{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T05:38:57Z","timestamp":1791610737789,"version":"4.3.4"},"reference-count":47,"publisher":"National Academy of Sciences","issue":"20","license":[{"start":{"date-parts":[[2020,11,5]],"date-time":"2020-11-05T00:00:00Z","timestamp":1604534400000},"content-version":"vor","delay-in-days":184,"URL":"https:\/\/www.pnas.org\/site\/aboutpnas\/licenses.xhtml"}],"funder":[{"DOI":"10.13039\/100000065","name":"HHS | NIH | National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["NS095753"],"award-info":[{"award-number":["NS095753"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2020,5,19]]},"abstract":"<jats:p>\n                    While several studies have shown that hypoxic preconditioning suppresses development of the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS), no one has yet examined the important clinically relevant question of whether mild hypoxia can impact the progression of preexisting disease. Using a relapsing\u2013remitting model of EAE, here we demonstrate that when applied to preexisting disease, chronic mild hypoxia (CMH, 10% O\n                    <jats:sub>2<\/jats:sub>\n                    ) markedly accelerates clinical recovery, leading to long-term stable reductions in clinical score. At the histological level, CMH led to significant reductions in vascular disruption, leukocyte accumulation, and demyelination. Spinal cord blood vessels of CMH-treated mice showed reduced expression of the endothelial activation molecule VCAM-1 but increased expression of the endothelial tight junction proteins ZO-1 and occludin, key mechanisms underlying vascular integrity. Interestingly, while equal numbers of inflammatory leukocytes were present in the spinal cord at peak disease (day 14 postimmunization; i.e., 3 d after CMH started), apoptotic removal of infiltrated leukocytes during the remission phase was markedly accelerated in CMH-treated mice, as determined by increased numbers of monocytes positive for TUNEL and cleaved caspase-3. The enhanced monocyte apoptosis in CMH-treated mice was paralleled by increased numbers of HIF-1\u03b1+ monocytes, suggesting that CMH enhances monocyte removal by amplifying the hypoxic stress manifest within monocytes in acute inflammatory lesions. These data demonstrate that mild hypoxia promotes recovery from preexisting inflammatory demyelinating disease and suggest that this protection is primarily the result of enhanced vascular integrity and accelerated apoptosis of infiltrated monocytes.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1920935117","type":"journal-article","created":{"date-parts":[[2020,5,5]],"date-time":"2020-05-05T17:17:28Z","timestamp":1588699048000},"page":"11126-11135","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":29,"title":["Chronic mild hypoxia accelerates recovery from preexisting EAE by enhancing vascular integrity and apoptosis of infiltrated monocytes"],"prefix":"10.1073","volume":"117","author":[{"given":"Sebok K.","family":"Halder","sequence":"first","affiliation":[{"name":"Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3327-3609","authenticated-orcid":false,"given":"Richard","family":"Milner","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2020,5,5]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"crossref","first-page":"530","DOI":"10.7861\/clinmedicine.17-6-530","article-title":"Multiple sclerosis, a treatable disease","volume":"17","author":"Doshi A.","year":"2017","unstructured":"A. Doshi, J. Chataway, Multiple sclerosis, a treatable disease. Clin. Med. (Lond.) 17, 530\u2013536 (2017).","journal-title":"Clin. Med. (Lond.)"},{"key":"e_1_3_4_2_2","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/j.mayocp.2013.11.002","article-title":"Multiple sclerosis: Current and emerging disease-modifying therapies and treatment strategies","volume":"89","author":"Wingerchuk D. M.","year":"2014","unstructured":"D. M. Wingerchuk, J. L. Carter, Multiple sclerosis: Current and emerging disease-modifying therapies and treatment strategies. Mayo Clin. Proc. 89, 225\u2013240 (2014).","journal-title":"Mayo Clin. Proc."