bluuebunny/crossref_metadata_2025 huggingface dataset:
APOE and sex impacts functional recovery after cervical spinal cord injury
Authors: Taylor Chase , Sunshine Michael , Devine Caroline , Patel Mohit , Johnson Lance , Alilain Warren
Published: May 2024

Genetic factors are key to understanding recovery following spinal cord injury (SCI). Prior work conducted in our laboratory demonstrated that APOE genotype impacts respiratory plasticity after cervical SCI. Specifically, female mice expressing the APOE4 allele had impairments in their ability to generate and maintain robust diaphragmatic activity following cervical SCI and intermittent hypoxia treatment relative to APOE3 counterparts. Subsequently we showed that different APOE alleles leads to altered neural respiratory control even without a spinal cord injury and that the effect is sex dependent. To extend these findings, we are now investigating the impact of APOE genotype and sex on locomotor and respiratory motor recovery in a humanized APOE knock-in mouse model homozygous for either the APOE3 and E4 alleles. Further, we examined how genotype and sex effected plasticity and serotonin levels below the lesion. We hypothesized that animals with the APOE4 allele will demonstrate impaired recovery following SCI across all measures. We performed a left C2 hemisection injury on male and female mice of both APOE3 and APOE4 genotype (n = 8/group). We recorded whole body plethysmography and CatWalk gait analysis weekly beginning at pre-injury through three weeks post injury. Consistent with our previous findings male APOE3 mice responded better than APOE4 counterparts during respiratory challenge even following SCI. Specifically APOE3 male mice showed greater improvements in respiratory rate during both normoxia and hypoxia challenge at early timepoints following injury. Interestingly during catwalk gait analysis APOE4 male mice recovered function faster than APOE3 counterparts in the weeks following SCI. This work is critical because it lays the foundation for understanding how diverse genotypes in the clinical SCI population may indicate the need to personalize treatment for individuals following injury.

AG065220 AG060056 Nielsen Foundation.

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.
Chronic circadian stress raises mean arterial pressure in male, but not female, Bmal1-knockout rats
Authors: Rhoads Megan , Latimer Mary , Monroe Brianna , Howard Kameron , Pollock David
Published: May 2024

Shiftwork and other forms of circadian disruption are associated with an increased risk of cardiovascular and kidney disease, however, the mechanisms driving these associations have yet to be elucidated. It has been suggested that dyssynchrony between the endogenous molecular clock and the external environment during shiftwork may be connected with the development of cardiorenal pathologies and the dysregulation of blood pressure (BP). Brain and muscle arntl-like protein 1, or Bmal1, is a core component of the molecular clock. Loss of Bmal1 in both male and female rats results in lower BP compared to wild-type (WT) littermate controls. We hypothesized that Bmal1 is necessary for the acclimation to circadian stress induced by chronic circadian stress (CCS). Telemeters were surgically implanted in the abdominal aorta of 12-14 week old rats. After a 2 week recovery, animals were placed in a light-controlled room on a 12:12hr light/dark cycle. After 1 week acclimation, lights were phase-advanced 6hrs every week for 4 weeks. Telemetry data was collected for 2 minutes every 10 minutes each hour at 1000 samples/second and analyzed using cosinor analysis. The MESOR of mean arterial pressure (MAP) was similar pre- and post- CCS in male WT rats (n=8, 107±1 vs. 109±1 mmHg; 2-way ANOVA, p>0.05) and in female WT rats (n=9, 110±1 vs. 112±2 mmHg; p>0.05). Male Bmal1-KO rats (n=9) had higher MAP MESOR after CCS (103±1 vs 108±1mmHg; p<0.05), but female Bmal1-KO rats (n=6) had no change in MAP MESOR after CCS (100±2. vs 100±2 mmHg, p>0.05). MAP amplitude was similar between WT and KO males before- (6.5±0.7 vs. 5.2±0.8 mmHg) and after-CCS (5.1±0.4 vs. 5.3±0.4 mmHg, p>0.05). WT and KO females had similar MAP amplitude before- (7.2±0.6 vs 5.5±0.9 mmHg) and after-CCS (5.7±1.1 vs. 5.6±0.6, p>0.05). In summary, loss of Bmal1 combined with circadian stress resulted in higher BP in a sex- dependent manner. Despite having lower blood pressures pre-CCS, male Bmal1-KO rats had higher MAP after CCS while female Bmal1-KO rats were protected from increased BP. This suggests that Bmal1, a crucial component of the molecular clock, has a sex-specific role in BP regulation and the response to stress.

This work is supported by NIH TL1DK139566-01.

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.
Chronic central leptin administration attenuates kidney dysfunction and injury in a model of ischemia/reperfusion-induced acute kidney injury
Authors: Luna-Suarez Emilio , da Silva Alexandre , Wang Zhen , Mouton Alan , Dai Xuemei , Larson Kylie , Ladnier Emily
Published: May 2024

