excision repair pathways. Mutagenesis. 2002;17:149-156.

     Not in our library10.1093/mutage/17.2.149

186. 186.

     Tran H, et al. DNA repair pathway stimulated by the forkhead transcription factor FOXO3a through the Gadd45 protein. Science. 2002;296:530-534.

     Not in our library10.1126/science.1068712

187. 187.

     Hughes KJ, et al. FoxO1 and SIRT1 regulate beta-cell responses to nitric oxide. J. Biol. Chem. 2011;286:8338-8348.

     Not in our library10.1074/jbc.m110.204768

188. 188.

     Qiang L, Banks AS, Accili D. Uncoupling of acetylation from phosphorylation regulates FoxO1 function independent of its subcellular localization. J. Biol. Chem. 2010;285:27396-27401.

     Not in our library10.1074/jbc.m110.140228

189. 189.

     Giannakou ME, Partridge L. The interaction between FOXO and SIRT1: tipping the balance towards survival. Trends Cell Biol. 2004;14:408-412.

     Not in our library10.1016/j.tcb.2004.07.006

190. 190.

     Motta MC, et al. Mammalian SIRT1 represses forkhead transcription factors. Cell. 2004;116:551-563.

     Not in our library10.1016/s0092-8674(04)00126-6

191. 191.

     Corbett JA, et al. Aminoguanidine, a novel inhibitor of nitric oxide formation, prevents diabetic vascular dysfunction. Diabetes. 1992;41:552-556.

     Not in our library10.2337/diab.41.4.552

192. 192.

     Johannesen J, et al. Strain-dependent difference in inducible nitric oxide synthesis (iNOS) expression in rat pancreatic islets correlates with interferon regulating factor 1 (IRF-1) and heat shock protein 70 (HSP70) expression. Eur. Cytokine Network. 2001;12:501-509.

     Not in our library

193. 193.

     Eizirik DL, Cardozo AK, Cnop M. The role for endoplasmic reticulum stress in diabetes mellitus. Endocr. Rev. 2008;29:42-61.

     Not in our library10.1210/er.2007-0015

194. 194.

     Andreone T, et al. Cytokine-mediated beta-cell damage in PARP-1-deficient islets. Am. J. Physiol. Endocrinol. Metabol. 2012;303:E172-E179.

     Not in our library10.1152/ajpendo.00055.2012

195. 195.

     Sareila O, et al. NOX2 complex-derived ROS as immune regulators. Antioxid Redox Signal. 2011;15:2197-2208.

     Not in our library10.1089/ars.2010.3635

Cited by papers we hold 9

• Mechanisms of Oxidative Stress in Metabolic Syndrome · 2023
  No notice
• The role of inflammation in immune system of diabetic retinopathy: Molecular mechanisms, pathogenetic role and therapeutic implications · 2022
  No notice
• Mitophagy protects β cells from inflammatory damage in diabetes · 2020
  No notice
• Regulation of Cytokine Production by the Unfolded Protein Response; Implications for Infection and Autoimmunity · 2018
  No notice
• Neutrophil Extracellular Traps and Its Implications in Inflammation: An Overview · 2017
  No notice
• Role of Pro-Inflammatory Cytokines and Biochemical Markers in the Pathogenesis of Type 1 Diabetes: Correlation with Age and Glycemic Condition in Diabetic Human Subjects. · 2016
  Not checked
• Suppressors of cytokine signaling in sickness and in health of pancreatic β-cells · 2016
  Not checked
• NSC23766, a Known Inhibitor of Tiam1-Rac1 Signaling Module, Prevents the Onset of Type 1 Diabetes in the NOD Mouse Model · 2016
  Not checked
• Calcium-independent phospholipases A2 and their roles in biological processes and diseases · 2015
  Not checked

Reads

A person counts once a day per paper. We keep no cookie and no address: a reader is a hash that changes every day. Any month under five reads shows no number.