},{"key":"e_1_3_4_3_2","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/S0140-6736(94)91118-5","article-title":"Pathogenesis of multiple sclerosis","volume":"343","author":"Ffrench-Constant C.","year":"1994","unstructured":"C. Ffrench-Constant, Pathogenesis of multiple sclerosis. Lancet 343, 271\u2013275 (1994).","journal-title":"Lancet"},{"key":"e_1_3_4_4_2","first-page":"323","volume-title":"McAlpine\u2019s Multiple Sclerosis","author":"Lassmann H.","year":"1998","unstructured":"H. Lassmann, \u201cMultiple sclerosis pathology\u201d in McAlpine\u2019s Multiple Sclerosis, A. Compston, Ed. (Churchill Livingstone, ed. 3, 1998), pp. 323\u2013358.","edition":"3"},{"key":"e_1_3_4_5_2","doi-asserted-by":"crossref","first-page":"1240","DOI":"10.1161\/01.STR.30.6.1240","article-title":"Ischemic preconditioning in 18- to 20-month-old gerbils: Long-term survival with functional outcome measures","volume":"30","author":"Dowden J.","year":"1999","unstructured":"J. Dowden, D. Corbett, Ischemic preconditioning in 18- to 20-month-old gerbils: Long-term survival with functional outcome measures. Stroke 30, 1240\u20131246 (1999).","journal-title":"Stroke"},{"key":"e_1_3_4_6_2","doi-asserted-by":"crossref","first-page":"1663","DOI":"10.1097\/00001756-200106130-00030","article-title":"Cerebral protection by hypoxic preconditioning in a murine model of focal ischemia-reperfusion","volume":"12","author":"Miller B. A.","year":"2001","unstructured":"B. A. Miller ., Cerebral protection by hypoxic preconditioning in a murine model of focal ischemia-reperfusion. Neuroreport 12, 1663\u20131669 (2001).","journal-title":"Neuroreport"},{"key":"e_1_3_4_7_2","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1002\/ana.22367","article-title":"Repetitive hypoxia extends endogenous neurovascular protection for stroke","volume":"69","author":"Stowe A. M.","year":"2011","unstructured":"A. M. Stowe, T. Altay, A. B. Freie, J. M. Gidday, Repetitive hypoxia extends endogenous neurovascular protection for stroke. Ann. Neurol. 69, 975\u2013985 (2011).","journal-title":"Ann. Neurol."},{"key":"e_1_3_4_8_2","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1007\/978-1-4419-7756-4_23","article-title":"Chronic mild hypoxia ameliorates chronic inflammatory activity in myelin oligodendrocyte glycoprotein (MOG) peptide induced experimental autoimmune encephalomyelitis (EAE)","volume":"701","author":"Dore-Duffy P.","year":"2011","unstructured":"P. Dore-Duffy, M. Wencel, V. Katyshev, K. Cleary, Chronic mild hypoxia ameliorates chronic inflammatory activity in myelin oligodendrocyte glycoprotein (MOG) peptide induced experimental autoimmune encephalomyelitis (EAE). Adv. Exp. Med. Biol. 701, 165\u2013173 (2011).","journal-title":"Adv. Exp. Med. Biol."},{"key":"e_1_3_4_9_2","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1186\/s12974-015-0407-4","article-title":"Endogenous adaptation to low oxygen modulates T-cell regulatory pathways in EAE","volume":"13","author":"Esen N.","year":"2016","unstructured":"N. Esen, V. Katyshev, Z. Serkin, S. Katysheva, P. Dore-Duffy, Endogenous adaptation to low oxygen modulates T-cell regulatory pathways in EAE. J. Neuroinflammation 13, 13 (2016).","journal-title":"J. Neuroinflammation"},{"key":"e_1_3_4_10_2","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1186\/s40478-018-0590-5","article-title":"Hypoxic pre-conditioning suppresses experimental autoimmune encephalomyelitis by modifying multiple properties of blood vessels","volume":"6","author":"Halder S. K.","year":"2018","unstructured":"S. K. Halder, R. Kant, R. Milner, Hypoxic pre-conditioning suppresses experimental autoimmune encephalomyelitis by modifying multiple properties of blood vessels. Acta Neuropathol. Commun. 