O2 Transport Research Articles

Fe‐N‐C in Proton Exchange Membrane Fuel Cells: Impact of Ionomer Loading on Degradation and Stability

AbstractFe single atoms in N‐doped C (Fe‐N‐C) present the most promising replacement for carbon‐supported Pt‐based catalysts for the O2 reduction reaction at the cathode of proton exchange membrane fuel cells (PEMFCs). However, it remains unclear how the I/C ratio affects Fe‐N‐C degradation and the stability of single Fe atom active sites (FeNx). Here, an accelerated stress test (AST) protocol is combined with emerging electrochemical techniques for a porous Fe‐N‐C in PEMFC with a range of I/C ratios. The PEMFC current density degradation rates are found to be comparable; however, with increased I/C ratio the additional FeNx sites accessed are more stable, as shown by their higher active site stability number (electrons passed per FeNx lost) at the end of the AST protocol. Meanwhile, the initial rate of TOF decay is suppressed with increasing I/C. Electrochemical process changes are studied via distribution of relaxation times analysis. Minor changes in H+ and O2 transport resistance at low current density prove kinetic degradation dominants at high potentials. These findings demonstrate how electrochemical techniques can be combined with stability metrics to determine and deconvolute changes from the active site to device level electrochemical processes in PEMFCs.

Apneic uptake of atmospheric O2 by deeply hypothermic nestlings of the white-footed mouse (Peromyscus leucopus): circulation and lungs.

Nestling white-footed mice (Peromyscus leucopus) are born in the earliest days of spring in cold climates. If the nestlings are by accident exposed to ambient temperatures near freezing (0-7°C) at early ages (2-10 days old), they may experience body temperatures (Tbs) equally low. During such hypothermia, although their heart keeps beating, they become apneic (cease inhaling and exhaling). However, they have an exceptional ability (e.g., compared to Mus musculus) to tolerate these conditions for at least several hours, after which they revive if rewarmed by parents. This paper addresses the physiology of the apneic period. We show that apneic, hypothermic nestlings undergo physiologically important exchanges of gases with the atmosphere. These gas exchanges do not occur across the skin. Instead they occur via the trachea and lungs even though the animals are apneic. Most significantly, when hypothermic neonates are in apnea in ordinary air, they take up O2 steadily from the atmosphere throughout the apneic period, and the evidence available indicates that this O2 uptake is essential for the nestlings' survival. At Tbs of 2-7°C, the nestlings' rate of O2 consumption varies quasi-exponentially with Tb and averages 0.04 mL O2 g- 1 h- 1, closely similar to the rate expressed by adult mammalian hibernators in hibernation at similar Tbs. Morphometric analysis indicates that, at all focal ages, O2 transport along the full length of the trachea can take place by diffusion at rates adequate to meet the measured rates of metabolic O2 consumption.

Soluble adenylyl cyclase is an acid-base sensor in rainbow trout red blood cells that regulates intracellular pH and haemoglobin-oxygen binding.

To identify the physiological role of the acid-base sensing enzyme, soluble adenylyl cyclase (sAC), in red blood cells (RBC) of the model teleost fish, rainbow trout. We used: (i) super-resolution microscopy to determine the subcellular location of sAC protein; (ii) live-cell imaging of RBC intracellular pH (pHi) with specific sAC inhibition (KH7 or LRE1) to determine its role in cellular acid-base regulation; (iii) spectrophotometric measurements of haemoglobin-oxygen (Hb-O2) binding in steady-state conditions; and (iv) during simulated arterial-venous transit, to determine the role of sAC in systemic O2 transport. Distinct pools of sAC protein were detected in the RBC cytoplasm, at the plasma membrane and within the nucleus. Inhibition of sAC decreased the setpoint for RBC pHi regulation by ~0.25 pH units compared to controls, and slowed the rates of RBC pHi recovery after an acid-base disturbance. RBC pHi recovery was entirely through the anion exchanger (AE) that was in part regulated by HCO3 --dependent sAC signaling. Inhibition of sAC decreased Hb-O2 affinity during a respiratory acidosis compared to controls and reduced the cooperativity of O2 binding. During invitro simulations of arterial-venous transit, sAC inhibition decreased the amount of O2 that is unloaded by ~11%. sAC represents a novel acid-base sensor in the RBCs of rainbow trout, where it participates in the modulation of RBC pHi and blood O2 transport though the regulation of AE activity. If substantiated in other species, these findings may have broad implications for our understanding of cardiovascular physiology in vertebrates.