Kidney disease occurs in approximately 15% of the adult population, accounting for 37 million people in the US alone. Lack of blood flow is a major driver of kidney injury and no therapeutic modalities have shown substantial effcacy in treating ischemia-induced acute kidney injury (AKI). We recently demonstrated that activation of the brain leptin-melanocortin system dramatically improves cardiomyocyte mitochondrial function, energy metabolism and contractility, preserving cardiac function and preventing progression of heart failure following myocardial infarction and ischemia/reperfusion injury. In the present study we examined whether chronic intracerebroventricular (ICV) leptin administration protects the kidney against ischemia/reperfusion (I/R)-induced AKI. Twelve-week old male rats were implanted with an ICV cannula into the right lateral ventricle and 8-10 days after surgery, leptin (0.021 mg/hr, n=8) or saline vehicle (0.5 ml/h, n=8) was infused via osmotic minipump connected to the ICV cannula for 12 days. On day 8 of leptin or vehicle infusion, rats were submitted to unilateral ischemia/reperfusion (UIR) by clamping the left pedicle for 30 min. To control for leptin-induced reductions in food intake, the vehicle group was pair-fed (UIR-PF) to match the same amount of food consumed by leptin-treated (UIR-Leptin) rats. On the 12th day of leptin or vehicle infusion (i.e. 4th day after AKI), single-left kidney glomerular filtration rate (GFR) was measured, blood samples were collected to quantify white blood cells, and kidneys were collected for histological assessment of injury. Chronic leptin infusion reduced body weight by 20±1% compared to only 10±1% reduction in UIR-PF. UIR-Leptin rats also showed reduced right and left kidney weights (right: 1040±24 vs. 1281±36 and left: 1127±71 vs. 1707±45 mg, for UIR-Leptin and UIR-PF, respectively). Leptin infusion improved GFR (0.50±0.06 vs. 0.13±0.03 ml/min/g KW) and reduced kidney injury scores. Leptin treatment also increased circulating white blood cells count compared to UIR-PF rats (16.3±1.3 vs. 9.8±0.6 k/mL). Thus, leptin, via its actions on the central nervous system, confers significant protection against major kidney dysfunction and damage in a model of ischemia/reperfusion-induced AKI.

NIH grants: (1R0DK1121411 (do Carmo), 1R0HL1630376 (da Silva/do Carmo), P20GM104357 (Hall), P30GM149404 (Hall) and U54GM115428 (Hall)).

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.
The Epithelial Na+ Channel Is a Zn2+ Sensitive Renal Na+ Reabsorption Pathway that Mediates Zn2+ Deficiency-induced Hypertension
Authors: McMichael Kelia , Yesomi Wenegieme Tara , Waite Aston , Williams Clintoria , McMichael Kelia
Published: May 2024

Background: Zinc (Zn2+) deficiency (ZnD) is comorbid with many chronic diseases including kidney disease and diabetes. Individuals in these vulnerable populations have a higher prevalence of hypertension. Recently, we reported that ZnD induces hypertension by promoting renal Na+ reabsorption. However, the renal Na+ reabsorption mechanisms involved continue to be identified. The renal epithelial Na+ channel (ENaC) plays an essential role in regulating whole-body Na+ and water balance and is involved in hypertension. We hypothesize that ENaC is a Zn2+-sensitive channel that mediates ZnD-induced hypertension. Experimental Design: To establish the role of ENaC in ZnD-induced hypertension, WT C57Bl/6 mice were switched from a Zn2+ adequate to a Zn2+ deficient diet for 10 weeks. During weeks 9 and 10, mice were treated with benzamil, an ENaC inhibitor. Systolic blood pressure (BP) was monitored by tail-cuff plethysmography; Renal ENaC expression was examined by immunohistochemistry and Western blot. To authenticate the Zn2+ sensitivity of ENaC, mouse distal convoluted tubule cells (mDCT) were treated with a Zn2+ chelator (TPEN) or vehicle (ethanol) for 24 hours. A subset of TPEN-treated cellular monolayers were supplemented with Zn2+ for 24 hours to replete intracellular Zn2+. Cellular ENaC expression was examined by Western blot analysis. Results: 1) Blood pressure: Compared to Zn2+ adequate mice (101.4 mm Hg ± 4.225), Zn2+ deficient mice had increased BP (154.6 mm Hg ± 2.422). However, benzamil treatment lowered BP (115.0 mm Hg ± 4.626) of Zn2+ deficient mice. 2)Immunohistochemistry: Next, Zn2+ effects on ENaC expression were examined. In Zn2+ deficient mice, αENaC protein abundance significantly increased compared with Zn2+ adequate mice. 3) Western blot analysis: To directly investigate Zn2+effects on ENaC expression, in vitro studies were performed using mDCT cells. Western blot analysis showed that TPEN-induced ZnD stimulated both αENaC and βENaC protein expression. Conclusion: Collectively, our findings reveal that (1) ENaC is a Zn2+ sensitive renal Na+ reabsorption pathway and (2) ENaC mediates ZnD-induced hypertension. Significance: Understanding the renal mechanisms by which Zn2+ regulates blood pressure may have an important therapeutic impact on hypertension.

Funding: R21 DK119879, R01 DK-133698 (National Institute of Diabetes and Digestive and Kidney Diseases); R25DK078381 (NIH NIDDK STEP-UP program);1742339 (National Science Foundation ASK Program).