6, 86 (2018).","journal-title":"Acta Neuropathol. Commun."},{"key":"e_1_3_4_11_2","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/S0165-5728(99)00084-3","article-title":"Adhesion molecule expression and regulation on cells of the central nervous system","volume":"98","author":"Lee S. J.","year":"1999","unstructured":"S. J. Lee, E. N. Benveniste, Adhesion molecule expression and regulation on cells of the central nervous system. J. Neuroimmunol. 98, 77\u201388 (1999).","journal-title":"J. Neuroimmunol."},{"key":"e_1_3_4_12_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.nbd.2003.12.016","article-title":"The blood-brain barrier: An overview: Structure, regulation, and clinical implications","volume":"16","author":"Ballabh P.","year":"2004","unstructured":"P. Ballabh, A. Braun, M. Nedergaard, The blood-brain barrier: An overview: Structure, regulation, and clinical implications. Neurobiol. Dis. 16, 1\u201313 (2004).","journal-title":"Neurobiol. Dis."},{"key":"e_1_3_4_13_2","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1016\/S0166-2236(00)02004-X","article-title":"Molecular physiology and pathophysiology of tight junctions in the blood-brain barrier","volume":"24","author":"Huber J. D.","year":"2001","unstructured":"J. D. Huber, R. D. Egleton, T. P. Davis, Molecular physiology and pathophysiology of tight junctions in the blood-brain barrier. Trends Neurosci. 24, 719\u2013725 (2001).","journal-title":"Trends Neurosci."},{"key":"e_1_3_4_14_2","doi-asserted-by":"crossref","first-page":"2238","DOI":"10.1152\/jappl.1992.72.6.2238","article-title":"Brain adaptation to chronic hypobaric hypoxia in rats","volume":"72","author":"LaManna J. C.","year":"1992","unstructured":"J. C. LaManna, L. M. Vendel, R. M. Farrell, Brain adaptation to chronic hypobaric hypoxia in rats. J. Appl. Physiol. 72, 2238\u20132243 (1992).","journal-title":"J. Appl. Physiol."},{"key":"e_1_3_4_15_2","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.mcn.2008.01.013","article-title":"Increased expression of fibronectin and the \u03b1 5 \u03b2 1 integrin in angiogenic cerebral blood vessels of mice subject to hypobaric hypoxia","volume":"38","author":"Milner R.","year":"2008","unstructured":"R. Milner ., Increased expression of fibronectin and the \u03b1 5 \u03b2 1 integrin in angiogenic cerebral blood vessels of mice subject to hypobaric hypoxia. Mol. Cell. Neurosci. 38, 43\u201352 (2008).","journal-title":"Mol. Cell. Neurosci."},{"key":"e_1_3_4_16_2","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1172\/JCI8607","article-title":"Role of passive T-cell death in chronic experimental autoimmune encephalomyelitis","volume":"105","author":"Issazadeh S.","year":"2000","unstructured":"S. Issazadeh ., Role of passive T-cell death in chronic experimental autoimmune encephalomyelitis. J. Clin. Invest. 105, 1109\u20131116 (2000).","journal-title":"J. Clin. Invest."},{"key":"e_1_3_4_17_2","first-page":"446","article-title":"Apoptosis of T lymphocytes in experimental autoimmune encephalomyelitis. Evidence for programmed cell death as a mechanism to control inflammation in the brain","volume":"143","author":"Schmied M.","year":"1993","unstructured":"M. Schmied ., Apoptosis of T lymphocytes in experimental autoimmune encephalomyelitis. Evidence for programmed cell death as a mechanism to control inflammation in the brain. Am. J. Pathol. 143, 446\u2013452 (1993).","journal-title":"Am. J. Pathol."},{"key":"e_1_3_4_18_2","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.jaut.2008.04.025","article-title":"B cells limit epitope spreading and reduce severity of EAE induced with PLP peptide in BALB\/c mice","volume":"31","author":"Lyons J. A.","year":"2008","unstructured":"J. A. Lyons, M. J. Ramsbottom, R. J. Mikesell, A. H. Cross, B cells limit epitope spreading and reduce severity of EAE induced with PLP peptide in BALB\/c mice. J. Autoimmun. 31, 149\u2013155 (2008).","journal-title":"J. Autoimmun."