bluuebunny/crossref_metadata_2025 huggingface dataset:
Behaviorally Inhibited Individuals Learn to Avoid Transdermal Stimulation More Quickly, and this Learning Is Accelerated Throughout the Study
Authors: Wiseman Connor M. , Ehlert Luke S. , Poff Hannah , Talens Kate , Martino Paul F. , Miller Daniel P. , Miller Justin R.
Published: May 2024

Information on how behavioral inhibition (BI) affects the amount of time it takes an individual to avoid a stressful situation could answer many questions about anxiety disorders and whether BI influences avoidance behavior. BI is a temperament characteristic associated with increased vulnerability to stress compared to their non-behaviorally inhibited (NBI) counterparts. Our previous study demonstrated that BI individuals have lower heart rate variability (HRV) than NBI individuals. This suggests that BI individuals have significantly less parasympathetic nervous system (PNS) output at rest; however, it is unknown how BI affects avoidance acquisition using a mildly stressful stimulus. Previous studies have shown differences in the behavior found in Wistar-Kyoto rats, which exhibit BI behavior, compared to Sprague-Dawley control rats. Our current study will test the hypothesis that BI individuals learn to make escape and avoidance responses using subdermal ulnar nerve transdermal electrical stimulation (TES) more rapidly than NBI individuals and also experience a more significant increase in heart rate (HR) and blood pressure (BP). BI individuals were identified through a series of self-reported questionnaires. Three levels (30 mV, 50 mV, and 70 mV) of subdermal ulnar nerve TES were delivered to participants while receiving warning signals that predicted the delivery of the TES. Participants had access to a button that, when pressed during the light, prevented the delivery of the TES. This was scored as an avoidance response. If the button was pressed during the TES, it terminated the stimulation and was scored as an escape. HR and BP were also measured using a BIOPAC data acquisition system during TES. Our preliminary results indicate that BI individuals show a decrease in latency in the amount of time it took them to make an avoidance as the study progressed, while NBI individuals show a slight increase in latency, highlighting the idea that BI individuals are more curious to press the button or they are more likely to want to avoid the TES quicker.

We would like to thank the Carthage College Research, Scholarship, and Creativity Committee as well as the Carthage College Neurophysiology Laboratory professors for their continued support throughout the study.

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.
Understanding the neural principles of interacting multiple internal states
Authors: Kim Jineun , Anderson David
Published: May 2024

In dynamic ethological environments, animals are constantly confronted with conflicting choices driven by interacting internal motivations. This intricate dance between internal states prompts the question: How do these states interact to determine the optimal innate behavior at any given moment? Specifically, when hungry animals encounter food and potential intruders, how do they navigate between feeding, attack, and mating behaviors? Despite extensive neuroscience research on instinctive behaviors, our understanding of the mechanisms governing adaptive behavioral decisions in the face of competing internal signals remains limited. This research aims to shed light on the complex interplay of internal physiological homeostasis in modulating defensive, aggressive, and sexual behaviors. Our focus lies on exploring the intricate network between the body and the brain to unravel the most adaptive responses within a concise time window. Currently, our investigations center around the hypothalamus, a crucial region known for representing emotional states upon encountering conspecifics or predators. Intriguingly, this same hypothalamic nucleus plays a pivotal role in regulating homeostatic metabolic states, including glucose homeostasis. Here, I will share the observation from innate behaviors of animals and the associated neural activity patterns in the hypothalamus. We will explore the current understanding of how these behaviors are modulated by internal physiological states and discuss the future directions of our research. Additionally, we aim to highlight the significance of combining the measurement of physiological signals to comprehensively address how multiple internal states interact with each other. By unraveling the complexities of these interactions, our research contributes to a deeper comprehension of the adaptive decision-making processes that animals employ in the face of conflicting choices.

Helen Hay Whitney Foundation, HHMI.

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.
HepScope: CNN-based single-cell discrimination of malignant hepatocytes
Authors: Lim Su Bin
Published: May 2024

Background: Hepatocellular carcinoma (HCC) poses a significant global health challenge. This study aims to identify robust single-cell biomarkers specifically designed to distinguish between malignant and non-malignant hepatocytes, thereby advancing precision medicine strategies for HCC. Methods: At the single-cell level, we investigated the reliability of established marker genes for malignant hepatocytes in distinguishing them from their non-malignant counterparts. Leveraging one of the largest integrated single-cell transcriptomics (scRNA-seq) datasets of healthy and diseased liver tissues, alongside independent scRNA-seq, spatial transcriptomics (stRNA-seq), bulk RNA-seq, and bulk proteome datasets, we defined a signature gene set, denoted as HepScope. Five other publicly available gene sets related to HCC were used for comparison with HepScope. The development of machine learning (ML) and 1-dimensional convolutional neural network (1D-CNN) models involved utilizing normalized expression of signature genes from scRNA-seq datasets. The HepScope-1D-CNN model was developed to assess differentiation performance by considering the expression values of each signature gene across different tissues and within the same tissue. Finally, we calculated a risk score based on the signature genes to evaluate its prognostic capability. Result: We demonstrated the lack of specificity and consistency among current HCC marker genes in distinguishing malignant hepatocytes from non-malignant hepatocytes. The differential expression (DEG) analysis identified 113 genes upregulated in malignant hepatocytes, forming the HepScope. In contrast to HepScope, the expression values of the five other publicly available gene sets did not exhibit the ability to discriminate between malignant and non-malignant hepatocytes. Utilizing the genes from HepScope, the Gaussian Naive Bayes ML model proficiently distinguished between malignant and non-malignant hepatocytes. The HepScope-CNN model showed the highest performance and effciency compared to other 1D-CNN models trained with different gene sets. Conclusion: In conclusion, our study reveals a novel gene set designed to precisely identify malignant hepatocytes at the single-cell level. This research holds promise for advancing precision medicine in HCC, providing valuable insights into the development of targeted therapies and personalized treatment strategies.