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.
Blood Pressure and Central Arterial Stiffness before and after a 161-km Ultra-Endurance Race
Authors: Vondrasek Joseph D. , Jeong Soolim , El-Kurd Omar B. , Linder Braxton A. , Stute Nina L. , Dormeier Christin , Bissen Thomas G.
Published: May 2024

BACKGROUND: Competing in ultra-endurance running events (>42.2 km) is a tremendous physiological stressor. Training for and competing in these events may be detrimental to cardiovascular (CV) health. However, previous findings on acute changes in key CV health measures like blood pressure (BP) and central arterial stiffness after a race remain equivocal. Therefore, we aimed to characterize the acute CV response to an ultra-endurance race. We hypothesized that BP would decrease while central arterial stiffness would increase following the race. Methods: We measured supine BP with an automated brachial cuff and carotid-to-femoral pulse wave velocity (cfPWV - index of central arterial stiffness) with applanation tonometry (SphygmoCor XCEL, AtCor Medical) among 41 finishers (9F/32M; Age: 44 ± 10 years; BMI: 22.7 ± 1.8 kg/m2) of the 2023 161-km Western States Endurance Run (WSER). Measures were taken 1–3 days before (pre) and ≤1 hour after race completion (post). We present data as mean ± SD after confirming normality using Shapiro-Wilk tests (α ≥ 0.05). We assessed differences between pre- and post- systolic BP (SBP), mean BP (MBP), diastolic BP (DBP), cfPWV, and cfPWV normalized to MBP using paired, two-tailed t-tests (α < 0.05). The magnitude of the difference between time points was represented as Cohen’s d ( d) effect sizes. Results: After the race, there was a significant decrease in SBP (129 ± 9 vs. 122 ± 10 mmHg, P < 0.001, d = 0.78), MBP (94 ± 7 vs. 89 ± 10 mmHg, P < 0.001, d = 0.58), and DBP (77 ± 7 vs. 74 ± 8, P = 0.02, d = 0.38) but no change in cfPWV (6.4 ± 1.0 vs. 6.2 ± 0.8 m/s, P = 0.10, d = 0.26) or cfPWV normalized to MBP (0.07 ± 0.01 vs. 0.07 ± 0.01 (m/s)/mmHg, P = 0.83, d = 0.00). CONCLUSION: We found that systolic, mean, and diastolic pressure were all lower after the 161-km WSER, but cfPWV did not change. These findings suggest that running a 161-km ultra-marathon race acutely lowers BP but does not affect central arterial stiffness. Further research is needed to understand the effect of chronic ultra-endurance training and competition on cardiovascular health.

FUNDING INFORMATION: Western States Endurance Run Medical Research Program (GJG), National Institutes of Health K01HL160772 (JCW), American Heart Association 23CDA1037938 (JCW).

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.
Whey Protein Isolate Supplementation Effects on Cortisol Awakening Response, Profile of Mood States, and Heart Rate Variability
Authors: Oldham Michael , Ben-Ezra Vic , Biggerstaff Kyle , Mills Nate , Brisebois Matthew , Castleberry Todd , Deemer Sarah
Published: May 2024

INTRODUCTION: Decreases in heart rate variability (HRV), disruptions in cortisol awakening response (CAR), and changes in Profile of Mood States (POMS), have been associated with fatigue and strenuous physical exercise. Whey protein isolate can affect stress responses. PURPOSE: To determine the effects of whey protein isolate supplementation on CAR, POMS, and HRV after strenuous exercise. Methods: Eleven recreationally active women (19 ± 2 yrs) completed a double blinded, crossover trial. Placebo was maltodextrin (PL), intervention was 25 g of maltodextrin and 25 g of whey protein isolate (WH). Exercise was 30 min at 70-75% VO2peak (21.7 ± 0.1 ml/kg/min), 5 min rest, and 30 s Wingate anaerobic test (WAnT). HRV and POMS were recorded. Repeated measures ANOVA were used to determine differences (p < 0.05) in salivary cortisol AUCg, POMS, HRV, and WAnT fatigue index (FI). Pearson correlation and multiple regression determined associations between CAR, POMS, and HRV to FI. Results: Cortisol AUC were significantly different (p = 0.033) between PL (33.4 ± 2.0 μg*hr/dL) and WH (30.9 ± 0.8 μg*hr/dL), with no significant differences in POMS, HRV, or FI (p > 0.05). Significant Pearson correlation on Day 3 during the PL, between POMS and FI (r = -.582, p = 0.030). Neither CAR, POMS, nor HRV was able to predict FI (all p > 0.05). CONCLUSIONS: Whey protein isolate may decrease CAR, but may have no effect on POMS, HRV, or FI, and no effect on short-duration sprint cycling performance, and or reduction in central fatigue may be minimal.

No supporting funding.

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.
Impact of Respiratory Muscle Training on Exercise Tolerance in Hypobaric Hypoxia
Authors: Ferguson Scott , Miller Michael , Yeager Luke , Wislowski Annie , Subudhi Andrew , Roach Robert
Published: May 2024

Hypoxia and certain chronic diseases can intensify the work of breathing, potentially impacting the muscle hyperemic response during exercise and overall exercise performance. Respiratory muscle training (RMT) has been observed to decrease perceived effort under hypoxic conditions; however, it remains unclear if RMT boosts exercise performance in acute hypoxia. We investigated whether 4 weeks of RMT could enhance maximal and submaximal exercise performance in hypoxia (PB=425 mmHg, ~4876 m). Seven adult males underwent a 250 kJ submaximal (RPE 15-17) cycling trial in hypoxia, followed by an incremental test to maximal exertion. After 4 weeks of RMT under normoxic conditions, these tests were repeated in hypoxia. Although six of the participants displayed improvements in submaximal exercise performance, these numerical differences failed to reach statistical significance. However, RMT did raise VO2max peak power (Pre-RMT: 242.62 ± 35, Post-RMT: 251.85 ± 38 W, p=0.04). Moreover, even with an increased HR during the submaximal exercise trial after RMT (Pre-RMT:154.14 ± 16, Post-RMT: 160.86 ± 12, p<0.05), the RPE showed no significant difference during the test (Pre-RMT: 17.43 ± 0.79, Post-RMT: 17.43 ± 0.53, P>0.05). Despite this, no substantial increase in hypoxic submaximal exercise performance was observed, likely due to the small sample size. These findings suggest RMT might increase hypoxic exercise tolerance by reducing perceived exertion for a given HR.