},{"key":"e_1_3_4_19_2","doi-asserted-by":"crossref","first-page":"7579","DOI":"10.4049\/jimmunol.166.12.7579","article-title":"Myelin antigen-specific CD8+ T cells are encephalitogenic and produce severe disease in C57BL\/6 mice","volume":"166","author":"Sun D.","year":"2001","unstructured":"D. Sun ., Myelin antigen-specific CD8+ T cells are encephalitogenic and produce severe disease in C57BL\/6 mice. J. Immunol. 166, 7579\u20137587 (2001).","journal-title":"J. Immunol."},{"key":"e_1_3_4_20_2","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1002\/ana.24006","article-title":"Neurological deficits caused by tissue hypoxia in neuroinflammatory disease","volume":"74","author":"Davies A. L.","year":"2013","unstructured":"A. L. Davies ., Neurological deficits caused by tissue hypoxia in neuroinflammatory disease. Ann. Neurol. 74, 815\u2013825 (2013).","journal-title":"Ann. Neurol."},{"key":"e_1_3_4_21_2","doi-asserted-by":"crossref","first-page":"e0167196","DOI":"10.1371\/journal.pone.0167196","article-title":"Gray matter hypoxia in the brain of the experimental autoimmune encephalomyelitis model of multiple sclerosis","volume":"11","author":"Johnson T. W.","year":"2016","unstructured":"T. W. Johnson ., Gray matter hypoxia in the brain of the experimental autoimmune encephalomyelitis model of multiple sclerosis. PLoS One 11, e0167196 (2016).","journal-title":"PLoS One"},{"key":"e_1_3_4_22_2","doi-asserted-by":"crossref","first-page":"16477","DOI":"10.1038\/srep16477","article-title":"Reduced cortical microvascular oxygenation in multiple sclerosis: A blinded, case-controlled study using a novel quantitative near-infrared spectroscopy method","volume":"5","author":"Yang R.","year":"2015","unstructured":"R. Yang, J. F. Dunn, Reduced cortical microvascular oxygenation in multiple sclerosis: A blinded, case-controlled study using a novel quantitative near-infrared spectroscopy method. Sci. Rep. 5, 16477 (2015).","journal-title":"Sci. Rep."},{"key":"e_1_3_4_23_2","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1007\/978-1-4615-4863-8_34","article-title":"Hypoxia-induced brain angiogenesis. Signals and consequences","volume":"454","author":"LaManna J. C.","year":"1998","unstructured":"J. C. LaManna, N. T. Kuo, W. D. Lust, Hypoxia-induced brain angiogenesis. Signals and consequences. Adv. Exp. Med. Biol. 454, 287\u2013293 (1998).","journal-title":"Adv. Exp. Med. Biol."},{"key":"e_1_3_4_24_2","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.1002\/glia.20995","article-title":"In the hypoxic central nervous system, endothelial cell proliferation is followed by astrocyte activation, proliferation, and increased expression of the \u03b1 6 \u03b2 4 integrin and dystroglycan","volume":"58","author":"Li L.","year":"2010","unstructured":"L. Li ., In the hypoxic central nervous system, endothelial cell proliferation is followed by astrocyte activation, proliferation, and increased expression of the \u03b1 6 \u03b2 4 integrin and dystroglycan. Glia 58, 1157\u20131167 (2010).","journal-title":"Glia"},{"key":"e_1_3_4_25_2","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.expneurol.2013.09.009","article-title":"Extensive vascular remodeling in the spinal cord of pre-symptomatic experimental autoimmune encephalomyelitis mice; increased vessel expression of fibronectin and the \u03b15\u03b21 integrin","volume":"250","author":"Boroujerdi A.","year":"2013","unstructured":"A. Boroujerdi, J. V. Welser-Alves, R. Milner, Extensive vascular remodeling in the spinal cord of pre-symptomatic experimental autoimmune encephalomyelitis mice; increased vessel expression of fibronectin and the \u03b15\u03b21 integrin. Exp. Neurol. 250, 43\u201351 (2013).","journal-title":"Exp. Neurol."