Low Oxygen Levels Research Articles

Hypoxemia and hypercapnia: Its relation to joint diseases and the natural treatments for some joint diseases: A review

The leading cause of disability worldwide is Arthritis. Arthritis can be either autoimmune joint disease or osteoarthritis. According to the Center for Disease Control (CDC), by 2040, 80 million U.S. adults will have some form of arthritis. The objective is to find the effect of Hypoxemia, hypercapnia and PH chemical imbalance of the blood on muscle loss and joint diseases, and to find natural remedies to treat these types of joint diseases. Three main types of joint diseases were found to be directly related to hypoxia (Low levels of oxygen in your body tissues), hypercapnia (Excess carbon dioxide build up), and blood PH imbalance: Rheumatoid Arthritis, Osteoarthritis, and gout joint diseases. The natural treatment of these joint diseases has been identified.

Hipoksi ve Obezite Olgusunda Malondialdehit ve İndirgenmiş Glutatyon’un Bazı Sıçan Dokularında Karşılaştırılması

Objective: Obesity is an important global public health problem that is associated with many chronic diseases and is increasing day by day in our country as well as in the world. The aim of this study is to compare malondialdehyde (MDA) and reduced glutathione (GSH) in some rat tissues due to obesity and hypoxia. 
 Material and Methods: In our study 24 male Sprague Dawley rats were used. Rats were divided into four groups (n:6) as standard diet/normal oxygen, standard diet/low oxygen, high-fat diet/normal oxygen, and high-fat diet/low oxygen. For the study, a special cage with low oxygen level of 17-18% in the closed system was used. Weight gain of 20-25% was achieved in obese rats. MDA and GSH levels were measured in liver, kidney and brain organ tissues of rats.
 Results: In our study it was determined that there were significant increases in the amount of MDA and GSH. It was observed that MDA and GSH had a protective effect against hypoxia and obesity in liver and brain tissue, but not in kidney tissue.
 Conclusion: As a result of our research we think that MDA and GSH may support the current criteria in the diagnosis and/or treatment of obesity and will contribute greatly to more comprehensive analyzes to be made in the future.

The close interaction between hypoxia-related proteins and metastasis in pancarcinomas

Many primary-tumor subregions exhibit low levels of molecular oxygen and restricted access to nutrients due to poor vascularization in the tissue, phenomenon known as hypoxia. Hypoxic tumors are able to regulate the expression of certain genes and signaling molecules in the microenvironment that shift it towards a more aggressive phenotype. The transcriptional landscape of the tumor favors malignant transformation of neighboring cells and their migration to distant sites. Herein, we focused on identifying key proteins that participate in the signaling crossroads between hypoxic environment and metastasis progression that remain poorly defined. To shed light on these mechanisms, we performed an integrated multi-omics analysis encompassing genomic/transcriptomic alterations of hypoxia-related genes and Buffa hypoxia scores across 17 pancarcinomas taken from the PanCancer Atlas project from The Cancer Genome Atlas consortium, protein–protein interactome network, shortest paths from hypoxia-related proteins to metastatic and angiogenic phenotypes, and drugs involved in current clinical trials to treat the metastatic disease. As results, we identified 30 hypoxia-related proteins highly involved in metastasis and angiogenesis. This set of proteins, validated with the MSK-MET Project, could represent key targets for developing therapies. The upregulation of mRNA was the most prevalent alteration in all cancer types. The highest frequencies of genomic/transcriptomic alterations and hypoxia score belonged to tumor stage 4 and positive metastatic status in all pancarcinomas. The most significantly associated signaling pathways were HIF-1, PI3K-Akt, thyroid hormone, ErbB, FoxO, mTOR, insulin, MAPK, Ras, AMPK, and VEGF. The interactome network revealed high-confidence interactions among hypoxic and metastatic proteins. The analysis of shortest paths revealed several ways to spread metastasis and angiogenesis from hypoxic proteins. Lastly, we identified 23 drugs enrolled in clinical trials focused on metastatic disease treatment. Six of them were involved in advanced-stage clinical trials: aflibercept, bevacizumab, cetuximab, erlotinib, ipatasertib, and panitumumab.