We acknowledge support provided by the National Research Foundation (NRF) of Korea (2020R1A6A1A03043539, 2020M3A9D8037604, and 2022R1C1C1004756) and the Korea Health Technology R&D Project of the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HR22C1734).

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.
Effects of Donepezil on Nonlinear Arterial Pressure and Pulse Interval Dynamics in Spontaneously Hypertensive Rats (SHR)
Authors: Wall de Almeida Camila , Silva Carlos , Fazan Jr Rubens , Virgilio da Silva Luiz Eduardo , Lataro Renata Maria , Salgado Helio
Published: May 2024

Objectives: This study aimed to evaluate the effects of donepezil, an anticholinesterase agent that potentiates parasympathetic function, in the nonlinear dynamics of blood pressure (BP) and pulse interval (PI) from spontaneously hypertensive rats (SHR). Entropy-based approaches which quantify the irregularity or unpredictability of time series were employed. Additionally, detrended fluctuation analysis (DFA) was applied to estimate the degree of self-similarity in the time series. We hypothesized that donepezil improves both entropy and DFA indices of BP and PI. Methods: Male SHR or Wistar-Kyoto (WKY) rats (5 weeks old) were implanted with subcutaneous osmotic mini-pumps for donepezil (DON) administration (1.4 mg/kg/day) or vehicle. At the end of the treatment (16 weeks), conscious WKY (N=12) and SHR treated with donepezil (N=8), or vehicle (N=9), had their BP directly recorded during 1h. Time series (15 min) from systolic BP and PI were generated and used to calculate sample (SampEn), fuzzy (FuzzyEn), and dispersion (DispEn) entropy, as well as DFA scale exponents in short (α1; 5≤n≤15), mid (α2; 20≤n≤100) and long (α3; 100≤n≤500) windows. The results are shown as mean ± SD. One-Way ANOVA, followed by Tukey’s post-test, evaluated differences between the WKY, SHR, and SHR+DON groups. Results: The data are displayed in the table. Lower PI DispEn was observed in SHR treated with DON compared to WKY. Entropy values of BP series were found smaller in SHR and SHR+DON compared to WKY rats. For DFA of the PI series, SHR+DON showed higher α1 compared to the WKY. Moreover, SHR displayed higher α3 when compared to the WKY. In the series of BP values, the results showed higher α2 and α3 in SHR compared to WKY.

[Formula: see text]

Conclusion: These findings showed that SHR exhibited lower BP entropy and higher DFA of BP and IP compared with WKY. However, donepezil did not prevent these changes of non-linear indices from BP and PI variability in SHR.

Funding Sources: FAPESP, Process 2020/06043-7. CNPq, Process 306994/2021-6 and 423999/2021-4. FAEPA. CAPES.

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.
Cardiomyocyte Ketone Metabolism Regulates Myocardial Hyperemia
Authors: Gouwens Kara , Chen Ning , Nong Yibing , Collins Helen , Hill Bradford , Nystoriak Matthew
Published: May 2024

Myocardial perfusion is inextricably coupled to metabolism, with increases in physiologic cardiac demand promoting coronary vasodilation. Despite its wide acceptance, the hypothesis that cardiomyocyte metabolism autoregulates myocardial perfusion lacks mechanistic detail; however, clinical and preclinical studies suggest a signaling role for intermediary metabolites in the vasodilatory response. In particular, the ketone body precursor, β-hydroxybutyrate (3-OHB), enhances myocardial blood flow in humans, but the mechanism by which it does so remains unclear. Here, we determined the extent to which 3-OHB influences myocardial hyperemia in mice. Intravenous 3-OHB infusion (0.5 g/kg) in adult mice (12–24 wks) raised circulating 3-OHB levels (0.5 ± 0.1 to 5.1 ± 0.6 mM; p=0.005) and increased myocardial perfusion (18.6 ± 4.4 to 50.9 ± 10.4 mL/min/g; p=0.024), as measured by myocardial contrast echocardiography. Enhanced perfusion induced by 3-OHB occurred in the absence of changes in cardiac output or systolic performance. Next, to determine if 3-OHB directly dilates the coronary vasculature, we exposed pressurized (80 mmHg), small-diameter (100–260 μm) coronary arteries from mice (C57/Bl6J and 6N) to 3-OHB (0.1–5 mM) but found no significant changes in diameter. Based on these results, we tested whether cardiomyocyte metabolism of 3-OHB is required for the vasodilatory response. We deleted β-hydroxybutyrate dehydrogenase (BDH1) selectively in cardiomyocytes using Bdh1fl/fl mice crossed with tamoxifen-inducible Cre recombinase mice (csBDH1−/−). Although 3-OHB robustly enhanced myocardial perfusion (6.9 ± 1.4 to 21.3 ± 5.6 mL/min/g; p=0.031) at sustained cardiac workloads and peripheral vascular resistance in Cre-negative littermate (control) mice, csBDH1−/− mice completely lacked the 3-OHB-induced hyperemic response (8.0 ± 2.5 to 6.3 ± 2.8 mL/min/g; p>0.999). Together, these data indicate that 3-OHB evokes workload-independent enhancement of myocardial perfusion through a mechanism that requires cardiomyocyte metabolism of 3-OHB. Our results support the general concept that acute changes in metabolic substrate availability may influence oxygen delivery to cardiomyocytes via a cardiomyocyte-vascular signaling nexus.