High-performance rechargeable zinc-air batteries enabled by cobalt iron anchored on nitrogen-doped carbon matrix as bifunctional electrocatalyst

Developing efficient bifunctional oxygen reduction reaction (ORR)/oxygen evolution reaction (OER) electrocatalysts is potential ways for achieving high rechargeable zinc-air (Zn-air) battery performance. Herein, we report an iron (II) acetate-assisted strategy to synthesize Co3Fe7-NC-OAc catalyst with cobalt iron (Co3Fe7) alloy anchored on nitrogen-doped carbon (NC) matrix, which can serve as efficient ORR/OER bifunctional electrocatalysts for rechargeable Zn-air batteries. Apart from alloying with Co to form ORR/OER active Co3Fe7 nanoparticles, the incorporation of iron (II) acetate has expanded the pore size inside the Co3Fe7-NC-OAc catalyst to serve as gas transfer channels, and has induced synergetic electronic coupling between Co3Fe7 nanoparticles and NC matrix for boosting catalytic activity. Therefore, Co3Fe7-NC-OAc exhibits favorable ORR activity with a most positive half-wave potential of 0.90 V vs. RHE, fast ORR kinetics with a highest kinetic current density of 57.4 mA cm−2 at 0.85 V vs. RHE, and fast O2 diffusion and transport that enables smaller mass transport overpotential at high current density up to 800 mA cm−2. Additionally, Co3Fe7-NC-OAc can catalyze OER with low overpotential of 310 mV at 10 mA cm−2. When employed as air electrode for Zn-air batteries, Co3Fe7-NC-OAc achieve high peak power densities of 193 mW cm−2 and 587 mW cm−2 in liquid and solid-state Zn-air batteries. The liquid battery also exhibits high specific capacity and remarkable cycling performance. This work opens up a new opportunity for developing highly efficient bifunctional electrocatalysts for Zn-air battery applications.

A microscopic oxygen transport model for ultra-high dose rate radiotherapy in vivo: The impact of physiological conditions on FLASH effect.

Ultra-high dose rate irradiation (≥40Gy/s, FLASH) has been shown to reduce normal tissue toxicity, while maintaining tumor control compared to conventional dose-rate radiotherapy. The radiolytic oxygen (O2) depletion (ROD) resulting from FLASH has been proposed to explain the normal tissue protection effect; however, in vivo experiments have not confirmed that FLASH induced global tissue hypoxia. Nonetheless, the experiments reported are based on volume-averaged measurement, which have inherent limitations in detecting microscopic phenomena, including the potential preservation of stem cells niches due to local FLASH-induced O2 depletion. Computational modeling offers a complementary approach to understand the ROD caused by FLASH at the microscopic level. We developed a comprehensive model to describe the spatial and temporal dynamics of O2 consumption and transport in response to irradiation in vivo. The change of oxygen enhancement ratio (OER) was used to quantify and investigate the FLASH effect as a function of physiological and radiation parameters at microscopic scale. We considered time-dependent O2 supply and consumption in a 3D cylindrical geometry, incorporating blood flow linking the O2 concentration ([O2]) in the capillary to that within the tissue through the Hill equation, radial and axial diffusion of O2, metabolic and zero-order radiolytic O2 consumption, and a pulsed radiation structure. Time-evolved distributions of [O2] were obtained by numerically solving perfusion-diffusion equations. The model enables the computation of dynamic O2 distribution and the relative change of OER (δROD) under various physiological and radiation conditions in vivo. Initial [O2] level and the subsequent changes during irradiation determined δROD distribution, which strongly depends on physiological parameters, i.e., intercapillary spacing, ultimately determining the tissue area with enhanced radioresistance. We observed that the δROD/FLASH effect is affected by and sensitive to the interplay effect among physiological and radiation parameters. It renders that the FLASH effect can be tissue environment dependent. The saturation of FLASH normal tissue protection upon dose and dose rate was shown. Beyond ∼60Gy/s, no significant decrease in radiosensitivity within tissue region was observed. In turn, for a given dose rate, the change of radiosensitivity became saturated after a certain dose level. Pulse structures with the same dose and instantaneous dose rate but with different delivery times were shown to have distinguishable δROD thus tissue sparing, suggesting the average dose rate could be a metric assessing the FLASH effect and demonstrating the capability of our model to support experimental findings. On a macroscopic scale, the modeling results align with the experimental findings in terms of dose and dose rate thresholds, and it also indicates that pulse structure can vary the FLASH effect. At the microscopic level, this model enables us to examine the spatially resolved FLASH effect based on physiological and irradiation parameters. Our model thus provides a complementary approach to experimental methods for understanding the underlying mechanism of FLASH radiotherapy. Our results show that physiological conditions can potentially determine the FLASH efficacy in tissue protection. The FLASH effect may be observed under optimal combination of physiological parameters, not limited to radiation conditions alone.

