bluuebunny/crossref_metadata_2025 huggingface dataset:
The impact of the pointless system of grading in an undergraduate physiology class
Authors: Safford Susan
Published: May 2023

The pointless system of assessment is a relatively new concept and few papers have been published demonstrating its usefulness in higher education, particularly in STEM classes. The current study was undertaken to determine the usefulness of this pedagogy in assisting students to master physiological concepts. The hypothesis is that students will respond positively to this assessment and show improved mastery of concepts. All assignments and tests require written answers that involve explanation of concepts and mechanisms. All work, except exams, can be revised, and detailed feedback and rubrics are given for each assignment. Student work is rated as exceeds, meets or approaches expectations. Class work is divided into categories (writing, exams, case studies, lab handouts, lab reports) and each category is rated as exceeds, meets or approaches expectations depending on the overall quality of the work in each category. Final grades are awarded based on a matrix of how many categories are rated at each level as shown in Table 1.

[Table: see text]

This approach was used in spring 2021 under IRB# LUIRB03022021SS with a physiology class while students were remote. In 2021, all the students revised some of their work and learned from their revisions as evidenced by improved first drafts in subsequent work. Students seemed to master concepts better with this system as 85% of the students scored exceeds expectations on comprehensive mid-term and final exams. Student comments on a reflective writing exercise indicated that most of the students liked this approach despite the perceived increase in workload. Students indicated that they believed they learned the concepts better and they were less concerned about trying to remember minutia. This approach is currently being used for the second time during the spring 2023 semester in a face-to-face physiology course. One goal for this year is to see if the outcomes are similar in a face-to-face class. The first student assignments are due shortly, so summary data for this semester is not yet available.

This is the full abstract presented at the American Physiology Summit 2023 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.
Investigation into the role of Apj and Vegf receptor signaling in the regulation of coronary angiogenesis
Authors: Kuschel Bryce , Sharma Bikram
Published: May 2023

Coronary artery disease (CAD) is one of the leading causes of death worldwide; however, a therapeutic remedy has not been developed. Coronary angiogenesis, a process by which new coronary vessels are formed in the embryos, is primarily a function of endothelial cells which form the inner lining of the vessel wall. Therefore, understanding coronary endothelial cells' cellular and molecular biology can teach us how to effectively stimulate the repair and regeneration of damaged coronary vessels. Investigations in mice have identified the Apelin receptor (alias: APJ) and Vascular endothelial growth factor receptor 2 (VEGFR2) signaling as regulators of coronary angiogenesis. However, it is unclear whether APJ and VEGFR2 signaling interact with one another in the regulation of coronary angiogenesis. To investigate this, we performed in vitro cell culture experiments using isolated coronary endothelial cells and in vivo experiments with APJ KO mice. We hypothesize that ELABELA/APJ signaling downregulates VEGFR2 expression in coronary endothelial cells. Our expression analysis using immunostaining and qPCR show that APJ loss-of-function in coronary endothelial cells results in increased VEGFR2 expression. Collectively, our results show that ELABELA/APJ suppresses VEGFR2 signaling during coronary angiogenesis.

This study is supported by the NIH R15 (1R15HL159660-01) research grant to BS.

This is the full abstract presented at the American Physiology Summit 2023 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.
Isolated Human Mesenteric Arteries from Organ Donors as a Model to Determine Arterial Reactivity
Authors: Bloom Charissa , Zimmermann Rollin Isabela , McQueen Jenna , Iyer Vishnu , Breslin Jerome
Published: May 2023

Few studies have explored reactivity of isolated human arteries to chemical mediators. The purpose of this research was to establish a model utilizing mesenteric arteries isolated from donated human organs to study tone. The general hypothesis was that the arteries would be viable and would respond to stimuli such as alpha-receptor agonists, thromboxane receptor agonists, and endothelin-1. Intact human small intestines were provided by LifeLink. Mesenteric arteries were carefully dissected and cut into 2 mm rings. Then they were mounted on parallel wires of a DMT Multi Wire Myograph System Model 620M and stretched to an internal vessel circumference corresponding to native transmural pressure (13.3 kPa). The vessels were bathed in a physiological salt solution at 37°C. Viability of the vessels was tested with a physiological salt solution containing 60 mM KCl. Afterwards, the vessels were treated with increasing concentrations of one of the following vasoconstrictive agents: U46619, phenylephrine (PE), and endothelin-1 (ET-1). Potential differences between age groups, sexes, and different health conditions among donors were investigated. Concentration-response curves were constructed and the EC50 and maximum tension were determined for each drug. The results show that the arteries were nearly always viable and responded to each of the three drugs. There was no significant difference among age groups or between sex for any of the agents. There was a significant difference in the maximum of the concentration-response curve for U46619 between donors who had diabetes vs. no diabetes. Also, donors with hypertension had a higher EC50 for phenylephrine, with rightward shift in the concentration-response curve, compared to individuals who did not have hypertension. Collectively, these findings suggest that human arteries isolated from organ donor mesentery are a reliable model for evaluating arterial contractile reactivity. In addition, insights into how different disease states impact arterial function can be gained from this type of study.

Supported by NIH Grant R21AA029213 and the generous donations of organs for research by LifeLink.

