Ascending to high altitudes can cause severe threats for the human body. Hypoxia, the lack of oxygen due to a low atmospheric pressure is a major danger in great heights.Millions of people live or travel in elevated areas, means that mountain sickness due to hypoxia is a public health problem. The worst forms of mountain illness, known as high-altitude pulmonary edema and high-altitude cerebral edema, are potentially fatal. Due to a lack infrastructure and especially bad accessibility it is very challenging to support people with first aid or transport. The aim of this master thesis in Advanced Product Design was to explore the field of hypoxia in extreme altitudes in order to create a product solution that can contribute to overcome this threat and protect people from it

archives@tulane.edu / The goal of this dissertation was to identify the large scale effects that seasonal hypoxia has on the benthic community, with a particular focus on groundfish, in the Gulf of Mexico (GOMEX) while also examining ecological and physiological factors that could explain how hypoxia alters benthic communities. Seasonal hypoxia is a rapidly growing threat, not just in the GOMEX, but globally. Hypoxic conditions are known to impact marine organisms at the individual level by altering behavior and reproductive physiology while also impacting marine communities by disrupting predator prey interactions, community biomass, community composition, and community spatial dynamics. Research into hypoxia in the GOMEX has historically been localized, focusing on specific sub-regions with temporally limited sampling. While this approach has produced findings of the highest quality and importance, it has also shown that the impacts of hypoxia can be variable making the overall impact of hypoxia on GOMEX benthic communities difficult to discern. In taking both a geographically and temporally broad approach in comparing the abundances of marine organisms between hypoxic sites and normoxic (normal levels of dissolved oxygen, not hypoxic) sites I found that hypoxic sites had significantly lower biodiversity compared to normoxic sites and that 102 out of 465 examined species had significantly lower abundances in hypoxic areas compared to normoxic areas. When I compared the diets of common groundfish species from hypoxic areas to the diets of the same species from normoxic areas a few key differences were noted for some species, while the diets of other species remained relatively unchanged. After comparing the reproductive condition and presence/absence of ovarian masculinization between hypoxic areas and normoxic areas in three species of groundfish, I found evidence of ovarian masculinization in all three species, and evidence of reproductive impairment in two species. In this dissertation I showed that hypoxia in the GOMEX alters the community composition and biodiversity of the benthic community, additionally finding evidence that hypoxic conditions alter the diets and reproductive biology of several fishes / 1 / Michael Vincent Cyrana

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To understand the ‘osmorespiratory compromise’ (the trade-off in gill function between ion and respiratory gas exchange) during hypoxia in freshwater fish, a species-specific approach was utilized where general ionoregulatory responses to hypoxia were compared in rainbow trout (Oncorhynchus mykiss, a hypoxia-intolerant freshwater fish), and in two hypoxia-tolerant species (the goldfish Carassius auratus and the Amazonian oscar Astronotus ocellatus). In the latter two species, the dual stress situation of hypoxia plus feeding was also explored. Measurements included unidirectional and net Na^+ flux rates, ammonia excretion rates, net K^+ loss rates, branchial Na^+/K^+- ATPase and H^+- ATPase activities, and branchial morphology by scanning electron microscopy (trout and oscar only). In trout, environmental hypoxia induced complex changes in gill ionoregulatory function, where the direction and magnitude varied with both the extent and duration of the hypoxia regime. The changes in ion-regulation observed in trout in response to hypoxia indicated that the osmorespiratory compromise in this hypoxia-intolerant species was different and more complex compared to its manifestation in oscar and goldfish. This could be attributed to the adaptive physiology of the trout to oxygen-rich environments and its intolerance to low environmental oxygen availability. In both of the hypoxia-tolerant species (oscar and goldfish), there was a general reduction in gill permeability in response to severe hypoxia regardless of feeding regime, rather different from the complex patterns seen in the hypoxia-intolerant trout. However, the effects of feeding on this phenomenon differed between these species. Fed goldfish had elevated branchial fluxes that were effectively turned down during hypoxia compared to baseline flux rates maintained by starved goldfish. In contrast, fed oscars had lower fluxes compared to starved fish. Although both fed and starved fish suppressed their branchial fluxes with severe hypoxia, fed oscars delayed the turning down of fluxes. Overall, our results indicate that feeding exerts opposite effects on gill ionoregulatory function in these two hypoxia-tolerant species, and thereby differentially modulates the responses to hypoxia. These differences may relate to differences in water chemistry. Furthermore, the manifestation of the osmorespiratory compromise during hypoxia appears to be rather different from the phenomenon during exercise. / Thesis / Master of Science (MSc)