},{"key":"e_1_3_4_26_2","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.neulet.2009.12.059","article-title":"Increased blood vessel density and endothelial cell proliferation in multiple sclerosis cerebral white matter","volume":"470","author":"Holley J. E.","year":"2010","unstructured":"J. E. Holley, J. Newcombe, J. L. Whatmore, N. J. Gutowski, Increased blood vessel density and endothelial cell proliferation in multiple sclerosis cerebral white matter. Neurosci. Lett. 470, 65\u201370 (2010).","journal-title":"Neurosci. Lett."},{"key":"e_1_3_4_27_2","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1186\/1742-2094-7-95","article-title":"Angiogenesis is present in experimental autoimmune encephalomyelitis and pro-angiogenic factors are increased in multiple sclerosis lesions","volume":"7","author":"Seabrook T. J.","year":"2010","unstructured":"T. J. Seabrook ., Angiogenesis is present in experimental autoimmune encephalomyelitis and pro-angiogenic factors are increased in multiple sclerosis lesions. J. Neuroinflammation 7, 95 (2010).","journal-title":"J. Neuroinflammation"},{"key":"e_1_3_4_28_2","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1186\/s40478-019-0659-9","article-title":"Absence of endothelial \u03b15\u03b21 integrin triggers early onset of experimental autoimmune encephalomyelitis due to reduced vascular remodeling and compromised vascular integrity","volume":"7","author":"Kant R.","year":"2019","unstructured":"R. Kant, S. K. Halder, G. J. Bix, R. Milner, Absence of endothelial \u03b15\u03b21 integrin triggers early onset of experimental autoimmune encephalomyelitis due to reduced vascular remodeling and compromised vascular integrity. Acta Neuropathol. Commun. 7, 11 (2019).","journal-title":"Acta Neuropathol. Commun."},{"key":"e_1_3_4_29_2","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1038\/356063a0","article-title":"Prevention of experimental autoimmune encephalomyelitis by antibodies against \u03b1 4 \u03b2 1 integrin","volume":"356","author":"Yednock T. A.","year":"1992","unstructured":"T. A. Yednock ., Prevention of experimental autoimmune encephalomyelitis by antibodies against \u03b1 4 \u03b2 1 integrin. Nature 356, 63\u201366 (1992).","journal-title":"Nature"},{"key":"e_1_3_4_30_2","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1097\/00005053-195810000-00002","article-title":"Pharmacological reduction of abnormality in multiple sclerosis within minutes: A statistical study","volume":"127","author":"Brickner R. M.","year":"1958","unstructured":"R. M. Brickner, Pharmacological reduction of abnormality in multiple sclerosis within minutes: A statistical study. J. Nerv. Ment. Dis. 127, 308\u2013322 (1958).","journal-title":"J. Nerv. Ment. Dis."},{"key":"e_1_3_4_31_2","first-page":"550","article-title":"Multiple sclerosis; treatment with histamine and d-tubocurarine","volume":"6","author":"Jonez H. D.","year":"1948","unstructured":"H. D. Jonez, Multiple sclerosis; treatment with histamine and d-tubocurarine. Ann. Allergy 6, 550\u2013563 (1948).","journal-title":"Ann. Allergy"},{"key":"e_1_3_4_32_2","doi-asserted-by":"crossref","first-page":"1142","DOI":"10.1038\/nn.2887","article-title":"Infiltrating monocytes trigger EAE progression, but do not contribute to the resident microglia pool","volume":"14","author":"Ajami B.","year":"2011","unstructured":"B. Ajami, J. L. Bennett, C. Krieger, K. M. McNagny, F. M. Rossi, Infiltrating monocytes trigger EAE progression, but do not contribute to the resident microglia pool. Nat. Neurosci. 14, 1142\u20131149 (2011).","journal-title":"Nat. Neurosci."},{"key":"e_1_3_4_33_2","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.jneuroim.2015.11.004","article-title":"Therapeutic depletion of monocyte-derived cells protects from long-term axonal loss in experimental autoimmune encephalomyelitis","volume":"290","author":"Moreno M. A.","year":"2016","unstructured":"M. A. Moreno ., Therapeutic depletion of monocyte-derived cells protects from long-term axonal loss in experimental autoimmune encephalomyelitis. J. Neuroimmunol. 290, 36\u201346 (2016).","journal-title":"J. Neuroimmunol."