Reduced Oxygen Availability Research Articles

The Role of Hypoxia, Hypoxia-Inducible Factor (HIF), and VEGF in Retinal Angiomatous Proliferation.

In industrialized countries, age-related macular degeneration (AMD) is the leading cause of blindness in elderly people. Hallmarks of the non-neovascular (dry) form of AMD are the formation of drusen and geographic atrophy, whereas the exudative (wet) form of the disease is characterized by invading blood vessels. In retinal angiomatous proliferation (RAP), a special form of wet AMD, intraretinal vessels grow from the deep plexus into the subretinal space. Little is known about the mechanisms leading to intraretinal neovascularization, but age-related changes such as reduction of choroidal blood flow, accumulation of drusen, and thickening of the Bruch's membrane may lead to reduced oxygen availability in photoreceptors. Such a chronic hypoxic situation may induce several cellular response pathways including the stabilization of hypoxia-inducible factors (HIFs) and the production of angiogenic factors, such as vascular endothelial growth factor (VEGF). Here, we discuss the potential contribution of hypoxia and HIFs in RAP disease pathology and in some mouse models for subretinal neovascularization.

Retinal energy demands control vascular supply of the retina in development and disease: The role of neuronal lipid and glucose metabolism.

Neuronal energy demands are met by a tightly coupled and adaptive vascular network that supplies nutrients and oxygen. The retina is one of the highest energy-consuming organs, exceeding the metabolic rate of the brain; blood vessels grow and regress in reaction to changes in these high demands (Ames et al., 1992b; Anderson and Saltzman, 1964; Yu and Cringle, 2001). Reduced nutrients and reduced oxygen availability instigate compensatory albeit misguided pathological neovascularization in proliferative retinopathies (Chen and Smith, 2007; Sapieha et al., 2010). Conversely, impaired retinal ganglion cell (RGC) and photoreceptor survival are correlated with abrogated vascular development (Pennesi et al., 2008) and as neurons degenerate, the retinal vasculature atrophies to match the reduced metabolic requirements (Wang et al., 2000). In mice, genetic ablation of retinal ganglion cell neurons suppresses the inner retinal vascular development (Sapieha et al., 2008). Ablation of amacrine interneurons also prevents the development of the intermediate vascular plexus (Usui et al., 2015), while photoreceptor degeneration is associated with thinning of the choroid and inner retinal blood vessels (Ayton et al., 2013; Dhoot et al., 2013; Toto et al., 2016). Thinning of the choriocapillaris, in turn, may exacerbate retinal degeneration (Bird, 2010; Whitmore et al., 2015). However, the specific mediators that link neuronal metabolism with retinal angiogenesis in the developing eye and retinal disease remain largely unknown. Conditions such as diabetic retinopathy, vaso-proliferative retinopathy of prematurity and neovascular age-related macular degeneration (AMD) have been characterized as diseases of the vasculature. However, it is becoming more evident that the metabolic needs of the neural retina profoundly influence blood vessel supply in development and in disease. Retinal oxygen sources and the vaso-proliferative response to low oxygen levels have been well characterized. However, understanding the specific fuels used in the retina to generate ATP and supply building blocks for biosynthesis, as well as understanding the vaso-proliferative response to the lack of fuel are also key to neurovascular development. The metabolic and energy needs of the retina have been assumed to be met by glucose, as the retina is part of the CNS, and the brain relies almost exclusively on glucose (Mergenthaler et al., 2013). There are two primary pathways that cells can use to generate ATP from glucose, glycolysis and oxidative phosphorylation. However, Cohen and Noell concluded in 1960 that a substantial portion of the energy produced through oxidation by the retina (around 65%) was not derived from glucose (Cohen and Noell, 1960). We recently showed that the retina (photoreceptors) can also oxidize lipid through fatty acid β-oxidation to produce ATP, accounting for the energy gap noted by Cohen (Joyal et al., 2016). Little is known about lipid versus glucose fuel substrate preference and its importance during retinal development and pathology. Here we review the neuronal energy demands of the retina, describing both glucose and lipid metabolism as forces that shape the vascular supply of the eye in development and in vaso-proliferative eye diseases.