This work was supported by funding from the United States Special Operations Command (USSOCOM) and the National Institutes of Health (2L30HL134123-03).

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.
Changes in preBötzinger Complex neuron discharge associated with changes in PCO2 in decerebrate rabbits
Authors: Feng Yin , Dillard Matthew L , Callison Jennifer J , Stuth Eckehard AE , Zuperku Edward J , Stucke Astrid G
Published: May 2024

Background: Maskrey and Nicol reported a strong increase in minute ventilation with increase in PCO2 (J Physiol 1980, 301: 49-58). We investigated a) whether there was a ceiling to this effect at high CO2 levels and b) whether the change in ventilation was associated with specific changes in respiratory neurons in the preBötzinger complex (preBC). Methods: The study was approved by the local Animal Care Committee and conformed to NIH standards. Adult New Zealand White rabbits (3-4 kg) were anesthetized, tracheotomized, ventilated, decerebrated and vagotomized. Phrenic nerve activity was recorded from the C5 rootlet, time averaged and used to calculate inspiratory (TI) and expiratory durations (TE) and peak phrenic activity (PPA). PPA was normalized to the value at PCO2 50mmHg. Individual neurons were recorded in the functionally identified preBC using multichannel electrodes at increasing CO2 levels. Statistical analysis used the Wilcoxon signed-rank test to determine changes in respiratory parameters between CO2 levels and Friedman RM-ANOVA to determine changes in neuronal discharge frequency (Fn). A generalized linear mixed model was used to determine associations between CO2-dependent changes in TI, TE, PPA, and changes in Fn for different neuron types. p<0.05 indicated a significant difference. Results: In 34 animals, the increase in minute ventilation with increasing PCO2 was due mostly to the change in PPA. The increase in respiratory rate was due mostly to a decrease in TE. There was little increase in respiratory output at PCO2 > 50 mmHg. In 209 neurons, increasing PCO2 increased Fn in inspiratory augmenting (I aug, n= 70, p<0.0001 for CO2 30 vs 40 and 40 vs 50mmHg), I parabolic (I para, n=43, p<0.0001 for CO2 40 vs 50 mmHg), pre-inspiratory (pre-I, n=35, p<0.01 for CO2 30 vs 40 mmHg), and expiratory decrementing (E dec, n=44, p<0.01 for CO2 40 vs 50 mmHg) neurons, but not in I dec (n=8) and non-respiratory modulated (NRM, n=9) neurons. The strongest correlation was found between the changes in phase timing and PPA and Fn in I aug and pre-I neurons. Conclusion: We found a ceiling effect to the increase in respiratory output at PCO2 levels > 50 mmHg. Inspiratory preBC neuron subtypes were more affected by the changes in PCO2.

NIH R01HL159546.

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.
High altitude sojourn elicits divergent effects in aortic and carotid stiffness in healthy-young adults
Authors: Romanowski Spencer , Burkhart Abigail , Steffen Carolyn , Smith Denise , Brutsaert Tom , Day Trevor , Lefferts Wesley
Published: May 2024

High altitude exposure challenges the cardiovascular system to compensate for barometric pressure-mediated reductions in arterial oxygen content. Reductions in oxygen content elicit simultaneous increases in sympathetic nervous system activity and vasodilation that may have competing effects on changes in large artery stiffness. The objective of this study was to examine changes in aortic and carotid stiffness during high altitude sojourn in healthy, young adults. We hypothesized that short-term high-altitude sojourn would increase both aortic and carotid stiffness. 17 Generally healthy adults (23±4 yrs, 25.0±3.0 BMI, n=9 females) underwent vascular assessments in the supine position at 1400 m and after an 8-day incremental ascent to 4300 m. Aortic stiffness and carotid β-stiffness were derived from carotid-femoral pulse wave velocity (cfPWV) via applanation tonometry and right common carotid artery ultrasonography, with blood pressure assessed via oscillometry. Ascent from 1400 m to 4300 m resulted in decreased arterial oxygen saturation (-11±4 %, p<0.001) and carotid β-stiffness (-4.48±2.73 au, p<0.001), and increased cfPWV, (+54.98±78.10 cm/s, p=0.01) and mean arterial pressure (+4±7 mmHg, p=0.02). Changes in cfPWV, arterial oxygen saturation, and blood pressure were moderately to strongly correlated (r=-0.425-0.503, p=0.09-0.04). Our data suggest that short term exposure to high altitude has differential effects on carotid versus aortic stiffness despite increases in mean blood pressure. Increases in aortic stiffness appear related to hypoxia-induced reductions in arterial oxygen saturation and concomitant increases in blood pressure, while reductions in carotid stiffness may stem, in-part, from compensatory carotid artery dilation necessary to increase cerebral blood flow at high altitude. Additional research is necessary to further understand mechanisms underlying differential changes in large artery stiffness during high altitude sojourn.