A Fe-NC electrocatalyst boosted by trace bromide ions with high performance in proton exchange membrane fuel cells

Replacement of expensive and rare platinum with metal–nitrogen–carbon catalysts for oxygen reduction reactions in proton exchange membrane fuel cells is hindered by their inferior activity. Herein, we report a highly active iron-nitrogen-carbon catalyst by optimizing the carbon structure and coordination environments of Fe-N4 sites. A critical high-temperature treatment with ammonium chloride and ammonium bromide not only enhances the intrinsic activity and density of Fe-N4 sites, but also introduces numerous defects, trace Br ions and creates mesopores in the carbon framework. Notably, surface Br ions significantly improve the interaction between the ionomer and catalyst particles, promoting ionomer infiltration and optimizing the O2 transport and charge transfer at triple-phase boundary. This catalyst delivers a high peak power density of 1.86 W cm−2 and 54 mA cm−2 at 0.9 ViR-free in a H2-O2 fuel cells at 80 °C. Our findings highlight the critical role of interface microenvironment regulation.

Mechanism study of replacing adsorbed O2 molecules in different pore sizes under different CO2/N2 inert gas conditions

Injecting inert gases into the goaf is a crucial method for inhibiting coal spontaneous combustion. Research has verified that the co-injection of CO2 and N2 provides a more effective control measure compared to a single gas, but the microscopic mechanism underlying the synergistic displacement of O2 by CO2 and N2 remains unclear. Injecting inert gases into the goaf is a crucial method for inhibiting coal spontaneous combustion. Research has verified that the co-injection of CO2 and N2 provides a more effective control measure compared to a single gas, but the microscopic mechanism underlying the synergistic displacement of O2 by CO2 and N2 remains unclear. Here, for the constructed multi-scale aperture slit model, the Grand Canonical Monte Carlo simulation (GCMC) and Molecular Dynamics (MD) simulation are used to investigate the mechanism of displacing adsorbed O2 molecules under different CO2/N2 inert gas conditions. The results indicate that CO2 and N2 aggregated on opposing sides of the coal molecules and dispersed within the slit layer, respectively. At 1 nm pore size, the relative concentration of O2 for optimal displacement was 1.054. The absolute value of the average binding energy is small when the CO2:N2 gas ratio is 80:20 and 40:60 at 2 nm and 4 nm apertures, respectively. This suggests that as the aperture size increases, the displacement effect on O2 shifts towards a higher proportion of N2, with a more conspicuous replacement effect as the aperture widens. The smaller pores ranging from 1-2 nm predominantly feature CO2 displacing adsorbed state O2, while larger pores exceeding 2 nm primarily N2 facilitate the transportation of free state O2.

A multi-step discharge/charge model of Li[sbnd]O2 batteries coupled with electrolyte decomposition and carbon electrode corrosion reactions

Electrolyte decomposition and electrode corrosion stand as two primary side reactions in lithium‑oxygen (LiO2) batteries during their discharge/charge cycles. In this work, a comprehensive LiO2 battery model combining multi-step lithium peroxide (Li2O2) formation, electrolyte decomposition, and electrode corrosion is proposed. Based on this model, the deposition behaviors and cycling performance of the LiO2 battery under deep discharge/charge cycles are investigated. The stop of discharge is mainly ascribed to the loss of active surface area for the battery using tetraethylene glycol dimethyl ether (TEGDME) electrolyte, while both O2 transport limitation and active surface area loss lead to the discharge termination for battery using dimethyl sulfoxide (DMSO) electrolyte. The incomplete decomposition of Li2O2 and lithium carbonate (Li2CO3) clogs electrode pores, leading to a continuous decline in the discharge capacity of the LiO2 battery. For the TEGDME-based battery, the undecomposed Li2CO3 gradually dominates the deposition with cycles, wherein electrode corrosion becomes the primary source of the undecomposed Li2CO3 after 3 cycles. For the DMSO-based battery, undecomposed Li2O2 is always a dominant trigger for battery discharge capacity degradation, although electrode corrosion remains a key contributor to Li2CO3 generation. Despite the DMSO-based battery exhibiting lower rates of electrolyte decomposition and electrode corrosion, it demonstrates poorer cyclic performance than the TEGDME-based battery due to the generation of more toroidal Li2O2. Moreover, when the charging cut-off voltage is reduced to 4.2 V, discharge capacity diminishes more rapidly due to the increased accumulation of undecomposed Li2O2, despite suppressed Li2CO3 deposition. Finally, the results confirm that thick electrodes lead to deteriorating cycling performance, stemming from increased discharge/charge overpotential and extended discharge/charge times, thus intensifying the side reactions.