Individuals with diabetes mellitus (DM) have a 2 to 4-fold increased risk of cardiovascular diseases (CVD) compared to those without DM. A contributing factor to the development of CVD is atherosclerosis, a chronic inflammatory disease causing plaque build-up in medium to larger arteries. Increasing evidence suggests that hypoxia within the arterial wall is known to promote atherosclerosis, however the underlying mechanisms remain unclear. Our lab has previously shown that hyperglycemic APOE-deficient mice have impaired angiogenesis of the aortic vasa vasorum, increased arterial hypoxia, elevated vascular inflammation and accelerated atherosclerosis development at 15 weeks of age compared to normoglycemic APOE-deficient controls. The objective of this study is to elucidate the mechanisms associated with these differences, specifically the reductions in vasa vasorum. The effects of hyperglycemia and specific interventions to modulate endoplasmic reticulum stress (4-phenylbutyric acid (4PBA)), oxidative stress (n-acetyl-cysteine (NAC)) and advanced glycation end products (pyridoxamine (PX)) are examined in vivo and in vitro. Results demonstrate that human cardiac microvascular endothelial cells (HMVEC-Cs) have reduced angiogenesis in high glucose compared to normal glucose conditions in both hypoxic and normoxic environments. This may be associated with reduced expression of vascular endothelial growth factor A (VEGF-A). Treatment with PX or NAC in hypoxic, high glucose conditions increased the angiogenesis and expression of VEGF-A in HMVEC-Cs. Pilot studies suggest that PX, NAC or 4PBA supplementation are well tolerated in drinking water using STZ mouse models. Future studies should assess the direct effects of each of the chemical interventions on vasa vasorum angiogenesis, arterial hypoxia and atherosclerosis. These results suggest that oxidative stress and advanced glycation end products play a more significant role in reducing microvessel angiogenesis in vitro. Understanding of the non-canonical pathways of atherosclerosis progression in the presence of DM will facilitate the development of novel and more specific treatments for this ongoing epidemic. / Thesis / Master of Science (MSc) / Individuals with diabetes have elevated blood glucose levels which can damage blood vessels throughout the body. This damage can result in the development of cardiovascular diseases. The vasa vasorum is a distinct microvessel network that surrounds the walls of large arteries. Damage to the vasa vasorum can result in decreased oxygen supply to the artery wall, triggering low oxygen environments and accelerated atherosclerosis development. In this study we aim to investigate the mechanisms associated with high glucose induced vasa vasorum damage. Results demonstrate reduced vessel formation of human endothelial cells in high glucose conditions. This decrease correlates with advanced glycation end products and oxidative stress inducing a decreased expression of vascular endothelial growth factor A, a known stimulator of vessel formation. Understanding of the unorthodox pathways of atherosclerosis in diabetes will facilitate the development of new and more effective treatment strategies for this ongoing epidemic.

No / The indolequinone compound EO9 has good pharmacodynamic properties in terms of bioreductive activation and selectivity for either NAD(P)H:quinone oxidoreductase-1 (NQO1)-rich aerobic or NQO1-deficient hypoxic cells. However, its pharmacokinetic properties are poor and this fact is believed to be a major reason for EO9's lack of clinical efficacy. The purpose of this study was to develop quinone-based bioreductive drugs that retained EO9's good properties, in terms of bioreductive activation, but have improved pharmacokinetic properties. Out of 11 naphthoquinone compounds evaluated, 2-aziridinyl-5-hydroxy-1,4-naphthoquinone (compound 2), 2,3-bis(aziridinyl)-5-hydroxy-1,4-naphthoquinone (compound 3), and 2-aziridinyl-6-hydroxymethyl-1,4-naphthoquinone (compound 11) were selected for further evaluation based on good substrate specificity for NQO1 and selectivity towards NQO1-rich cells in vitro. Compound 3 was of particular interest as it also demonstrated selectivity for NQO1-rich cells under hypoxic conditions. Compound 3 was not metabolised by murine whole blood in vitro (in contrast to compounds 2, 11 and EO9) and pharmacokinetic studies in non-tumour-bearing mice in vivo (at the maximum soluble dose of 60 mg kg¿1 administered intraperitoneally) demonstrated significant improvements in plasma half-life (16.2 min) and AUC values (22.5 ¿M h) compared to EO9 (T1/2 = 1.8 min, AUC = 0.184 ¿M h). Compound 3 also demonstrated significant anti-tumour activity against H460 and HCT-116 human tumour xenografts in vivo, whereas EO9 was inactive against these tumours. In conclusion, compound 3 is a promising lead compound that may target both aerobic and hypoxic fractions of NQO1-rich tumours and further studies to elucidate its mechanism of action and improve solubility are warranted.

