Publications

2021

Cho CS, Xi J, Si Y, Park SR, Hsu JE, Kim M, Jun G, Kang HM, Lee JH. Microscopic examination of spatial transcriptome using Seq-Scope. Cell. 2021 Jun 24;184(13):3559-3572.e22. doi: 10.1016/j.cell.2021.05.010. Epub 2021 Jun 10. PubMed PMID: 34115981; PubMed Central PMCID: PMC8238917.

Kim M, Kowalsky AH, Lee JH. Sestrins in Physiological Stress Responses. Annu Rev Physiol. 2021 Feb 10;83:381-403. doi: 10.1146/annurev-physiol-031620-092317. Epub 2020 Oct 28. PubMed PMID: 33113341; PubMed Central PMCID: PMC7878365.

Park SR, Cho CS, Xi J, Kang HM, Lee JH. Holistic characterization of single-hepatocyte transcriptome responses to high-fat diet. Am J Physiol Endocrinol Metab. 2021 Feb 1;320(2):E244-E258. doi: 10.1152/ajpendo.00391.2020. PubMed PMID: 33103450; PubMed Central PMCID: PMC8260362.

Yang BA, Castor-Macias J, Fraczek P, Cornett A, Brown LA, Kim M, Brooks SV, Lombaert IMA, Lee JH, Aguilar CA. Sestrins regulate muscle stem cell metabolic homeostasis. Stem Cell Reports. 2021 Jul 29;. doi: 10.1016/j.stemcr.2021.07.014. [Epub ahead of print] PubMed PMID: 34388363.

Klionsky DJ, et al. Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1. Autophagy. 2021 Jan;17(1):1-382. doi: 10.1080/15548627.2020.1797280. Epub 2021 Feb 8. PubMed PMID: 33634751; PubMed Central PMCID: PMC7996087.

2020

Kim M, Sujkowski A, Namkoong S, Gu B, Cobb T, Kim B, Kowalsky AH, Cho CS, Semple I, Ro SH, Davis C, Brooks SV, Karin M, Wessells RJ, Lee JH. Sestrins are evolutionarily conserved mediators of exercise benefits. Nat Commun. 2020 Jan 13;11(1):190. doi: 10.1038/s41467-019-13442-5. PubMed PMID: 31929512; PubMed Central PMCID: PMC6955242.

Park SR, Namkoong S, Friesen L, Cho CS, Zhang ZZ, Chen YC, Yoon E, Kim CH, Kwak H, Kang HM, Lee JH. Single-Cell Transcriptome Analysis of Colon Cancer Cell Response to 5-Fluorouracil-Induced DNA Damage. Cell Rep. 2020 Aug 25;32(8):108077. doi: 10.1016/j.celrep.2020.108077. PubMed PMID: 32846134; PubMed Central PMCID: PMC7486130.

Kowalsky AH, Namkoong S, Mettetal E, Park HW, Kazyken D, Fingar DC, Lee JH. The GATOR2-mTORC2 axis mediates Sestrin2-induced AKT Ser/Thr kinase activation. J Biol Chem. 2020 Feb 14;295(7):1769-1780. doi: 10.1074/jbc.RA119.010857. Epub 2020 Jan 8. PubMed PMID: 31915252; PubMed Central PMCID: PMC7029113.

Cho CS, Kowalsky AH, Lee JH. Pathological Consequences of Hepatic mTORC1 Dysregulation. Genes (Basel). 2020 Aug 5;11(8). doi: 10.3390/genes11080896. Review. PubMed PMID: 32764389; PubMed Central PMCID: PMC7465966.

Pereira BI, De Maeyer RPH, Covre LP, Nehar-Belaid D, Lanna A, Ward S, Marches R, Chambers ES, Gomes DCO, Riddell NE, Maini MK, Teixeira VH, Janes SM, Gilroy DW, Larbi A, Mabbott NA, Ucar D, Kuchel GA, Henson SM, Strid J, Lee JH, Banchereau J, Akbar AN. Sestrins induce natural killer function in senescent-like CD8+ T cells. Nat Immunol. 2020 Jun;21(6):684-694. doi: 10.1038/s41590-020-0643-3. Epub 2020 Mar 30. PubMed PMID: 32231301; NIHMSID:NIHMS1598079.

