bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of aging on aortic arterial stiffness and wave reflection in healthy mid-life adults
Authors: Chang Keng-Yu , Hibner Brooks , Phillips Shane , Piano Mariann , Liu Zhaoli , Hwang Chueh-Lung 
Published: May 2023

Introduction: Aging is associated with arterial stiffening which increases pressure reflection to the heart and contributes to the development of cardiovascular disease. However, most vascular aging studies have focused on comparing young adults versus adults 65 or older, and comorbidities, such as hypertension and obesity, confounded the findings. The extent of vascular aging in healthy mid-life adults (age 50-64) is unclear. Therefore, the purpose of this study was to compare arterial stiffness and wave reflection in healthy young adults (18-35 years) and healthy mid-life adults. Methods: Twenty-six apparently healthy, nonsmoking, adults underwent assessments of arterial stiffness and wave reflection. Young adults (YA; n=15, 6 eumenorrheic women; age: 28±4 yr; systolic blood pressure [SBP]: 109±8 mmHg; body mass index [BMI]: 24.1±2.5 kg/m2; mean±SD) were compared to mid-life adults (MA; n=11, 8 postmenopausal women; age: 59±4 yr; SBP: 109±10 mmHg; BMI: 25.6±4.1 kg/m2). Using SphygmoCor XCEL (AtCor Medical), aortic arterial stiffness was measured as carotid to femoral pulse wave velocity (cfPWV) and wave reflection was measured as augmentation index normalized at heart rate of 75 (Alx75), augmented pressure (AP), backward wave pressure (Pb), and reflection magnitude (RM). Results: No significant differences between YA and MA were found in brachial and aortic SBP, diastolic blood pressure, and pulse pressure (P≥0.07). Compared to YA, MA had higher cfPWV (MA vs. YA: 6.8±0.9 m/s vs. 5.8±0.6 m/s, p=0.001), Alx75 (30±10% vs. 4±10%, p<0.001), AP (13±4 mmHg vs. 4±3 mmHg, p<0.001), Pb (16±2 mmHg vs. 13±2 mmHg, p=0.001), and RM (67.7±6.8% vs. 48.0±5.6%, p<0.001). Conclusions: Our findings suggest that mid-life adults exhibit increased arterial stiffness and wave reflection compared to young adults. These data suggest that vascular aging may already be present in mid-life adults, despite normal peripheral blood pressure. These findings help extend our understanding of the sequence of age-related changes in vascular function throughout the lifespan. This work was supported by NIAAA K99/R00 AA028537 to CLH. 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.
Gender affirming hormone therapy in the male rat is associated with differential effects on cardiovascular risk factors
Authors: Crudup Breland , Mallette Jordan , Oudomrath Speyrer Adrian , Rawls Adam , Cockrell Kathy , Davenport Kacey , Willis Alex , Yanes Cardozo Licy , Shawky Noha , Alexander Barbara 
Published: May 2023

Gender-Affirming Hormone Therapy (GAHT) in transgender females (male to female) involves administration of 17ß-estradiol (E2) with an anti-androgen (AA) or castration (CTX). GAHT is used to treat individuals that are born one sex but identify as the other gender. Numerous clinical studies indicate that cardiovascular (CV) risk is elevated in GAHT transgender females. Yet, the mechanisms involved remain unknown. Thus, the purpose of this study was to develop an experimental model of the transgender female and to test the hypothesis GAHT is associated with increased CV risk. Methods: Male Sprague Dawley rats were randomly assigned to the following groups: Control (n=8), E2 [5 mg/day, pellet sc, replaced every 3 weeks, N=6], E2+AA [E2 + Spironolactone, 10 ng/kg/day, diet, N=8], and E2+CTX (N=8). AA and E2 were initiated at 14 weeks of age; CTX rats were exposed to AA for 2 weeks prior to CTX at 16 weeks of age. At 28 weeks of age, EchoMRI for measurement of body weight, fat and lean mass was followed by 24-hour metabolic studies. E2 (ELISA), testosterone (RIA) and analytes (Chemistry Analyzer) were analyzed end of study at 28 weeks of age. Data were analyzed using GraphPad Prism 9 with one-way ANOVA with multi-group comparisons. Statistical significance was set at a P value of <0.05. Results: ( Table 1 ) E2 alone was sufficient to decrease testosterone in male rats. Administration of E2 in the male rat was associated with a significant decrease in body weight, lean mass and average kidney and testes weight. Creatinine was decreased in E2 alone. Yet, BUN was decreased in E2+CTX. E2 + AA was associated with a significant increase in total cholesterol compared to Control; an increase not observed in E2 or E2+CTX. HDL was elevated in E2+AA, whereas LDL-C was decreased in E2, E2+AA and E2+CTX mimicking what is observed in the transfemale population. Collectively, these results demonstrate differential effects of E2+AA versus E2+CTX on CV risk factors in male rats indicating that long-term studies are needed to determine the effect of GAHT on CV risk across the lifespan. [Table: see text] Funding: HL143459, P20-GM-104357, P20-GM121334, T32-HL105324, and LGBTQ Fund of MS 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.