Yes / Tumour hypoxia is associated with poor patient prognosis and therapy resistance. A unique transcriptional response is initiated by hypoxia which includes the rapid activation of numerous transcription factors in a background of reduced global transcription. Here, we show that the biological response to hypoxia includes the accumulation of R-loops and the induction of the RNA/DNA helicase SETX. In the absence of hypoxia-induced SETX, R-loop levels increase, DNA damage accumulates, and DNA replication rates decrease. Therefore, suggesting that, SETX plays a role in protecting cells from DNA damage induced during transcription in hypoxia. Importantly, we propose that the mechanism of SETX induction in hypoxia is reliant on the PERK/ATF4 arm of the unfolded protein response. These data not only highlight the unique cellular response to hypoxia, which includes both a replication stress-dependent DNA damage response and an unfolded protein response but uncover a novel link between these two distinct pathways. / SR, KBL, PV and MH were supported by a CRUK grant C5255/A23755 (awarded to E.M.H.). N.N. was supported by an MRC studentship (MC_ST_U16007). I. P.F. was supported by CRUK Oxford Centre Prize DPhil Studentship C38302/A12981. N.G. was supported by a Royal Society University Research fellowship. W.-C.C. was funded by CRUK grant 23969 (awarded to F.M.B.). S.F.E.-K. was supported by a Wellcome Trust Investigator Award (103844) and a Lister Institute of Preventative Medicine Fellowship (137661). J.G. was supported by a Jean Shanks Foundation/ Pathological Society of Great Britain and Ireland Clinical PhD Fellowship (JSPS CPhD 2018 01).

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 3 uppsatser.

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Orientador: Kênia Cardoso Bícego / Banca: Wilfried Klein / Banca: Glauber dos Santos Ferreira da Silva / Resumo: O oxigênio é essencial para o desenvolvimento e a funcionalidade celular nos organismos aeróbicos. A exposição de embriões à hipóxia pode alterar a trajetória de desenvolvimento geneticamente estabelecida e gerar alterações morfofisiológicas em diversos órgãos e sistemas. Em aves precoces, a hipóxia durante a incubação é conhecida por alterar tamanho dos órgãos, taxa metabólica e ventilação em pintinhos recém-eclodidos. Nestes animais o desenvolvimento das estruturas parabrônquiais envolvidas em trocas gasosas e condução de ar, ocorre principalmente durante a segunda metade da incubação. Baseados nos fatos expostos, nós hipotetizamos que a hipóxia durante esta fase de desenvolvimento pode induzir um remodelamento nestas estruturas, favorecendo as trocas gasosas na vida pós-natal. Para testar esta hipótese, os embriões foram expostos à normóxia durante toda a incubação, ou à 15% O2 (dia 12 ao 18 de incubação) e as estruturas parabrônquiais, incluindo capilares aéreos, capilares sanguíneos, infundíbulo, átrio, lúmen parabronquial, vasos sanguíneos maiores que capilares, e tecido interparabronquial, foram analisados através de método estereológico em pintinhos com 1 e 10 dias de idade. A hipóxia aumentou os volumes relativos das estruturas diretamente relacionadas com trocas gasosas, como capilares aéreos e sanguíneos, enquanto não afetou o volume dos pulmões, e o volume relativo de infundíbulo, vasos sanguíneos maiores que capilares e tecido interparabronquial em pintinhos de 1 e 10 dias. A menor concentração de oxigênio, diminuiu o volume relativo dos átrios em ambas idades e o lúmen parabronquial nos pintinhos mais velhos. Concluímos que a hipóxia durante a fase embrionária de desenvolvimento parabronquial pode trazer um remodelamento morfológico, caracterizado por aumento de estruturas responsáveis diretamente por trocas gasosas... / Abstract: Oxygen is essential for cell development and function in aerobic organisms. Exposure of embryos to hypoxia can change the genetically estabilished developmental trajectory and generate morphological and physiological changes of several organs and systems. In precocious birds, hypoxia during incubation is known to change size of organs, metabolic rate and ventilation in hatchlings. In these animals, embryonic development of the parabronchial structures, involved in gas exchange and conduction, occurs mainly during the second half of incubation time. Based on the above facts, we can hypothesize that hypoxia during this phase of development can induce a remodeling of such structures, favoring gas exchange, later in post-hatch life. To test this hypothesis, embryos were exposed to normoxia for the entire incubation or to 15% O2 (from day 12 to 18 of incubation) and their parabronchial structures, including air capillaries, blood capillaries, infundibula, atria, parabronchial lumen, blood vessels larger than capillaries and interparabronchial tissue, were analyzed by stereological method in 1 and 10-day old chicks. Hypoxia increased the relative volume of structures directly involved in gas exchange such as air and blood capillaries, while did not change total lung volume and relative volumes of infundibula, blood vessels larger than capillaries and interparabronchial tissue of 1 and 10 days-old chicks. The lower concentration of oxygen decreased the relative volume of atria in both groups of chicks, and parabronchial lumen in the older ones. It can be concluded that hypoxia during the embryonic phase of parabronchial development can lead to a morphological remodeling characterized by increase of structures responsible directly for gas exchange at the expense of regions that participate in the conduction of air in chicks up to 10 days after hatch / Mestre