bluuebunny/crossref_metadata_2025_split huggingface dataset:
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.
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

Abstract

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