Airway luminal area in long COVID patients compared to acute COVID-19 patients
Authors: Zaremba Solomiia , Miller Alex , Ovrom Erik , Senefeld Jonathon , Wiggins Chad , Dominelli Paolo , Joyner Michael , Welch Brian , Ramsook Andrew 
Published: May 2023

Background: Patients with respiratory manifestations of acute COVID-19 infection have enlarged luminal areas of central conducting airways demonstrated on computed tomography imaging and abnormal pulmonary function. In some cases, COVID-19 symptoms may persist for more than 4 weeks, referred to as long COVID, and the effect on airway luminal area remains unknown. Herein, we report airway luminal cross-sections areas among a long COVID group, compared to individuals with an acute COVID-19. We aim to investigate if large conducting airways sizes are different between acute COVID-19 and long COVID patients. Methods: A cohort of 181 people with long COVID were screened, of which 20 people (9 men, 11 women; 55.9 ± 14.1 years) were included in analyses. Twenty age, height, and sex matched patients with an acute (< 4 weeks of persistent symptoms from diagnosis) COVID-19 infection (55.7 ± 15.2 years) served as a comparison group. We used a three-dimensional reconstruction of computed tomography imaging to measure luminal areas of the trachea, right and left main bronchi, bronchus intermediate, right and left upper lobe, and left lower lobe bronchi at proximal, middle, and distal cross-sectional points in both groups. Airway luminal area was taken as the average of the three points. We compared average lumen area of long COVID patients with acute COVID-19 individuals, using an independent samples t-test. Results: We found no significant difference comparing measurements of the following airway luminal cross-sectional areas: trachea (277.7 ± 100.4 vs. 268.0 ± 70.5 mm2 p=0.73), right main bronchus (191.0 ± 66.1 vs. 190.1 ± 49.0 mm2, p=0.96), bronchus intermediate (112.3 ± 33.4 vs. 109.3 ± 27.9 mm2, p=0.76), right upper lobe bronchus (74.4 ± 21.0 vs. 73.7 ± 25.5 mm2, p=0.92), left main bronchus (129.1 ± 50.1 vs. 136.9 ± 38.0 mm2, p=0.58), left lower lobe bronchus (57.8 ± 18.2 vs. 59.0 ± 13.4 mm2, p=0.82), and left upper lobe bronchus (80.1 ± 19.5 vs. 77.9 ± 22.9 mm2, p=0.75) in the long COVID and acute COVID-19 groups respectively. Conclusion: In patients with long COVID, compared to those with an acute COVID-19 infection, we did not see differences in central airway luminal areas. Further analysis of a larger cohort is needed to determine whether enlarged airway luminal areas, associated with acute COVID-19, persist in long COVID. This research will expand knowledge on functional consequences for patients with long COVID. Funding: F32HL154320 to JWS; 5R35HL139854 to MJJ. 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.
