MD 2


Gene Symbol: MD 2
Description: lymphocyte antigen 96
Alias: ESOP-1, MD-2, MD2, lymphocyte antigen 96, ly-96, myeloid differentiation factor-2, myeloid differentiation protein-2, protein MD-2
Species: mouse
Products:     MD 2

Top Publications

  1. Kawasaki K, Nogawa H, Nishijima M. Identification of mouse MD-2 residues important for forming the cell surface TLR4-MD-2 complex recognized by anti-TLR4-MD-2 antibodies, and for conferring LPS and taxol responsiveness on mouse TLR4 by alanine-scanning mutagenesis. J Immunol. 2003;170:413-20 pubmed
    ..In addition, the required residues at codon numbers 34, 85, 101, 122, and 153 for the ability of mouse MD-2 to confer LPS responsiveness are partly different from those for Taxol responsiveness. ..
  2. Montminy S, Khan N, McGrath S, Walkowicz M, Sharp F, Conlon J, et al. Virulence factors of Yersinia pestis are overcome by a strong lipopolysaccharide response. Nat Immunol. 2006;7:1066-73 pubmed
    ..pestis virulence. Evading TLR4 activation by lipid A alteration may contribute to the virulence of various Gram-negative bacteria. ..
  3. Tsukamoto H, Fukudome K, Takao S, Tsuneyoshi N, Kimoto M. Lipopolysaccharide-binding protein-mediated Toll-like receptor 4 dimerization enables rapid signal transduction against lipopolysaccharide stimulation on membrane-associated CD14-expressing cells. Int Immunol. 2010;22:271-80 pubmed publisher
    ..This early activation was blocked by inhibitory anti-CD14 mAb. These studies suggest that LPS-induced TLR4/MD-2 receptor dimerization is not essential for signaling but prompts rapid signaling during innate immune responses. ..
  4. Kim H, Park B, Kim J, Kim S, Lee J, Oh S, et al. Crystal structure of the TLR4-MD-2 complex with bound endotoxin antagonist Eritoran. Cell. 2007;130:906-17 pubmed
    ..The interaction with Eritoran is mediated by a hydrophobic internal pocket in MD-2. Based on structural analysis and mutagenesis experiments on MD-2 and TLR4, we propose a model of TLR4-MD-2 dimerization induced by LPS. ..
  5. Akashi S, Shimazu R, Ogata H, Nagai Y, Takeda K, Kimoto M, et al. Cutting edge: cell surface expression and lipopolysaccharide signaling via the toll-like receptor 4-MD-2 complex on mouse peritoneal macrophages. J Immunol. 2000;164:3471-5 pubmed
    ..Moreover, LPS-induced TNF-alpha production by peritoneal macrophages was inhibited by MTS510. Collectively, the TLR4-MD-2 complex is expressed on macrophages in vivo and senses and signals the presence of LPS. ..
  6. Shimazu R, Akashi S, Ogata H, Nagai Y, Fukudome K, Miyake K, et al. MD-2, a molecule that confers lipopolysaccharide responsiveness on Toll-like receptor 4. J Exp Med. 1999;189:1777-82 pubmed
    ..MD-2 is thus a link between TLR4 and LPS signaling. Identification of this new receptor complex has potential implications for understanding host defense, as well as pathophysiologic, mechanisms. ..
  7. Nagai Y, Akashi S, Nagafuku M, Ogata M, Iwakura Y, Akira S, et al. Essential role of MD-2 in LPS responsiveness and TLR4 distribution. Nat Immunol. 2002;3:667-72 pubmed
    ..Thus, MD-2 is essential for correct intracellular distribution and LPS-recognition of TLR4. ..
  8. Meng J, Gong M, Bjorkbacka H, Golenbock D. Genome-wide expression profiling and mutagenesis studies reveal that lipopolysaccharide responsiveness appears to be absolutely dependent on TLR4 and MD-2 expression and is dependent upon intermolecular ionic interactions. J Immunol. 2011;187:3683-93 pubmed publisher
    ..Hence, we concluded that ionic interactions between lipid A and TLR4 are essential for optimal LPS receptor activation. ..