This is the full abstract presented at the American Physiology Summit 2023 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.
Investigating the effects of thermoneutral housing on skeletal and cardiac muscle function in D2 mdx mice
Authors: Wasilewicz Luc , Hamstra Sophie , Hockey Briana , Braun Jessica , Marcella Bianca , Baranowski Ryan , MacPherson Rebecca , Fajardo Val
Published: May 2023

Since its discovery, the mdx mouse has been the foundation for research on Duchenne muscular dystrophy (DMD) and its potential therapies. Although, nearly all studies using mdx mice as an experimental model have been conducted under “standard” lab conditions using room (22C) instead of thermoneutral (TN, 30C) temperature housing. Room temperature (RT) is a mild cold stress to mice, causing metabolic adaptations that can confound experimental results, limiting their interpretation and translation to humans. This study investigated the effects of housing temperature on whole-body metabolism and skeletal and cardiac muscle function in the mdx mouse. To this end, 20 D2 mdx mice (age 5 weeks, n = 10 per group) were housed at RT and TN for 10 weeks. Metabolic cage analysis demonstrated that TN housed mdx mice displayed significantly decreased VO2 consumption and reduced food intake that was likely due to lowered daily energy expenditure. TN housed mice also had significantly lower respiratory exchange ratio values, indicative of increased fat metabolism. However, there were no differences in body mass or composition (i.e., % lean and fat mass). Treadmill-to-fatigue experiments revealed no differences in exercise performance. Furthermore, ex vivo muscle contractility analysis displayed no differences in extensor digitorum longus or soleus specific force generation between TN and RT housed mice. Analysis of cardiac structure/function demonstrated that TN housed mdx mice exhibited a reduction in cardiac output, which we attributed to diastolic dysfunction. While ejection fraction and fractional shortening were not different among the two groups, TN housing led to a significant reduction in end diastolic volume (EDV) and left ventricle internal diameter (diastole, LVID;d), as well as increased relative wall thickness (diastole, RWT;d) compared to RT housed mice. Though isovolumic relaxation time was prolonged in TN-housed mice, this did not reach statistical significance. Taken together, our results demonstrate that TN housing had minimal effects on skeletal muscle contractility, but did lead to signs of diastolic dysfunction in young mdx mice. Future studies will examine the effects of TN housing in aged mdx mice, when systolic dysfunction occurs, as well as any influence of TN housing on the efficacy of potential muscle wasting therapeutics. Overall, our results support the growing literature that highlights the importance of selecting the appropriate housing temperature when studying metabolism or muscle wasting conditions in mice.

NSERC

This is the full abstract presented at the American Physiology Summit 2023 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.
Protonic Action Potential: Better understanding neural stimulation by touch
Authors: Lee James
Published: May 2023

The 2021 Nobel Prize in Physiology or Medicine was recently awarded to David Julius and Ardem Patapoutian “for their discoveries of receptors for temperature and touch.” It is now well established that touch receptors provide sensory inputs to inform the brain about objects in our environment. Touch sensation is vital for survival and, without it, even simple activities such as feeding, dressing, or standing would be exceedingly difficult to accomplish. Like hearing, balance, and proprioception, touch is initiated by mechanosensory receptor cells. These cells contain mechanotransduction channels (such as PIEZO), which convert physical stimuli into membrane potential changes, called receptor potentials, that trigger neuronal action potentials. These action potentials are transmitted by sensory afferents to the brain, where sensory percepts are formed. However, exactly how the transient ion transport activity of touch receptors can stimulate the firing of action potentials seems still not entirely clear. In this presentation, we will employ the latest transmembrane-electrostatic proton localization theory with a newly formulated membrane potential equation to better understand neural resting and action potential as the voltage contributed by the transmembrane-electrostatically localized protons/cations charges (TELC) at a neural liquid-membrane interface. Accordingly, the neural stimulation by touch can now be better elucidated through analysis of PIEZO conduction and TELC activity with the newly formulated membrane potential equation.

This research was supported in part by a Multidisciplinary Biomedical Research Seed Funding Grant from the Graduate School, the College of Sciences, and the Center for Bioelectrics at Old Dominion University, Norfolk, Virginia, USA.

This is the full abstract presented at the American Physiology Summit 2023 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.
Novel regulatory role of post-translational structural modification in modulating Src kinase activity in pulmonary arterial hypertension
Authors: Alhawaj Raed , Ghadhanfar Elham , Cherian Susan
Published: May 2023