Natural Selection on Genes Related to Cardiovascular Health in High-Altitude Adapted Andeans

The increase in red blood cell mass (polycythemia) due to the reduced oxygen availability (hypoxia) of residence at high altitude or other conditions is generally thought to be beneficial in terms of increasing tissue oxygen supply. However, the extreme polycythemia and accompanying increased mortality due to heart failure in chronic mountain sickness most likely reduces fitness. Tibetan highlanders have adapted to high altitude, possibly in part via the selection of genetic variants associated with reduced polycythemic response to hypoxia. In contrast, high-altitude-adapted Quechua- and Aymara-speaking inhabitants of the Andean Altiplano are not protected from high-altitude polycythemia in the same way, yet they exhibit other adaptive features for which the genetic underpinnings remain obscure. Here, we used whole-genome sequencing to scan high-altitude Andeans for signals of selection. The genes showing the strongest evidence of selection-including BRINP3, NOS2, and TBX5-are associated with cardiovascular development and function but are not in the response-to-hypoxia pathway. Using association mapping, we demonstrated that the haplotypes under selection are associated with phenotypic variations related to cardiovascular health. We hypothesize that selection in response to hypoxia in Andeans could have vascular effects and could serve to mitigate the deleterious effects of polycythemia rather than reduce polycythemia itself.

Root Bending Is Antagonistically Affected by Hypoxia and ERF-Mediated Transcription via Auxin Signaling.

When plants encounter soil water logging or flooding, roots are the first organs to be confronted with reduced gas diffusion resulting in limited oxygen supply. Since roots do not generate photosynthetic oxygen, they are rapidly faced with oxygen shortage rendering roots particularly prone to damage. While metabolic adaptations to low oxygen conditions, which ensure basic energy supply, have been well characterized, adaptation of root growth and development have received less attention. In this study, we show that hypoxic conditions cause the primary root to grow sidewise in a low oxygen environment, possibly to escape soil patches with reduced oxygen availability. This growth behavior is reversible in that gravitropic growth resumes when seedlings are returned to normoxic conditions. Hypoxic root bending is inhibited by the group VII ethylene response factor (ERFVII) RAP2.12, as rap2.12-1 seedlings show exaggerated primary root bending. Furthermore, overexpression of the ERFVII member HRE2 inhibits root bending, suggesting that primary root growth direction at hypoxic conditions is antagonistically regulated by hypoxia and hypoxia-activated ERFVIIs. Root bending is preceded by the establishment of an auxin gradient across the root tip as quantified with DII-VENUS and is synergistically enhanced by hypoxia and the auxin transport inhibitor naphthylphthalamic acid. The protein abundance of the auxin efflux carrier PIN2 is reduced at hypoxic conditions, a response that is suppressed by RAP2.12 overexpression, suggesting antagonistic control of auxin flux by hypoxia and ERFVII. Taken together, we show that hypoxia triggers an escape response of the primary root that is controlled by ERFVII activity and mediated by auxin signaling in the root tip.

P 120 - Dietary Sulforaphane supplementation induces Nrf2, attenuating hypoxia-induced vascular smooth muscle cell proliferation and remodelling following carotid artery ligation

We sought to assess whether dietary sulforaphane (SFN) supplementation to C57BL/6 J mice attenuates injury following carotid artery ligation, in which the endothelium remains intact. We also sought to establish whether SFN-induced induction of Nrf2 redox defence genes underlies hypoxia-induced proliferation of vascular smooth muscle cells and may therefore contribute towards vascular injury protection. Pre-treatment with a physiologically achievable (0.5 mg/kg) dose of SFN and continued administration 2 and 4 weeks post ligation was associated with Nrf2-dependent gene expression (e.g. heme oxygenase 1, HO-1) and reduced neointimal formation assessed by Van Gieson staining. Using an oxygen regulated work station, exposure of primary mouse aortic smooth muscle cells (MASMC, P2) to hypoxia (1% O2) enhanced proliferation when assessed by cell count and protein expression. In SFN (2.5 µM) treated MASMC, proliferation was attenuated following serum challenge (10% FCS) for 72 h and correlated with Nrf2 target gene induction. Overall our results suggest that independent of endothelial oxidative damage, reduced oxygen availability enhances vascular smooth muscle cell proliferation. SFN supplementation induces Nrf2 defences and reduces smooth muscle cell proliferation, suggesting dietary Nrf2 supplementation may provide a useful therapeutic intervention to promote vascular health.