Direct activation of Airway Sensory C-fibers by SARS-CoV-2 Spike protein
Authors: Kim Joyce , Ru Fei , Meeker Sonya , Undem Bradley 
Published: May 2023

Activation of sensory nerves, in particular nociceptive C-fibers, is a feature of most respiratory viruses. Evidence of such activation is found in the classical consequences of C-fiber activation including sneezing, sore throat, coughing, and reflex secretions. As well as causing the troubling symptoms of viral infection, the activation of these nerves allows viruses to escape the body and be transmitted to other hosts, i.e. nociceptor activation amplifies spread in a community. In addition, activation of airway vagal C-fibers can lead to strong reflex bronchoconstriction and excessive secretions that likely contribute to the exacerbation of asthma particularly in children. In theory, viral infection leads to C-fiber activation by two general mechanisms. The first is that viral infection of epithelial cells leads to the production of a mediator(s) that stimulates the C-fiber terminals. The second is that the virus itself directly activates the nerves. We used three orthogonal approaches to address our hypothesis that the coronavirus spike protein directly activates (evokes action potential discharge) vagal C-fibers in mouse airways. We used male C57/BL6 mice to evaluate whether coronavirus spike protein interacts; directly with C-fiber terminals in an isolated vagus-trachea/lung preparation. Action potentials were recorded using extracellular electrodes positioned near the relevant cell bodies in the vagal sensory nodose/jugular ganglion complex. Spike protein S1 (4ug/ml) was perfused through the mouse trachea into the receptive field of an identified C-fiber (c.v. <1 m/s). 40% of C-fibers (12 out of 30) responded acutely to the S1 protein with action potential discharge. In the same type of ex-vivo experimental set-up, two-photon imaging technique was also used to evaluate the % of fibers activated by spike protein. Consistent with our electrophysiological studies we found that 45% of the C-fibers (241 fibers out of 538 fibers in 4 experiments) were stimulated by the S1protein. To determine whether spike protein was indirectly activating C-fibers in the lung, i.e. requiring other cells within the airway tissue, we evaluated its effect on neurons dissociated from the vagal ganglia with Fura-2 calcium imaging. Again, ~ 40% of the isolated neurons (65 out of 163 neurons) responded to spike protein. These data support our hypothesis that the spike protein can directly activate neurons independently of airway tissue. This supports the hypothesis that some of the nerve-related effects of SARS CoV-2 infection may involve the direct activation of sensory C-fibers. R35 HL144887 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.
Exploring sex differences in inhibitory synaptic transmission in the kolliker-fuse of rett syndrome mice
Authors: Whitaker-Fornek Jessica , Levitt Erica 
Published: May 2023

Rett Syndrome (RTT) is a rare neurodevelopmental disorder characterized by severe motor impairments including breathing problems. RTT is caused by mutations in the methyl CpG binding protein 2 (MeCP2) gene located on the X chromosome. Accordingly, girls and women account for the majority of RTT patients. The genetic nature of RTT lends itself to study in mice with loss of function mutations in the MeCP2 gene. Importantly, RTT mice display breathing irregularities similar to human patients. Insufficient inhibitory neurotransmission in the brainstem respiratory network is thought to contribute to the breathing problems in RTT. In the pontine Kölliker-Fuse (KF) area of RTT mice, there are fewer GABAergic neurites and injection of a GABA reuptake antagonist alleviates breathing irregularity in vivo. However, no one has examined the physiology of inhibitory synaptic transmission in the KF of RTT mice. In the present work, we tested the hypothesis that inhibitory synaptic transmission was deficient in the respiratory-controlling KF of MeCP2Bird mice. Although girls and women make up the majority of RTT patients, most studies examining synaptic physiology in the brainstem have been performed using male MeCP2-deficient mice. Hemizygous male MeCP2Bird mice lack MeCP2 protein and exhibit rapid onset of severe RTT symptoms which leads to short life spans. Due to partial X-inactivation, MeCP2 expression in heterozygous female MeCP2-deficient mice is mosaic, leading to variable symptom severity and delayed onset, which more closely resembles the human condition. In the present study, we examined inhibitory synaptic transmission in the KF of female heterozygous MeCP2Bird mice compared to male hemizygous MeCP2Bird mice and wild type littermates. Whole-cell voltage-clamp recordings from KF neurons contained in acute brain slices were used to measure inhibitory currents. Most notably, the frequency of spontaneous inhibitory postsynaptic currents is reduced in the KF of male, but not female, MeCP2Bird mice compared to wild type littermates. To better understand this sex difference in inhibitory neurotransmission, we assessed the influence of estrous cycle stage and MeCP2 expression status in the recorded neuron. The outcomes of this research will increase our understanding of synaptic function in respiratory control neurons in female Rett Syndrome mice. This research was supported by the International Rett Syndrome Foundation Basic Research Grant 3608. 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.