A High Capacity Gas Diffusion Electrode for Li-O2 Batteries.

The very high theoretical specific energy of the lithium-air (Li-O2) battery (3500Wh kg-1) compared with other batteries makes it potentially attractive, especially for the electrification of flight. While progress has been made in realizing the Li-air battery, several challenges remain. One such challenge is achieving a high capacity to store charge at the positive electrode at practical current densities, without which Li-air batteries will not outperform lithium-ion. The capacity is limited by the mass transport of O2 throughout the porous carbon positive electrode. Here it is shown that by replacing the binder in the electrode by a polymer with the intrinsic ability to transport O2, it is possible to reach capacities as high as 31 mAh cm-2 at 1mA cm-2 in a 300µm thick electrode. This corresponds to a positive electrode energy density of 2650Wh L-1 and specific energy of 1716Wh kg-1, exceeding significantly Li-ion batteries and previously reported Li-O2 cells. Due to the enhanced oxygen diffusion imparted by the gas diffusion polymer, Li2O2 (the product of O2 reduction on discharge) fills a greater volume fraction of the electrode and is more homogeneously distributed.

The role of the heart in the evolution of aerobic performance.

Aerobic metabolism underlies vital traits such as locomotion and thermogenesis, and aerobic capacity influences fitness in many animals. The heart is a key determinant of aerobic capacity, but the relative influence of cardiac output versus other steps in the O2 transport pathway remains contentious. In this Commentary, we consider this issue by examining the mechanistic basis for adaptive increases in aerobic capacity (thermogenic V̇O2,max; also called summit metabolism) in deer mice (Peromyscus maniculatus) native to high altitude. Thermogenic V̇O2,max is increased by acclimation to cold hypoxia (simulating high-altitude conditions), and high-altitude populations generally have greater V̇O2,max than their low-altitude counterparts. This plastic and evolved variation in V̇O2,max is associated with corresponding variation in maximal cardiac output, along with variation in other traits across the O2 pathway (e.g. arterial O2 saturation, blood haemoglobin content and O2 affinity, tissue O2 extraction, tissue oxidative capacity). By applying fundamental principles of gas exchange, we show that the relative influence of cardiac output on V̇O2,max depends on the O2 diffusing capacity of thermogenic tissues (skeletal muscles and brown adipose tissues). Functional interactions between cardiac output and blood haemoglobin content determine circulatory O2 delivery and thus affect V̇O2,max, particularly in high-altitude environments where erythropoiesis can increase haematocrit and blood viscosity. There may also be functional linkages between cardiac output and tissue O2 diffusion due to the role of blood flow in determining capillary haematocrit and red blood cell flux. Therefore, the functional interactions between cardiac output and other traits in the O2 pathway underlie the adaptive evolution of aerobic capacities.

Simultaneously inhibit cadmium and arsenic uptake in rice (Oryza sativa L.) by Selenium enhanced iron plaque: Performance and mechanism

Selenium (Se) fortification is witnessed to simultaneously inhibit absorbing Cadmium (Cd) and Arsenic (As) by rice plants, but the mechanism is unclear. Here, the effects of Se on the root morphology, iron plaque (IP) content, soil Fe2+ content, radial oxygen loss (ROL), and enzyme activities of the rice plants in the soil contaminated by Cd and As were intensively investigated through the hydroponic and soil experiments. Se effectively alleviated the toxic effects of Cd and As on the plants and the dry weight, root length, and root width were increased by 203.18%, 33.41%, and 52.81%, respectively. It also elucidated that ROL was one of the key factors to elevate IP formation by Se and the specific pathways of Se enhancing ROL were identified. ROL of the plants in the experiment group treated by Se was increased 36.76%, and correspondingly IP was magnified 50.37%, compared to the groups with Cd and As. It was owing to Se significantly increased the root porosity (62.11%), facilitating O2 transport to the roots. Additionally, Se enhanced the activities of catalase (CAT) and superoxide dismutase (SOD) to promote the catalytic degradation of ROS induced by Cd and As stress. It indirectly increased O2 release in the rhizosphere, which benefit to form more robust IP serve as stronger barrier to Cd and As. The results of our study provide a novel molecular level insight for Se promoting root IP to block Cd and As uptake by the rice plants.