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.
Associations between Illicit Drug Use, Academic Performance and Self Esteem Among College Students
Authors: Patrissy Cara , Kvirikashvili Rusudan , Sajnani Suraj , Raymond Antonietta , Bonventre Samantha , Begdache Lina
Published: May 2024

Many college students place a high value on their grade-point average (GPA) as a representative of their academic performance. Due to this pressure to achieve, students often feel overwhelmed to the point where it starts affecting their mental wellbeing. Several students resort to study aids to enhance their GPA, while others rely on illicit drug use to cope with the stress. Reports have associated GPAs with a sense of self-worth, suggesting that students with low GPAs presumably have lower self-esteem. In addition, self-worth is closely associated with mental health and drug use. However, it is unknown how these factors interact. Thus, the purpose of the study is to assess the association between drug use, mental distress and GPA in relation to self-esteem. This study included 702 undergraduate college students from different universities across the United States. The anonymous survey, which was distributed online via Google Forms, assessed self-reported drug usage, and different aspects of mental distress were assessed by the Kessler Psychological Distress Scales (K10+) and the Perceived Stress Scale (PSS). The data were analyzed in SPSS, Version 28.0, using a Pearson’s correlation coeffcient. The results suggest that GPA is correlated with traits of self-esteem (p<0.01), such as self-rated mental wellbeing, feelings of worthlessness, and hopelessness. Additionally, GPA is correlated with the belief that they are able to effectively cope with troubles in their lives (p<0.01), and is negatively correlated with loss of control (p<0.05). Feelings of distress and lack of control may cause students to turn to negative coping strategies such as abusing substances such as alcohol (p<0.01), marijuana (p<0.01), cocaine (p<0.01), and illicit ADHD medication use (p<0.05), all of which were found to be negatively correlated with GPA. Our results propose a possible cyclic relationship between illicit drug use as coping mechanisms, GPA, and not only low self-worth but different aspects of mental distress.

This research received no specific grant from any funding agency, commercial or not-for-profit sectors.

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.
Role of ASIC3 in Evoking the Exercise Pressor Reflex in Type 1 Diabetes Mellitus Rats
Authors: Mossayebi Ali , Samora Milena , Harrison Michelle , Stone Audrey
Published: May 2024

Previous studies have suggested that the exercise pressor reflex is exaggerated in individuals with type 1 diabetes mellitus (T1DM); however, the mechanisms responsible for this altered reflex are poorly understood. Acid-sensing ion channel 3 (ASIC3) likely contributes to this exaggeration as previous studies found that peripheral blockade, as well as functional knockout (KO) of the ASIC3 gene, prevented the exaggeration of exercise pressor reflex in rats with cardiovascular-related diseases. However, whether ASIC3 plays a similar role in the exaggerated exercise pressor reflex in T1DM is currently unknown. Therefore, the purpose of this study was to determine whether ASIC3 contributes to the exaggerated exercise pressor reflex in T1DM rats. We hypothesized that the exaggerated exercise pressor reflex would be attenuated in ASIC3 KO T1DM rats compared to their wild-type (WT) counterparts. To test this, we used adult, male and female Wistar-Kyoto ASIC3 KO (n=3; body weight: 348 ± 84 g) and WT counterparts (n=5; body weight: 318 ± 112 g) rats. Streptozotocin (50 mg/kg) was injected intraperitoneally in fasted anesthetized rats to induce T1DM, and a random blood glucose over 300 mg/dl was used to diagnose diabetes. One week later, the exercise pressor reflex was evoked in unanesthetized, decerebrated rats by statically contracting the hindlimb muscles for 30 s. Peak mean arterial pressure (MAP) and heart rate (HR) were calculated as the highest change (Δ) during 30 s contraction baseline. We found that the peak pressor and cardioaccelerator responses to static contraction, although is not statistically significant, appear to be lower in ASIC3 KO (ΔMAP: 17 ± 14 mmHg; ΔHR: 13 ± 12 bpm), compared to WT rats (ΔMAP: 23 ± 11 mmHg; P=0.26 ΔHR:23 ± 9 bpm; P=0.11). Furthermore, we found that within female rats, the peak pressor and heart rate responses were lower in ASIC3 KO (n=1) rat (ΔMAP: 7 mmHg; ΔHR: 15 bpm) compared to WT rats (n=3) (ΔMAP: 27 ± 12 mmHg; ΔHR: 27 ± 11 bpm). Our preliminary findings suggest that ASIC3 may play a role in the exaggerated exercise pressor reflex in T1DM rats and that sex differences may also be present. Further studies involving larger sample sizes will reveal if trends from the current results become significant.

This project was supported by NIH R01HL 166323-01A1.

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.
The progestinic drug, etonogestrel, rescues breathing in a rodent model of central chemoreflex impairment
Authors: Janes Tara , Cardani Silvia , Pagliardini Silvia
Published: May 2024

The central CO2-chemoreflex is crucial in regulating breathing, providing stimulation at rest and during challenges to homeostasis. The retrotrapezoid nucleus (RTN), located in the ventral brainstem, is essential to this process. Impaired RTN function is linked to hypoventilation syndromes, including congenital central hypoventilation syndrome (CCHS) characterized by apnea and blunted responsiveness to inhaled CO2. Intriguingly, progestins stimulate breathing and CO2-chemoreflexes, and the high-affnity ligand etonogestrel (ETO) has been proposed as a treatment option in CCHS. Our objectives were to address two important gaps-in-knowledge: 1) assess ETO’s ability to “rescue” breathing in a rat model of central CO2-chemoreflex impairment, and 2) determine ETO’s site of action. We generated a model of CO2-chemoreflex impairment in adult female Sprague-Dawley rats using targeted injections of substance-P conjugated saporin toxin. Resulting RTN lesions were classified by the number of surviving chemosensitive neurons vs. non-surgical controls. We first administered systemic ETO (acute/vehicle:1h; or chronic/sham: 28 days) and measured resting ventilation and chemoreflexes (hypercapnia, 7.2% CO2; hypoxia, 10% O2) using whole-body plethysmography. In separate ongoing experiments, ETO was infused directly into target brain regions expressing progesterone receptors. We observed a positive relationship between lesion size and CO2-chemoreflex impairment (hypoxic response was intact). Twenty-one days of systemic ETO reversed CO2-impairment selectively in rats with moderate RTN lesions; large-lesion rats were refractory to ETO’s effects. These data suggest that ETO may enhance the CO2-chemoreflex by inducing neuroplasticity in brain structures with connectivity to surviving RTN chemosensitive neurons. Experiments are ongoing to parse out the site of ETO’s restorative action in the brain.