R01HL163818, R01HL142710, R01HL163003, P30GM127607, P30GM127607-05S1, Jewish Heritage Fund for Excellence (JHFE), S10OD025178.

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.
Cerebrovascular Carbon Dioxide Reactivity Is Intact in Chronic Kidney Disease
Authors: Sprick Justin , Sabino-Carvalho Jeann , Mekonnen Elsa , Mcgranahan Melissa , Zanuzzi Matias , DaCosta Dana , Park Jeanie
Published: May 2024

Introduction: Chronic Kidney Disease (CKD) is associated with a substantially elevated risk of stroke. One factor that might contribute to this heightened risk is an impairment in cerebrovascular carbon dioxide reactivity (CVR), the mechanism through which cerebral vessels dilate and constrict in response to fluctuations in arterial carbon dioxide tension (PaCO2). CVR is known to be impaired in other chronic disease states associated with stroke risk; thus, we aimed to determine if CVR is also impaired in patients with moderate to severe CKD (stages III-IV). We hypothesized that CKD patients would exhibit impaired CVR compared to a control group (CON) matched for age, hypertension, and diabetes status. Methods: 9 CKD participants (age=56 ± 17y, eGFR=39 ± 4 mL/min/1.73m2), and 9 CON participants (age=61 ± 6y) underwent a single experimental protocol in which PaCO2 was manipulated via 2-min of hypercapnia (5% CO2) followed by 2-min hypocapnia (voluntary hyperventilation) while heart rate (via ECG), blood pressure (via finger photoplethysmography), middle cerebral artery blood velocity (MCAv; via transcranial Doppler ultrasonography), and end-tidal carbon dioxide (etCO2) were measured continuously. CVR was quantified as the slope of the linear relationship between breath-by-breath etCO2 and MCAv while accounting for blood pressure as a covariate. Hyper-, hypo- and, integrated (hyper + hypo) CVR was compared between groups via a 2-tailed, unpaired T-test. Results: We observed no differences in CVR between groups. Hypercapnic CVR: CKD = 1.4 ± 1.0 cm/s/mmHg, CON = 1.5 ± 0.8 cm/s/mmHg, Hypocapnic CVR: CKD = 1.5 ± 0.8 cm/s/mmHg, CON = 1.5 ± 0.8 cm/s/mmHg, Integrated CVR: CKD = 1.7 ± 1.2 cm/s/mmHg, CON = 1.7 ± 0.6 cm/s/mmHg, P ≥ 0.90. Conclusions: Contrary to our hypothesis, CVR remains intact in CKD stages III-IV. These findings suggest that other mechanisms contribute to the elevated stroke risk observed in this population.

Funding: This work was supported by the American Heart Association (Career Development Award #929040, PI: Sprick), and NIH grants R01HL135183 and R33AT010457.

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.
Low methyl nutrition microenvironment as a key regulator in modulating epigenetic regulation and switching energy metabolism to stimulate hepatocellular carcinoma stemness properties
Authors: Chen Wan-Jing , Huang Kai-Wen
Published: May 2024

The influence of changes in dietary habits, chemical treatments, variations in the activity of one-carbon enzyme gene modifications, and liver function impairment make hepatocellular carcinoma (HCC) patients prone to marginal methyl nutrient deficiency. Hepatocellular carcinoma has consistently ranked among the top five cancer incidence rates around the world, yet the issue of methyl nutrient deficiency still lacks systematic basic scientific assessment. This study aims to investigate whether the deficiency of methyl nutrients, specifically folate, choline, and betaine, induces the stem cell-like properties of hepatocellular carcinoma cells and promotes malignant progression, as well as to clarify the potential mechanisms involved. We found that human hepatocellular carcinoma cells (HepG2) cultured in a low methyl nutrient environment exhibited the following: (1) Methyl nutrient deficiency induced self-renewal cancer stem cell characteristics in hepatocellular carcinoma cells, forming tumor spheres on the seventh day, with a greater number and larger volume observed in environments with low folate and low choline. Upon isolating the tumor spheres and re-culturing, we found that the sphere cells induced by methyl nutrient deficiency (2) showed increased intracellular NADPH, accompanied by elevated lactate concentration in the microenvironment and changes in energy-related indicators of Warburg metabolism. At the same time, the expression of post-reprogramming related proteins Sirt1 and DNMT1 was altered. In summary, methyl nutrient deficiency may promote the malignant progression of hepatocellular carcinoma through both epigenetic modifications and energy conversion.