Segalés J, Perdiguero E, Serrano AL, Sousa-Victor P, Ortet L, Jardí M, Budanov AV, Garcia-Prat L, Sandri M, Thomson DM, Karin M, Hee Lee J, Muñoz-Cánoves P. Sestrin prevents atrophy of disused and aging muscles by integrating anabolic and catabolic signals. Nat Commun. 2020 Jan 13;11(1):189. doi: 10.1038/s41467-019-13832-9. PubMed PMID: 31929511; PubMed Central PMCID: PMC6955241.

2019

Cho CS, Kowalsky AH, Namkoong S, Park SR, Wu S, Kim B, James A, Gu B, Semple IA, Tohamy MA, Solanki S, Cho US, Greenson JK, Shah YM, Kim M, Lee JH. Concurrent activation of growth factor and nutrient arms of mTORC1 induces oxidative liver injury. Cell Discov. 2019;5:60. doi: 10.1038/s41421-019-0131-9. eCollection 2019. PubMed PMID: 31754457; PubMed Central PMCID: PMC6868011.

Li R, Huang Y, Semple I, Kim M, Zhang Z, Lee JH. Cardioprotective roles of sestrin 1 and sestrin 2 against doxorubicin cardiotoxicity. Am J Physiol Heart Circ Physiol. 2019 Jul 1;317(1):H39-H48. doi: 10.1152/ajpheart.00008.2019. Epub 2019 Apr 26. PubMed PMID: 31026186; PubMed Central PMCID: PMC6692737.

Ries RJ, Zaccara S, Klein P, Olarerin-George A, Namkoong S, Pickering BF, Patil DP, Kwak H, Lee JH, Jaffrey SR. m6A enhances the phase separation potential of mRNA. Nature. 2019 Jul;571(7765):424-428. doi: 10.1038/s41586-019-1374-1. Epub 2019 Jul 10. PubMed PMID: 31292544; PubMed Central PMCID: PMC6662915.

Ding B, Haidurov A, Chawla A, Parmigiani A, van de Kamp G, Dalina A, Yuan F, Lee JH, Chumakov PM, Grossman SR, Budanov AV. p53-inducible SESTRINs might play opposite roles in the regulation of early and late stages of lung carcinogenesis. Oncotarget. 2019 Dec 10;10(65):6997-7009. doi: 10.18632/oncotarget.27367. eCollection 2019 Dec 10. PubMed PMID: 31857853; PubMed Central PMCID: PMC6916756.

Liu X, Yao Z, Jin M, Namkoong S, Yin Z, Lee JH, Klionsky DJ. Dhh1 promotes autophagy-related protein translation during nitrogen starvation. PLoS Biol. 2019 Apr;17(4):e3000219. doi: 10.1371/journal.pbio.3000219. eCollection 2019 Apr. PubMed PMID: 30973873; PubMed Central PMCID: PMC6459490.

2018

Namkoong S, Ho A, Woo YM, Kwak H, Lee JH. Systematic Characterization of Stress-Induced RNA Granulation. Mol Cell. 2018 Apr 5;70(1):175-187.e8. doi: 10.1016/j.molcel.2018.02.025. Epub 2018 Mar 22. PubMed PMID: 29576526; PubMed Central PMCID: PMC6359928.

Cho CS, Park HW, Ho A, Semple IA, Kim B, Jang I, Park H, Reilly S, Saltiel AR, Lee JH. Lipotoxicity induces hepatic protein inclusions through TANK binding kinase 1-mediated p62/sequestosome 1 phosphorylation. Hepatology. 2018 Oct;68(4):1331-1346. doi: 10.1002/hep.29742. Epub 2018 May 21. PubMed PMID: 29251796; PubMed Central PMCID: PMC6005718.

Namkoong S, Cho CS, Semple I, Lee JH. Autophagy Dysregulation and Obesity-Associated Pathologies. Mol Cells. 2018 Jan 31;41(1):3-10. doi: 10.14348/molcells.2018.2213. Epub 2018 Jan 23. Review. PubMed PMID: 29370691; PubMed Central PMCID: PMC5792710.