Under conditions that lead to pulmonary arterial hypertension (PAH), the pro-proliferative oncoprotein Src kinase activity is elevated, contributing to pulmonary arterial smooth muscle cell remodeling, increasing vascular resistance, and leading to PAH. In addition, reactive oxygen species (ROS), including Hydrogen peroxide (H2O2), are elevated in the pulmonary vasculature under pro-PAH conditions. Therefore, we hypothesized that Src kinase is subject to redox modulation by elevated hydrogen peroxide (H2O2) under pro-PAH conditions. We intended to explore whether increased H2O2 can cause the oxidation of Src kinase thiol groups resulting in an inter-molecular disulfide bond forming Src kinase homodimer, increasing its catalytic activity. The results of this study detected evidence that Src kinase undergoes redox-induced homodimer formation as illustrated by western blot analysis under non-reducing conditions of rat MCT-induced PAH lung lysates. Furthermore, the redox-mediated Src kinase homodimer formation was associated with the increased catalytic activity of Src kinase, as seen in its intra-molecular auto-phosphorylation of its tyrosine 416 residue. This process was accompanied by activating one of Src kinase downstream substrates, STAT3, via the phosphorylation of its tyrosine 705 residue. Moreover, these mechanistic changes were associated with a PAH disease state confirmed with elevated right ventricle systolic pressure and right ventricle hypertrophy through right ventricle catheterization and the Fulton index, respectively. From the results above, we can conclude that in rat MCT-PAH lung lysates, Src kinase undergoes a redox-induced modulation that results in a structural modification associated with increased Src kinase activity, as observed in its autophosphorylation and the phosphorylation of its downstream substrate STAT3. In conclusion, under conditions that lead to PAH, Src kinase undergoes a post-translational structural modification. This modification occurs in redox-induced oxidation of Src kinase thiol groups. This process results in an inter-molecular disulfide bond formation yielding a homodimer associated with elevated Src kinase catalytic activity, further adding a mechanistic layer to Src kinase regulation in PAH.

Kuwait University Research Sector

This is the full abstract presented at the American Physiology Summit 2023 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.
MCT4 Deficiency Enhances High-intensity Interval Training-induced Metabolic Adaptations in Skeletal Muscle
Authors: Tamura Yuki
Published: May 2023

The purpose of this study was to understand the effect of increased lactate accumulation in skeletal muscle by MCT4 deficiency on the adaptation of skeletal muscle to high-intensity interval training. To address this challenge, we first developed MCT4-deficient mice with a genetic background of the Jcl:ICR strain which is capable of performing high-intensity exercise. We found that MCT4 deficiency enhances high-intensity interval training-induced improvement of endurance exercise capacity at high intensity. Furthermore, it was also shown that the combination of MCT4 deficiency and high-intensity interval training, coupled with the physiological context of such adaptation, increases enzyme activity of the glycolysis and the mitochondrial oxidative capacity of pyruvate. The findings of this study would help us understand the physiological significance of lactate accumulation in skeletal muscle with high-intensity exercise.

This is the full abstract presented at the American Physiology Summit 2023 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.
Hypertension Reduces Aortic Strain in Both Sexes, but only Aorta from Female Rats Showed Increase in Stress: The Role of Appropriate Normalization Method to Evaluate Strain-Stress Parameters
Authors: Shiota Timmers Montandon Ian , Fontes Milene , Gebere Mengistu , Costa Tiago , Townsend Paul , Moura Kawane , Azhar Mohamad , Uline Mark , Webb Clinton , McCarthy Cameron , Wenceslau Camilla
Published: May 2023

The gold standard of arterial stiffness measurements in isolated aorta is the stress-strain (SS) relationship. Wall thickness (WT) and artery inner diameter (ID) are variables that plot the SS curve and should be normalized to the dimensions of the individual subject. Previously, we used measurements from the current literature, but the data collected were not accurate. Therefore, we hypothesized that the measurements of the vascular structure using echocardiogram (ECHO) should be applied to evaluate tissue puller to obtain SS data. With that, we also hypothesized that aorta from spontaneously hypertensive rats (SHR) has greater stress and lower strain levels than normotensive Wistar rats. To test this hypothesis, thoracic aorta parameters from 3-month-old male Wistar (WM) (body weight: 449±6.87g, n=4), SHR male (SM) (body weight: 295±3.34g, n=4), Wistar Female (WF) (body weight: 250±8.50g, n=4), and SHR Female (SF 169.4±2.69g, n=4) rats were measured from an ECHO. After, animals were killed and aortas were cut in 2 mm segments and mounted on Tissue Puller to measure SS. The inner diameter (ID) and wall thickness (WT) were measured by the ECHO for all animals: [WM (WT: 0.519±0.014mm, ID: 2.042±0.11mm), SM (WT: 0.485±0.026mm, ID: 2.023±0.055mm), WF (WT: 0.504±0.01mm, ID: 1.628±0.092mm), SF (WT: 0.521±0.011mm, ID: 1.64±0.099mm)] and there were no significant difference between these values. We then normalized the SS curves to each of the arteries’ parameters for ECHO and we found there were significant decreases in the strain values in aorta from hypertensive rats, regardless of sex (WM: 1.775±0.108 vs SM: 1.370±0.058; p=0.0146), and (WF: 2.056±0.218 vs. SF: 1.713±0.224; p=0.0517). We found a trend in the stress from female rats (WF: 1367±61 mN/mm2 vs SF 2361±391 mN/mm2; p=0.0597). There were no differences between male rats (WM:1.269±153 mN/mm2 vs SM: 1319±80 mN/mm2; p=0.671).Overall, these data show that ECHO should be used to accurately measure rat aorta structural parameters under the tissue puller. They also show SHR and Wistar were different in both sexes in strain, but only female SHR vs Wistar showed differences in stress.