  9. Tanimura N, Saitoh S, Ohto U, Akashi Takamura S, Fujimoto Y, Fukase K, et al. The attenuated inflammation of MPL is due to the lack of CD14-dependent tight dimerization of the TLR4/MD2 complex at the plasma membrane. Int Immunol. 2014;26:307-14 pubmed publisher

More Information


  1. Hajjar A, Ernst R, Yi J, Yam C, Miller S. Expression level of human TLR4 rather than sequence is the key determinant of LPS responsiveness. PLoS ONE. 2017;12:e0186308 pubmed publisher
    ..Using in vitro and in vivo assays we found that the expression level rather than the sequence of TLR4 played a larger role in recognition of LPS, especially hypoacylated LPS. ..
  2. Hadina S, Weiss J, McCray P, Kulhankova K, Thorne P. MD-2-dependent pulmonary immune responses to inhaled lipooligosaccharides: effect of acylation state. Am J Respir Cell Mol Biol. 2008;38:647-54 pubmed publisher
    ..Hyporesponsiveness in MD-2-null mice after nasal aspiration of wild-type LOS indicate its essential role in airway responsiveness to endotoxin...
  3. Tissieres P, Dunn Siegrist I, Schappi M, Elson G, Comte R, Nobre V, et al. Soluble MD-2 is an acute-phase protein and an opsonin for Gram-negative bacteria. Blood. 2008;111:2122-31 pubmed
    ..This suggests that sMD-2 plays a key role in the host innate immune response to Gram-negative infections. ..
  4. Morita N, Yamazaki T, Murakami Y, Fukui R, Yamai I, Ichimonji I, et al. C4b-binding protein negatively regulates TLR4/MD-2 response but not TLR3 response. FEBS Lett. 2017;591:1732-1741 pubmed publisher
    ..These findings indicate that C4BP binds to cell surface TLRs and inhibits the TLR-TLR ligand interaction, thereby inhibiting TLR activation. ..
  5. Resman N, Oblak A, Gioannini T, Weiss J, Jerala R. Tetraacylated lipid A and paclitaxel-selective activation of TLR4/MD-2 conferred through hydrophobic interactions. J Immunol. 2014;192:1887-95 pubmed publisher
    ..These results provide an insight into the molecular mechanism of TLR4 activation by two structurally very different agonists. ..
  6. Zhang Y, Wu B, Zhang H, Ge X, Ying S, Hu M, et al. Inhibition of MD2-dependent inflammation attenuates the progression of non-alcoholic fatty liver disease. J Cell Mol Med. 2018;22:936-947 pubmed publisher
    ..basis of NAFLD progressing to NASH is currently unknown, but growing evidence suggests MD2 (myeloid differentiation factor 2), an accessory protein of TLR4, is an important signalling component contributing to this disease...
  7. Walsh C, Gangloff M, Monie T, Smyth T, Wei B, McKinley T, et al. Elucidation of the MD-2/TLR4 interface required for signaling by lipid IVa. J Immunol. 2008;181:1245-54 pubmed
  8. Zanoni I, Ostuni R, Capuano G, Collini M, Caccia M, Ronchi A, et al. CD14 regulates the dendritic cell life cycle after LPS exposure through NFAT activation. Nature. 2009;460:264-8 pubmed publisher
  9. Chen H, Song Z, Ying S, Yang X, Wu W, Tan Q, et al. Myeloid differentiation protein 2 induced retinal ischemia reperfusion injury via upregulation of ROS through a TLR4-NOX4 pathway. Toxicol Lett. 2018;282:109-120 pubmed publisher
    ..Activation of TLRs requires specific accessory proteins such as myeloid differentiation protein 2 (MD2), which facilitate in ligand responsiveness...
  10. Ey B, Eyking A, Klepak M, Salzman N, Gothert J, Runzi M, et al. Loss of TLR2 worsens spontaneous colitis in MDR1A deficiency through commensally induced pyroptosis. J Immunol. 2013;190:5676-88 pubmed publisher
  11. Kayagaki N, Wong M, Stowe I, Ramani S, Gonzalez L, Akashi Takamura S, et al. Noncanonical inflammasome activation by intracellular LPS independent of TLR4. Science. 2013;341:1246-9 pubmed publisher
    ..coli LPS. These data unveil a TLR4-independent mechanism for innate immune recognition of LPS. ..