Improving anion exchange membrane fuel cell performance via enhanced ionomer–carbon interaction in cathode catalyst layers with carbon-supported Pt catalyst using a pyrene carboxyl acid coating

While there have been substantial strides in anion exchange membrane and ionomer, engineering the catalyst layers (CLs) of anion exchange membrane fuel cells (AEMFCs) is still an unexplored domain despite its significance. Conventional anion exchange ionomers (AEIs) tend to be locally agglomerated in the CLs due to their weak interaction with the carbon support of catalyst, resulting in pore clogging in the CLs. Herein, we report that the coating of pyrene carboxyl acid (PCA) on the carbon surface increases ionomer–carbon interaction. PCA has a strong interaction with carbon surface via π–π interaction and with AEI via coulombic interaction. The use of PCA prevents the aggregation of ionomer chains, leading to homogeneous ionomer distribution and meso-porous CL structure. Due to the expanded catalyst/ionomer interface and promoted O2 transport, PCA coating improves the electrochemical performance of AEMFC. Controlling the ionomer–carbon interaction opens a new avenue for realizing high-performance AEMFCs.

Modulation of the allosteric and vasoregulatory arms of erythrocytic oxygen transport.

Efficient distribution of oxygen (O2) to the tissues in mammals depends on the evolved ability of red blood cell (RBC) hemoglobin (Hb) to sense not only O2 levels, but metabolic cues such as pH, PCO2, and organic phosphates, and then dispense or take up oxygen accordingly. O2 delivery is the product of not only oxygen release from RBCs, but also blood flow, which itself is also governed by vasoactive molecular mediators exported by RBCs. These vascular signals, including ATP and S-nitrosothiols (SNOs) are produced and exported as a function of the oxygen and metabolic milieu, and then fine-tune peripheral metabolism through context-sensitive vasoregulation. Emerging and repurposed RBC-oriented therapeutics can modulate either or both of these allosteric and vasoregulatory activities, with a single molecule or other intervention influencing both arms of O2 transport in some cases. For example, organic phosphate repletion of stored RBCs boosts the negative allosteric effector 2,3 biphosphoglycerate (BPG) as well as the anti-adhesive molecule ATP. In sickle cell disease, aromatic aldehydes such as voxelotor can disfavor sickling by increasing O2 affinity, and in newer generations, these molecules have been coupled to vasoactive nitric oxide (NO)-releasing adducts. Activation of RBC pyruvate kinase also promotes a left shift in oxygen binding by consuming and lowering BPG, while increasing the ATP available for cell health and export on demand. Further translational and clinical investigation of these novel allosteric and/or vasoregulatory approaches to modulating O2 transport are expected to yield new insights and improve the ability to correct or compensate for anemia and other O2 delivery deficits.

Effect of Degree of Smoking Based on Brinkman Index on Hemoglobin Levels in Adults

Cigarette consumption is the main cause of death in the world because it affects various physiological conditions in the body. Various ingredients in cigarette smoke such as tar, nicotine, carbon monoxide, and others can cause health problems, especially in the O2 transportation system. Hemoglobin is a protein in red blood cells that carries oxygen from the lungs to all tissues. The carbon monoxide contained in cigarette smoke is competitive with O2 in binding to hemoglobin so that the oxygen distributed to the tissues is reduced. The body will compensate for peripheral hypoxia that occurs by increasing hemoglobin levels in the body so that oxygen transport to the tissues can be maintained. Research regarding the relationship between the degree of smoking and hemoglobin levels is still controversial. Analytical research with cross-sectional design. A total of 184 respondents were taken using purposive sampling and it was found that the majority (94%) were men who worked as security officers, cleaners, parking attendants, or technicians. Based on the Brinkman Index, 73.9% of respondents were classified as light smokers, only 1.6% were classified as heavy smokers and 50.5% of respondents had low hemoglobin levels. Analysis showed that the majority of respondents in the light smoker group had normal hemoglobin levels (58.1%), while moderate and heavy smokers had lower hemoglobin levels. In statistical analysis, a significant p-value (0.001) was found between the degree of smoking and hemoglobin levels.