Seed Coating Increases Seed Moisture Uptake and Restricts Embryonic Oxygen Availability in Germinating Cereal Seeds.

Seed coating is a technology to improve germination and homogenize stand establishment. Although coating often results in lower germination rates, seeds that do germinate grow more vigorously and show strongly reduced respiratory losses during reserve mobilization. We hypothesize that the higher mobilization efficiency is due to a shift in the enzymatic cleavage of sucrose from invertase to sucrose synthase in the embryonic tissue caused by a reduced oxygen availability induced by oversaturation with water caused by the coating during early germination. We investigated the effect of coating on barley, rye, and wheat seed imbibition during the first 30 h after seeds were placed in moisture. We profiled oxygen in the embryos and measured sucrose and acid invertase levels as imbibition progressed. We found that seeds within coatings absorbed significantly more moisture than uncoated seeds. Coating resulted in near anoxic oxygen concentrations in the developing embryonic tissues in all three species. In barley, sucrose was not cleaved via the invertase pathway, despite the fact that invertase activity in coated seeds was increased. In rye and wheat, invertase activities were significantly lower in embryos from coated seeds without significantly changing the sugar composition.

Endocrine targets of hypoxia-inducible factors.

Endocrine is an important and tightly regulated system for maintaining body homeostasis. Endocrine glands produce hormones, which are released into blood stream to guide the target cells responding to all sorts of stimulations. For maintaining body homeostasis, the secretion and activity of a particular hormone needs to be adjusted in responding to environmental challenges such as changes in nutritional status or chronic stress. Hypoxia, a status caused by reduced oxygen availability or imbalance of oxygen consumption/supply in an organ or within a cell, is a stress that affects many physiological and pathological processes. Hypoxic stress in endocrine organs is especially critical because endocrine glands control body homeostasis. Local hypoxia affects not only the particular gland but also the downstream cells/organs regulated by hormones secreted from this gland. Hypoxia-inducible factors (HIFs) are transcription factors that function as master regulators of oxygen homeostasis. Recent studies report that aberrant expression of HIFs in endocrine organs may result in the development and/or progression of diseases including diabetes, endometriosis, infertility and cancers. In this article, we will review recent findings in HIF-mediated endocrine organ dysfunction and the systemic syndromes caused by these disorders.

Ecological implications of hypoxia-triggered shifts in secondary metabolism.

Members of the actinomycete genus Streptomyces are non-motile, filamentous bacteria that are well-known for the production of biomedically relevant secondary metabolites. While considered obligate aerobes, little is known about how these bacteria respond to periods of reduced oxygen availability in their natural habitats, which include soils and ocean sediments. Here, we provide evidence that the marine streptomycete strain CNQ-525 can reduce MnO2 via a diffusible mechanism. We investigated the effects of hypoxia on secondary metabolite production and observed a shift away from the antibiotic napyradiomycin towards 8-amino-flaviolin, an intermediate in the napyradiomycin biosynthetic pathway. We purified 8-amino-flaviolin and demonstrated that it is reversibly redox-active (midpoint potential -474.5 mV), indicating that it has the potential to function as an endogenous extracellular electron shuttle. This study provides evidence that environmentally triggered changes in secondary metabolite production may provide clues to the ecological functions of specific compounds, and that Gram-positive bacteria considered to be obligate aerobes may play previously unrecognized roles in biogeochemical cycling through mechanisms that include extracellular electron shuttling.

Cell survival: Interplay between hypoxia and pre-mRNA splicing

RNA splicing takes place in the nucleus and occurs either co- or post-transcriptionally. Noncoding sequences (introns) in nuclear mRNA precursors (pre-mRNA) are removed by dedicated splicing machinery. The coding sequences (exons) are joined to generate the mature mRNA that is exported to the cytoplasm and translated into protein. Splicing events are tissue-specific. This process plays an important role in cellular differentiation and organism development. The splicing machinery heavily contributes to biological complexity and especially to the ability of cells to adapt to different developmental stages and altered cellular conditions.A striking change has been observed in alternative splicing pattern of genes and alterations in splicing factor expression under pathologic conditions especially in human cancers. Cancer cells are often confronted with a significant reduction in oxygen availability, which is a major reason for changeover of major cellular processes. Hypoxic regions have been identified within all solid tumors and their presence has been linked to malignant progression, metastasis, resistance to therapy, and poor clinical outcomes following treatment. Cellular responses to hypoxia are mediated by hypoxia inducible transcription factors (HIFs). This review focuses on currently available data how pre-mRNAs splicing contributes to cellular adaptation to hypoxic conditions, to genes which alternative splicing is regulated dependent on hypoxia and how regulation of alternative splicing under hypoxic conditions is achieved.