  12. Deguchi A, Tomita T, Ohto U, Takemura K, Kitao A, Akashi Takamura S, et al. Eritoran inhibits S100A8-mediated TLR4/MD-2 activation and tumor growth by changing the immune microenvironment. Oncogene. 2016;35:1445-56 pubmed publisher
    ..Taken together, S100A8 appears to play a crucial role in the activation of the TLR4/MD-2 pathway and the promotion of a tumor growth-enhancing immune microenvironment. ..
  13. Choi S, Kim J, Gonen A, Viriyakosol S, Miller Y. MD-2 binds cholesterol. Biochem Biophys Res Commun. 2016;470:877-80 pubmed publisher
    ..These results help understand the molecular basis of TLR4 activation by OxCE and mechanisms of chronic inflammation in atherosclerosis. ..
  14. Fang Q, Wang J, Zhang Y, Wang L, Li W, Han J, et al. Inhibition of myeloid differentiation factor-2 attenuates obesity-induced cardiomyopathy and fibrosis. Biochim Biophys Acta Mol Basis Dis. 2018;1864:252-262 pubmed publisher
    ..Myeloid differentiation factor-2 (MD2), a binding protein of lipopolysaccharide, is functionally essential for the activation of proinflammatory pathways ..
  15. Dejkhamron P, Thimmarayappa J, Kotlyarevska K, Sun J, Lu C, Bonkowski E, et al. Lipopolysaccharide (LPS) directly suppresses growth hormone receptor (GHR) expression through MyD88-dependent and -independent Toll-like receptor-4/MD2 complex signaling pathways. Mol Cell Endocrinol. 2007;274:35-42 pubmed
    ..LPS directly modulates the activity of the dominant GHR promoter via interaction with Toll-like receptor(s) (TLR)/MD2 complex and activation of cognate signaling pathway(s). In transient transfection experiments with RAW 264...
  16. Riquelme S, Bueno S, Kalergis A. Carbon monoxide down-modulates Toll-like receptor 4/MD2 expression on innate immune cells and reduces endotoxic shock susceptibility. Immunology. 2015;144:321-32 pubmed publisher
    ..been suggested that CO impairs the stimulation of the Toll-like receptor 4 (TLR4)/myeloid differentiation factor-2 (MD2) complex located on the surface of immune cells...
  17. Ogata H, Su I, Miyake K, Nagai Y, Akashi S, Mecklenbrauker I, et al. The toll-like receptor protein RP105 regulates lipopolysaccharide signaling in B cells. J Exp Med. 2000;192:23-9 pubmed
    ..These data suggest the existence of the TLR4-RP105 signaling module in the LPS-induced B cell activation. ..
  18. Koyama D, Maruoka S, Gon Y, Shintani Y, Sekiyama T, Hiranuma H, et al. Myeloid differentiation-2 is a potential biomarker for the amplification process of allergic airway sensitization in mice. Allergol Int. 2015;64 Suppl:S37-45 pubmed publisher
    ..Serum MD-2 may represent a potential biomarker for the amplification of allergic sensitization and allergic inflammation. ..
  19. Kunda P, Cavicchia J, Acosta C. Lipopolysaccharides and trophic factors regulate the LPS receptor complex in nodose and trigeminal neurons. Neuroscience. 2014;280:60-72 pubmed publisher
    ..extent the regulation of TLR4 and its auxiliary proteins (myeloid differentiation protein 1 (MD1), myeloid differentiation protein 2 (MD2) and cluster of differentiation 14 (CD14)), are both poorly understood in trigeminal and nodose ..
  20. Meng J, Drolet J, Monks B, Golenbock D. MD-2 residues tyrosine 42, arginine 69, aspartic acid 122, and leucine 125 provide species specificity for lipid IVA. J Biol Chem. 2010;285:27935-43 pubmed publisher
    ..Thus, surface charge differences at the two MD-2/TLR4 interfaces determine the species-specific activation of lipid IV(A). ..