National Science and Technology Council (NSTC112-2320-B-567-001).

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.
A novel preclinical model of human lung cancer cachexia
Authors: Snoke Deena , Van der velden Jos , Bellefleur Emma , Heininger Skyler , Ather Jennifer , Lenahan Sean , Dearborn Jacob
Published: May 2024

Most patients with lung cancer are afflicted with cancer cachexia (CC), a syndrome characterized by wasting of muscle and fat tissues, which leads to poor treatment response and increased mortality. Pre-clinical models used to study CC often do not mimic the human condition, which may explain why there are no approved treatments for CC. To overcome this barrier, we sought to develop a model of lung CC that better recapitulates the pathoetiological characteristics of human lung CC using mice with a tamoxifen-inducible, lung epithelial cell (club cell)-specific KrasG12D allele ( G12D mice). We hypothesized that this model would mimic human CC in tumor location and burden, rate of progression, and tumor-driven tissue wasting. Following induction by tamoxifen injection, adenocarcinomas developed in the terminal bronchioles as early as 3.5 weeks post-induction and were accompanied by loss of 15% of animal body weight over a 12-week period. This weight loss began at 6 weeks and yielded a slow rate of CC progression (-1.9%/week) relative to currently available lung CC models (-5-10%/week). Body weight loss resulted from reductions in hindlimb muscle mass (18-30%) and profound depletion of inguinal and gonadal adipose tissue depots (60-70%) compared to age-matched wild-type (WT) littermates. At 6 weeks post-induction, fat tissue was reduced at the tissue and cellular levels while reductions in hindlimb muscle weight and fiber size were not observed. This fat loss corresponded with increased serum glycerol levels at 6 and 12 weeks, a metabolic characteristic that was also found in patients with lung cancer receiving treatment. Lung organoids were developed from G12D and WT mice. G12D organoids exhibited similarities in gene expression to human lung tumors ( RNAseq) and their conditioned medium (CM) elicited glycerol release from cultured 3T3L1 adipocytes compared to CM from WT organoids, suggesting that tumor-derived factors may contribute to early adipose tissue atrophy. Collectively, these findings suggest that G12D mice may be a valuable model, well-suited to identify mechanisms leading to CC and test preventative therapies.

NIH R01 AR065826(MJT), NCI R21 CA283492(MJT), T32- HL076122-18(DBS/MEP), R01 CA273238 (YJ-H) and the University of Vermont Cancer Center. Funding support for RNAseq provided by Zymo Impact Initiative Grant (DBS).

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.
Racial Disparity in Microvascular Function in Men with Newly Diagnosed Prostate Cancer
Authors: Simon Abigayle B , Looney Jacob C , Blackburn Marsha , Crandall Reva , Thomas Jeffrey , Guha Avirup , Mukundi Tiffany
Published: May 2024

BACKGROUND:Cardiovascular disease (CVD) is a leading cause of death in men with prostate cancer. In addition, non-Hispanic Black (NHB) men experience worse CVD-related mortality compared to their non-Hispanic White (NHW) counterparts, although the reason for this racial disparity remains unclear. Notably, vascular endothelial dysfunction often precedes the emergence of overt CVD. Indeed, conduit-vessel dysfunction, micro-vascular dysfunction, and arterial stiffness are independent predictors of CVD risk. Thus, the purpose of this study was to comprehensively assess vascular health in recently diagnosed NHB and NHW men with prostate cancer. Methods: Twenty-eight men (10 NHW, 18 NHB) with a new clinical diagnosis of prostate cancer (within 3 months) participated in this study. Flow-mediated dilation (FMD) was performed to represent conduit-vessel vascular endothelial function. Cutaneous post occlusive reactive hyperemia (PORH) with local thermal heating (LTH) and iontophoresis of acetylcholine were performed to represent various mechanisms regulating microvascular function. Lastly, pulse wave velocity (PWV) and pulse wave analysis (PWA) were performed to assess central and aortic stiffness, respectively. Data are reported as mean ± SD. Results: A 4-year age difference ( p=0.131) was observed between NHB (65±7 years) and NHW (69±6 years) men. No differences in BMI or clinical laboratory values were observed between NHB and NHW patients (all p>0.05). NHB men exhibited significantly lower microvascular function compared to NHW men, including PORH (NHB: 117±44 PU vs NHW: 207±47 PU; p<0.001), LTH (NHB: 180±73 PU vs NHW: 281±65 PU; p=0.003), and iontophoresis (NHB: 67±28 PU vs NHW: 136±38 PU; p<0.001). No differences in FMD ( p=0.596), PWV ( p=0.695), or PWA ( p=0.883) were observed between groups. CONCLUSION: The results of the current study provide compelling evidence that microvascular dysfunction is present in NHB men who are recently diagnosed with prostate cancer compared to their NHW counterparts. Given that NHB men were 4 years younger, these data support that the microvascular dysfunction may accelerate vascular aging and contribute to the racial disparity in CVD following prostate cancer diagnosis.

Supported by: AHA SFRN 863621 (RAH).