National Institutes of Health - R00GM118885, R01HL149762, and R00HL151889. and McNair Junior Fellows (MJF) Program

This is the full abstract presented at the American Physiology Summit 2023 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.
Targeting p21-highly-expressing Endothelial Senescent Cells Prevent Vascular Dysfunction Induced by High-Fat Diet
Authors: Kwon Oh Sung , Noh Sung Gi , Wang Lichao , Xu Ming
Published: May 2023

BACKGROUND: Cardiovascular diseases are the leading cause of death worldwide. Overweight and obesity are strongly associated with comorbidities such as hypertension and insulin resistance, which collectively contribute to the development of cardiovascular disease. Although high-fat diet shows increased vascular senescence and vascular dysfunction, it remains unclear how obesity could induce cellular senescence and whether vascular dysfunction is associated with senescence of cells in the vasculature. p21 is one of the major regulators and most recognized cellular markers for senescent cells. Recent evidence demonstrated that high fat diet induces the accumulation of p21 high cells in the endothelial cells. However, the relationship between p21 high cells and vascular function is not identified yet. Therefore, this study investigated the linkage between vasodilation and p21 high cells in aging or high-fat diet-induced vascular dysfunction. METHODS: Five p21-Cre/+; +/+ (P) and p21-Cre/+; DTA/+ (PD) obese mice fed by high fat diet were administrated with tamoxifen for twice. Five P lean mice fed by normal chow were adopted as normal control. We previously demonstrated that p21high cells accumulate in obese P mice, and can be eliminated in obese PD mice by tamoxifen treatment. Using pressure myography, vasodilation in femoral arteries was assessed in response to flow-induced shear stress, acetylcholine (ACh), and sodium nitroprusside (SNP). Free Radical Production were measured by Amplex Red Assays. One-way ANOVAs with Bonferroni post-hoc were used to determine differences between groups (P < 0.05). RESULTS: Endothelium-dependent vasodilation was significantly attenuated in the old, induced by both flow (Lean P: 62 ± 4, Obese P: 23 ± 3 %; p < 0.05) and ACh (Lean P: 77 ± 4, Obese P: 35 ± 4 %; p < 0.05). However, the clearance of p21 high cells using tamoxifen enhanced vasodilatory function response to both flow (Obese P: 23 ± 3 %, Obese PD: 58 ± 3 %; p < 0.05) and ACh (Obese P: 35 ± 4 %, Obese PD: 70 ± 3 %; p < 0.05) while endothelium-independent vasodilation was not altered by high fat diet. Also, high fat diet increased free radical production, but the clearance of p21 high cells using tamoxifen attenuated free radical production (Lean P: 10.16 ± 0.41 pmol·s-1·mg-1; Obese P: 26.83 ± 0.54 pmol·s-1·mg-1; Obese PD: 12.23 ± 0.54 pmol·s-1·mg-1; P<0.05). CONCLUSION: These results demonstrated that p21high cells may play a causal role in vascular dysfunction with obesity and other chronic disease. Therefore, targeting p21high cells may enhance vasodilatory function through decreasing oxidative stress.

This is the full abstract presented at the American Physiology Summit 2023 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.
Tumor arteriolar function in a novel orthotopic model of breast cancer
Authors: Kunkel Olivia , Horn Andrew , Behnke Brad
Published: May 2023

Introduction: For women in the United States, breast cancer is the most diagnosed non-skin cancer and second leading cause of cancer-related deaths. While the overall 5-year survival rate of all stages of breast cancer is 90%, several features of the tumor microenvironment contribute to an individual patient’s treatment success. The efficacy of radiation is dependent upon the presence of oxygen, and many solid tumors are hypoxic. In addition to its effect on treatment success, tumor hypoxia also leads to a more aggressive phenotype and increases metastatic potential. Therefore, improving tumor blood flow and thus, hypoxia, may improve the efficacy of radiation as well as reduce metastatic potential. The purpose of this study was to understand the vasomotor function of arterioles from orthotopic breast tumors to determine the potential mechanisms to improve tumor blood flow. Methods: Female Fischer 344 (retired breeder) rats were randomly assigned to non-tumor control (CON; n=4) and tumor bearing (TB; n=6) groups. TB rats were injected with 3x103 Mat B III cells into the mammary duct. Once tumors reached 10-15 mm in diameter, rats were euthanized and tumor feed arterioles were harvested. Blood vessels from CON rats were harvested from the mammary tissue. Vessels were cannulated on glass micro-pipettes, pressurized at 90 cmH2O, and allowed to equilibrate for one hour. Alpha (α)-adrenergic and myogenic contractile responses were assessed and vessel diameter recorded. Data were analyzed using a Two-Way Repeated Measures ANOVA and determined to be significant if p ≤ 0.05. Results: There were no differences between groups in α-adrenergic vasoconstriction or between active and passive pressure-diameter responses. There was no difference in maximal constriction to norepinephrine for CON vs. TB (53.07 ± 19.4% vs. 40.68 ± 13.9%) or maximal pressure-induced constriction (myogenic response) for CON vs. TB (11.2 ± 2.6% vs. 13.03 ± 5.0%). Conclusions: The vascular bed of rodent mammary tumors may be unique given that, unlike other solid tumor arterioles (i.e. prostate), breast tumor arterioles do not exhibit significant impairments in contractile response to norepinephrine or in myogenic vasoconstriction. Further investigation is needed to determine the vascular response to other stimuli (flow, bradykinin, etc.) and to quantify tumor hypoxia, but tumor blood flow may depend more heavily on vessel patency and vascular density than on the functional nature of the tumor vascular supply.