P-183 Effect of oxygen levels, temperature, and interruptive evaluation practices during embryo culture on embryo developmental arrest. A systematic review and network meta-analysis

Abstract Study question Do different culture conditions and practices, regarding oxygen levels, temperature, and culture interruption for evaluation purposes, effect embryo developmental arrest? Summary answer Ultra-low oxygen levels at 2-3.5%, a temperature below 37oC, and more than one interruption during culture are associated with a higher developmental arrest rate. What is known already Literature indicates that embryo culture microenvironment differs among laboratories. According to data, oxygen levels range between 2%-20%, while the optimal temperature during embryo culture, ranging from 36oC-37oC, has not yet been validated. What is more, interrupting embryo culture to evaluate morphology disrupts the stable conditions of the incubator’s microenvironment, while various models of interruptive evaluation practices have been reported on time-points and assessment frequency. Data are lacking on the extent that oxygen levels, temperature and morphology evaluation practices affect the embryos’ developmental potential. Interestingly, reporting on optimal culture conditions and embryo evaluation practices still appears to be timely and essential. Study design, size, duration A systematic search of the literature was performed in Pubmed/Medline, Embase, and Cochrane Central Library up to October 2021. Seventeen published prospective studies were included in the three arms of this network meta-analysis. The outcome measure was developmental arrest rate prior to the blastocyst stage. To rank oxygen levels and interruption times, the P-Score was employed. Molecular pathways implicated in developmental arrest associated with each examined parameter were investigated as part of the systematic review. Participants/materials, setting, methods A network meta-analysis was performed regarding oxygen levels, temperature, and culture interruption practices for evaluation purposes. The population consisted of preimplantation embryos. Atmospheric conditions (20% O2), low-oxygen levels (5% O2) and ultra-low oxygen levels (2-3.5% O2), along with temperature below or at 37oC were compared. Finally, no interruptions (time-lapse microscopy), one interruption (fertilization evaluation), 2 and 3 interruptions for morphological evaluation were compared. The estimated network effect comprises of direct and indirect effects. Main results and the role of chance Eight studies reporting on the effect of different oxygen levels, presented with high heterogeneity I2=88%. No statistically significant difference was observed between atmospheric and low-oxygen level regarding arrest rate (RR:1.07; 95%CI:0.88-1.30). A significantly higher developmental arrest rate was observed in ultra-low oxygen levels versus low (RR:1.29; 95%CI:1.02-1.64). No statistically significant difference was observed between ultra-low oxygen levels and atmospheric conditions (RR:1.21; 95%CI:0.89-1.63). The optimal oxygen levels are low (P-Score=0.87), followed by atmospheric conditions (P-Score=0.57) and ultra-low (P-Score=0.06). Three studies reporting on the effect of different temperatures presented with low heterogeneity I2=30%. Temperature below 37oC presented with a statistically significant higher developmental arrest rate (RR:1.10; 95%CI:1.03-1.17). Six studies reporting on the effect of interruptive evaluation practices showed high heterogeneity I2=84%. Uninterrupted culture presented with no statistically significant difference with the other groups (1-interruption vs Uninterrupted: RR:0.93; 95%CI:0.78-1.12; 2-interruptions vs Uninterrupted: RR:1.08; 95%CI:0.91-1.28; 3-interruptions vs Uninterrupted: RR:1.11; 95%CI:0.92-1.34). A single-interruption presented with marginally no statistically significant difference when compared to two-interruptions (RR:0.87; 95%CI:0.74-1.02), however presented with a lower developmental arrest rate when compared to three-interruptions (RR:0.84; 95%CI:0.71-0.99). Two versus three-interruptions indicated no difference (RR:0.97; 95%CI:0.82-1.14). The optimal interruptive evaluation practice is one (P-Score=0.90) followed by uninterrupted (P-Score=0.63), two-interruptions (P-Score=0.30) and three-interruptions (P-Score=0.16). Limitations, reasons for caution The limited number of studies included and the heterogeneity are limitations of this study. The different number of studies and embryos included in each comparison group, along with the fact that randomization was not performed in all studies, present as reasons for caution when interpreting the results of this study. Wider implications of the findings Oxygen levels at 5%, 37oC temperature, and single or no-interruption embryo evaluation practices reduce developmental arrest rate. This systematic review indicates potential pathways implicated in developmental arrest as follows: oxygen tension influencing histone modifications, temperature influencing regulatory proteins’ activity, and stress-related cytokines’ differential expression when culture is interrupted multiple times. Trial registration number Not applicable

Could respiration-driven blood oxygen changes modulate neural activity?

