{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T23:03:20Z","timestamp":1782860600276,"version":"3.54.5"},"reference-count":139,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2024,2,13]],"date-time":"2024-02-13T00:00:00Z","timestamp":1707782400000},"content-version":"vor","delay-in-days":12,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2024,2]]},"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>\n                      Recent thermodynamic modelling indicates that maintaining the brain tissue ratio of O\n                      <jats:sub>2<\/jats:sub>\n                      to CO\n                      <jats:sub>2<\/jats:sub>\n                      (abbreviated tissue O\n                      <jats:sub>2<\/jats:sub>\n                      \/CO\n                      <jats:sub>2<\/jats:sub>\n                      ) is critical for preserving the entropy increase available from oxidative metabolism of glucose, with a fall of that available entropy leading to a reduction of the phosphorylation potential and impairment of brain energy metabolism. This provides a novel perspective for understanding physiological responses under different conditions in terms of preserving tissue O\n                      <jats:sub>2<\/jats:sub>\n                      \/CO\n                      <jats:sub>2<\/jats:sub>\n                      . To enable estimation of tissue O\n                      <jats:sub>2<\/jats:sub>\n                      \/CO\n                      <jats:sub>2<\/jats:sub>\n                      in the human brain, a detailed mathematical model of O\n                      <jats:sub>2<\/jats:sub>\n                      and CO\n                      <jats:sub>2<\/jats:sub>\n                      transport was developed, and applied to reported physiological responses to different challenges, asking: how well is tissue O\n                      <jats:sub>2<\/jats:sub>\n                      \/CO\n                      <jats:sub>2<\/jats:sub>\n                      preserved? Reported experimental results for increased neural activity, hypercapnia and hypoxia due to high altitude are consistent with preserving tissue O\n                      <jats:sub>2<\/jats:sub>\n                      \/CO\n                      <jats:sub>2<\/jats:sub>\n                      . The results highlight two physiological mechanisms that control tissue O\n                      <jats:sub>2<\/jats:sub>\n                      \/CO\n                      <jats:sub>2<\/jats:sub>\n                      : cerebral blood flow, which modulates tissue O\n                      <jats:sub>2<\/jats:sub>\n                      ; and ventilation rate, which modulates tissue CO\n                      <jats:sub>2<\/jats:sub>\n                      . The hypoxia modelling focused on humans at high altitude, including acclimatized lowlanders and Tibetan and Andean adapted populations, with a primary finding that decreasing CO\n                      <jats:sub>2<\/jats:sub>\n                      by increasing ventilation rate is more effective for preserving tissue O\n                      <jats:sub>2<\/jats:sub>\n                      \/CO\n                      <jats:sub>2<\/jats:sub>\n                      than increasing blood haemoglobin content to maintain O\n                      <jats:sub>2<\/jats:sub>\n                      delivery to tissue. This work focused on the function served by particular physiological responses, and the underlying mechanisms require further investigation. The modelling provides a new framework and perspective for understanding how blood flow and other physiological factors support energy metabolism in the brain under a wide range of conditions.\n                      <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                        <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp15917-gra-0001-m.png\">\n                          <jats:alt-text>image<\/jats:alt-text>\n                        <\/jats:graphic>\n                      <\/jats:boxed-text>\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key points<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>\n                            Thermodynamic modelling indicates that preserving the O\n                            <jats:sub>2<\/jats:sub>\n                            \/CO\n                            <jats:sub>2<\/jats:sub>\n                            ratio in brain tissue is critical for preserving the entropy change available from oxidative metabolism of glucose and the phosphorylation potential underlying energy metabolism.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            A detailed model of O\n                            <jats:sub>2<\/jats:sub>\n                            and CO\n                            <jats:sub>2<\/jats:sub>\n                            transport was developed to allow estimation of the tissue O\n                            <jats:sub>2<\/jats:sub>\n                            \/CO\n                            <jats:sub>2<\/jats:sub>\n                            ratio in the human brain in different physiological states.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            Reported experimental results during hypoxia, hypercapnia and increased oxygen metabolic rate in response to increased neural activity are consistent with maintaining brain tissue O\n                            <jats:sub>2<\/jats:sub>\n                            \/CO\n                            <jats:sub>2<\/jats:sub>\n                            ratio.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            The hypoxia modelling of high\u2010altitude acclimatization and adaptation in humans demonstrates the critical role of reducing CO\n                            <jats:sub>2<\/jats:sub>\n                            with increased ventilation for preserving tissue O\n                            <jats:sub>2<\/jats:sub>\n                            \/CO\n                            <jats:sub>2<\/jats:sub>\n                            .\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            Preservation of tissue O\n                            <jats:sub>2<\/jats:sub>\n                            \/CO\n                            <jats:sub>2<\/jats:sub>\n                            provides a novel perspective for understanding the function of observed physiological responses under different conditions in terms of preserving brain energy metabolism, although the mechanisms underlying these functions are not well understood.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n       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