Johnson Cancer Research Center

This is the full abstract presented at the American Physiology Summit 2023 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.
Comparison of the EndoPAT device with a unique vascular assessment of reactive hyperemia
Authors: Ramraj Olivia , Badhwar Smriti , Edgell Heather
Published: May 2023

The EndoPAT device (Itamar Medical) is used to determine endothelial function by using peripheral arterial tonometry during reactive hyperemia. It has been shown to be related to the gold standard non-invasive technique of flow-mediated dilation ultrasound assessment. These methodologies have technical requirements and/or ongoing operational costs that could be prohibitive to under-resourced clinics or researchers. We hypothesized that using a re-usable and cost-effective procedure of determining the reactive hyperemic response using piezo-electric pulse transducers (ADInstruments) would give similar results to the EndoPAT. Reactive hyperemia was induced by occluding blood flow to the forearm for 5 minutes using a blood pressure cuff inflated to +50mmHg above systolic blood pressure. The vascular response to the release of the occlusion was assessed using EndoPAT on the index fingers and using piezo-electric transducers on the middle fingers, concurrently. Twenty-five healthy participants (15 female; 31±12years) participated in the study. Participants refrained from caffeine, alcohol, fatty foods, smoking and strenuous exercise for at least 12 hours prior to testing. The EndoPAT reactive hyperemia index (RHI) was determined using proprietary software. The area under the curve (AUC) of the finger pulse waves from the piezoelectric pulse transducers was also determined. The ratio of the AUC of the peak hyperemic response (10s average) compared to the baseline period (3.5min) in the occluded arm was compared to the equivalent ratio in the control arm to determine the pulse-wave reactive hyperemia index (PWRHI). Univariate linear regression and correlation analysis was conducted between RHI and PWRHI. When comparing the two methods, Spearman’s r was 0.67 (p=0.0002) with a coefficient of determination of 0.58. We have found that the two methods correlate well to each other and the PWRHI technique has the potential to make microvascular assessments more accessible to clinicians and researchers. Our PWRHI method still needs to be validated in larger populations with vascular dysfunction and over a wider age-range.

Funding provided by the Natural Sciences and Engineering Research Council of Canada.

This is the full abstract presented at the American Physiology Summit 2023 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.
Endothelial-Specific Expression of CIDEC Protects From Age-Induced Skeletal Muscle Capillary Rarefaction and Declined Muscle Performance
Authors: Balakrishnan Bijinu , Becker Chloe , Tenerowicz Kate , Puri Vishwajeet
Published: May 2023

We recently found that Cell death-inducing DNA fragmentation factor-a–like effector C (CIDEC), originally identified as lipid droplet-associated protein in adipocytes, is abundantly expressed in endothelial cells. We described its novel role in regulating vascular function in humans. To study the effect of endothelial-specific CIDEC in whole-body physiology and its molecular action in regulating vascular function, we generated a humanized mice model expressing endothelial-specific human CIDEC transgene (E-CIDECtg). E-CIDECtg mice showed protection against HFD-induced glucose intolerance and dyslipidemia. We also identified a molecular pathway of action whereby CIDEC directly regulates the VEGFA-VEGFR2 axis promoting eNOS signaling, angiogenesis, and vasodilation to improve metabolic health. Since aging and age-related declines in physical activity are associated with physical and metabolic impairment, and skeletal muscle capillarization is reduced in older adults, the objective of the present study was to evaluate the role of endothelial-specific CIDEC in the regulation of microvasculature remodeling in muscle, as well as muscle performance with aging. One-year to 14 months old E-CIDECtg mice (around 60 yrs human age) and their littermate controls were tested for muscle endurance and capillary density in the skeletal muscle. E-CIDECtg mice displayed enhanced muscle performance and higher capillary density in the skeletal muscle. Serum lipid parameters, LDL, triglycerides, fatty acids, and total cholesterol were lower, and the metabolic parameters including respiratory exchange ratio (muscle’s oxidative capacity), insulin tolerance and glucose tolerance were higher in aged E-CIDECtg mice. Overall, our study highlights endothelial-specific role of CIDEC in improving age-related decline in capillary density, muscle performance, and metabolic health.

R01HL140836 and funds from Osteopathic Heritage Foundation's Vision 2020 to Heritage College of Osteopathic Medicine at Ohio University

This is the full abstract presented at the American Physiology Summit 2023 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.
Impacts of high altitude on cognitive function and hearing during acclimatization and after return to sea level
Authors: Nasr Ledia , Frost Shyleen , Kannan Lakshmi , Pham Kathy , Bazzani Lorenzo , Jacuinde Diego , Seitz Aaron , Heinrich Erica
Published: May 2023