Association Between Pain Perception and Blood Pressure Responsiveness During a Cold Pressor Test in Young Adults
Authors: Miller Kayla , Hanson Brady , Casey Darren 
Published: May 2023

The cold pressor test (CPT) has been widely used as a stressor in laboratory settings to examine blood pressure (BP) responsiveness in both healthy and patient populations. Current literature indicates considerable inter-individual variability in BP responsiveness to a CPT. This variability may be due to the level of perceived pain associated with the cold stress. Therefore, in the present study we tested the hypothesis that BP responsiveness would demonstrate a positive association with ratings of perceived pain during the CPT in young adults. Since sex-related differences in BP responsiveness to a CPT have been reported, we also examined if the hypothesized association between BP responsiveness and pain perception during a CPT differs between young males and females. 26 young adults (13M/13F; 21±4 yr) underwent a CPT consisting of a 2-min baseline followed by immersion of the left hand in ice water (~4°C) for 2-min. Beat-by-beat BP was recorded continuously and averaged every 30s of the CPT. Subjects provided verbal pain scores (0-10 scale) every 30s. Two-way repeated measures ANOVAs were used to assess BP and pain over time and to determine if responses differed between sex. Additionally, Pearson correlations were used to examine the association between BP responsiveness (change (Δ) in diastolic (DBP), systolic (SBP) and mean arterial pressure (MAP)), and rating of perceived pain for the entire cohort as well as for each sex. All indices of BP and perceived pain increased in response to the CPT in young adults (P<0.05 for all), with no sex-related differences noted. ΔDBP, ΔSBP, ΔMAP were not associated with pain perception for the group as a whole. When examined within sex, no association was observed between ΔDBP, ΔSBP, ΔMAP and pain perception for males at any point during the CPT. However, within females, ΔDBP, ΔSBP, and ΔMAP were positively associated with pain perception at 1-min (r=0.77, 0.57, 0.66, respectively; P<0.05 for all) but not at 2-min (r=0.36, 0.24, 0.33, respectively; P>0.05 for all) of the CPT. Contrary to previous findings, we did not observe sex-related differences in BP responsiveness to a CPT in young adults. Additionally, BP responsiveness is not associated with pain perception during the CPT in our group as a whole. However, when analyzed by sex, an association between BP responsiveness and pain perception was found in females at the early stages of the CPT (i.e. 1-min). Funding: American Physiological Society SURF Program (K.A.M.) 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.
Orphan GPRC5B activation modulates airway contractility
Authors: Varadharajan Subashini , Balraj Premanand , Kale Narendra , Campos Luana Janaina de , Conda Sheridan Martin , Mallik Sanku , Pabelick Christina M , YS Prakash , Sathish Venkatachalem 
Published: May 2023

Background: Multiple asthma phenotypes are driven by pathobiological heterogeneity. Almost 25% of asthma patients do not respond well to current treatments like inhaled corticosteroids, urging researchers and clinicians to propose novel treatment targets and strategies. Orphan type C G-protein coupled receptor GPRC5B is one such novel target abundantly expressed in various tissues, but there are no known ligands for GPRC5B. Previously, we demonstrated that orphan type C G-protein coupled receptor GPRC5B is increasingly expressed in human asthmatic airways and plays a crucial role in regulating intracellular calcium ([Ca2+]i) in human airway smooth muscle (ASM) cells. However, the role of GPRC5B activation on airway contraction is not identified yet. Our objective for this study is to design and synthesize a novel ligand for GPRC5B and determine the effect of GPRC5B activation on [Ca2+]i responses in ASM cells and airway contractility in ex vivo murine airways. Methods: ZincPharmer was used for pharmacophore search. After energy minimization, the top hit compound was synthesized using a standard amide coupling reaction, purified by flash chromatography, and characterized by NMR spectroscopy. Human ASM cells loaded with Fura-2 AM