},{"key":"e_1_3_4_34_2","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.expneurol.2018.05.021","article-title":"Csf1R inhibition attenuates experimental autoimmune encephalomyelitis and promotes recovery","volume":"307","author":"Nissen J. C.","year":"2018","unstructured":"J. C. Nissen, K. K. Thompson, B. L. West, S. E. Tsirka, Csf1R inhibition attenuates experimental autoimmune encephalomyelitis and promotes recovery. Exp. Neurol. 307, 24\u201336 (2018).","journal-title":"Exp. Neurol."},{"key":"e_1_3_4_35_2","doi-asserted-by":"crossref","first-page":"9038","DOI":"10.1128\/MCB.24.20.9038-9047.2004","article-title":"Vhlh gene deletion induces Hif-1-mediated cell death in thymocytes","volume":"24","author":"Biju M. P.","year":"2004","unstructured":"M. P. Biju ., Vhlh gene deletion induces Hif-1-mediated cell death in thymocytes. Mol. Cell. Biol. 24, 9038\u20139047 (2004).","journal-title":"Mol. Cell. Biol."},{"key":"e_1_3_4_36_2","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1165\/rcmb.2004-0314OC","article-title":"Role of hypoxia-inducible factor-1alpha in hypoxia-induced apoptosis of primary alveolar epithelial type II cells","volume":"32","author":"Krick S.","year":"2005","unstructured":"S. Krick ., Role of hypoxia-inducible factor-1alpha in hypoxia-induced apoptosis of primary alveolar epithelial type II cells. Am. J. Respir. Cell Mol. Biol. 32, 395\u2013403 (2005).","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"e_1_3_4_37_2","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1186\/1471-2407-6-26","article-title":"Hypoxia-inducible transcription factor-1\u03b1 promotes hypoxia-induced A549 apoptosis via a mechanism that involves the glycolysis pathway","volume":"6","author":"Luo F.","year":"2006","unstructured":"F. Luo ., Hypoxia-inducible transcription factor-1\u03b1 promotes hypoxia-induced A549 apoptosis via a mechanism that involves the glycolysis pathway. BMC Cancer 6, 26 (2006).","journal-title":"BMC Cancer"},{"key":"e_1_3_4_38_2","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1006\/bbrc.1999.2049","article-title":"The effect of apoptosis inhibitors on experimental autoimmune encephalomyelitis: Apoptosis as a regulatory factor","volume":"267","author":"Okuda Y.","year":"2000","unstructured":"Y. Okuda, S. Sakoda, H. Fujimura, T. Yanagihara, The effect of apoptosis inhibitors on experimental autoimmune encephalomyelitis: Apoptosis as a regulatory factor. Biochem. Biophys. Res. Commun. 267, 826\u2013830 (2000).","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"e_1_3_4_39_2","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1111\/j.1600-0404.1967.tb05733.x","article-title":"On the fine structure of the distribution of multiple sclerosis","volume":"43","author":"Kurtzke J. F.","year":"1967","unstructured":"J. F. Kurtzke, On the fine structure of the distribution of multiple sclerosis. Acta Neurol. Scand. 43, 257\u2013282 (1967).","journal-title":"Acta Neurol. Scand."},{"key":"e_1_3_4_40_2","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1186\/s12974-018-1103-y","article-title":"Hypoxia mimetic activity of VCE-004.8, a cannabidiol quinone derivative: Implications for multiple sclerosis therapy","volume":"15","author":"Navarrete C.","year":"2018","unstructured":"C. Navarrete ., Hypoxia mimetic activity of VCE-004.8, a cannabidiol quinone derivative: Implications for multiple sclerosis therapy. J. Neuroinflammation 15, 64 (2018).","journal-title":"J. Neuroinflammation"},{"key":"e_1_3_4_41_2","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1126\/science.aad9642","article-title":"Hypoxia as a therapy for mitochondrial disease","volume":"352","author":"Jain I. H.","year":"2016","unstructured":"I. H. Jain ., Hypoxia as a therapy for mitochondrial disease. Science 352, 54\u201361 (2016).","journal-title":"Science"},{"key":"e_1_3_4_42_2","doi-asserted-by":"crossref","first-page":"2993","DOI":"10.1523\/JNEUROSCI.23-07-02993.2003","article-title":"Synaptic pathways to phrenic motoneurons are enhanced by chronic intermittent hypoxia after cervical spinal cord injury","volume":"23","author":"Fuller D. D.","year":"2003","unstructured":"D. D. Fuller, S. M. Johnson, E. B. J. Olson, Jr, G. S. Mitchell, Synaptic pathways to phrenic motoneurons are enhanced by chronic intermittent hypoxia after cervical spinal cord injury. J. Neurosci. 