High-altitude exposure and associated acute hypoxemia have been shown to impact several cognitive function domains, including reaction times and sustained attention. However, questions remain regarding the mechanisms underlying these impairments. In this study, we aimed to determine if hyperventilation-induced hypocapnia played a role in these effects. Twenty healthy participants were recruited (n=13 men, 7 women) between the ages of 18 and 38 with no history of cardiovascular or pulmonary disease. Participants completed a 45-min cognitive function test battery once at sea-level (SL) in the laboratory (340 m elevation), 2-3 times at home prior to ascent, over three days at high-altitude (HA) (3800 m elevation), and 2-3 times at home after return to sea level (SL-R). During the lab and high-altitude sessions, participants were fitted with an oronasal facemask and were provided with room air (RA) or a mild hypercapnic gas mixture (sea-level equivalent of 4% inspired CO2) (HC) to stimulate increased cerebral blood flow. All participants received room air at sea-level. At high altitude, participants were divided evenly into RA or HC treatment groups in a participant-blinded randomized order. In a single-talker hearing task, hearing acuity was significantly reduced on the first 2 days at high altitude (p<0.001 for each) but returned to baseline levels by day 3 (SL: 28.7 ± 3.9 dB, HA1: 35.6 ± 3.4 dB, HA2: 36.5 ± 4.3 dB, HA3: 27.2 ± 5.2 dB). Hearing acuity also showed a trend for improvement in the RA group on the first day at high altitude compared to the HC group (RA: 34.3 ± 3.8 dB, HC: 37.1 ± 2.2 dB, p=0.070). Hearing acuity was also reduced following return to sea level (SL: 28.7 ± 3.9 dB, SL-R: 31.5 ± 5.7 dB, p=0.024). Total time spent on a trail making task showed a trend for an increase on the first day at high altitude (SL: 42.8 ± 6.6 sec, HA1: 46.5 ± 8.2 sec, p=0.062), but improved on the third day at high altitude (HA3: 33.3 ± 10.0 sec, p<0.001), with no impact of treatment on performance. Overall, this data supports previous work illustrating a mild impact of moderate high-altitude exposure (3800 m) on cognitive performance, which appear to improve with acclimatization. However, performance on these tasks was not improved with mild hypercapnia to increase cerebral blood flow. In addition, we provide new evidence of potential persistent impacts of high-altitude exposure on hearing after return to sea level.

Support for this research was provided by a Chancellor's Research Fellowship to ECH, and a White Mountain Mini Grant to KP.

This is the full abstract presented at the American Physiology Summit 2023 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.
Orexinergic signaling in the commissural nucleus of solitary tract participates in the hypercapnic ventilatory response during wakefulness in light phase of the diurnal cycle
Authors: Da Silva Eliandra , e Horta-Júnior José de Anchieta , Dias Mirela
Published: May 2023

Despite of the unquestionable role of different body systems to acid-base balance, chemosensitive neurons distributed in different brain regions coordinate respiratory patterns to appropriately restore the PCO2 and thus, contributes to correction of variations in pH. Orexinergic (OX) neurons in the lateral hypothalamus/perifornical area acts on central chemosensitivity modulation in a vigilant state dependent manner, synchronized with the diurnal cycle and send projections to respiratory network in the brainstem. Considering that the commissural nucleus of NTS (NTSc) receives orexinergic projections and has notable participation in ventilatory responses to the increase of CO2 levels, our hypothesis is that orexin-A, acting on the orexin receptor-1 in the NTSc, influence the hypercapnic ventilatory response of rats across the diurnal cycle. To test this hypothesis, we measured the pulmonary ventilation (E) of unanesthetized male Wistar rats (250–320 g) in a whole-body plethysmograph system together with body temperature, EEG and EMG recordings during microdialysis of orexin receptor-1 antagonist (SB-334867; N-(2-metil-6-benzoxazolil)-N′-1,5-nafitridina-4-yl-ureia – 5 mM) into the NTSc. Experiments were performed in normocapnic and hypercapnic hyperoxic conditions (7% CO2 – 93% de O2) in the light and dark phase of diurnal cycle of the animals. All procedures were approved by Animal Care and Use Committee for the Institute of Biosciences at Botucatu – Brazil (CEUA – protocol nº. 6766090620). The results showed that microdialysis of the antagonist into NTSc caused a significant attenuation in CO2 ventilatory responses, compared with vehicle (aCSF), during wakefulness (VE= 1743 ± 224 mL kg-1min-1 versus VE= 2002 ± 232; n = 06; p < 0.05) but not during sleep (VE= 1793 ± 433 mL kg-1min-1 versus VE= 1725 ± 0; n = 04; p > 0.05) in the light phase of the diurnal cycle. Thus, our data suggest that orexinergic signaling in the NTSc contribute to CO2 ventilatory response in awake rats in the light phase of the diurnal cycle.

Grant 2019/17693-5 São Paulo Research Foundation (FAPESP) and Higher Education Improvement Coordination (CAPES - 001)

This is the full abstract presented at the American Physiology Summit 2023 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.
Implications of alcohol and western diet on omental adipose metabolic phenotype in rhesus macaques
Authors: Poret Jonquil , Simon Liz , Molina Patricia
Published: May 2023