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.
Hypertension and Ventilatory Ineffciency During Exercise in the Fitness Registry and the Importance of Exercise National Database (FRIEND)
Authors: Watso Joseph , Robinson Austin , Arena Ross , Harber Matthew , Kaminsky Leonard , Myers Jonathan
Published: May 2024

Background: Ventilatory ineffciency (high minute ventilation/rate of carbon dioxide production [V̇E/V̇CO2] slope) during exercise is more common in patients with metabolic syndrome and cardiovascular disease, and is prognostic of cardiovascular mortality. Interestingly, new data suggest that adults with controlled or untreated, but not uncontrolled, primary hypertension (HTN) have ventilatory ineffciency during exercise. However, the sample sizes were modest (n=~20/group). Therefore, we used a large database to test the hypothesis that adults with controlled or untreated, but not uncontrolled, primary HTN have higher V̇E/V̇CO2 slope than adults with no HTN. Methods: We used American Heart Association guidelines for HTN as systolic blood pressure [BP] ≥130mmHg, diastolic BP ≥80, or anti-HTN medication in the Fitness Registry and the Importance of Exercise National Database (FRIEND). To isolate primary HTN, we excluded those with any disease other than HTN, any medication use other than anti-HTN medication(s), current smoking status, and/or obesity (body mass index [BMI]≥30). The V̇E/V̇CO2 slope was determined from a peak cycling exercise test. We excluded adults with a peak respiratory exchange ratio <1.00 during exercise. All data are presented as median[IQR]. We compared groups using linear regression unadjusted and adjusted for sex, fitness, and age. Results: The sample (n=4,659) characteristics were age: 42[18] years old (range 18-91 years); 52% with HTN; 18% female; BMI: 26.0[4.0] kg/m2; cardiorespiratory fitness: 28.5[11.0] mL O2/kg/min; race/ethnicity: <1% American Indian, 3% Asian, 12% Black, 8% Hispanic, 4% Other, & 73% White. The V̇E/V̇CO2 slope during exercise was higher in adults without HTN (n=2,410; 24.9[3.8]) compared to those with uncontrolled HTN (n=252; 24.7[3.0]; standard error of the estimate[SE]: -0.20, 95% confidence interval[CI]: -0.33 to -0.07, p=0.003), but not controlled HTN (n=132; 24.4[3.4]; SE: -0.14, 95%CI: -0.31 to 0.04, p=0.12) or untreated HTN (n=1,865; 24.7[3.7]; SE: -0.05, 95%CI: -0.11 to 0.009, p=0.09) (model: R2=0.002, F3,4655=3.83, p=0.009). However, no pairwise differences were observed after covariate adjustment (model: R2=0.117, F6,4652=103, p<0.001). Conclusion: In contrast to our hypothesis, these data from the FRIEND indicate that primary HTN is not associated with ventilatory ineffciency (i.e., higher V̇E/V̇CO2 slope).

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.
Development of an Exercise-based EV Therapy to Improve Skeletal Muscle Recovery After Immobilization
Authors: Fliflet Alexander , Spradlin Ray , Bludgen Tom , Meehan Madeleine , Burger Jayna , Reddy Manasi , Boppart Marni
Published: May 2024

Introduction: Immobilization is necessary for recovery from illness or bone fractures; however, prolonged immobilization can result in significant loss of muscle mass and function. It is critical to recover muscle mass quickly following immobilization as severe muscle atrophy is correlated with increased likelihood of metabolic disorders, disability, and mortality. Physical rehabilitation can improve outcomes but is not always feasible. The purpose is to determine the extent to which EVs circulating in blood after endurance exercise training (EnVs) act as a safe and effective therapy to recover skeletal muscle mass following disuse. Methods: Donor C57BL/6 mice (n = 8-10, 4-month-old) were provided access to horizontal running wheels in a locked (sedentary) or unlocked (exercise) condition. After 4 weeks of voluntary running, EVs (SedVs or EnVs) were isolated from plasma using size exclusion chromatography according to manufactures guidelines, and concentration confirmed via nanoparticle tracking analysis (NanoSight NS3000). Recipient C57BL6/J mice (n = 5-8, 4-month-old) were subjected to single limb immobilization for 14 days. Upon remobilization, mice received a single intramuscular injection of PBS, SedVs, EnVs, or endurance plasma proteins, and remobilized for 3 and 14 days. Muscle samples were collected after remobilization and assessed for muscle cross-sectional-area (CSA) and capillarization. Results: Upon 3-day remobilization, EnVs did not significantly recover global fiber CSA and fiber-type specific CSA (Type IIa, Type IIx or Type IIb) or capillarization. Upon 14-day remobilization, EnVs did not significantly improve global fiber CSA and fiber-type specific CSA. However, a significant treatment effect was observed for capillary density (P = 0.0445), with increases observed for both SedV (P = 0.034) and EnV (P = 0.0117). Conclusion: EVs isolated from plasma after exercise can significantly improve skeletal muscle vascularization after immobilization, which may represent an important step toward full recovery of skeletal muscle mass.

Partially support by NIH (NIAMS R01AR072735).