Woo YM, Kwak Y, Namkoong S, Kristjánsdóttir K, Lee SH, Lee JH, Kwak H. TED-Seq Identifies the Dynamics of Poly(A) Length during ER Stress. Cell Rep. 2018 Sep 25;24(13):3630-3641.e7. doi: 10.1016/j.celrep.2018.08.084. PubMed PMID: 30257221.

2017

Cho CS, Lombard DB, Lee JH. SIRT3 as a regulator of hepatic autophagy. Hepatology. 2017 Sep;66(3):700-702. doi: 10.1002/hep.29271. Epub 2017 Jul 20. PubMed PMID: 28520180; PubMed Central PMCID: PMC5570665.

Kim M, Ho A, Lee JH. Autophagy and Human Neurodegenerative Diseases-A Fly's Perspective. Int J Mol Sci. 2017 Jul 23;18(7). doi: 10.3390/ijms18071596. Review. PubMed PMID: 28737703; PubMed Central PMCID: PMC5536083.

Lanna A, Gomes DC, Muller-Durovic B, McDonnell T, Escors D, Gilroy DW, Lee JH, Karin M, Akbar AN. A sestrin-dependent Erk-Jnk-p38 MAPK activation complex inhibits immunity during aging. Nat Immunol. 2017 Mar;18(3):354-363. doi: 10.1038/ni.3665. Epub 2017 Jan 23. PubMed PMID: 28114291; PubMed Central PMCID: PMC5321575.

2016

Ho A, Cho CS, Namkoong S, Cho US, Lee JH. Biochemical Basis of Sestrin Physiological Activities. Trends Biochem Sci. 2016 Jul;41(7):621-632. doi: 10.1016/j.tibs.2016.04.005. Epub 2016 May 10. Review. PubMed PMID: 27174209; PubMed Central PMCID: PMC4930368.

Kim M, Sandford E, Gatica D, Qiu Y, Liu X, Zheng Y, Schulman BA, Xu J, Semple I, Ro SH, Kim B, Mavioglu RN, Tolun A, Jipa A, Takats S, Karpati M, Li JZ, Yapici Z, Juhasz G, Lee JH, Klionsky DJ, Burmeister M. Mutation in ATG5 reduces autophagy and leads to ataxia with developmental delay. Elife. 2016 Jan 26;5. doi: 10.7554/eLife.12245. PubMed PMID: 26812546; PubMed Central PMCID: PMC4786408.

Ro SH, Xue X, Ramakrishnan SK, Cho CS, Namkoong S, Jang I, Semple IA, Ho A, Park HW, Shah YM, Lee JH. Tumor suppressive role of sestrin2 during colitis and colon carcinogenesis. Elife. 2016 Feb 25;5:e12204. doi: 10.7554/eLife.12204. PubMed PMID: 26913956; PubMed Central PMCID: PMC4805551.

Lee JH, Cho US, Karin M. Sestrin regulation of TORC1: Is Sestrin a leucine sensor?. Sci Signal. 2016 Jun 7;9(431):re5. doi: 10.1126/scisignal.aaf2885. Review. PubMed PMID: 27273098; PubMed Central PMCID: PMC4902175.

Burmeister M, Lee JH, Schulman BA, Yapici Z, Tolun A, Juhasz G, Li JZ, Klionsky DJ. A role of autophagy in spinocerebellar ataxia-Rare exception or general principle?. Autophagy. 2016 Jul 2;12(7):1208-9. doi: 10.1080/15548627.2016.1170266. Epub 2016 Apr 22. PubMed PMID: 27105143; PubMed Central PMCID: PMC4990986.

Klionsky DJ, et al. Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy. 2016;12(1):1-222. doi: 10.1080/15548627.2015.1100356. PubMed PMID: 26799652; PubMed Central PMCID: PMC4835977.

2015

Kim H, An S, Ro SH, Teixeira F, Park GJ, Kim C, Cho CS, Kim JS, Jakob U, Lee JH, Cho US. Janus-faced Sestrin2 controls ROS and mTOR signalling through two separate functional domains. Nat Commun. 2015 Nov 27;6:10025. doi: 10.1038/ncomms10025. PubMed PMID: 26612684; PubMed Central PMCID: PMC4674687.