Oxygen is critical for neural metabolism, but under most physiological conditions, oxygen levels in the brain are far more than are required. Oxygen levels can be dynamically increased by increases in respiration rate that are tied to the arousal state of the brain and cognition, and not necessarily linked to exertion by the body. Why these changes in respiration occur when oxygen is already adequate has been a long-standing puzzle. In humans, performance on cognitive tasks can be affected by very high or very low oxygen levels, but whether the physiological changes in blood oxygenation produced by respiration have an appreciable effect is an open question. Oxygen has direct effects on potassium channels, increases the degradation rate of nitric oxide, and is rate limiting for the synthesis of some neuromodulators. We discuss whether oxygenation changes due to respiration contribute to neural dynamics associated with attention and arousal.

MIF/CXCR4 signaling axis contributes to survival, invasion, and drug resistance of metastatic neuroblastoma cells in the bone marrow microenvironment

BackgroundThe bone marrow (BM) is the most common site of dissemination in patients with aggressive, metastatic neuroblastoma (NB). However, the molecular mechanisms underlying the aggressive behavior of NB cells in the BM niche are still greatly unknown. In the present study, we explored biological mechanisms that play a critical role in NB cell survival and progression in the BM and investigated potential therapeutic targets.MethodsPatient-derived bone marrow (BM) primary cultures were generated using fresh BM aspirates obtained from NB patients. NB cell lines were cultured in the presence of BM conditioned media containing cell-secreted factors, and under low oxygen levels (1% O2) to mimic specific features of the BM microenvironment of high-risk NB patients. The BM niche was explored using cytokine profiling assays, cell migration-invasion and viability assays, flow cytometry and analysis of RNA-sequencing data. Selective pharmacological inhibition of factors identified as potential mediators of NB progression within the BM niche was performed in vitro and in vivo.ResultsWe identified macrophage migration inhibitory factor (MIF) as a key inflammatory cytokine involved in BM infiltration. Cytokine profiling and RNA-sequencing data analysis revealed NB cells as the main source of MIF in the BM, suggesting a potential role of MIF in tumor invasion. Exposure of NB cells to BM-conditions increased NB cell-surface expression of the MIF receptor CXCR4, which was associated with increased cell viability, enhanced migration-invasion, and activation of PI3K/AKT and MAPK/ERK signaling pathways. Moreover, subcutaneous co-injection of NB and BM cells enhanced tumor engraftment in mice. MIF inhibition with 4-IPP impaired in vitro NB aggressiveness, and improved drug response while delayed NB growth, improving survival of the NB xenograft model.ConclusionsOur findings suggest that BM infiltration by NB cells may be mediated, in part, by MIF-CXCR4 signaling. We demonstrate the antitumor efficacy of MIF targeting in vitro and in vivo that could represent a novel therapeutic target for patients with disseminated high-risk NB.

Transcriptomic Profiling of JEG-3 cells using human leiomyoma derived matrix

Oxygen tension varies during placental and fetal development. Although hypoxia drives early trophoblast invasion, low placental oxygen levels during pregnancy show association with pregnancy complications including fetal growth restriction and preeclampsia. JEG-3 cells are often used as a trophoblast model. We studied transcriptional changes of JEG-3 cells on a uterine leiomyoma derived matrix Myogel. This might be the closest condition to the real uterine environment that we can get for an in vitro model. We observed that culturing JEG-3 cells on the leiomyoma matrix leads to strong stimulation of ribosomal pathways, energy metabolism, and ATP production. Furthermore, Myogel improved JEG-3 cell adherence in comparison to tissue culture treated plastic. We also included PDMS microchip hypoxia creation, and observed changes in oxidative phosphorylation, oxygen related genes and several hypoxia genes. Our study highlights the effects of Myogel matrix on growing JEG-3 cells, especially on mitochondria, energy metabolism, and protein synthesis.

Abstract 1742: Molecular characterization of CRPC pathogenesis and development of a novel anti-PSMA-drug conjugated hybrid nanoparticle therapy with reduced cellular toxicity

