Research Library
The references below reflect the broader scientific literature relevant to the physiological concepts used in RedPlus. They cover hypoxia signalling, oxygen sensing, EPO response, red blood cell adaptation, spleen response, and breath-hold physiology. RedPlus uses this body of research as part of the background for its internal methodology, modelling, and interpretation framework.

References:
Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M, Salic A, Asara JM, Lane WS, Kaelin WG Jr (2001) HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science 292:464–468 Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, von Kriegsheim A, Hebestreit HF, Mukherji M, Schofield CJ, Maxwell PH, Pugh CW, Ratcliffe PJ (2001) Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 292:468–472 Le Hir M, Eckardt KU, Kaissling B, Koury ST, Kurtz A (1991). Structure-function correlations in erythropoietin formation and oxygen sensing in the kidney. Klin Wochenschr 69:567–575 Maxwell PH, Pugh CW, Ratcliffe PJ (1993) Inducible operation of the erythropoietin 3' enhancer in multiple cell lines: evidence for a widespread oxygen-sensing mechanism. Proc Natl Acad Sci U S A 90:2423–2427 Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME, Wykoff CC, Pugh CW, Maher ER, Ratcliffe PJ (1999) The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399:271–275 Wang GL, Semenza GL (1993) General involvement of hypoxia inducible factor 1 in transcriptional response to hypoxia. Proc Natl Acad Sci U S A 90:4304–4308 Wang GL, Jiang BH, Rue EA, Semenza GL (1995) Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci U S A 92:5510–5514 Astrand, P.O and Rodhal, K (1986). Textbook of Work Physiology. New York: McGraw Hill International Editions 2019 Nobel Prize in Physiology or Medicine. The Nobel Assembly at Karolinska Institutet jointly awarded to: William G. Kaelin, Jr., Sir Peter J. Ratcliffe and Gregg L. Semenza. For their discoveries of how cells sense and adapt to oxygen availability Waypa GB, Smith KA, Schumacker PT. O2 sensing, mitochondria and ROS signaling: The fog is lifting. Mol Aspects Med. 2016 Feb-Mar;47-48:76-89. doi: 10.1016/j.mam.2016.01.002. Epub 2016 Jan 14. PMID: 26776678; PMCID: PMC4750107. Jensen PK. Antimycin-insensitive oxidation of succinate and reduced nicotinamide-adenine dinucleotide in electron-transport particles. Biochim Biophys Acta. 1966; 122:157–66. [PubMed: 4291041] Boveris A, Oshino N, Chance B. The cellular production of hydrogen peroxide. Biochem J. 1972; 128(3):617–30. [PubMed: 4404507] Cross CE, Halliwell B, Borish ET, Pryor WA, Ames BN, Saul RL, McCord JM, Harman D. Oxygen radicals and human disease. Ann Intern Med. 1987; 107:526–45. [PubMed: 3307585] McCord JM. Oxygen-derived free radicals in postischemic tissue injury. N Engl J Med. 1985; 3:159–63. [PubMed: 2981404] Sabharwal SS, Schumacker PT. Mitochondrial ROS in cancer: initiators, amplifiers or an Achilles' heel? Nat Rev Cancer. 2014 Oct 24; 14(11):709–21. [PubMed: 25342630] Sena LA, Chandel NS. Physiological roles of mitochondrial reactive oxygen species. Mol Cell. 2012 Oct 26; 48(2):158–67. [PubMed: 23102266] Chandel NS, Maltepe E, Goldwasser E, Mathieu CE, Simon MC, Schumacker PT. Mitochondrial reactive oxygen species trigger hypoxia-induced transcription. Proc Natl Acad Sci USA. 1998; 95:11715–20. [PubMed: 9751731] Chandel NS, Schumacker PT. Cellular oxygen sensing by mitochondria: old questions, new insight. J Appl Physiol. 2000 May; 88(5):1880–9. [PubMed: 10797153] Fuhrmann DC, Brüne B. Mitochondrial composition and function under the control of hypoxia. Redox Biol. 2017 Aug;12:208-215. doi: 10.1016/j.redox.2017.02.012. Epub 2017 Feb 24. PMID: 28259101; PMCID: PMC5333533. J. Schodel, S. Oikonomopoulos, J. Ragoussis, C.W. Pugh, P.J. Ratcliffe, D.R. Mole, High-resolution genome-wide mapping of HIF-binding sites by ChIP-seq, Blood117 (2011) e207–e217. R.J. Appelhoff, Y.M. Tian, R.R. Raval, H. Turley, A.L. Harris, C.W. Pugh P.J. Ratcliffe, J.M. Gleadle, Differential function of the prolyl hydroxylases PHD1, PHD2, and PHD3 in the regulation of hypoxia-inducible factor, J. Biol. Chem. 279 (2004) 38458–38465. N. Fujita, D. Markova, D.G. Anderson, K. Chiba, Y. Toyama, I.M. Shapiro, M.V. Risbud, Expression of prolyl hydroxylases (PHDs) is selectively controlled by HIF-1 and HIF-2 proteins in nucleus pulposus cells of the intervertebral disc: distinct roles of PHD2 and PHD3 proteins in controlling HIF-1alpha activity in hypoxia, J. Biol. Chem. 287 (2012) 16975–16986 N.A. Smirnova, D.M. Hushpulian, R.E. Speer, I.N. Gaisina, R.R. Ratan, I.G. Gazaryan, Catalytic mechanism and substrate specificity of HIF prolyl hydroxylases, Biochemistry (Mosc.) 77 (2012) 1108–1119. X. Xia, M.E. Lemieux, W. Li, J.S. Carroll, M. Brown, X.S. Liu, A.L. Kung, Integrative analysis of HIF binding and transactivation reveals its role in maintaining histone methylation homeostasis, Proc. Natl. Acad. Sci. USA 106 (2009) 4260–4265. R.H. Wenger, D.P. Stiehl, G. Camenisch, Integration of oxygen signaling at the consensus HRE, Sci. STKE 2005 (2005) re12. K.J. Briggs, P. Koivunen, S. Cao, K.M. Backus, B.A. Olenchock, H. Patel, Q. Zhang, S. Signoretti, G.J. Gerfen, A.L. Richardson, A.K. Witkiewicz, B.F. Cravatt, J. Clardy, W.G. Kaelin Jr., Paracrine induction of HIF by glutamate in breast cancer: EglN1 senses cysteine, Cell 166 (2016) 126–139. Z. Li, X. Xu, X. Leng, M. He, J. Wang, S. Cheng, H. Wu, Roles of reactive oxygen species in cell signaling pathways and immune responses to viral infections, Arch. Virol. (2016). M. Redza-Dutordoir, D.A. Averill-Bates, Activation of apoptosis signalling path ways by reactive oxygen species, Biochim. Biophys. Acta 1863 (2016) 2977–2992. E.S. Hanson, E.A. Leibold, Regulation of the iron regulatory proteins by reactive nitrogen and oxygen species, Gene Expr. 7 (1999) 367–376

Suggested note:
Not every reference relates directly to RedPlus as a product; rather, these studies document the underlying physiological mechanisms and training principles relevant to the RedPlus approach.