Adipose tissue maladaptation is central to metabolic dysregulation seen with calorie-dense, or Western, diets and at-risk alcohol use. We hypothesized that combining these conditions would produce greater adipose tissue maladaptation. The objective of this study was to determine the combined effects of a calorie-dense diet and chronic binge alcohol (CBA) on omental adipose tissue expression of genes that contribute to mitochondrial and metabolic alterations. Omental adipose samples used in the present study were obtained from a subset of animals included in an ongoing parent longitudinal study. Male rhesus macaques were fed ad libitum a high fat, high sucrose diet (HFSD; 41.7% fat and 27% sucrose) for 15.5 months. Starting at 3 months, animals received water (VEH) or CBA (13-14 g/kg/week) through a gastric catheter for the remainder of the study. Omental adipose biopsy samples were collected at the 3- and 7-month timepoints of HFSD feeding and 24 hours following the last alcohol dose. Samples included in this study were as follows: 3-months HFSD (n=5, HFSD), 7-months HFSD + VEH (n=5, VEH/HFSD), 7-months HFSD + CBA (n=5, CBA/HFSD), and bio-banked control-diet fed macaques (n=6, CTRL). Expression of genes associated with glucose and lipid metabolism, insulin sensitivity and mitochondrial health were determined using qRT-PCR. Gene expression of peroxisome proliferator-activated receptor γ, carbohydrate response element binding protein and adiponectin were decreased in HFSD compared to CTRL macaques. HFSD increased gene expression of interleukin 6 compared to CTRL macaques. Gene expression of peroxisome proliferator-activated receptor γ, hormone sensitive lipase and peroxisome proliferator-activated receptor γ coactivator 1-beta were decreased in macaques fed CBA/HFSD compared to VEH/HFSD macaques. Preliminary results indicate HFSD and CBA alter gene expression reflecting omental adipose metabolic and insulin dyshomeostasis and possibly decreased mitochondrial biogenesis and favors an inflammatory milieu. We predict these alterations in omental adipose tissue gene expression may translate into more severe metabolic dysregulation in HFSD fed CBA-treated animals.

Supported by NIH/NIAAA P60 AA009803 and 1F31AA028459-01

This is the full abstract presented at the American Physiology Summit 2023 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.
LIM kinase inhibition reduces endothelial cell cortical stiffness in diabetic arteries
Authors: Power Gavin , Gonzalez-Vallejo Juan , Ramirez-Perez Francisco , Lateef Olubodun , Manrique-Acevedo Camila , Martinez-Lemus Luis , Padilla Jaume
Published: May 2023

Type 2 diabetes is associated with endothelial stiffening, which precedes the development of increased arterial stiffness. The role of endothelial cell stiffening in the pathogenesis of vascular disease is increasingly recognized. Indeed, evidence exists that cellular pathways that result in polymerization of endothelial cell actin filaments (F-actin) and increased cellular stiffness impair the formation of nitric oxide, a potent vasodilator and anti-inflammatory molecule. We and others have shown that, in vascular smooth muscle cells, LIM kinase (LIMK) is a critical regulator of actin dynamics and cellular stiffness via the phosphorylation and consequent inactivation of the F-actin severing molecule, cofilin. However, whether LIMK regulates actin polymerization and stiffness in endothelial cells remains unknown. Here we report that pharmacological inhibition of LIMK with LIMKi3 in cultured human endothelial cells for 18 hours decreases cofilin phosphorylation and cortical stiffness, as assessed by atomic force microscopy. These endothelial softening effects are accompanied with a reduction in F-actin content. Reduced F-actin in endothelial cells is also recapitulated with S3, a cofilin mimetic. Furthermore, we show that the aortic endothelium of diabetic ( i.e., db/db) male mice is stiffer than that of wild-type counterparts, and that stiffer diabetic arteries also exhibit a tendency for increased p-cofilin. Notably, treatment of diabetic aortas with LIMKi3 for 18 hours also reduces endothelial cortical stiffness. Collectively, our findings demonstrate that LIMK inhibition reduces endothelial cortical stiffness in naïve cultured endothelial cells and in diabetic arteries ex vivo. These findings support the hypothesis that LIMK may serve as a potential target for reversing endothelial stiffening in type 2 diabetes.

Funding: R01HL151384, R01HL153264, and R01HL137769

This is the full abstract presented at the American Physiology Summit 2023 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.
Oral Carnosine Supplementation Restores Insulin Sensitivity but not Glucose Tolerance in Mice With Glutathione Peroxidase-4 Deficiency
Authors: Berdaweel Islam , Mahoney Jo , Alowaisi Amany , Berns Kaitlyn , Anderson Ethan
Published: May 2023

Obesity presents in about 90% of the diabetic patients, a risk factor that makes them more susceptible to cardiometabolic disorders, particularly insulin resistance and ultimately T2 diabetes. Increased oxidative stress and specifically lipid peroxidation are known to be major pathogenic factors driving these disorders in obesity. We recently reported that diabetic patients were found to have significantly lower level of glutathione peroxidase 4 (GPx4)- an antioxidant selenoenzyme which neutralizes lipid peroxides. Carnosine, a histidine-containing dipeptide which is highly concentrated in muscle and brain, has shown a remarkable therapeutic potential for preventing diabetes and its complications when administered orally in experimental and clinical studies of obesity. The extent to which carnosine can mitigate these disorders in the presence of GPx4 deficiency is not known however, and this is critical to determining its efficacy in diabetes patients. To address this question, wild-type (WT) and GPx4+/− male were randomly assigned to either standard chow (CNTL) or high fat high sucrose diet (HFHS) for 16 weeks. Seven weeks after starting the diet, half of the HFHS diet groups received 80 mM carnosine oral carnosine supplementation in their drinking water. Glucose and insulin tolerance tests performed 8 weeks after starting the diet revealed that carnosine significantly improved glucose tolerance in obese WT (P<0.05) but not obese GPx4+/− mice. Interestingly, carnosine treatment did significantly improve insulin sensitivity in the GPx4+/− mice, and to a lesser extent the WT mice. At the molecular level, we observed that HFHS diet up-regulated GPx4 protein in cardiac tissue from WT but not GPx4+/− mice, and protein oxidation was significantly reduced with carnosine treatment in both genotypes. Collectively, these findings indicate that carnosine supplementation could potentially mitigate insulin resistance even in patients with compromised antioxidant capacity (e.g., diabetes). Further analysis is in progress to evaluate the effectiveness of carnosine supplementation on additional cardiometabolic complications that are associated with diet induced obesity.