Abstract Background: Metastatic castration-resistant prostate cancer (mCRPC) is responsible for most of PCa deaths. Androgen deprivation therapy (ADT), taxanes and enzalutamide are the standard care for CRPC and mCRPC. Unfortunately, these approaches often fail to prevent tumor relapse due to at least in part, the inherently low oxygen levels within the prostate tumor environment. In addition to this, lower drug stability and fast drug clearance among ADT patients are the major therapeutic limitations in drug delivery and drug efficacy. Therefore, it is clinically warranted to develop an increased drug stability system to enhance the drug efficacy. Recent developments in drug delivery system including our earlier report, nanoparticle loaded drugs shows greater stability and better drug efficacy with sub-optimal drug concentrations in vitro. It is an essential to develop an ideal CRPC preclinical model system to test the anti-PSMA-drug conjugated hybrid nanoparticle efficacy with high drug stability with limited cellular toxicity. Materials and Methods: CRPC lines were developed from PSMA proficient LNCaP, LAPC4, C4-2, 22Rv1, and PSMA deficient PC3-ML cells with intermittent hypoxia. CRPC cells were analyzed for proliferation, RB status, AR signaling, migration invasion and drug resistance in both in vitro and in vivo. Further, CRPC bone metastases clinical samples from Thomas Jefferson University Hospital were compared with preclinical CRPC model. Efficient anti-PSMA-drug conjugated hybrid nanoparticle therapy was established. Results: Hypoxia resistance models show CRPC, RB loss, hormone therapy resistance in vitro and in vivo. Anti-PSMA-drug conjugated hybrid nanoparticle shows enhanced drug stability and drug efficacy in vitro and in vivo. Interestingly we observed fibrosis, immune impairment and inactive RB in bone metastatic CRPC samples correlated with our preclinical studies. Further, our clinical bone metastases samples present osteoblastic, osteolytic and osteoblastic & osteolytic nature. Anti-PSMA conjugated-drug loaded hybrid nanoparticles localized to PSMA specific cells in vitro & in vivo, causing cell cycle arrest. Drug loaded anti-PSMA conjugated hybrid nanoparticles did not cause major toxicities in mice. Conclusion: Hypoxia resistant mCRPC models are ideal and are comparable with CRPC induced bone metastases in patient’s samples. Drug-loaded anti-PSMA conjugated hybrid nanoparticles targets PSMA specific prostate cancer cells and show enhanced drug stability and drug efficacy in CRPC preclinical model. Citation Format: Thangavel Chellappagounder. Molecular characterization of CRPC pathogenesis and development of a novel anti-PSMA-drug conjugated hybrid nanoparticle therapy with reduced cellular toxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1742.

Small RNAs in the Antarctic bacterium Pseudomonas extremaustralis responsive to oxygen availability and oxidative stress.

Bacterial small non-coding RNAs (sRNAs) play key roles as genetic regulators, mediating in the adaptability to changing environmental conditions and stress responses. In this work, we analysed putative sRNAs identified by RNA-seq experiments in different aeration conditions in the extremophile bacterium P. extremaustralis. These analyses allowed the identification of 177 putative sRNAs under aerobiosis (A), microaerobiosis (M) and microaerobiosis after H2 O2 exposure (m-OS). The size and transcription profile of eight sRNAs with differential expression were verified by Northern blot. sRNA40, with unknown function but conserved in other Pseudomonas species, was selected to perform overexpression experiments followed by RNA-seq analysis. The overexpression of sRNA40 in P. extremaustralis resulted in significant expression changes of 19 genes with 14 differentially upregulated and five downregulated. Among the upregulated genes, eight transcripts corresponded to components of secretion systems, such as gspH, gspK, and gspM, belonging to the Type II secretion system, and rspO and rspP from Type III secretion system. Our results showed a novel sRNA which expression was triggered by low oxygen levels, and whose overexpression was associated with upregulation of selected components of protein secretion systems.

Altitude-adaption of gut microbiota in Tibetan chicken

Low oxygen levels and extremely cold weather in high-altitude environments requires more energy intake to maintain body temperature in animals. However, little is known about the characteristics of cecal and ileac microbiota in Tibetan chicken and how the high and low altitude environments affect the gut microbiota communities in Tibetan chicken. In the present study, In the present study, Tibetan chickens (Group HA, 3572 m, 578.5 Pa) and their introduced flatland counterparts (Group LA, 580 m, 894.6 Pa) in the cecum and ileum to identify the possible bacterial species that are helpful for their host in environmental adaption. High-throughput sequencing was used to sequence the V3 to V4 hypervariable regions of the bacterial 16S rRNA gene. By comparing the gut microbial diversity of HA chicken with that of LA, the results indicated that the microbial diversity of the cecum and ileum in group HA was significantly lower (P < 0.05) than those in group LA. The cecum microbiome maintained higher population diversity and richness than the ileum (P < 0.05). Four phyla Firmicutes, Bacterioidetes, Actinobacteria, and Proteobacteria were dominant in two groups. Interestingly, there were significant differences in abundance ratio among the four groups (P < 0.05). The predominant bacteria in HA and LA ileum belong to Proteobacteria and Firmicutes, whereas in cecum, Bacterioidetes and Actinobacteria were predominant in both groups (P < 0.05). Correlation analysis showed that Sporosarcina, Enterococcus, and Lactococcus were strongly related to air pressure, and Peptoclostridium and Ruminococcaceae_UCG-014 are related to altitude and gut microbiota of LA group was influenced by altitude, while HA group affected by air pressure. Meanwhile, the Ruminococcus-torques-group was negatively correlated with the relative abundance of Paenibacillus, and positive correlated with those of other microorganisms. Furthermore, HA has higher abundance of microbiota involved in energy and glycan biosynthesis metabolism pathway, while LA has higher abundance of microbiota involved in membrane transport, signal transduction, and xenobiotics biodegradation and metabolism. Generally, our results suggested that the composition and diversity of gut microbes changed after Tibetan chickens were introduced to the plain. Tibetan chicken may adapt to new environment via reshaping the gut microbiota. Gut microbes may contribute to the host adaption to high altitude environments by increasing host energy and glycan biosynthesis.