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.
Improving hydration in underhydrated, free-living young adults results in better running performance
Authors: Kooima Parker , Colburn Abigail , Vento Kaila , Chan Yat , Doyle Amanda , Hoel Tyler , Boro Tanner
Published: May 2024

Dehydration impairs endurance exercise performance, especially in the heat. However, it is unclear how exercise performance is affected by improved hydration status in underhydrated individuals. Therefore, this study examined the impact of a one-week hydration intervention on endurance running performance. We hypothesized better hydration would lead to a faster 2-mile running time. Eighty-nine healthy and moderately fit individuals completed a 2-mile run as fast as possible before (PRE) and after (POST) a 1-week hydration intervention. Performance was incentivized by providing prize money based on ranked average times. First-morning urine samples were collected on the day of each run. If PRE urine specific gravity was >1.020, the subjects were instructed to increase their water intake for one week before the second run. The remaining subjects were instructed to maintain their water intake. All subjects were provided with a filter water bottle. Of the 89 subjects that completed both runs, 44 (18% female, age: 21±2 y, weight: 73.3±12.5 kg, height: 1.76±0.10 m, body mass index: 23.6±3.2 kg/m2) were included in the analysis. Subjects were classified as improved hydration (IMP) if UOsm decreased between PRE and POST by ≥100 mmol/kg and POST was <800 mmol/kg. Subjects were classified as diminished hydration (DIM) if UOsm increased between PRE and POST by ≥100 mmol/kg and POST was >500 mmol/kg. The subjects were removed from the analysis if they met any of the following three conditions: a) had a small UOsm change (<100 mmol/kg) between PRE and POST, b) lowered UOSM but it was still >800 mmol/kg, and c) increased UOsm but it was still <500 mmol/kg. The 2-mile runs took place in Phoenix, Arizona, during the morning (0700 hours) with a maximum ambient temperature of 22±2℃, relative humidity of 37±10%, and WBGT of 16±2℃. UOsm significantly decreased for IMP from PRE: 791±197 to POST: 419±136 mmol/kg (p<0.05) and increased for DIM from PRE: 532±283 to POST: 799±235 mmol/kg (p<0.05). The 2-mile run time significantly improved in IMP from PRE: 13.5±1.8 to POST: 13.3±1.8 min (-11.4±25.8 sec, P=0.03), but did not change in DIM from PRE: 14.2±2.7 to POST: 14.3±2.6 min (+4.8±19.9 sec, P>0.05). The results suggest that improving hydration in underhydrated subjects via one week of increased water intake may improve 2-mile running performance in moderately fit individuals.

This study was funded by a grant from the Arizona State University’s Global Sport Institute. Brita donated the filter water bottles.

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.
Endothelial PPARD regulates nutrient transport and exercise endurance in mice
Authors: Tian Xiao-Yu , Wu Yalan , Wong Wing Tak Jack
Published: May 2024

Vascular endothelial cell function is important for regulating vascular perfusion, which is increased in the skeletal muscle during exercise. Our previous research identified endothelial selective PPARD, a transcription factor, which is critical for endothelial cell function and homeostasis. Loss of PPARD in endothelium enhances vascular inflammation and disrupts endothelial integrity. In the present study, we aims to investigate whether endothelial PPARD is involved in nutrient transport in the muscle endothelial cells and whether it is involved in exercise endurance and training effcacy. The Cdh5-Cre driven deletion of the floxed Ppard allele was used for making the endothelium selective Ppard knockout (PpardEC-KO) mice and wild type littermates (PpardEC-WT). Human endothelial cells were used to examine glucose and fatty acid uptake and its transport to myocytes. Treadmill exercise with incremental speed and inclination was used. Both PpardEC-WT and PpardEC-KO mice were viable and did not show abnormalities at baseline. Both PpardEC-WT and PpardEC-KO mice were put on treadmill to test their running endurance. Deletion of Ppard in endothelium resulted in early exhaustion, shortened distance, and less speed. Running exercise for 4 weeks partially improved endurance in the PpardEC-KO mice. PpardEC-KO mice had less oxidative muscle fibers both at baseline and after training. Higher blood lactate level and less glucose preservation were found in PpardEC-KO mice after running the same distance as PpardEC-WT mice. In human endothelial cells, PPARD knockdown resulted in less glucose and fatty acid uptake. Glucose transport to myocyte from endothelial cells was also attenuated with PPARD knockdown. PPARD may act through SGK1 responsible for GLUT1 expression and glucose uptake. Our study showed an important role of endothelial cell in regulating nutrient transport into skeletal muscle during physical exercise. Impaired endothelial transport of glucose and fatty acid reduces exercise endurance.

This study is funded by the General Research Funds 14107822 and 14105321 from the Hong Kong University Grant Council.

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.
Insights into Disease Progression with spatial transcriptomics
Authors: Jin Yufang , Paniagua Karla , Flores Mario
Published: May 2024

In this work we present a pipeline (DeepTME) that integrates single cells transcription, spatial location of cells, cell type composition, and tissue morphology, using deep learning. DeepTME classifies the tissue microenvironments (TME) at single cell resolution by learning low-dimensional features from all transcription profiles, images similarity, neighboring information, and cell type composition, The proposed approach is able to capture important TME features than can used to quantify disease progression and severity and ultimately identify the molecular components of disease progression and obtain insight into their mechanisms.

National Institutes of Health.