Ro SH, Semple I, Ho A, Park HW, Lee JH. Sestrin2, a Regulator of Thermogenesis and Mitohormesis in Brown Adipose Tissue. Front Endocrinol (Lausanne). 2015;6:114. doi: 10.3389/fendo.2015.00114. eCollection 2015. Review. PubMed PMID: 26257706; PubMed Central PMCID: PMC4513567.

Kim M, Semple I, Kim B, Kiers A, Nam S, Park HW, Park H, Ro SH, Kim JS, Juhász G, Lee JH. Drosophila Gyf/GRB10 interacting GYF protein is an autophagy regulator that controls neuron and muscle homeostasis. Autophagy. 2015;11(8):1358-72. doi: 10.1080/15548627.2015.1063766. PubMed PMID: 26086452; PubMed Central PMCID: PMC4590642.

Kim JS, Ro SH, Kim M, Park HW, Semple IA, Park H, Cho US, Wang W, Guan KL, Karin M, Lee JH. Sestrin2 inhibits mTORC1 through modulation of GATOR complexes. Sci Rep. 2015 Mar 30;5:9502. doi: 10.1038/srep09502. PubMed PMID: 25819761; PubMed Central PMCID: PMC4377584.

Kim M, Lee JH. Identification of an AMPK phosphorylation site in Drosophila TSC2 (gigas) that regulate cell growth. Int J Mol Sci. 2015 Mar 27;16(4):7015-26. doi: 10.3390/ijms16047015. PubMed PMID: 25826530; PubMed Central PMCID: PMC4425001.

Morrison A, Chen L, Wang J, Zhang M, Yang H, Ma Y, Budanov A, Lee JH, Karin M, Li J. Sestrin2 promotes LKB1-mediated AMPK activation in the ischemic heart. FASEB J. 2015 Feb;29(2):408-17. doi: 10.1096/fj.14-258814. Epub 2014 Nov 3. PubMed PMID: 25366347; PubMed Central PMCID: PMC4314228.

2014

Park HW, Park H, Semple IA, Jang I, Ro SH, Kim M, Cazares VA, Stuenkel EL, Kim JJ, Kim JS, Lee JH. Pharmacological correction of obesity-induced autophagy arrest using calcium channel blockers. Nat Commun. 2014 Sep 5;5:4834. doi: 10.1038/ncomms5834. PubMed PMID: 25189398; PubMed Central PMCID: PMC4157315.

Ro SH, Semple IA, Park H, Park H, Park HW, Kim M, Kim JS, Lee JH. Sestrin2 promotes Unc-51-like kinase 1 mediated phosphorylation of p62/sequestosome-1. FEBS J. 2014 Sep;281(17):3816-27. doi: 10.1111/febs.12905. Epub 2014 Jul 28. PubMed PMID: 25040165; PubMed Central PMCID: PMC4156532.

Park HW, Park H, Ro SH, Jang I, Semple IA, Kim DN, Kim M, Nam M, Zhang D, Yin L, Lee JH. Hepatoprotective role of Sestrin2 against chronic ER stress. Nat Commun. 2014 Jun 20;5:4233. doi: 10.1038/ncomms5233. PubMed PMID: 24947615; PubMed Central PMCID: PMC4074707.

Ro SH, Nam M, Jang I, Park HW, Park H, Semple IA, Kim M, Kim JS, Park H, Einat P, Damari G, Golikov M, Feinstein E, Lee JH. Sestrin2 inhibits uncoupling protein 1 expression through suppressing reactive oxygen species. Proc Natl Acad Sci U S A. 2014 May 27;111(21):7849-54. doi: 10.1073/pnas.1401787111. Epub 2014 May 13. PubMed PMID: 24825887; PubMed Central PMCID: PMC4040599.

Park HW, Lee JH. Calcium channel blockers as potential therapeutics for obesity-associated autophagy defects and fatty liver pathologies. Autophagy. 2014;10(12):2385-6. doi: 10.4161/15548627.2014.984268. Review. PubMed PMID: 25484079; PubMed Central PMCID: PMC4502701.

Umemura A, Park EJ, Taniguchi K, Lee JH, Shalapour S, Valasek MA, Aghajan M, Nakagawa H, Seki E, Hall MN, Karin M. Liver damage, inflammation, and enhanced tumorigenesis after persistent mTORC1 inhibition. Cell Metab. 2014 Jul 1;20(1):133-44. doi: 10.1016/j.cmet.2014.05.001. Epub 2014 Jun 5. PubMed PMID: 24910242; PubMed Central PMCID: PMC4079758.