Did high temperature rather than low O2 hinder the evolution of eukaryotes in the Precambrian?

The emergence and diversity of eukaryotes that occurred in the Proterozoic Eon (2.5–0.541 Ga) are the most important parts of life’s evolution on the Earth. However, the critical time and key environmental factor(s) are still controversial. Herein, we systematically compiled the reported fossils and convinced biomarkers of Proterozoic eukaryotes. The Proterozoic eukaryotic evolutionary timeline was proposed to be divided into four stages: (1) ambiguous origin (2.3–1.8 Ga), (2) slow evolution (1.8–0.8 Ga), (3) diversity fluctuation (0.8–0.635 Ga), and (4) first radiation (0.635–0.541 Ga). As aerobic organisms, the emergence and evolution of eukaryotes have been proposed to be hindered by low oxygen levels during the Proterozoic Eon. However, increasing evidence suggests that the Proterozoic oxygen content might have been higher than 1% PAL (present atmospheric level) since 2.3 Ga, allowing eukaryotes, including early animals, to survive. The Great Oxygenation Event (GOE) did not wake up eukaryotes. The Mesoproterozoic Oxygenation Event (MOE) did not accelerate the evolution of eukaryotes. The first and rapid radiation of eukaryotes after the Neoproterozoic Oxygenation Event (NOE) and global glaciations acted like the opening of Pandora's box. Hence atmospheric oxygen alone cannot be invoked as the only control on the evolution of eukaryotes. Instead, we suggest that oceanic temperature may have been an important environmental factor that limited eukaryotic physiology until the end-Proterozoic.

Oxygen sensor of the heart.

How oxygen is sensed by the heart and what mechanisms mediate its sensing remain poorly understood. As recent reports show that low PO2 levels are detected by the cardiomyocytes in a few seconds, the rapid and short applications of low levels of oxygen (acute hypoxia), which avoid multiple effects of chronic hypoxia, may be used to probe the oxygen-sensing pathway of the heart. Here, we explored the oxygen-sensing pathway, focusing primarily on cellular surface membrane proteins that were first exposed to low PO2. Such studies suggest that acute hypoxia primarily targets the cardiac calcium channels, where either the channel itself or moieties closely associated with it, for instance heme-oxygenase-2 (HO-2) interacting through kinase phosphorylation, signal the α-subunit of the channel to the altered levels of PO2. Amino acids 1572-1651, the CaMKII phosphorylation sites (S1487 and S1545), CaM-binding sites (I1624 and Q1625), and Ser1928 of the carboxyl tail of the α-subunit appear to be critical residues that sense oxygen. Future studies on HO-2 knockout mice or CRISPR/Cas9 gene-edited human-induced pluripotent stem-cell-derived cardiomyocytes that reduce CaM-binding affinity are likely to provide deeper insights into the O2-sensing mechanisms.

SUMOylation in peripheral tissues under low perfusion-related pathological states.

SUMOylation is described as a posttranslational protein modification (PTM) that is involved in the pathophysiological processes underlying several conditions related to ischemia- and reperfusion-induced damage. Increasing evidence suggests that, under low oxygen levels, SUMOylation might be part of an endogenous mechanism, which is triggered by injury to protect cells within the central nervous system. However, the role of ischemia-induced SUMOylation in the periphery is still unclear. This article summarizes the results of recent studies regarding SUMOylation profiles in several diseases characterized by impaired blood flow to the cardiorenal, gastrointestinal, and respiratory systems. Our review shows that although ischemic injury per sedoes not always increase SUMOylation levels, as seen in strokes, it seems that in most cases the positive modulation of protein SUMOylation after peripheral ischemia might be a protective mechanism. This complex relationship warrants further investigation, as the role of SUMOylation during hypoxic conditions differs from organ to organ and is still not fully elucidated.