Embryonic hypoxia programmes postprandial cardiovascular function in adult common snapping turtles (Chelydra serpentina).

Reduced oxygen availability (hypoxia) is a potent stressor during embryonic development, altering the trajectory of trait maturation and organismal phenotype. We previously documented that chronic embryonic hypoxia has a lasting impact on the metabolic response to feeding in juvenile snapping turtles (Chelydra serpentina). Turtles exposed to hypoxia as embryos [10% O2 (H10)] exhibited an earlier and increased peak postprandial oxygen consumption rate, compared with control turtles [21% O2 (N21)]. In the current study, we measured central blood flow patterns to determine whether the elevated postprandial metabolic response in H10 turtles is linked to lasting impacts on convective transport. Five years after hatching, turtles were instrumented to quantify systemic ([Formula: see text]) and pulmonary ([Formula: see text]) blood flows and heart rate (fH) before and after a ∼5% body mass meal. In adult N21 and H10 turtles, fH was increased significantly by feeding. Although total stroke volume (VS,tot) remained at fasted values, this tachycardia contributed to an elevation in total cardiac output ([Formula: see text]). However, there was a postprandial reduction in a net left-right (L-R) shunt in N21 snapping turtles only. Relative to N21 turtles, H10 animals exhibited higher [Formula: see text] due to increased blood flow through the right systemic outflow vessels of the heart. This effect of hypoxic embryonic development, reducing a net L-R cardiac shunt, may support the increased postprandial metabolic rate we previously reported in H10 turtles, and is further demonstration of adult reptile cardiovascular physiology being programmed by embryonic hypoxia.

Low oxygen availability and malignant evolution of non-invasive breast tumors: potential protective role of all-trans retinoic acid (ATRA)

Reduced oxygen availability plays a crucial role in malignancy of solid tumors, including breast cancer. Even if the presence of hypoxic areas is common in all breast lesions, no data clearly correlate low oxygenation with the acquisition of malignant features by non-invasive cells, particularly by cells from ductal carcinoma in situ (DCIS), the most frequently diagnosed tumor in women in industrialized countries [1]. We demonstrated that 96 hours of culture under moderate hypoxia is sufficient to induce in DCIS-derived cells motility and epithelial-to-mesenchymal transition (EMT) and to enlarge the number of cells expressing the stem cell marker CD133, indicative of their increased malignant potential. Administration of all-trans retinoic acid (ATRA), a well-known anti-leukemic drug with an anti-tumor role in invasive breast tumor cells [2], supports the epithelial phenotype of DCIS-derived cells cultured under hypoxia and reduces the number of CD133 positive cells, abrogating almost completely the effects of poor oxygenation. In DCIS-derived cells, as in leukemic cells, ATRA up-regulates the β2 isoform of PI-PLC (PLC-β2), ectopically expressed in invasive breast tumors in which counteracts the effects of hypoxia on both EMT and CD133 levels [3]. This suggests that the mechanisms triggered by ATRA in non-invasive breast tumor cells cultured under hypoxia may, at least in part, depend on PLC-β2 activity. Overall, we assigned to hypoxia a role in increasing the malignant potential of DCIS-derived cells and identified in ATRA, currently used in treating acute promyelocytic leukemia (APL), an agonist potentially useful in preventing malignant progression of non-invasive breast lesions with hypoxic areas.

Lingzhi or Reishi Medicinal Mushroom, Ganoderma lucidum (Agaricomycetes), as a Cardioprotectant in an Oxygen-Deficient Environment.