T.A.J.:Canadian Lung Association BaO Fellowship, Canadian Institutes of Health Research (CIHR) Postdoctoral Fellowships. S.C.: Canadian Lung Association BaO Fellowship. S.P.: Women and Children’s Health Research Institute Innovation Grant, CIHR Project scheme grant. Nexplanon was kindly donated by Merck through the Investigator-Initiated Study Program (IISP # 55869; SP).

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.
Sex Differences in Hemodynamic and Autonomic Reactivity during Cold Pressor Test in Chronic Kidney Disease
Authors: Zanuzzi Matias , Sabino-Carvalho Jeann , Mekonnen Elsa , Newton Kammeron , Jeong Jinhee , DaCosta Dana , Park Jeanie
Published: May 2024

Introduction: Chronic kidney disease (CKD) is characterized by sympathetic nervous system (SNS) overactivity that contributes to increased cardiovascular risk. Hemodynamic reactivity during the cold pressor test (CPT) has been widely used to evaluate sympathetic neural control in patient populations, and increased neurocardiovascular reactivity to CPT has been shown to predict greater risk of future cardiovascular events. Prior studies have suggested that males with CKD have higher long-term cardiovascular disease risk compared to females with CKD; however, whether sex differences in neurocardiovascular responsivity during CPT exists within CKD remains unknown. Objectives: Our primary objective was to evaluate potential sex differences in hemodynamic and autonomic reactivity during CPT in patients with CKD. Hypothesis: Males with CKD have an augmented pressor and sympathetic response to sympathoexcitation induced by CPT compared with females with CKD. Methods: Patients with CKD (Stage III and IV) with stable renal function were included. Continuous beat to beat blood pressure (BP), heart rate (HR) and muscle sympathetic nerve activity (MSNA) by microneurography were measured at rest for 10 minutes and during CPT that consisted of immersion of the hand to the wrist in ice water (4–5 °C) for one minute, followed by a 5-min recovery period. Results: 25 participants with CKD were included (N= 14 male, N=11 female). There were no differences in baseline characteristics, resting hemodynamics or MSNA between male and female groups. Males with CKD had a steeper rate of increase and higher peak levels of diastolic BP (DBP, 101±3 vs 87±3; p=0.008) and mean arterial BP (MAP, 130±4 vs 112±5 mm Hg, p=0.023) during CPT compared to females with CKD, respectively. Conversely, females with CKD had a steeper rate of increase in HR during CPT compared to males. MSNA increased in both males and females during CPT; however, there was no difference in MSNA reactivity during CPT between groups. Conclusions: Males with CKD had greater BP reactivity during CPT compared to females with CKD, while females with CKD had greater HR reactivity during CPT compared to males. There was no difference in sympathetic reactivity between groups. Augmented BP reactivity during CPT in males with CKD may contribute to sex differences in cardiovascular disease risk in patients with CKD.

Supported by NIH Grants R33AT010457 and R01HL135183.

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.
Remodeled Extracellular Matrix Guides Endothelial Cell Phenotype and Transcriptome to Fibrotic Niche
Authors: Datta Sayanti , Akhter Md Zahid , Balaji Ragunathrao Vijay Avin , Banerjee Somenath , Mehta Dolly
Published: May 2024

Impairment of endothelial barrier integrity causes vascular injury leading to acute lung injury (ALI), which, if not resolved, can compromise a patient’s lung functions and mortality. While it is known that both endothelial cells (EC) and their underlying extracellular matrix (ECM) are required for preserving lung homeostasis and functions, much of the efforts to understand mechanisms regulating these functions have focused mainly on EC. A fundamental unresolved question is whether lung-remodeled ECM formed due to leaky endothelium impacts EC functions, and if so, how? Herein, using lung ECM derived from a mouse lacking focal adhesion kinase (FAK), specifically in the endothelium (remodeled ECM), we assessed ECM components and their role in regulating EC functions and their relevance in vivo. Previously, we have shown that conditional deletion of FAK in endothelium increases EC permeability and induces vascular injury at homeostasis. Mass spectrometric analysis showed 805 proteins in control ECM (FAKfl/fl mice lung derived ECM) consisting of glycoproteins, matrisome-associated proteins, and secreted factors. However, the remodeled ECM had 722 proteins and was highly enriched with fibrillin 1, fibrinogen, and collagen I. Moreover, the remodeled ECM was two-fold stiffer than the control ECM. Remodeled ECM with its inherent composition recapitulates the 3D microenvironment, encouraging EC morphological alteration, increased cell stiffness, and enhanced focal adhesion (FA) formation compared to control ECM. In addition, RNA sequencing identified increased expression of genes linked with fibrosis, including integrin b8, TGFb2, GDF15, SMAD7, COL1A1, IL33, ID3, BMPR1A, and ADAMTS4 in EC seeded on remodeled ECM. Interestingly, fibrotic signaling observed in EC plated on remodeled ECM mimicked in vivo in EC-FAK−/− mice as they showed increased hydroxyproline content and collagen deposition in the lungs, indicating loss of EC-FAK as the crucial initiator of fibrotic signaling. In summary, studies for the first time show disrupted EC signaling as the instructor of fibrotic niche in the lungs for targeting pulmonary fibrosis.