  21. Davey M, Liu X, Ukai T, Jain V, Gudino C, Gibson F, et al. Bacterial fimbriae stimulate proinflammatory activation in the endothelium through distinct TLRs. J Immunol. 2008;180:2187-95 pubmed
  22. Balamayooran G, Batra S, Balamayooran T, Cai S, Jeyaseelan S. Monocyte chemoattractant protein 1 regulates pulmonary host defense via neutrophil recruitment during Escherichia coli infection. Infect Immun. 2011;79:2567-77 pubmed publisher
    ..coli-induced MCP-1 causes neutrophil recruitment directly via chemotaxis as well as indirectly via modulation of keratinocyte cell-derived chemokine, macrophage inflammatory protein 2, and LTB(4). ..
  23. Bauernfeind F, Horvath G, Stutz A, Alnemri E, MacDonald K, Speert D, et al. Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J Immunol. 2009;183:787-91 pubmed publisher
    ..Signals provided by NF-kappaB activators are necessary but not sufficient for NLRP3 activation, and a second stimulus such as ATP or crystal-induced damage is required for NLRP3 activation. ..
  24. Nagai Y, Yanagibashi T, Watanabe Y, Ikutani M, Kariyone A, Ohta S, et al. The RP105/MD-1 complex is indispensable for TLR4/MD-2-dependent proliferation and IgM-secreting plasma cell differentiation of marginal zone B cells. Int Immunol. 2012;24:389-400 pubmed publisher
    ..These responses contributed to TLR4-mediated anti-apoptotic responses in MZ B cells. Thus, RP105 contributes in a unique way to the TLR4-dependent survival, proliferation and plasma cell generation of MZ B cells. ..
  25. Leal S, Cowden S, Hsia Y, Ghannoum M, Momany M, Pearlman E. Distinct roles for Dectin-1 and TLR4 in the pathogenesis of Aspergillus fumigatus keratitis. PLoS Pathog. 2010;6:e1000976 pubmed publisher
  26. Björk P, Björk A, Vogl T, Stenstrom M, Liberg D, Olsson A, et al. Identification of human S100A9 as a novel target for treatment of autoimmune disease via binding to quinoline-3-carboxamides. PLoS Biol. 2009;7:e97 pubmed publisher
    ..end products (RAGE) and also an endogenous Toll ligand in that it shows a highly specific interaction with TLR4/MD2. Both these interactions are inhibited by quinoline-3-carboxamides...
  27. Meng J, Lien E, Golenbock D. MD-2-mediated ionic interactions between lipid A and TLR4 are essential for receptor activation. J Biol Chem. 2010;285:8695-702 pubmed publisher
  28. Yanagimoto S, Tatsuno K, Okugawa S, Kitazawa T, Tsukada K, Koike K, et al. A single amino acid of toll-like receptor 4 that is pivotal for its signal transduction and subcellular localization. J Biol Chem. 2009;284:3513-20 pubmed publisher
    ..These results suggest that the leucine at position 815 is required for the normal maturation of TLR4 and for formation of the TLR4.MD-2 complex. ..
  29. Wang L, Han J, Shan P, You S, Chen X, Jin Y, et al. MD2 Blockage Protects Obesity-Induced Vascular Remodeling via Activating AMPK/Nrf2. Obesity (Silver Spring). 2017;25:1532-1539 pubmed publisher
    ..Myeloid differentiation 2 (MD2), an important protein in innate immunity, is requisite for endotoxin lipopolysaccharide responsiveness...
  30. Alugupalli K, Akira S, Lien E, Leong J. MyD88- and Bruton's tyrosine kinase-mediated signals are essential for T cell-independent pathogen-specific IgM responses. J Immunol. 2007;178:3740-9 pubmed
    ..These results suggest that MyD88 specifically promotes T cell-independent BCR signaling and that, in the absence of Btk, this TLR-mediated stimulation is a required component of this signal. ..
  31. Spiller S, Dreher S, Meng G, Grabiec A, Thomas W, Hartung T, et al. Cellular recognition of trimyristoylated peptide or enterobacterial lipopolysaccharide via both TLR2 and TLR4. J Biol Chem. 2007;282:13190-8 pubmed
    ..On the other hand, simultaneous blockage of both of the two TLRs might effectively inhibit infection-induced pathology. ..
  32. Bozza S, Campo S, Arseni B, Inforzato A, Ragnar L, Bottazzi B, et al. PTX3 binds MD-2 and promotes TRIF-dependent immune protection in aspergillosis. J Immunol. 2014;193:2340-8 pubmed publisher
    ..In this study, we demonstrate that PTX3 binds myeloid differentiation protein 2 (MD-2) in vitro and exerts its protective antifungal activity in vivo through TLR4/MD-2-mediated ..