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.
MAL-based, Cost-Effective Digital Complementary Alternative to the Traditional/Classic R&D Mindset
Authors: Chou Ting-Chao
Published: May 2024

In the search for the fundamental unified, integrated principle of science in biology, Chemistry, Physics, Mathematics, and Philosophy, the Mass-action Law (MAL) is the common denominator. This unique system study leads to the MAL dynamics/algorithm of biodynamics, pharmacodynamics, combination index, and bioinformatics (MAL-BD/PD/CI/BI). The theme is that one problem may be solved in multiple ways. Three basic revelations are i. The median-effect equation (MEE) for Action (Chou, 1976). It is also called the Doctrine of the Median (DOM); ii. The combination index equation (CIE) for Interaction (Chou-Talalay, 1984), where CI=1, <1, and >1 indicate additive effect, synergism, and antagonism, respectively, for all systems; iii. The dose-reduction index equation (DRIE) was introduced in 1988 (Chou et al.) for the consequence of interaction. All mathematical terms of MEE, CIE, and DRIE are dimensionless relativity ratios; thus, they have unlimited applicability independent of the unit, physical state, structure, size, and mechanism. This unified theory-based concept of the “top-down” approach is a departure from the observation/statistics-based traditional, classical R&D mindset. These two approaches are opposite yet complementary alternatives to one another. The MEE, CIE, and DRIE of MAL are all based on “One,” thus leading to the Unity of One Theory (UOT) as reported at AACR-NCI-EORTC (DOI: 10.1158/1535-7163.TARG-23-LB_B20, Boston, October 2023). The above MAL-based theory/algorithm has been largely neglected or encountered resistance for over two decades, but now, it achieves broad enthusiasm internationally, as indicated by citations in over 1,540 scientific journals and 1,328 patents or patent applications. The related MAL theory and algorithm have been discussed at ASBMB Dicovery-2023 (DOI: 10.1016/j.jbc.2023.103419), Meetings of ASPET -2023 (DOI: 10.1124/jpet.122.185320), and AACR -2023 (DOI: 10.1158/1535-7163.TARG-23-A017). More details will be given in an 11-chapter book, “Mass-Action Law Dynamics Theory and Algorithm for Translational and Precision Medicine Informatics.” (Academic Press 2024, in press). The same mathematical approach of MAL led to the discovery of the Second Degree Pascal Triangle, where all element numbers are squared, and introduced the algorithm for the weighted h-index for n-authored papers ( wh-index) for a fair attribution. This author will present an overview of this MAL-fundamental approach and further updates on new advancements in this research field at the APS Physiology Summit 2024.

No. Retired Director at MSKCC, since June 1, 2013.Founder, PD Science3, LLC (USA).

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.
Cardiorespiratory Disturbances in Alzheimer's Disease: A Focus on the Contribution of Sympathetic Premotor Neurons
Authors: Toledo Camilo , Del Rio Rodrigo
Published: May 2024

While therapeutic approaches targeting neurodegenerative mechanisms associated with cognitive impairment in Alzheimer's disease (AD) have been intensively explored, other comorbidities closely linked to AD progression, such as sleep-disordered breathing and autonomic dysfunction, have not been thoroughly investigated. In preliminary studies, we showed an increase in neural activity of catecholaminergic premotor neurons located in the rostral ventrolateral medulla region (RVLM-C1), a main region involved in cardiorespiratory regulation, in experimental AD. Therefore, in the present study, we aimed first to characterize cardiorespiratory function in AD patients and then to determine the role of RVLM-C1 neurons in autonomic and sleep-disordered breathing in APP/PS1 double transgenic mice, an experimental model showing AD-like pathology. Sixteen subjects (8 AD and 8 age-matched controls) were enrolled to assess sleep breathing disorders and to record cardiac autonomic function. Whole-body plethysmography and blood pressure monitoring in freely moving mice were used to study sleep-associated cardiorespiratory disorders. Bilateral stereotaxic injections of anti-dopamine β-hydroxylase-saporin (DβH-SAP) into the RVLM were used to selectively destroy C1 neurons. Compared to age-matched healthy subjects, patients with AD showed larger increases in neural sympathetic discharges during autonomic testing. In addition, heart rate variability analysis in AD patients showed a shift in spectral components towards a more sympathetic influence. Remarkably, we found that autonomic function impairment in the APP/PS1 mice resembles what we found in AD patients. Compared to wild type (WT), APP/PS1 mice displayed sympatho-excitation (ΔHR: -80±5 vs -125±10, WT vs APP/PS1, respectively), a higher incidence of cardiac arrhythmias (events/h 6.0±1.0 vs 12±1.5, WT vs APP/PS1, respectively), and sleep-disordered breathing (AHI: 8.5±2.0 vs 18.0±3.0, WT vs APP/PS1, respectively). Partial ablation of RVLM-C1 neurons (~70%) in APP/PS1 mice resulted in a two-fold and three-fold reduction in cardiac sympathetic drive and arrhythmogenesis, respectively. Furthermore, APP/PS1 mice treated with DβH-SAP showed marked improvements in breathing regularity (IS: 7.9±1.1 vs 16.9±2.2, APP/PS1DβH-SAP vs APP/PS1, respectively) and a restoration of normal sleep effciency (SE: 75.5±4.3 vs 58.1±6.4, APP/PS1DβH-SAP vs APP/PS1, respectively) compared to untreated APP/PS1 mice. Our results show that RVLM-C1 neurons play a main role in the development/maintenance of cardiorespiratory disorders in experimental AD.