Imbalanced oxygen availability is detrimental to normal cell function. Oxygen-sensitive cells such as cardiomyoblasts experience severe irreversible pathophysiological damage under conditions of reduced oxygen availability, such as hypoxia. A number of natural therapeutic agents have been explored for their potential cytoprotective effects, of which medicinal mushrooms are an important source. Ganoderma lucidum, commonly known as lingzhi, is one such mushroom that has been elaborately studied for its potential pharmacological properties. In this study, aqueous and alcoholic extracts of a natural Himalayan variety of G. lucidum were evaluated for their efficiency as remedial agents in treating hypoxic injury to H9c2 cardiomyoblasts. The alcoholic extract of G. lucidum effectively restored cellular viability at a concentration of 600 μg/mL and aided in maintaining cellular redox balance under hypoxia. Substantial reduction in caspase-3 and -7 activation was observed with fluorescent-activated cell sorting. Alcoholic extract of G. lucidum minimized oxidative stress as indicated by measuring reactive oxygen species, lipid peroxidation, and reduced glutathione-to-oxidized glutathione ratio, and also by determining changes in hypoxia-inducible factor 1α and associated genes. To ascertain these positive outcomes of administration of G. lucidum extracts, certain phytoconstituents (nucleobases and flavonoids) were identified using high-performance thin-layer chromatography; antioxidant potential was also evaluated. Results indicated that both extracts contained notable quantities of nucleobases and flavonoids. The extracts also effected high free radical scavenging activities.

Hypoxia-inducible factors: coupling glucose metabolism and redox regulation with induction ofthe breast cancer stem cell phenotype.

Reduced oxygen availability (hypoxia) leads to increased production of reactive oxygen species (ROS) by the electron transport chain. Here, I review recent work delineating mechanisms by which hypoxia-inducible factor 1 (HIF-1) mediates adaptive metabolic responses to hypoxia, including increased flux through the glycolytic pathway and decreased flux through the tricarboxylic acid cycle, in order to decrease mitochondrial ROS production. HIF-1 also mediates increased flux through the serine synthesis pathway and mitochondrial one-carbon (folate cycle) metabolism to increase mitochondrial antioxidant production (NADPH and glutathione). Dynamic maintenance of ROS homeostasis is required for induction of the breast cancer stem cell phenotype in response to hypoxia or cytotoxic chemotherapy. Consistently, inhibition of phosphoglycerate dehydrogenase, the first enzyme of the serine synthesis pathway, in breast cancer cells impairs tumor initiation, metastasis, and response to cytotoxic chemotherapy. I discuss how these findings have important implications for understanding the logic of the tumor microenvironment and for improving therapeutic responses in women with breast cancer.

A Mineralized Alga and Acritarch Dominated Microbiota from the Tully Formation (Givetian) of Pennsylvania, USA

Sphaeromorphic algal cysts, most probably of the prasinophyte Tasmanites, and acanthomorphic acritarch vesicles, most probably Solisphaeridium, occur in a single 20 cm thick bed of micritic limestone in the lower part of the Middle Devonian (Givetian) Tully Formation near Lock Haven, Pennsylvania. Specimens are composed of authigenic calcite and pyrite crystals about 5–10 µm in length. Some specimens are completely calcitic; some contain both pyrite and calcite; and many are composed totally of pyrite. The microfossils are about 80 to 150 µm in diameter. Many show signs of originally containing a flexible wall composed of at least two layers. Some appear to have been enclosed in a mucilaginous sheath or membrane when alive. The acanthomorphic forms have spines that are up to 20 µm in length, expand toward the base, and are circular in cross-section. The microflora occurs with microscopic molluscs, dacryoconarids, the enigmatic Jinonicella, and the oldest zooecia of ctenostome bryozoans known from North America. The microalgal horizon lacks macrofossils although small burrows are present. Microalgae and acritarchs have been preserved via a complex preservational process involving rapid, bacterially-mediated post-mortem mineralization of dead cells. The microfossil horizon, and possibly much of the Tully Formation at Lock Haven with similar lithology, formed in a relatively deep, off-shore basin with reduced oxygen availability in the substrate.

Impact of hypoxia inducible factors on estrogen receptor expression in breast cancer cells

In women breast cancer is still the most commonly diagnosed cancer. This type of cancer is classified as a hormone-dependent tumor. Estrogen receptor (ER) expression and functional status contribute to breast cancer development and progression. Another important factor associated with cancer is hypoxia which is defined as the state of reduced oxygen availability in tissues. Intratumoral hypoxia results in the activation of the hypoxia inducible factors (HIFs). HIFs are heterodimeric transcription factors involved in the regulation of many cellular processes, such as angiogenesis, anaerobic metabolism, cell proliferation/survival, and promotion of metastasis. In this study we evaluated the interplay between hypoxia, HIF stabilization and the ER-α/β-ratio in several ER-positive breast cancer cell lines. Hypoxia was shown to inhibit ER expression in ER-positive breast cancer cells. Further experiments using the hypoxia mimetic CoCl2 and HIF-1α knockdown cells indicated that the influence of hypoxia on breast cancer cells involves other pathways than the molecular oxygen sensing pathway. Moreover, we demonstrated that MCF-7 cells in long-term culture lost part of their ability to respond to hypoxic incubation. Understanding the relationships between HIF, ER-α and ER-β expression holds the promise of the development of new therapeutic agents and may provide future advances in prognosis.

