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1. The adaptive benefit of evolved increases in hemoglobin-O2 affinity is contingent on tissue O2 diffusing capacity in high-altitude deer mice

   https://doi.org/10.1186/s12915-021-01059-4  

   Wearing, Oliver H. ; Ivy, Catherine M. ; Gutiérrez-Pinto, Natalia ; Velotta, Jonathan P. ; Campbell-Staton, Shane C. ; Natarajan, Chandrasekhar ; Cheviron, Zachary A. ; Storz, Jay F. ; Scott, Graham R. ( June 2021 , BMC Biology)

   Complex organismal traits are often the result of multiple interacting genes and sub-organismal phenotypes, but how these interactions shape the evolutionary trajectories of adaptive traits is poorly understood. We examined how functional interactions between cardiorespiratory traits contribute to adaptive increases in the capacity for aerobic thermogenesis (maximal O₂consumption,V̇O₂max, during acute cold exposure) in high-altitude deer mice (Peromyscus maniculatus). We crossed highland and lowland deer mice to produce F₂inter-population hybrids, which expressed genetically based variation in hemoglobin (Hb) O₂affinity on a mixed genetic background. We then combined physiological experiments and mathematical modeling of the O₂transport pathway to examine the links between cardiorespiratory traits andV̇O₂max.

   Physiological experiments revealed that increases in Hb-O₂affinity of red blood cells improved blood oxygenation in hypoxia but were not associated with an enhancement inV̇O₂max. Sensitivity analyses performed using mathematical modeling showed that the influence of Hb-O₂affinity onV̇O₂max in hypoxia was contingent on the capacity for O₂diffusion in active tissues.

   These results suggest that increases in Hb-O₂affinity would only have adaptive value in hypoxic conditions if concurrent with or preceded by increases in tissue O₂diffusing capacity. In high-altitude deer mice, the adaptive benefit of increasing Hb-O₂affinity is contingent on the capacity to extract O₂from the blood, which helps resolve controversies about the general role of hemoglobin function in hypoxia tolerance.

    

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2. In Vitro Assay for Single-cell Characterization of Impaired Deformability in Red Blood Cells under Recurrent Episodes of Hypoxia

   https://doi.org/10.1039/D1LC00598G  

   QIANG, YUHAO ; Liu, Jia ; Dao, Ming ; Du, E ( January 2021 , Lab on a Chip)

   null (Ed.)

   Red blood cells (RBCs) are subjected to recurrent changes in shear stress and oxygen tension during blood circulation. The cyclic shear stress has been identified as an important factor that alone can weaken cell mechanical deformability. The effects of cyclic hypoxia on cellular biomechanics have yet to be fully investigated. As the oxygen affinity of hemoglobin plays a key role in the biological function and mechanical performance of RBCs, the repeated transitions of hemoglobin between its R (high oxygen tension) and T (low oxygen tension) states may impact their mechanical behavior. The present study focuses on developing a novel microfluidics-based assay for characterization of the effect of cyclic hypoxia on cell biomechanics. The capability of this assay is demonstrated by a longitudinal study of individual RBCs in health and sickle cell disease subjected to cyclic hypoxia conditions of various durations and levels of low oxygen tension. Viscoelastic properties of cell membranes are extracted from tensile stretching and relaxation processes of RBCs induced by the electrodeformation technique. Results demonstrate that cyclic hypoxia alone can significantly reduce cell deformability, similar to the fatigue damage accumulated through cyclic mechanical loading. RBCs affected by sickle cell disease are less deformable (significantly higher membrane shear modulus and viscosity) than normal RBCs. The fatigue resistance of sickle RBCs to the cyclic hypoxia challenge is significantly inferior to normal RBCs, and this trend is more significant in mature erythrocytes of sickle cells. When oxygen affinity of sickle hemoglobin is enhanced by anti-sickling drug treatment of 5-hydroxymethyl-2-furfural (5-HMF), sickle RBCs show ameliorated resistance to fatigue damage induced by cyclic hypoxia. These results illustrate that an important biophysical mechanism underlying RBC senescence in which cyclic hypoxia challenge alone can lead to mechanical degradation of the RBC membrane. We envision the application of this assay can be further extended to RBCs in other blood diseases and other types of cells. 