were imaged for [Ca2+]i responses. Silencer select siRNA was used for transient silencing of GPRC5B in ASM cells. Myosin light chain (MLC) phosphorylation was measured using immunoblot analysis. Precision-cut lung slices (PCLS) (~200 μm thickness) of wild-type C57BL6 mice were used for contractile studies. Results: Based on molecular docking data, the top compound N-(5-chloro-2-hydroxybenzyl)-2-((tetrahydro-2H-pyran-4-yl)oxy) acetamide (L1) was synthesized. Concentration-dependent [Ca2+]i responses were observed on human ASM cells stimulated with L1 (1 nM - 1 μM) that were comparable to the known contractile agonist histamine (10 μM). L1-induced [Ca2+]i response was significantly reduced in GPRC5B knockdown ASM cells. GPRC5B knockdown in ASM cells was verified by Western analysis. Further, L1 exposure increased the MLC phosphorylation (Thr18/Ser19) in human ASM cells compared to vehicle. Acute exposure of L1 (1 μM) increased airway contractility of PCLS (~17%-25%) compared to vehicle exposure. Conclusion: These findings suggest that GPRC5B activation modulates intracellular calcium and airway contractility in human ASM cells and murine PCLS. Thus, GPRC5B could potentially be considered for a novel therapeutic regimen to tackle asthma. This work was partly supported by NIH grants R01-HL146705 (Venkatachalem), R01-HL088029 (Prakash), and R01-HL142061 (Pabelick, Prakash). 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.
Long Term Effects on Metabolic Parameters of Significant Weight Reduction (>25%) by Very Low Calorie Diet Compared to Roux-en-Y Gastric Bypass in Diabetic Obese vs Obese Without Diabetes (Patients vs Nonhuman Primates)
Authors: Harrison Daniel , Nguyen Tam , Shah Ria , Kavanaugh Megan , Mahler Raegan , Alford Nicholas , Hansen Barbara 
Published: May 2023

Background: Obesity has similar effects in both monkeys and humans, including the development of metabolic syndrome, which is often followed by type 2 diabetes mellitus (DM). The effects of short term and intermittent very low-calorie diets (VLCD) suggest improvement in glycemic control, however, the long term (two year or more) effects of a VLCD have not been examined in obesity with or without diabetes. Methods: The metabolic and glycemic effects of major weight reduction in nonhuman primates using VLCD was compared to major weight reduction in humans using gastric bypass at 2 years post-surgery. In 14 spontaneously obese rhesus monkeys, half with overt T2DM were compared to 18 obese humans, ten with DM and eight without (OB). All humans underwent Roux-en-Y gastric bypass surgery and were followed for two years. The metabolic indices of the NHP and humans were obtained at the beginning and end of the two-year period. Results: All four groups experienced significant weight loss ranging from 22% to 37% reduction. Fasting glucose decreased significantly in both DM groups but were unchanged in both obese groups. In both humans and monkeys, fasting glucose of the DM and OB groups initially differed significantly from each other, but after surgery and after VLCD, did not differ. ß cell function, assessed by the acute insulin response to IV glucose, decreased in both OB groups and increased in both DM groups. In both species, after weight loss, the OB groups retained a higher acute insulin response compared to the DM groups, however, the differences between the OB and DM groups were significant (p-value of 0.032 for monkeys and 0.03 in humans). Insulin sensitivity in humans increased in both DM and OB groups (p <0.001 and 0.003, respectively). However, there was a larger change in the OB group. Conclusion: These results demonstrate a significant improvement in glycemic control (temporarily) from both long-term very low-calorie diets and gastric bypass. Pancreatic ß-cell function, however, cannot be restored to normal, even after significant weight loss (and sustained weight loss maintenance) in the diabetic groups. These results strongly support much earlier intervention to reduce obesity long before T2DM develops, as the reversibility of ß-cell defects disappears with overt T2DM, despite some limited improvement in glycemia. NIH grants NO1AG3 1012, NIA, and NIDDK 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.