Reactive transport modelling of iron bentonite interaction in the FEBEX in situ experiment

The evolution of steel/bentonite interfaces in engineered barrier systems of radioactive waste disposal is governed by the corrosion of the steel and the interaction of corrosion products with the bentonite. In the early post-closure phase of the repository, the transition from aerobic to anaerobic corrosion in combination with evolving temperature conditions and chemical gradients due to the hydration of the bentonite take place. In situ tests in underground laboratories provide a high degree of representativeness for the early transient evolution of the interfaces. Complex Fe-bentonite interaction patterns have been observed, which include a concave Fe accumulation front and distinct coloured halos around the corroding steel. A reactive transport model for the FEBEX in situ test is presented, which describes the transition from aerobic to anaerobic corrosion, the transport of O2 in the gas and liquid phase and the chemical evolution of the steel/bentonite interface during the 18 years of the experiment. The model successfully reproduces the major steps of the interface evolution: an aerobic corrosion phase characterized by accumulation of goethite in the corrosion layer, and an anaerobic corrosion phase, where Fe(II) and Fe(II)/Fe(III) corrosion products form, including a gradual re-dissolution of the aerobic corrosion products. In the anaerobic corrosion phase, some of the Fe(II) diffuses into the bentonite, where it partly reacts with remaining O2 to form Fe(III) precipitates or interacts with the clay minerals via surface complexation or cation exchange. Two different approaches for the implementation of a potential electron transfer from sorbed Fe(II) to structural Fe(III) are presented, but the lack of experimental data does not allow evaluation of their representativeness for the FEBEX in situ experiment. The model calculations qualitatively reproduce the concave shape of the Fe accumulation front in the bentonite and a distinct zonation with an iron-oxide precipitation dominated zone adjacent to the steel and a Fe(II) sorption dominated zone further into the bentonite. Sensitivity cases with respect to the hydration of the bentonite and the transport parameters point to the importance of the fast O2 diffusion in the gas phase for the formation of these characteristic interface features. The calculated thickness of the Fe-bentonite interaction zone varies from 1 to 4 cm, which is smaller than observed in some areas of the experiment, where locally this zone extended >10 cm into the bentonite. It is possible that this difference is due to a more complex flow pattern in the in situ experiment that is not captured by the model or due to an additional decoupled electron transport across oxide rich layers.

#1001 Model-based profiling of bicarbonate supplementation during a hemodialysis cycle

Abstract Background and Aims Bicarbonate is delivered to hemodialysis (HD) patients via diffusion following a concentration gradient across the dialyzer membrane. However, the concentration of bicarbonate in the dialysis fluid ([HCO3]d) is usually not individualized for the specific patient's conditions, as no clear guidelines are provided, which leads to suboptimal pre- and post-dialytic plasma bicarbonate concentrations ([HCO3]p) during each treatment cycle. We used a mathematical model to predict the outcomes of a week-long HD cycle with time-dependent [HCO3]d in 24 patients, tuning the [HCO3]d prescription to keep the simulated pre-dialytic [HCO3]p in the range 22-24 mEq/L throughout the week. The [HCO3]d profiles thus developed were then tested, and [HCO3]p during HD compared with those using a constant [HCO3]d in the same patients. Method The compartmental model (Pietribiasi et al PLOS ONE 2023) describes the transport of total CO2, O2, and total buffer base in arterial and mixed-venous blood (plasma and red blood cells), tissues (interstitial and intracellular fluid), and lung capillaries and alveoli, calculating derivate quantities such as bicarbonate concentration, pH, partial pressure of CO2. The patients underwent one week of standard HD with constant [HCO3}d (Week 1, [HCO3]d = 33.6 ± 1.8 mEq/L) consisting of 3 sessions (HD1, HD2, HD3) to estimate the baseline model parameters and, successively, an intervention week (Week 2), during which the model-derived [HCO3]d profiles were implemented. Each profile consisted of a single step increase after 2 hours of HD, the two values of [HCO3]d chosen for each session and patient according to the model's simulations. Blood samples for the blood gas analyzer were taken before and after each session, and each hour during HD2. Results [HCO3]p profiles in Week 2 showed a more linear increase compared those of Week 1 (Fig. 1). The efficacy of the response to the model-based treatment was different depending on whether the intervention aimed to decrease or increase pre-dialytic [HCO3]p during Week 2 (Fig. 2). In the group of patients attempting to decrease pre-dialytic [HCO3]p (Decrease group, n = 10, average [HCO3]d = 31.3 ± 1.5 mEq/L), a significant fraction of sessions achieved the target (60% across the whole week). In contrast, among the patients attempting to increase pre-dialytic [HCO3]p (Increase group, n = 6, average [HCO3]d = 35.3 ± 2.0 mEq/L), the model-based prescription was effective only in increasing post-dialytic concentration (20% of sessions achieved pre-dialytic targets). By comparison, during Week 1 only 30% and 10% of sessions were in the target range for Decrease and Increase groups, respectively. Patients for which we didn't want to alter pre-dialytic [HCO3]p were termed the Neutral group (n = 8, average [HCO3]d = 33.3 ± 2.1 mEq/L, 40% and 50% of sessions in the target [HCO3]p range in Week 1 and 2, respectively). Conclusion The model-based profiling intervention was only partially successful in achieving the targets for pre-dialytic [HCO3]p in Week 2. The reasons why pre-dialytic [HCO3]p were resistant to the model-based [HCO3]d in the Increase group are not clear, but it could be that the increase in the average [HCO3]d was too small (6-7% higher than Week 1). However, in the Decrease group a similar difference was sufficient to produce a more marked decrease in pre-dialytic [HCO3]p. The profiling of [HCO3]d was shown to be effective in reducing the time the patients spend at higher [HCO3]p. Nevertheless, our study demonstrated that, upon refinement, mathematical modeling can be used to develop individualized treatments to pilot the markers of the acid-base response to HD towards desired values.