Effects of reduced oxygen availability on the vascular response and oxygen consumption of the activated human visual cortex.

To identify the impact of reduced oxygen availability on the evoked vascular response upon visual stimulation in the healthy human brain by magnetic resonance imaging (MRI). Functional MRI techniques based on arterial spin labeling (ASL), blood oxygenation level-dependent (BOLD), and vascular space occupancy (VASO)-dependent contrasts were utilized to quantify the BOLD signal, cerebral blood flow (CBF), and volume (CBV) from nine subjects at 3T (7M/2F, 27.3 ± 3.6 years old) during normoxia and mild hypoxia. Changes in visual stimulus-induced oxygen consumption rates were also estimated with mathematical modeling. Significant reductions in the extension of activated areas during mild hypoxia were observed in all three imaging contrasts: by 42.7 ± 25.2% for BOLD (n = 9, P = 0.002), 33.1 ± 24.0% for ASL (n = 9, P = 0.01), and 31.9 ± 15.6% for VASO images (n = 7, P = 0.02). Activated areas during mild hypoxia showed responses with similar amplitude for CBF (58.4 ± 18.7% hypoxia vs. 61.7 ± 16.1% normoxia, P = 0.61) and CBV (33.5 ± 17.5% vs. 25.2 ± 13.0%, P = 0.27), but not for BOLD (2.5 ± 0.8% vs. 4.1 ± 0.6%, P = 0.009). The estimated stimulus-induced increases of oxygen consumption were smaller during mild hypoxia as compared to normoxia (3.1 ± 5.0% vs. 15.5 ± 15.1%, P = 0.04). Our results demonstrate an altered vascular and metabolic response during mild hypoxia upon visual stimulation. 2 Technical Efficacy: Stage 2 J. MAGN. RESON. IMAGING 2017;46:142-149.

Whether disturbances alter salt marsh soil structure dramatically affects Spartina alterniflora recolonization rate

AbstractDisturbance regimes are shifting in response to climate change, land‐use change, species' invasions, and other stressors, challenging ecologists to improve understanding of the mechanisms controlling plant recovery under different conditions. In this study, we investigate mechanisms that underpin plant recolonization of two types of disturbance: disturbances that remove standing plant biomass, but leave the underlying soil structure largely intact, and those that remove standing biomass and physically disrupt soil structure. In the southeastern United States, salt marshes, drought and invasive feral hogs (Sus scrofa) are associated with disturbances of these respective types and both leave behind mudflats dotted with patches of cordgrass (Spartina alterniflora), the system's dominant foundation species. To test how disturbance type and remnant patch size may interact to affect cordgrass recolonization, we transplanted replicate cordgrass patches of three sizes into one mudflat that experienced vegetation‐only disturbance (VD) during a recent drought, and a second mudflat where hog activities had disrupted the soil structure creating a soil + vegetation disturbance (soil + VD). Over one year, we monitored plant performance and properties of soil. Compared with the drought‐associated VD where patches, regardless of their size, expanded vigorously, large and medium patches grew little and smaller patches even less in the hog‐associated soil + VD mudflat. Moreover while biogeochemical properties varied little in the VD compared with adjacent vegetated marsh areas, the mudflats with soil + VD had less soil‐binding organic matter and, hence, were too soft to support crab burrows, leading to a reduction in oxygen availability and cordgrass expansion. These results indicate that cordgrass recovery is far faster from disturbances that do not degrade soil structure than those that do and therefore advocate for disturbance‐specific management strategies. Specifically, while transplanting patches is effective in restoring marshes disturbed by drought, wrack, or other factors that leave soil structure intact, preventative measures, like hog population culling, are essential to mitigating the ecological impacts of soil structure‐altering disturbances.