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3. Beyond corticosterone: The acute stress response increases DNA damage in house sparrows

   https://doi.org/10.1002/jez.2405  

   Gormally, Brenna M. G. ; Estrada, Rodolfo ; McVey, Mitch ; Romero, L. Michael ( August 2020 , Journal of Experimental Zoology Part A: Ecological and Integrative Physiology)

   Although corticosterone (Cort) has been the predominant metric used to assess acute stress in birds, it does not always accurately reflect how an animal copes with a stressor. Downstream measurements may be more reliable. In the current study, we tested the hypothesis that acute increases in DNA damage could be used to assess stressor exposure. Studies have shown DNA damage increases in response to stress‐related hormones in vitro; however, this has not yet been thoroughly applied in wild animals. We exposed house sparrows (Passer domesticus) to a 30‐ or 120‐min restraint stressor and took blood samples at 0, 30, 60, and 120 min to measure Cort, DNA damage, and uric acid. Both treatments increased DNA damage and Cort, and decreased uric acid. It thus appears that DNA damage can reflect acute stressor exposure. To improve the usability of DNA damage as a metric for stress, we also tested the impacts of sample storage on DNA damage. Leaving red blood cells on ice for up to 24 hr, only slightly influenced DNA damage. Freezing blood samples for 1–4 weeks substantially increased DNA damage. These findings emphasize the importance of reducing variation between samples by assaying them together whenever possible. Overall, these results indicate that assessing DNA damage is a valid method of assessing acute stressor exposure that is suitable for both laboratory‐ and field‐based studies; however, additional research is needed on the molecular dynamics of nucleated red blood cells, including whether and how their DNA is repaired.

    

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4. Establishing a hemoglobin adjustment for 129Xe gas exchange MRI and MRS

   https://doi.org/10.1002/mrm.29712  

   Bechtel, Aryil ; Lu, Junlan ; Mummy, David ; Bier, Elianna ; Leewiwatwong, Suphachart ; Mugler, III, John ; Kabir, Sakib ; Church, Alex ; Driehuys, Bastiaan ( May 2023 , Magnetic Resonance in Medicine)

   ¹²⁹Xe MRI and MRS signals from airspaces, membrane tissues (M), and red blood cells (RBCs) provide measurements of pulmonary gas exchange. However,¹²⁹Xe MRI/MRS studies have yet to account for hemoglobin concentration (Hb), which is expected to affect the uptake of¹²⁹Xe in the membrane and RBC compartments. We propose a framework to adjust the membrane and RBC signals for Hb and use this to assess sex‐specific differences in RBC/M and establish a Hb‐adjusted healthy reference range for the RBC/M ratio.

   We combined the 1D model of xenon gas exchange (MOXE) with the principle of TR‐flip angle equivalence to establish scaling factors that normalize the dissolved‐phase signals with respect to a standard (14 g/dL).¹²⁹Xe MRI/MRS data from a healthy, young cohort (n = 18, age = 25.0 3.4 years) were used to validate this model and assess the impact of Hb adjustment on M/gas and RBC/gas images and RBC/M.

   Adjusting for Hb caused RBC/M to change by up to 20% in healthy individuals with normal Hb and had marked impacts on M/gas and RBC/gas distributions in 3D gas‐exchange maps. RBC/M was higher in males than females both before and after Hb adjustment (p < 0.001). After Hb adjustment, the healthy reference value for RBC/M for a consortium‐recommended acquisition of TR = 15 ms and flip = 20° was 0.589 0.083 (mean SD).

   MOXE provides a useful framework for evaluating the Hb dependence of the membrane and RBC signals. This work indicates that adjusting for Hb is essential for accurately assessing¹²⁹Xe gas‐exchange MRI/MRS metrics.

    

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5. Evolved increases in hemoglobin-oxygen affinity and the Bohr effect coincided with the aquatic specialization of penguins

   https://doi.org/https://doi.org/10.1073/pnas.2023936118  

   Signore, Anthony V ; Tift, Michael S ; Hoffman, Federico G ; Schmitt, Todd L ; Moriyama, Hideaki ; Storz, Jay F. ( March 2021 , Proceedings of the National Academy of Sciences of the United States of America)

   Somero, George N. (Ed.)

   Dive capacities of air-breathing vertebrates are dictated by onboard O2 stores, suggesting that physiologic specialization of diving birds such as penguins may have involved adaptive changes in convective O2 transport. It has been hypothesized that increased hemoglobin (Hb)-O2 affinity improves pulmonary O2 extraction and enhances the capacity for breath-hold diving. To investigate evolved changes in Hb function associated with the aquatic specialization of penguins, we integrated comparative measurements of whole-blood and purified native Hb with protein engineering experiments based on site-directed mutagenesis. We reconstructed and resurrected ancestral Hb representing the common ancestor of penguins and the more ancient ancestor shared by penguins and their closest nondiving relatives (order Procellariiformes, which includes albatrosses, shearwaters, petrels, and storm petrels). These two ancestors bracket the phylogenetic interval in which penguin-specific changes in Hb function would have evolved. The experiments revealed that penguins evolved a derived increase in Hb-O2 affinity and a greatly augmented Bohr effect (i.e., reduced Hb-O2 affinity at low pH). Although an increased Hb-O2 affinity reduces the gradient for O2 diffusion from systemic capillaries to metabolizing cells, this can be compensated by a concomitant enhancement of the Bohr effect, thereby promoting O2 unloading in acidified tissues. We suggest that the evolved increase in Hb-O2 affinity in combination with the augmented Bohr effect maximizes both O2 extraction from the lungs and O2 unloading from the blood, allowing penguins to fully utilize their onboard O2 stores and maximize underwater foraging time. 

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