23, 2993\u20133000 (2003).","journal-title":"J. Neurosci."},{"key":"e_1_3_4_43_2","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1007\/s11055-010-9320-6","article-title":"Prevention of neurodegenerative damage to the brain in rats in experimental Alzheimer\u2019s disease by adaptation to hypoxia","volume":"40","author":"Manukhina E. B.","year":"2010","unstructured":"E. B. Manukhina ., Prevention of neurodegenerative damage to the brain in rats in experimental Alzheimer\u2019s disease by adaptation to hypoxia. Neurosci. Behav. Physiol. 40, 737\u2013743 (2010).","journal-title":"Neurosci. Behav. Physiol."},{"key":"e_1_3_4_44_2","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1016\/j.brainres.2014.03.032","article-title":"Chronic intermittent hypoxic preconditioning suppresses pilocarpine-induced seizures and associated hippocampal neurodegeneration","volume":"1563","author":"Zhen J. L.","year":"2014","unstructured":"J. L. Zhen ., Chronic intermittent hypoxic preconditioning suppresses pilocarpine-induced seizures and associated hippocampal neurodegeneration. Brain Res. 1563, 122\u2013130 (2014).","journal-title":"Brain Res."},{"key":"e_1_3_4_45_2","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/0165-5728(92)90016-E","article-title":"Induction of active and adoptive relapsing experimental autoimmune encephalomyelitis (EAE) using an encephalitogenic epitope of proteolipid protein","volume":"38","author":"McRae B. L.","year":"1992","unstructured":"B. L. McRae ., Induction of active and adoptive relapsing experimental autoimmune encephalomyelitis (EAE) using an encephalitogenic epitope of proteolipid protein. J. Neuroimmunol. 38, 229\u2013240 (1992).","journal-title":"J. Neuroimmunol."},{"key":"e_1_3_4_46_2","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1084\/jem.182.1.75","article-title":"Functional evidence for epitope spreading in the relapsing pathology of experimental autoimmune encephalomyelitis","volume":"182","author":"McRae B. L.","year":"1995","unstructured":"B. L. McRae, C. L. Vanderlugt, M. C. Dal Canto, S. D. Miller, Functional evidence for epitope spreading in the relapsing pathology of experimental autoimmune encephalomyelitis. J. Exp. Med. 182, 75\u201385 (1995).","journal-title":"J. Exp. Med."},{"key":"e_1_3_4_47_2","doi-asserted-by":"crossref","first-page":"1149","DOI":"10.3758\/BRM.41.4.1149","article-title":"Statistical power analyses using G*power 3.1: Tests for correlation and regression analyses","volume":"41","author":"Faul F.","year":"2009","unstructured":"F. Faul, E. Erdfelder, A. Buchner, A. G. Lang, Statistical power analyses using G*power 3.1: Tests for correlation and regression analyses. Behav. Res. Methods 41, 1149\u20131160 (2009).","journal-title":"Behav. Res. Methods"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.pnas.org\/syndication\/doi\/10.1073\/pnas.1920935117","content-type":"unspecified","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.1920935117","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,6,7]],"date-time":"2022-06-07T17:34:33Z","timestamp":1654623273000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.1920935117"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,5,5]]},"references-count":47,"journal-issue":{"issue":"20","published-print":{"date-parts":[[2020,5,19]]}},"alternative-id":["10.1073\/pnas.1920935117"],"URL":"https:\/\/doi.org\/10.1073\/pnas.1920935117","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,5,5]]},"assertion":[{"value":"2020-05-05","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}