This is the full abstract presented at the American Physiology Summit 2023 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.
Epithelial heme oxygenase-1 promotes colitis associated tumorigenesis through regulation of tumor epithelial differentiation and survival
Authors: Callahan Rosemary , Onyiah Joseph , Bhagavatula Geetha , Schaefer Rachel , Staley Alyse , Murphy Emily , Zhou Liheng , Orlicky David , Atif Shaikh , Cartwright Ian , Hall Caroline , Colgan Sean
Published: May 2023

Damage from chronic inflammation in the setting of inflammatory bowel disease has been linked to increased rates of small and large bowel cancer. Colonic inflammation is often associated with hemorrhage resulting in release of heme from damaged erythrocytes. Heme oxygenase-1 (HO-1) protects against oxidative DNA damage from heme. We hypothesized that deletion of intestinal epithelial cell (IEC) HO-1 would increase colitis associated tumorigenesis. Inflammation associated hemorrhage correlated with mucosal Hmox1 expression in a murine model of colitis, but conditional deletion of IEC Hmox1 (Hmox1ΔIEC) did not influence inflammatory outcomes. However, in a colitis associated cancer model, we unexpectedly observed decreased number and size of colonic tumors in Hmox1ΔIEC mice compared to controls. Single cell RNA sequencing revealed a similar tumor leukocyte profile, but the tumor epithelial population displayed increased colonocyte differentiation in Hmox1ΔIEC mouse tumors relative to stem/secretory epithelial populations. Deficiency of HO-1 also lead to increased cell death and cell cycle arrest in murine colonoids and colon cancer cells, which was exacerbated by heme. Findings define a previously unreported role for epithelial HO-1 in supporting tumorigenesis in the colitic microenvironment.

US Department of Veterans Affairs

This is the full abstract presented at the American Physiology Summit 2023 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.
The Role of Mitochondrial ABCB8 in Exercise-Induced Protection Against DOX Cardiotoxicity
Authors: Doerr Vivian , Montalvo Ryan , Jacintho Moritz Cesar , Boeno Franccesco , Dowllah Imtiaz , Smuder Ashley
Published: May 2023

Doxorubicin (DOX) is a highly effective chemotherapeutic used in cancer treatment. However, its use is associated with the development of cardiac dysfunction, which can negatively affect patient outcomes and reduce overall survival. While no clinical countermeasure exists to combat DOX cardiotoxicity, endurance exercise preconditioning is sufficient to preserve cardiac function following acute DOX exposure. In this regard, it is established that DOX cardiotoxicity is associated with increased mitochondrial reactive oxygen species (ROS) production and iron accumulation and that endurance exercise training stimulates an increase in the expression of the mitochondria-localized ATP-binding cassette subfamily B member 8 (ABCB8) transporter. Overexpression of ABCB8 has been shown to prevent DOX cardiac dysfunction. Therefore, we tested the hypothesis that increased levels of ABCB8 are required for exercise-induced cardioprotection against DOX toxicity. Cause and effect were determined by preventing the exercise-induced increase in ABCB8 expression using an antisense oligonucleotide (AO) designed to specifically target ABCB8. Young adult female Sprague-Dawley rats remained sedentary (SED) or were treadmill exercise trained (EX) for 2 weeks (70% VO2MAX, 1hr/day, 10 days). Immediately following each exercise bout or at identical time points, rats received either AO (10mg/kg i.p.) or saline. Rats then received either a bolus dose of DOX (20mg/kg i.p.) or saline (SAL) treatment 24 hours after the last exercise bout. Dependent measures were evaluated 48 hours after DOX or saline administration. Body weight change following DOX/SAL treatment showed significant weight loss in all DOX-treated groups, with the greatest weight change occurring in the EX-AO-DOX rats. Additionally, EX-AO-DOX treatment prevented the rescue of heart weight/tibia length seen in the EX-DOX group. Exercise capacity was assessed via a graded exercise tolerance test and revealed a significant reduction in running time in both the SED-DOX and EX-AO-DOX groups compared to SED-SAL. Interestingly, mitochondrial ROS emission was not elevated in the EX-AO-DOX treatment group compared to SED-SAL. Collectively, these results reveal that exercise-induced ABCB8 expression contributes to the protective effect of exercise against DOX cardiotoxicity.

NIH R01 HL146443, NIH R01 HL144858, T32 HD043730

This is the full abstract presented at the American Physiology Summit 2023 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.