2011-2013

Kim M, Park HL, Park HW, Ro SH, Nam SG, Reed JM, Guan JL, Lee JH. Drosophila Fip200 is an essential regulator of autophagy that attenuates both growth and aging. Autophagy. 2013 Aug;9(8):1201-13. doi: 10.4161/auto.24811. Epub 2013 May 14. PubMed PMID: 23819996; PubMed Central PMCID: PMC3748192.

Li N, Wu X, Holzer RG, Lee JH, Todoric J, Park EJ, Ogata H, Gukovskaya AS, Gukovsky I, Pizzo DP, VandenBerg S, Tarin D, Atay C, Arkan MC, Deerinck TJ, Moscat J, Diaz-Meco M, Dawson D, Erkan M, Kleeff J, Karin M. Loss of acinar cell IKKα triggers spontaneous pancreatitis in mice. J Clin Invest. 2013 May;123(5):2231-43. doi: 10.1172/JCI64498. Epub 2013 Apr 8. PubMed PMID: 23563314; PubMed Central PMCID: PMC3635720.

Lee JH, Budanov AV, Karin M. Sestrins orchestrate cellular metabolism to attenuate aging. Cell Metab. 2013 Dec 3;18(6):792-801. doi: 10.1016/j.cmet.2013.08.018. Epub 2013 Sep 19. Review. PubMed PMID: 24055102; PubMed Central PMCID: PMC3858445.

Lee JH, Budanov AV, Talukdar S, Park EJ, Park HL, Park HW, Bandyopadhyay G, Li N, Aghajan M, Jang I, Wolfe AM, Perkins GA, Ellisman MH, Bier E, Scadeng M, Foretz M, Viollet B, Olefsky J, Karin M. Maintenance of metabolic homeostasis by Sestrin2 and Sestrin3. Cell Metab. 2012 Sep 5;16(3):311-21. doi: 10.1016/j.cmet.2012.08.004. PubMed PMID: 22958918; PubMed Central PMCID: PMC3687365.

PI's Previous Publications (2001-2010)

Kong SD, Zhang W, Lee JH, Brammer K, Lal R, Karin M, Jin S. Magnetically vectored nanocapsules for tumor penetration and remotely switchable on-demand drug release. Nano Lett. 2010 Dec 8;10(12):5088-92. doi: 10.1021/nl1033733. Epub 2010 Nov 1. PubMed PMID: 21038917.

Sun D, Lee G, Lee JH, Kim HY, Rhee HW, Park SY, Kim KJ, Kim Y, Kim BY, Hong JI, Park C, Choy HE, Kim JH, Jeon YH, Chung J. A metazoan ortholog of SpoT hydrolyzes ppGpp and functions in starvation responses. Nat Struct Mol Biol. 2010 Oct;17(10):1188-94. doi: 10.1038/nsmb.1906. Epub 2010 Sep 5. PubMed PMID: 20818390.

Budanov AV, Lee JH, Karin M. Stressin' Sestrins take an aging fight. EMBO Mol Med. 2010 Oct;2(10):388-400. doi: 10.1002/emmm.201000097. Review. PubMed PMID: 20878915; PubMed Central PMCID: PMC3166214.

Lee JH, Bodmer R, Bier E, Karin M. Sestrins at the crossroad between stress and aging. Aging (Albany NY). 2010 Jun;2(6):369-74. doi: 10.18632/aging.100157. Review. PubMed PMID: 20606249; PubMed Central PMCID: PMC2919257.

Lee JH, Budanov AV, Park EJ, Birse R, Kim TE, Perkins GA, Ocorr K, Ellisman MH, Bodmer R, Bier E, Karin M. Sestrin as a feedback inhibitor of TOR that prevents age-related pathologies. Science. 2010 Mar 5;327(5970):1223-8. doi: 10.1126/science.1182228. PubMed PMID: 20203043; PubMed Central PMCID: PMC2866632.

Park EJ, Lee JH, Yu GY, He G, Ali SR, Holzer RG, Osterreicher CH, Takahashi H, Karin M. Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell. 2010 Jan 22;140(2):197-208. doi: 10.1016/j.cell.2009.12.052. PubMed PMID: 20141834; PubMed Central PMCID: PMC2836922.