How decreasing oxygenase activity helps cells cope with hypoxia

The ability of our bodies to adapt to reduced oxygen availability (hypoxia) by increasing red blood cell formation was recognized in the 19th century, but almost 200 years passed before the molecular mechanism underlying this hypoxic response was revealed. In animals, hypoxia tolerance is enabled by turning on a plethora of genes, all under the control of the hypoxia inducible transcription factor protein, HIF. Crucially, levels of HIF are controlled by a set of enzymes, whose activity is exquisitely sensitive to oxygen availability. A low-oxygen response system is arguably more important for plants which, as sessile organisms, cannot employ behavioural responses to hypoxia, and recent findings reveal a distinct yet analogous mechanism. It seems that in plants as well as in animals, oxygen-dependent enzymes are the linchpins connecting oxygen availability with the cellular response to hypoxia.

Expression and analyses of the HIF-1 pathway in the lungs of humans with pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is characterized by endothelial dysfunction and structural remodeling of the pulmonary vasculature, mediated initially by reduced oxygen availability in the lungs. Hypoxia inducible factor (HIF), consisting of the functional subunit, HIF‑1α, and the constitutively expressed HIF‑1β, is involved in the pathological processes associated with hypoxia. In the current study, the sequences of cDNAs and amino acids of HIF were characterized and analyzed using online bioinformatics tools. To further evaluate whether HIF accounts for the occurrence of PAH, the present study determine the expression and phosphorylation levels of HIF and its associated pathways, including extracellular signal‑regulated kinase (Erk)1/2 and phosphoinositide 3‑kinase (PI3K)/Akt, in the lungs of patients with PAH by reverse transcription‑quantitative polymerase chain reaction and western blotting. The mRNA expression levels of PI3K, Erk2, and HIF‑1α in the patients with PAH were significantly higher, compared with those in the control group, by 3.6‑fold (P<0.01), 4.06‑fold and 2.64‑fold (P<0.05), respectively. No significant differences were found in the mRNA and protein levels of Akt between the two groups (P>0.05). The protein levels of phosphorylated (p‑)Akt, Erk1/2, p‑Erk1/2, HIF‑1α and HIF‑1β were significantly increased by 5.89‑, 0.5‑, 0.59‑, 1.46‑ and 0.92‑fold, respectively, in the patients with PAH, compared with those in the controls group (P<0.01 for p‑Akt, Erk1/2; P<0.05 for p‑Erk1/2, HIF‑1α and HIF‑1β). These findings suggested that the mitogen‑activated protein kinase and PI3K/Akt signaling pathways, and HIF‑1 may perform a specific function in the pathogenesis of PAH.

Effects of Oxygen Availability on Acetic Acid Tolerance and Intracellular pH in Dekkera bruxellensis.

The yeast Dekkera bruxellensis, associated with wine and beer production, has recently received attention, because its high ethanol and acid tolerance enables it to compete with Saccharomyces cerevisiae in distilleries that produce fuel ethanol. We investigated how different cultivation conditions affect the acetic acid tolerance of D. bruxellensis We analyzed the ability of two strains (CBS 98 and CBS 4482) exhibiting different degrees of tolerance to grow in the presence of acetic acid under aerobic and oxygen-limited conditions. We found that the concomitant presence of acetic acid and oxygen had a negative effect on D. bruxellensis growth. In contrast, incubation under oxygen-limited conditions resulted in reproducible growth kinetics that exhibited a shorter adaptive phase and higher growth rates than those with cultivation under aerobic conditions. This positive effect was more pronounced in CBS 98, the more-sensitive strain. Cultivation of CBS 98 cells under oxygen-limited conditions improved their ability to restore their intracellular pH upon acetic acid exposure and to reduce the oxidative damage to intracellular macromolecules caused by the presence of acetic acid. This study reveals an important role of oxidative stress in acetic acid tolerance in D. bruxellensis, indicating that reduced oxygen availability can protect against the damage caused by the presence of acetic acid. This aspect is important for optimizing industrial processes performed in the presence of acetic acid. This study reveals an important role of oxidative stress in acetic acid tolerance in D. bruxellensis, indicating that reduced oxygen availability can have a protective role against the damage caused by the presence of acetic acid. This aspect is important for the optimization of industrial processes performed in the presence of acetic acid.