Estimation of differential pathlength factor from NIRS measurement in skeletal muscle

The utilization of continuous wave (CW) near-infrared spectroscopy (NIRS) device to measure non-invasively muscle oxygenation in healthy and disease states is limited by the uncertainties related to the differential path length factor (DPF). DPF value is required to quantify oxygenated and deoxygenated heme groups’ concentration changes from measurement of optical densities by NIRS. An integrated approach that combines animal and computational models of oxygen transport and utilization was used to estimate the DPF value in situ. The canine model of muscle oxidative metabolism allowed measurement of both venous oxygen content and tissue oxygenation by CW NIRS under different oxygen delivery conditions. The experimental data obtained from the animal model were integrated in a computational model of O2 transport and utilization and combined with Beer-Lambert law to estimate DPF value in contracting skeletal muscle. A 2.1 value was found for DPF by fitting the mathematical model to the experimental data obtained in contracting muscle (T3) (Med.Sci.Sports.Exerc.48(10):2013–2020,2016). With the estimated value of DPF, model simulations well predicted the optical density measured by NIRS on the same animal model but with different blood flow, arterial oxygen contents and contraction rate (J.Appl.Physiol.108:1169–1176, 2010 and 112:9–19,2013) and demonstrated the robustness of the approach proposed in estimating DPF value. The approach used can overcome the semi-quantitative nature of the NIRS and estimate non-invasively DPF to obtain an accurate concentration change of oxygenated and deoxygenated hemo groups by CW NIRS measurements in contracting skeletal muscle under different oxygen delivery and contraction rate.

Nuclear receptor Rev-erbα role in fine-tuning erythropoietin gene expression

AbstractThe regulation of red blood cell (RBC) homeostasis by erythropoietin (EPO) is critical for O2 transport and maintaining the adequate number of RBCs in vertebrates. Therefore, dysregulation in EPO synthesis results in disease conditions such as polycythemia in the case of excessive EPO production and anemia, which occurs when EPO is inadequately produced. EPO plays a crucial role in treating anemic patients; however, its overproduction can increase blood viscosity, potentially leading to fatal heart failure. Consequently, the identification of druggable transcription factors and their associated ligands capable of regulating EPO offers a promising therapeutic approach to address EPO-related disorders. This study unveils a novel regulatory mechanism involving 2 pivotal nuclear receptors (NRs), Rev-ERBA (Rev-erbα, is a truncation of reverse c-erbAa) and RAR-related orphan receptor A (RORα), in the control of EPO gene expression. Rev-erbα acts as a cell-intrinsic negative regulator, playing a vital role in maintaining erythropoiesis at the correct level. It accomplishes this by directly binding to newly identified response elements within the human and mouse EPO gene promoter, thereby repressing EPO production. These findings are further supported by the discovery that a Rev-erbα agonist (SR9011) effectively suppresses hypoxia-induced EPO expression in mice. In contrast, RORα functions as a positive regulator of EPO gene expression, also binding to the same response elements in the promoter to induce EPO production. Finally, the results of this study revealed that the 2 NRs, Rev-erbα and RORα, influence EPO synthesis in a negative and positive manner, respectively, suggesting that the modulating activity of these 2 NRs could provide a method to target disorders linked with EPO dysregulation.