Lee JH, Koh H, Kim M, Kim Y, Lee SY, Karess RE, Lee SH, Shong M, Kim JM, Kim J, Chung J. Energy-dependent regulation of cell structure by AMP-activated protein kinase. Nature. 2007 Jun 21;447(7147):1017-20. doi: 10.1038/nature05828. Epub 2007 May 7. PubMed PMID: 17486097.

Kim M, Lee JH, Lee SY, Kim E, Chung J. Caspar, a suppressor of antibacterial immunity in Drosophila. Proc Natl Acad Sci U S A. 2006 Oct 31;103(44):16358-63. doi: 10.1073/pnas.0603238103. Epub 2006 Oct 18. PubMed PMID: 17050695; PubMed Central PMCID: PMC1637587.

Kim M, Lee JH, Koh H, Lee SY, Jang C, Chung CJ, Sung JH, Blenis J, Chung J. Inhibition of ERK-MAP kinase signaling by RSK during Drosophila development. EMBO J. 2006 Jul 12;25(13):3056-67. doi: 10.1038/sj.emboj.7601180. Epub 2006 Jun 8. PubMed PMID: 16763554; PubMed Central PMCID: PMC1500987.

Lee JH, Koh H, Kim M, Park J, Lee SY, Lee S, Chung J. JNK pathway mediates apoptotic cell death induced by tumor suppressor LKB1 in Drosophila. Cell Death Differ. 2006 Jul;13(7):1110-22. doi: 10.1038/sj.cdd.4401790. Epub 2005 Nov 4. PubMed PMID: 16273080.

Kim M, Cha GH, Kim S, Lee JH, Park J, Koh H, Choi KY, Chung J. MKP-3 has essential roles as a negative regulator of the Ras/mitogen-activated protein kinase pathway during Drosophila development. Mol Cell Biol. 2004 Jan;24(2):573-83. doi: 10.1128/mcb.24.2.573-583.2004. PubMed PMID: 14701731; PubMed Central PMCID: PMC343793.

Cha GH, Cho KS, Lee JH, Kim M, Kim E, Park J, Lee SB, Chung J. Discrete functions of TRAF1 and TRAF2 in Drosophila melanogaster mediated by c-Jun N-terminal kinase and NF-kappaB-dependent signaling pathways. Mol Cell Biol. 2003 Nov;23(22):7982-91. doi: 10.1128/mcb.23.22.7982-7991.2003. PubMed PMID: 14585960; PubMed Central PMCID: PMC262421.

Lee JH, Lee E, Park J, Kim E, Kim J, Chung J. In vivo p53 function is indispensable for DNA damage-induced apoptotic signaling in Drosophila. FEBS Lett. 2003 Aug 28;550(1-3):5-10. doi: 10.1016/s0014-5793(03)00771-3. PubMed PMID: 12935877.

Lee JH, Cho KS, Lee J, Kim D, Lee SB, Yoo J, Cha GH, Chung J. Drosophila PDZ-GEF, a guanine nucleotide exchange factor for Rap1 GTPase, reveals a novel upstream regulatory mechanism in the mitogen-activated protein kinase signaling pathway. Mol Cell Biol. 2002 Nov;22(21):7658-66. doi: 10.1128/mcb.22.21.7658-7666.2002. PubMed PMID: 12370312; PubMed Central PMCID: PMC135652.

Lee JH, Cho KS, Lee J, Yoo J, Lee J, Chung J. Diptericin-like protein: an immune response gene regulated by the anti-bacterial gene induction pathway in Drosophila. Gene. 2001 Jun 27;271(2):233-8. doi: 10.1016/s0378-1119(01)00515-7. PubMed PMID: 11418244.

Cho KS, Lee JH, Kim S, Kim D, Koh H, Lee J, Kim C, Kim J, Chung J. Drosophila phosphoinositide-dependent kinase-1 regulates apoptosis and growth via the phosphoinositide 3-kinase-dependent signaling pathway. Proc Natl Acad Sci U S A. 2001 May 22;98(11):6144-9. doi: 10.1073/pnas.101596998. Epub 2001 May 8. PubMed PMID: 11344272; PubMed Central PMCID: PMC33436