NIH.

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.
Mechanisms of norepinephrine induced calcium responses in perivascular adipocytes
Authors: Jamka Julia , Gulbransen Brain
Published: May 2024

Perivascular adipose tissue (PVAT) has emerged as a key regulator of vascular tone and blood pressure making it an intriguing avenue for research related to pervasive aliments such as high blood pressure. PVAT surrounds the majority of blood vessels where it releases anticontractile factors such as nitric oxide, hydrogen sulfide, adiponectin, and leptin. The production of these anticontractile factors is driven by the sympathetic neurotransmitter norepinephrine (NE), but there is little known about mechanisms which mediate the NE response in PVAT. Based on the known role of beta adrenergic receptors in other fat depots, we hypothesized that NE primarily acts on beta II and III adrenergic receptors. Adiponectin cre positive transgenic mice genetically encoded with calcium indicators were used for live calcium imaging. The peaks of the NE response before and after the receptor antagonists were applied by comparing the change in fluorescence. The beta receptor antagonist, SR 59230A, was used at 6.5μM to block both beta II and III receptors. In addition, the A1a antagonist RS 100329 at 1μM was used to block alpha receptors present. Both antagonists were chosen because they have previously used in the literature successfully at these concentrations. The beta II and beta III antagonist significantly decreased the calcium response in the mesenteric PVAT (p=<0.0001) by 33% and a 27% significant decrease in the subcutaneous fat pad (p=). The alpha 1a antagonist significantly decreased the calcium response in the mesenteric PVAT (p=<0.0001) by 59%, as well as an 86% significant decrease in the subcutaneous fat pad (p=<0.0001), and a 60% significant decrease in the aortic PVAT (p=<0.0001). The combination of both antagonists significantly decreased the calcium response in the mesenteric PVAT (p=<0.0001) by 33%, as well as 46% in the subcutaneous fat pad (p=<0.0001), and 37% decrease in the aortic PVAT (p=0.0354). Both beta and alpha adrenergic receptors are present in mesenteric PVAT and subcutaneous fat, while primarily alpha adrenergic receptors are present in aortic PVAT. These observations suggest the mechanisms responsible for NE induced calcium responses are tissue dependent.

HL152951.

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.
Reduced Fascicle Area Demonstrated in Ilioinguinal Nerves Resected from Primary Inguinal Herniorrhaphy Patients as Evidence of Compression Neuropathy
Authors: Wright Robert , Born Donald E. , Sanders Troy , Landes Jordan , Salisbury Troy , Kumar Anjali S. , Horne Makena
Published: May 2024

Background and Aim. Previous studies have reported 63% of primary inguinal hernia patients present with apparent enlargement of the ilioinguinal nerve beyond the inguinal ring. This may be due to hernia-related pressure on the canal portion of the ilioinguinal nerve, a form of compression neuropathy. The ilioinguinal nerve of 30 patients was resected near the external inguinal ring during herniorrhaphy and histologically characterized to investigate the underlying cause of the size discrepancy. Methods. 30 male patients with primary inguinal hernias undergoing primary inguinal herniorrhaphy were prospectively recruited for ilioinguinal nerve resection and evaluation. Three samples of the resected ilioinguinal nerve (proximal, canal, and distal) were evaluated using Masson’s trichrome stain to measure fascicle and total nerve cross-sectional area and detect changes in collagen. Results. The fascicle cross-sectional area in the canal segment was significantly decreased compared to the proximal control with a large effect size observed (p=0.016,η2 =0.16). There was no significant difference in the nerve cross-sectional area between locations, but there was a moderate to large effect size observed between locations (p=0.165,η2 =0.105). There was no significant difference in collagen content nor effect size observed between locations (p=0.99,η2 =1.503×10−4). Interpretation. The decrease in the fascicle cross-sectional area within the inguinal canal further suggests that there is chronic pressure applied by hernia tissue consistent with axon degeneration. Collagen content is uniformly distributed along the length of the nerve. Further studies with larger samples are needed to confirm the observed effect of nerve location on the total nerve cross-sectional area and axon loss.
Evaluating Debio 1347 in Patients with FGFR Fusion-Positive Advanced Solid Tumors from the FUZE Multicenter, Open-Label, Phase II Basket Trial
Authors: Grivas Petros , Garralda Elena , Meric-Bernstam Funda , Mellinghoff Ingo K. , Goyal Lipika , Harding James J. , Dees E. Claire , Bahleda Rastislav , Azad Nilofer S. , Karippot Asha , Kurzrock Razelle , Tabernero Josep , Kononen Juha , Ng Matthew C.H. , Mehta Rutika , Uboha Nataliya V. , Bigot Frédéric , Boni Valentina , Bowyer Samantha E. , Breder Valeriy , Cervantes Andrés , Chan Nancy , Cleary James M. , Dhawan Mallika , Eefsen Rikke L. , Ewing James , Graham Donna M. , Guren Tormod K. , Won Kim Jin , Koynov Krassimir , Oh Do-Youn , Redman Rebecca , Yen Chia-Jui , Spetzler David , Roubaudi-Fraschini Marie-Claude , Nicolas-Metral Valerie , Ait-Sarkouh Rafik , Zanna Claudio , Ennaji Abdallah , Pokorska-Bocci Anna , Flaherty Keith T.
Published: May 2024

Purpose:

This multicenter phase II basket trial investigated the efficacy, safety, and pharmacokinetics of Debio 1347, an investigational, oral, highly selective, ATP-competitive, small molecule inhibitor of FGFR1–3, in patients with solid tumors harboring a functional FGFR1–3 fusion.