Modeling the impact of spatial oxygen heterogeneity on radiolytic oxygen depletion during FLASH radiotherapy

Purpose. It has been postulated that the delivery of radiotherapy at ultra-high dose rates (‘FLASH’) reduces normal tissue toxicities by depleting them of oxygen. The fraction of normal tissue and cancer cells surviving radiotherapy depends on dose and oxygen levels in an exponential manner and even a very small fraction of tissue at low oxygen levels can determine radiotherapy response. To quantify the differential impact of FLASH radiotherapy on normal and tumour tissues, the spatial heterogeneity of oxygenation in tissue should thus be accounted for. Methods. The effect of FLASH on radiation-induced normal and tumour tissue cell killing was studied by simulating oxygen diffusion, metabolism, and radiolytic oxygen depletion (ROD) over domains with simulated capillary architectures. To study the impact of heterogeneity, two architectural models were used: (1) randomly distributed capillaries and (2) capillaries forming a regular square lattice array. The resulting oxygen partial pressure distribution histograms were used to simulate normal and tumour tissue cell survival using the linear quadratic model of cell survival, modified to incorporate oxygen-enhancement ratio effects. The ratio (‘dose modifying factors’) of conventional low-dose-rate dose and FLASH dose at iso-cell survival was computed and compared with empirical iso-toxicity dose ratios. Results. Tumour cell survival was found to be increased by FLASH as compared to conventional radiotherapy, with a 0–1 order of magnitude increase for expected levels of tumour hypoxia, depending on the relative magnitudes of ROD and tissue oxygen metabolism. Interestingly, for the random capillary model, the impact of FLASH on well-oxygenated (normal) tissues was found to be much greater, with an estimated increase in cell survival by up to 10 orders of magnitude, even though reductions in mean tissue partial pressure were modest, less than ∼7 mmHg for the parameter values studied. The dose modifying factor for normal tissues was found to lie in the range 1.2–1.7 for a representative value of normal tissue oxygen metabolic rate, consistent with preclinical iso-toxicity results. Conclusions. The presence of very small nearly hypoxic regions in otherwise well-perfused normal tissues with high mean oxygen levels resulted in a greater proportional sparing of normal tissue than tumour cells during FLASH irradiation, possibly explaining empirical normal tissue sparing and iso-tumour control results.

Human Fungal Infection, Immune Response, and Clinical Challenge-a Perspective During COVID-19 Pandemic.

Fungi are a small but important part of the human microbiota and several fungi are familiar to the immune system, yet certain can cause infections in immunocompromised hosts and referred as opportunistic pathogens. The fungal coinfections in COVID-19 hosts with predisposing conditions and immunosuppressive medications are posing higher severity and death. The immunological counteraction (innate/adaptive immunity) is triggered when the PRRs on the host cells recognize the fungal PAMPs. However, in simultaneous infections (COVID-19 and fungal coinfection), the synergism of TLR and NLR may hyperactivate the immune cells which dramatically increase the cytokine level and generate cytokine storm. Fungal colonization in the human gut assists the development of microbiome assembly, ecology, and shaping immune response. However, SARS-CoV-2 infection represented unstable mycobiomes and long-term dysbiosis in a large proportion in COVID-19 patients. Normally, amphotericin B is considered as first-line treatment for invasive fungal infection. So, amphotericin B therapy is recommended in COVID-19 hosts with serious fungal infections. Still, the long-term corticosteroid supplementation prescribed in case of severe pneumonia and lower oxygen levels may result in systemic fungal infection in COVID-19 patients, eventually limiting the lifesaving benefits of available medications. Also, due to the evolution of fungal resistance to available antibiotics, the current treatments are becoming ineffective. Therefore, this review summarizes the concerns, needed to deal with the impending crises.

Coastlines at Risk of Hypoxia From Natural Variability in the Northern Indian Ocean

