Hypoxia modulates the purine salvage pathway and decreases red blood cell and supernatant levels of hypoxanthine during refrigerated storage

Hypoxanthine catabolism in vivo is potentially dangerous as it fuels production of urate and, most importantly, hydrogen peroxide. However, it is unclear whether accumulation of intracellular and supernatant hypoxanthine in stored red blood cell units is clinically relevant for transfused recipients. Leukoreduced red blood cells from glucose- 6-phosphate dehydrogenase-normal or-deficient human volunteers were stored in AS-3 under normoxic, hyperoxic, or hypoxic conditions (with oxygen saturation ranging from <3% to >95%). Red blood cells from healthy human volunteers were also collected at sea level or after 1-7 days at high altitude (>5000 m). Finally, C57BL/6J mouse red blood cells were incubated in vitro with 13 C 1 -aspartate or 13 C 5 -adenosine under normoxic or hypoxic conditions, with or without deoxycoformycin, a purine deaminase inhibitor. Metabolomics analyses were performed on human and mouse red blood cells stored for up to 42 or 14 days, respectively, and correlated with 24 h post-transfusion red blood cell recovery. Hypoxanthine increased in stored red blood cell units as a function of oxygen levels. Stored red blood cells from human glucose-6-phosphate dehydrogenase-deficient donors had higher levels of deaminated purines. Hypoxia in vitro and in vivo decreased purine oxidation and enhanced purine salvage reactions in human and mouse red blood cells, which was partly explained by decreased adenosine monophosphate deaminase activity. In addition, hypoxanthine levels negatively correlated with post-transfusion red blood cell recovery in mice and – preliminarily albeit significantly- in humans. In conclusion, hypoxanthine is an in vitro metabolic marker of the red blood cell storage lesion that negatively correlates with post-transfusion recovery in vivo. Storage-dependent hypoxanthine accumulation is ameliorated by hypoxia-induced decreases in purine deamination reaction rates. © 2018 Ferrata Storti Foundation

Evidence for possible climatic forcing of late-Holocene vegetation changes in Norfolk broadland floodplain mires, UK.

Plant macrofossil analyses of five peat cores from undisturbed fens in the flood-plain of the Ant Valley of the Norfolk Broadland show the sequence of vegetation development during the last two millennia. Macrofossil assemblages have been grouped into five regional phases and are interpreted largely in terms of the response of the vegetation to changes in sea level, climate and management. Phase 1 represents pre-Roman fen woodland communities (>2000 cal. BP); phase 2 represents salt-marsh communities formed during an estuarine phase in Romano-British times (c. 2000–1600 cal. BP); phase 3 represents ‘tussock-fen’ and carr communities suggestive of drier conditions in the post-Roman to early Medieval period (c. 1600–800 cal. BP); phase 4 represents aquatic communities indicative of wetter conditions from the late Medieval period to c. 300 cal. BP; phase 5 represents communities comparable with present-day vegetation. The biostratigraphic development of the Ant Valley floodplain mires has analogues in climatically induced humification changes of some British ombrotrophic mires, suggesting a response to similar climatic controls. Widespread human interference and control of the fen vegetation may be a relatively recent phenomenon (beginning possibly,400 cal. BP). Peat-accumulation rates in the undisturbed mire sites suggest that the original Medieval turbaries which later flooded to form the Norfolk Broads may have been at least 0.5 m shallower when dug than their present depth. The wide range of environmental conditions experienced by the mires during the last two millennia is of relevance to the development of strategies for their conservation