  33. Erridge C, Kennedy S, Spickett C, Webb D. Oxidized phospholipid inhibition of toll-like receptor (TLR) signaling is restricted to TLR2 and TLR4: roles for CD14, LPS-binding protein, and MD2 as targets for specificity of inhibition. J Biol Chem. 2008;283:24748-59 pubmed publisher
    ..Binding experiments and functional assays identified MD2 as a novel additional target of OxPAPC inhibition of LPS signaling...
  34. Deguchi A, Tomita T, Omori T, Komatsu A, Ohto U, Takahashi S, et al. Serum amyloid A3 binds MD-2 to activate p38 and NF-?B pathways in a MyD88-dependent manner. J Immunol. 2013;191:1856-64 pubmed publisher
    ..Taken together, these results suggest that SAA3 directly binds MD-2 and activates the MyD88-dependent TLR4/MD-2 pathway. ..
  35. Koo J, Park Z, Kim N, Lee J. Sulforaphane inhibits the engagement of LPS with TLR4/MD2 complex by preferential binding to Cys133 in MD2. Biochem Biophys Res Commun. 2013;434:600-5 pubmed publisher
    ..LPS interacts with TLR4 through binding to a hydrophobic pocket in myeloid differentiation 2 (MD2), a co-receptor of TLR4...
  36. Ohto U, Fukase K, Miyake K, Shimizu T. Structural basis of species-specific endotoxin sensing by innate immune receptor TLR4/MD-2. Proc Natl Acad Sci U S A. 2012;109:7421-6 pubmed publisher
    ..Together, the results provide structural evidence of the agonistic property of lipid IVa on mouse TLR4/MD-2 and deepen understanding of the ligand binding and dimerization mechanism by the structurally diverse LPS variants. ..
  37. Zimmer S, Liu J, Clayton J, Stephens D, Snyder J. Paclitaxel binding to human and murine MD-2. J Biol Chem. 2008;283:27916-26 pubmed publisher
    ..In particular, Phe(126) appears to operate as a bridge for TLR4.MD-2 dimerization in the mouse but not the human protein. ..
  38. Honda H, Nagai Y, Matsunaga T, Saitoh S, Akashi Takamura S, Hayashi H, et al. Glycyrrhizin and isoliquiritigenin suppress the LPS sensor toll-like receptor 4/MD-2 complex signaling in a different manner. J Leukoc Biol. 2012;91:967-76 pubmed publisher
  39. Stewart C, Stuart L, Wilkinson K, van Gils J, Deng J, Halle A, et al. CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer. Nat Immunol. 2010;11:155-61 pubmed publisher
  40. Yang H, Wang H, Ju Z, Ragab A, Lundbäck P, Long W, et al. MD-2 is required for disulfide HMGB1-dependent TLR4 signaling. J Exp Med. 2015;212:5-14 pubmed publisher
    ..Here we demonstrate that the extracellular TLR4 adaptor, myeloid differentiation factor 2 (MD-2), binds specifically to the cytokine-inducing disulfide isoform of HMGB1, to the exclusion of ..
  41. Sun Y, Karmakar M, Roy S, Ramadan R, Williams S, Howell S, et al. TLR4 and TLR5 on corneal macrophages regulate Pseudomonas aeruginosa keratitis by signaling through MyD88-dependent and -independent pathways. J Immunol. 2010;185:4272-83 pubmed publisher
    ..IL-1? and IL-1? are also produced, which activate an IL-1R1/MyD88-positive feedback loop in macrophages and IL-1R on other resident cells in the cornea. ..
  42. Kobayashi M, Saitoh S, Tanimura N, Takahashi K, Kawasaki K, Nishijima M, et al. Regulatory roles for MD-2 and TLR4 in ligand-induced receptor clustering. J Immunol. 2006;176:6211-8 pubmed
    ..These results support a principal role for MD-2 in LPS recognition. ..
  43. Jain V, Halle A, Halmen K, Lien E, Charrel Dennis M, Ram S, et al. Phagocytosis and intracellular killing of MD-2 opsonized gram-negative bacteria depend on TLR4 signaling. Blood. 2008;111:4637-45 pubmed publisher
    ..The presented results extend our understanding of the role of the TLR4/MD-2 signaling axis in bacterial recognition by phagocytes. ..