AbstractCoastal hypoxia—harmfully low levels of oxygen—is a mounting problem that jeopardizes coastal ecosystems and economies. The northern Indian Ocean is particularly susceptible due to human‐induced impacts, vast naturally occurring oxygen minimum zones, and strong variability associated with the seasonal monsoons and interannual Indian Ocean Dipole (IOD). We assess how natural factors influence the risk of coastal hypoxia by combining a large set of oxygen measurements with satellite observations to examine how the IOD amplifies or suppresses seasonal hypoxia tied to the Asian Monsoon. We show that on both seasonal and interannual timescales hypoxia is controlled by wind‐ and coastal Kelvin wave‐driven upwelling of oxygen‐poor waters onto the continental shelf and reinforcing biological feedbacks (increased subsurface oxygen demand). Seasonally, the risk of hypoxia is highest in the western Arabian Sea in summer/fall (71% probability of hypoxia). Major year‐to‐year impacts attributed to the IOD occur during positive phases along the eastern Bay of Bengal (EBoB), where the risk of coastal hypoxia increases from moderate to high in summer/fall (21%–46%) and winter/spring (31%–42%), and along the eastern Arabian Sea (i.e., India, Pakistan) where the risk drops from high to moderate in summer/fall (53%–34%). Strong effects are also seen in the EBoB during negative IOD phases, when the risk reduces from moderate to low year‐round (∼25% to ∼5%). This basin‐scale mapping of hypoxic risk is key to aid national and international efforts that monitor, forecast, and mitigate the impacts of hypoxia on coastal ecosystems and ecosystem services.

Hyperspectral evaluation of liver oxygenation in a murine model of metabolic associated liver disease and hepatocellular carcinoma

Abstract Objective Untreated MAFLD is a continuum of disease ranging from hepatic steatosis to cirrhosis and hepatocellular carcinoma (HCC). Throughout the disease progression, a change in hepatic hemodynamics occurs as portal hypertension. Hepatic arterial buffer response is a compensatory mechanism to maintain liver perfusion facing reduction of portal flow. These changes could also impair hepatic oxygenation homeostasis. The aim of this study is to test this hypothesis in mouse models and to shed light on the oxygenation of fatty, portal hypertensive liver and its impact on HCC carcinogenesis. Methods C57BL/6 mice were fed a HFD starting from 4 weeks of age, porto-systemic shunts (or sham) were created at 8 weeks, and monitored up to 40 weeks. ND-fed non-shunted mice were used as control group. Hyperspectral imaging (HSI) was utilized to quantify tissue oxygenation (StO2) of ND, HFD and HFD-shunted mice. In a second set of experiment, we explored the role of a common hepatic artery ligation in the studied DEN-induced HFD mouse model. Results HFD induced hepatic steatosis and portal pressure compared to ND. Porto-systemic shunt could deviate about 67% of the portal flow through the spleen to the systemic circulation, thus reducing portal pressure close-to-normal levels. Compared to control mice, HFD feeding increased liver oxygenation (p=0.0004), while shunting restored a close to normal level (p&amp;lt;0.001). The oxygenation of small bowel is decreased in a similar manner in both HFD and HFD-shunted mice. In HFD-fed mice, artery ligation led to less carcinogenesis compared to mice without artery ligation (p=0.026). In addition, artery ligation was also associated with smaller HCCs (p=0.027). Conclusion Early stages of MAFLD alter hepatic oxygen homeostasis. Fatty liver, when associated to portal hypertension, express higher liver oxygenation levels, compared to control group. This could due to hepatocyte ballooning with a narrowing of portal system, thus bring portal hypertension state with a simultaneous arterial buffer response. Additionally, small bowel of portal hypertensive mice showed lower oxygen levels mirroring an intestinal venous congestion typical of portal hypertension. Oxygen deprivation, through artery ligation, decreases HCC carcinogenesis and reduces HCC nodules volume. Yet further research is needed but oxygen homeostasis seems play a role in MAFLD progression as well in HCC pathophysiology.

0718 Is There a way to Predict abnormal Polysomnography Following a Negative Home Sleep Apnea Test?

Abstract Introduction Obstructive sleep apnea (OSA) is characterized by recurrent episodes of obstruction of the upper airway that cause decreased or absent breathing during sleep. An OSA diagnosis is made when the patient experiences recurrent episodes of partial or complete collapse of the upper airway during sleep, which results in apneas or hypopneas, respectively. Polysomnography (PSG) is the gold standard test for diagnosis. HSATs (Home Sleep Apnea Tests) are types of sleep tests that can be conducted in a patient's home to detect obstructive sleep apnea. These tests are becoming increasingly common due to their affordability and convenience. Currently, an in-lab PSG is recommended if the initial HSAT is negative and there is a high clinical suspicion of OSA. Aim of this study is to identify a predictive component of negative HSAT which in turn shows positive PSG. Methods We reviewed 50 electronic medical records of patients who underwent an HSAT followed by an in-lab PSG at our Sleep Disorders Center. Patient demographics, comorbidities, HSAT data and PSG data were analyzed. Chi-square test and independent sample t-test were used to compare groups. Predictors of the negative PGA was assessed with Logistic regression. Statistical analysis was performed using Statistical Package of Social Science (SPSS) for Windows, version 15.0 (SPSS Inc, Chicago, IL). A p value &amp;lt;0.05 was considered as statistically significant. Results There was no correlation between age, gender, body mass index, comorbidities, and lowest oxygen level in HSAT to predict the result of following PSG. Conclusion The results of this study showed no statistically significant predictor in patients who underwent an HSAT followed by an in-lab PSG, although there seems to be a weak correlation between the lowest oxygen levels in HSAT and positive PSG. The gold standard for diagnosing OSA remains in-laboratory PSG; HSAT is an alternative in a select group of patients. For most patients with suspected mild OSA, in-laboratory PSG is preferred since HSAT may under-detect sleep-related events. Support (If Any)