Elucidating the Role of O2 Uncoupling for the Adaptation of Bacterial Biodegradation Reactions Catalyzed by Rieske Oxygenases.

Oxygenation of aromatic and aliphatic hydrocarbons by Rieske oxygenases is the initial step of various biodegradation pathways for environmental organic contaminants. Microorganisms carrying Rieske oxygenases are able to quickly adapt their substrate spectra to alternative carbon and energy sources that are structurally related to the original target substrate, yet the molecular events responsible for this rapid adaptation are not well understood. Here, we evaluated the hypothesis that reactive oxygen species (ROS) generated by unproductive activation of O2, the so-called O2 uncoupling, in the presence of the alternative substrate exert a selective pressure on the bacterium for increasing the oxygenation efficiency of Rieske oxygenases. To that end, we studied wild-type 2-nitrotoluene dioxygenase from Acidovorax sp. strain JS42 and five enzyme variants that have evolved from adaptive laboratory evolution experiments with 3- and 4-nitrotoluene as alternative growth substrates. The enzyme variants showed a substantially increased oxygenation efficiency toward the new target substrates concomitant with a reduction of ROS production, while mechanisms and kinetics of enzymatic O2 activation remained unchanged. Structural analyses and docking studies suggest that amino acid substitutions in enzyme variants occurred at residues lining both substrate and O2 transport tunnels, enabling tighter binding of the target substrates in the active site. Increased oxygenation efficiencies measured in vitro for the various enzyme (variant)-substrate combinations correlated linearly with in vivo changes in growth rates for evolved Acidovorax strains expressing the variants. Our data suggest that the selective pressure from oxidative stress toward more efficient oxygenation by Rieske oxygenases was most notable when O2 uncoupling exceeded 60%.

Linking red blood cell functional phenotypes to environmental tolerance in high-altitude adapted deer mice

Oxygen (O2) is essential for vertebrate life, and complex cardio-respiratory systems have evolved to transport the gas from the environment to each individual cell. Even short disruptions of this O2 flux can have deleterious effects that are linked to numerous disease states. Animals that have adapted to hypoxic environments, such as deer mice ( Peromyscus maniculatus) native to high altitude, can provide valuable insight into naturally evolved solutions to O2 deprivation. Previous work has shown that high-altitude deer mice have evolved a higher hemoglobin O2 affnity and other coordinated changes across the O2 transport cascade that enable higher metabolic rates in hypoxia. Red blood cells (RBC) are the functional unit of O2 and carbon dioxide transport in the blood and play central roles in matching O2 supply and demand in the microcirculation by releasing signaling molecules such as ATP and gasotransmitters; but how these cellular mechanisms respond to hypoxic environments has not been studied. We hypothesized that high-altitude adaptation in deer mice has improved the function of RBCs for cardiovascular gas transport in hypoxia. Lab-raised breeding colonies of deer-mice were established from wild mice caught at low altitude (~400 m in the Great Plains of Nebraska) and at high altitude (~4300 m in the Rocky Mountains of Colorado). Using a common-garden experimental design, third-generation deer mice from high- and low-altitude populations were acclimated to warm normoxia (21°C, 21 kPa O2) or cold hypobaric hypoxia (5°C, 12 kPa O2) for 8 weeks. Blood samples were collected for measurements of hematocrit, hemoglobin concentration, RBC volume, plasma erythropoietin concentration, RBC contents of membrane transport and channel proteins (anion exchanger, aquaporin 1 and rhesus associated glycoprotein) by immunocytochemistry and western blotting, and carbonic anhydrase activity using biochemical techniques. The release of ATP from RBCs was measured in tonometers at decreasing levels of O2 by luminometry, and the vascular sensitivity to ATP was determined by wire myography on second-order mesenteric arteries. Finally, bone marrow samples were collected from the femurs to measure gene expression levels in the erythropoietic tissue. Our experimental design allowed us to examine the interactive effects of cold hypoxic environments on RBC phenotype, by untangling environmentally-induced plasticity from the signatures of adaptation that are unique to high-altitude natives. This work is providing a better understanding of how RBC function participates in matching cardiovascular O2 supply and demand in extreme hypoxia, which has important applications in animal and human health. This work was supported by a NSERC Canada Banting Postdoctoral Fellowship to TSH and a Discovery Grant to GRS. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.