Patients and Methods:

Eligible adults had a previously treated locally advanced (unresectable) or metastatic biliary tract (cohort 1), urothelial (cohort 2), or another histologic cancer type (cohort 3). Debio 1347 was administered at 80 mg once daily, continuously, in 28-day cycles. The primary endpoint was the objective response rate. Secondary endpoints included duration of response, progression-free survival, overall survival, pharmacokinetics, and incidence of adverse events.

Results:

Between March 22, 2019, and January 8, 2020, 63 patients were enrolled and treated, 30 in cohort 1, 4 in cohort 2, and 29 in cohort 3. An unplanned preliminary statistical review showed that the efficacy of Debio 1347 was lower than predicted, and the trial was terminated. In total, 3 of 58 evaluable patients had partial responses, representing an objective response rate of 5%, with a further 26 (45%) having stable disease (≥6 weeks duration). Grade ≥3 treatment-related adverse events occurred in 22 (35%) of 63 patients, with the most common being hyperphosphatemia (13%) and stomatitis (5%). Two patients (3%) discontinued treatment due to adverse events.

Conclusions:

Debio 1347 had manageable toxicity; however, the efficacy in patients with tumors harboring FGFR fusions did not support further clinical evaluation in this setting. Our transcriptomic-based analysis characterized in detail the incidence and nature of FGFR fusions across solid tumors.

See related commentary by Hage Chehade et al., p. 4549
TABLE 2 from A Phase II Study of ERK Inhibition by Ulixertinib (BVD-523) in Metastatic Uveal Melanoma
Authors: Buchbinder Elizabeth I. , Cohen Justine V. , Tarantino Giuseppe , Lian Christine G. , Liu David , Haq Rizwan , Hodi F. Stephen , Lawrence Donald P. , Giobbie-Hurder Anita , Knoerzer Deborah , Sullivan Ryan J.
Published: May 2024

Grade 3 and 4 toxicities and AEs, all attributions. Patients may have experienced more than one toxicity
FIGURE 3 from A Phase II Study of ERK Inhibition by Ulixertinib (BVD-523) in Metastatic Uveal Melanoma
Authors: Buchbinder Elizabeth I. , Cohen Justine V. , Tarantino Giuseppe , Lian Christine G. , Liu David , Haq Rizwan , Hodi F. Stephen , Lawrence Donald P. , Giobbie-Hurder Anita , Knoerzer Deborah , Sullivan Ryan J.
Published: May 2024

(A) NanoString data nSolver normalized log2 counts of DUSP6 pretreatment and on-treatment. B, MAPK signature evaluated at pretreatment and on-treatment using four genes included in the NanoString panel, specifically DUSP6, MYC, TNFAIP3, and PMAIP1. C, GSEA against the Hallmark database; enriched signatures on treatment are depicted in orange, while enriched signatures pretreatment are in blue. D, Enrichment scores of two signatures related to IFN gamma and alpha responses, which are enriched in the on-treatment samples.
Nail Disease in a Nail Consultation at a Tertiary Referral Center: A 10-Year Retrospective Study
Authors: Rosca Aureliu , Magalhães César , Matos Joana , Teixeira Diogo , Guedes Rita
Published: May 2024

Introduction: The primary objective of this study was to determine the prevalence of nail diseases and its population in nail consultation. Methods: A retrospective study of clinical records between 2012 and 2022 was conducted. The 1,372 established diagnoses were categorized into nosological groups, which included physical signs, infectious diseases, dermatological diseases, systemic diseases, drug reactions, occupational disorders, congenital diseases, traumatic disorders, and tumors. Results: Overall, 1,239 records were enrolled, with 64% (n = 788) involving female patients. The median age was 50 years. In 71.5% of cases (n = 886), it was possible to establish an etiological diagnosis or a causative relationship based on physical findings, while 28% of patients (n = 347) presented nonspecific physical signs. Conclusion: Onychomycosis was the most prevalent diagnosis and revealed a descending trend over the 10-year period study.
Las nuevas tecnologías y el re-encantamiento del mundo
Authors: Manuel Moran José
Published: May 2024

Con frecuencia leemos que las tecnologías de comunicación están provocando profundas transformaciones en todas las dimensiones de nuestra vida. Sin duda dichas tecnologías vienen colaborando en la transformación del mundo. La máquina de vapor, la electricidad, el teléfono, el carro, el avión, la televisión, el computador, las redes electrónicas, contribuyeron en la extraordinaria expansión del capitalismo, en el fortalecimiento del modelo urbano y en la disminución de las distancias. Pero, en esencia, las tecnologías no son las que transforman la sociedad, antes bien, el agente transformador es la utilización que se hace de ellas en el modo de producción capitalista, que busca el lucro, la expansión, la internacionalización de todo lo que tiene un valor económico.