Modelling the effect of vascular status on tumour evolution and outcome after thermal therapy

Microscale oxygenation plays a prominent role in tumour progression. Spatiotemporal variability of oxygen distribution in the tumour microenvironment contributes to cellular heterogeneity and to the emergence of normoxic and hypoxic populations. Local levels of oxygen strongly affect the response of tumours to the administration of different therapeutic modalities and, more generally, to the phenomenon of resistance to treatments. Several interventions have been proposed to improve tumour oxygenation, being the elevation of the local temperature (hyperthermia) an important one. While other factors such as the metabolic activity have to be considered, the proficiency of the tumour vascular system is a key factor both for the tissue oxygenation and for its temperature maps. Consequently, the interplay of these factors has attracted considerable attention from the mathematical modelling perspective. Here we put forward a transport-based system of partial differential equations aimed at describing the dynamics of healthy and tumour cell subpopulations at the microscale in a region placed between two blood vessels. By using this model with diverse flow conditions, we analyse the oxygen and temperature profiles that arise in different scenarios of vascular status, both during free progression and under thermal therapy. We find that low oxygen levels are associated to elevations of temperature in locations preferentially populated by hypoxic cells, and hyperthermia-induced cell death, being strongly dependent on blood flow, would only appear under highly disrupted conditions of the local vasculature. This results in a noticeable effect of heat on hypoxic cells. Additionally, when pronounced cell death occurs, it is followed by a significant increase in the oxygen levels. Our results provide quantitative insight to the physiological and biological processes taking place at sub-voxel sizes, currently not accessible to standard functional imaging due to spatial resolution limitations.

Optimized S-nitrosohemoglobin Synthesis in Red Blood Cells to Preserve Hypoxic Vasodilation Via βCys93.

Classic physiology links tissue hypoxia to oxygen delivery through control of microvascular blood flow (autoregulation of blood flow). Hemoglobin (Hb) serves both as the source of oxygen and the mediator of microvascular blood flow through its ability to release vasodilatory S-nitrosothiol (SNO) in proportion to degree of hypoxia. β-globin Cys93Ala (βCys93Ala) mutant mice deficient in S-nitrosohemoglobin (SNO-Hb) show profound deficits in microvascular blood flow and tissue oxygenation that recapitulate microcirculatory dysfunction in multiple clinical conditions. However, the means to replete SNO in mouse red blood cells (RBCs) to restore RBC function is not known. In particular, although methods have been developed to selectively S-nitrosylate βCys93 in human Hb and intact human RBCs, conditions have not been optimized for mouse RBCs that are used experimentally. Here we show that loading SNO onto Hb in mouse RBC lysates can be achieved with high stoichiometry and β-globin selectivity. However, S-nitrosylation of Hb within intact mouse RBCs is ineffective under conditions that work well with human RBCs, and levels of metHb are prohibitively high. We developed an optimized method that loads SNO in mouse RBCs to maintain vasodilation under hypoxia and shows that loss of SNO loading in βCys93Ala mutant RBCs results in reduced vasodilation. We also demonstrate that differences in SNO/met/nitrosyl Hb stoichiometry can account for differences in RBC function among studies. RBCs loaded with quasi-physiologic amounts of SNO-Hb will produce vasodilation proportionate to hypoxia, whereas RBCs loaded with higher amounts lose allosteric regulation, thus inducing vasodilation at both high and low oxygen level. SIGNIFICANCE STATEMENT: Red blood cells from mice exhibit poor hemoglobin S-nitrosylation under conditions used for human RBCs, frustrating tests of vasodilatory activity. Using an optimized S-nitrosylation protocol, mouse RBCs exhibit hypoxic vasodilation that is significantly reduced in hemoglobin βCys93Ala mutant RBCs that cannot carry S-nitrosothiol allosterically, providing genetic validation for the role of βCys93 in oxygen delivery.