  44. Hajjar A, Ernst R, Fortuno E, Brasfield A, Yam C, Newlon L, et al. Humanized TLR4/MD-2 mice reveal LPS recognition differentially impacts susceptibility to Yersinia pestis and Salmonella enterica. PLoS Pathog. 2012;8:e1002963 pubmed publisher
    ..Thus, Y. pestis exploits temperature-dependent shifts in LPS acylation to selectively evade recognition by human TLR4/MD-2 uncovered with "humanized" TLR4/MD-2 transgenic mice...
  45. Vasl J, Oblak A, Gioannini T, Weiss J, Jerala R. Novel roles of lysines 122, 125, and 58 in functional differences between human and murine MD-2. J Immunol. 2009;183:5138-45 pubmed publisher
    ..These findings reveal novel roles of lysines 122, 125, and 58 in human MD-2 that contribute to the functional differences between human and murine MD-2 and, potentially, to differences in the sensitivity of humans and mice to endotoxin. ..
  46. Peng Y, Gong J, Liu C, Li X, Gan L, Li S. Expression of toll-like receptor 4 and MD-2 gene and protein in Kupffer cells after ischemia-reperfusion in rat liver graft. World J Gastroenterol. 2004;10:2890-3 pubmed
    ..Anti TLR4 antibody can inhibit the production of TNF-alpha induced by LPS. TLR4 and its partner molecule MD-2 may play an important role in Kupffer cell activation and IR injury. ..
  47. Muroi M, Tanamoto K. Structural regions of MD-2 that determine the agonist-antagonist activity of lipid IVa. J Biol Chem. 2006;281:5484-91 pubmed
  48. Cai S, Zemans R, Young S, Worthen G, Jeyaseelan S. Myeloid differentiation protein-2-dependent and -independent neutrophil accumulation during Escherichia coli pneumonia. Am J Respir Cell Mol Biol. 2009;40:701-9 pubmed publisher
    ..coli-induced neutrophil accumulation and pulmonary host defense. ..
  49. Patenaude J, D Elia M, Côté Maurais G, Bernier J. LPS response and endotoxin tolerance in Flt-3L-induced bone marrow-derived dendritic cells. Cell Immunol. 2011;271:184-91 pubmed publisher
    ..Overall, DCs generated from bone marrow with Flt-3 ligand have similar characteristics to DC subtypes found in the steady state in vivo, which can acquire endotoxin tolerance in some circumstances. ..
  50. Casella C, Mitchell T. Inefficient TLR4/MD-2 heterotetramerization by monophosphoryl lipid A. PLoS ONE. 2013;8:e62622 pubmed publisher
    ..As further tests of sMLA's ability to activate TLR4/Myeloid differentiation factor 2 (MD-2), we used the antibody MTS510 as an indicator for TLR4/MD-2 heterotetramer formation...
  51. Kondo Y, Ikeda K, Tokuda N, Nishitani C, Ohto U, Akashi Takamura S, et al. TLR4-MD-2 complex is negatively regulated by an endogenous ligand, globotetraosylceramide. Proc Natl Acad Sci U S A. 2013;110:4714-9 pubmed publisher
    Although endogenous ligands for Toll-like receptor (TLR)4-myeloid differentiation factor 2 (MD2) have not been well-understood, we here report that a globo-series glycosphingolipid, globotetraosylceramide (Gb4), attenuates the toxicity of ..
  52. Zhou R, Zhang R, Sun Y, Platt S, Szczotka Flynn L, Pearlman E. Innate immune regulation of Serratia marcescens-induced corneal inflammation and infection. Invest Ophthalmol Vis Sci. 2012;53:7382-8 pubmed publisher
    ..S. marcescens induces corneal inflammation by activation of TLR4/MD-2/MyD88 and the IL-1R1/MyD88 pathways, which are potential therapeutic targets for inhibition of S. marcescens-induced corneal inflammation. ..
  53. Doronin K, Flatt J, Di Paolo N, Khare R, Kalyuzhniy O, Acchione M, et al. Coagulation factor X activates innate immunity to human species C adenovirus. Science. 2012;338:795-8 pubmed publisher