FONDECYT 11220962, 1220950.

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.
Neuropeptide Y affects B-cell activation functions
Authors: Millet Antoine , Zhu Fengli , Jendzjowsky Nicholas
Published: May 2024

Introduction: Sympathetic nerves secrete neurotransmitters in response to pathogenic organisms in various immunological contexts. Most studies have focused on norepinephrine (NE) which has shown numerous immunomodulatory effects involving pro- and anti-inflammatory responses. However, sympathetic neurons contain also varicosities where neuropeptides, mainly neuropeptide Y (NPY), are stored. NPY play roles in various physiological processes, including regulating metabolism, vascular function, and immune function but little is known on its action during bacterial respiratory infection. The regulation of its secretion and its impact on the immune system during infection remains unclear. We investigated the role of NPY in B-cell responses during bacterial infection. Methods: Naïve B-cells isolated from mice splenocytes (2M/2F) were stimulated with IL-4 and LPS, along with NE or NPY. After 96 hours, cells were stained and analyzed by flow cytometry and transcripts were isolated for quantitative real-time PCR. Media was collected until immunoglobulin analysis. To investigate NPY role during infection, we used a mice model of bacterial lung infection. Mice were intranasally exposed twice with streptococcus pneumoniae (serotype 19F on day 0: 104 CFU and on day 9: 108 CFU); experiments took place 16 hours later. Control animals were infused with vehicle only. Results: Apart from beta2-adrenergic receptor, isolated B-cells were found to express alpha2- and beta1-adrenergic receptor transcripts. In vitro stimulation of B-cell with IL-4 and LPS (T-cell independent activation) downregulated beta-adrenergic and upregulated alpha2-adrenergic, as well as NPY receptors (Npy1r, Npy2r, Npy4r, Npy5r). Unlike NE, NPY has shown to affect B-cell proliferation and drastically increases IgG positive-cells during stimulation. However, neither NE nor NPY seem to regulate IgG release in this condition. In vivo experiments indicate that NPY level increased in the lung in response to streptococcal challenge, contrasting with the unchanged levels of NE. Conclusion: Our findings contribute to our understanding of how sympathetic neurotransmitters regulates B-cell expansion, memory, and antibody production during infection. Furthermore, our research gives new insights into the function(s) and antimicrobial capacity of neuropeptide Y. These findings allow for the development of new and more effective therapeutic strategies for invasive bacterial infections.

1R21AI159221, UCOP TRDRP T32KT4708.

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 Opioid Mu1-Recptors (μ1Rs) in The Inhalation of Carfentanil (CRF) Aerosol-Induced Respiratory Disorder in Awake Rats
Authors: Gao Xiuping , Zhuang Jianguo , Chen Zikuan , Shi Shan , Xu Fadi
Published: May 2024

Our previous study has shown that inhalation of fentanyl (100 mg/m3) for 10 min initially induces apnea, hypotension and bradycardia, leading to ventilatory and then cardiac arrest within 15 min in anesthetized rats (Zhuang J., et al, 2024). CRF acts on opioid mu-receptors (MORs) with a potency 100 times that of fentanyl. Inhalation of aerosolized CRF as a chemical weapon has been reported to cause sudden death in humans (Wax PM et al, 2003), but the cause of the death is not fully understood. Moreover, though the opioid-induced respiratory disorder is known to mainly result from the action of μ1Rs, the contribution of μ1Rs to the CRF-induced cardiorespiratory disorder remains unknown. Therefore, we asked whether acute inhalation of overdose CRF would induce cardiorespiratory disorder and sudden death via acting on μ1R in awake rats. The rats were exposed to aerosolized vehicle and CRF at 12.86 (low dose) or 20 mg/m3 (high dose) for 15 min with cardiorespiratory (VE, VT, fR, and HR) responses recorded for 60 min. The low and high doses of CRF induced sudden death in 1/6 and 2/2 rats respectively. Compared to aerosolized vehicle, the low dose of CRF initially decreased VE and HR by ~50% within 3 min exposure, which were maintained to the end of experiment, and all responses disappeared on the next day in the survived rats. Interestingly, the responses of breathing pattern to the CRF exposure were sequentially characterized by the rapid shallow breathing (within several seconds of the exposure), slow and deep breathing and then only slow breathing. In comparison, the dVE and bradycardia became much more aggravated after 15 min CRF aerosol-delivery in the dead rats than the survived ones, resulting in ventilatory and cardiac arrest within ~25 min post exposure. The cardiorespiratory responses to the low dose of CRF aerosol exposure were also performed after pretreatment with naloxone hydrochloride (NLX to systemically antagonize opioid receptors) or naloxonazine (NALZ to selectively antagonize μ1Rs). The CRF-induced dVE and bradycardia were fully blocked by NLX and largely alleviated by NALZ. In conclusion, our experiments not only establish a rat model of acute inhalation of CRF-induced cardiorespiratory disorder and sudden death, but also demonstrate a key role of opioid receptors, especially μ1Rs, in the CRF-induced cardiorespiratory disorder.

Supported by NIH R01 grants HL163512 and DA059063.

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.