bluuebunny/crossref_metadata_2025_split huggingface dataset:
Strategies for Teaching About Physiological Mechanisms of Obesity in Undergraduate Pathophysiology Courses
Authors: Walton Kristen 
Published: May 2024

Obesity is often viewed as a consequence of “lack of willpower” or other behavioral choices, rather than a complex array of biological and other factors. Many undergraduates in pre-nursing or biology programs have minimal exposure to the physiology and pathophysiology of obesity, including learning about leptin and other hormones involved in appetite control. Because obesity was not previously explicitly covered as s standalone topic in the pre-nursing pathophysiology course at my institution, I developed materials for teaching about the pathophysiology of obesity. These materials were designed at two different levels for use in two different pathophysiology courses: one, a survey of pathophysiology topics for pre-nursing majors, and the other, an in-depth exploration of the molecular and cellular basis of selected diseases for upper division biology majors. In both courses, a case of human leptin deficiency and the ob/ob mouse model are used to introduce the importance of hormones in appetite control and body weight. In the molecular basis of disease course, obesity is covered as part of a unit organized around metabolic syndrome. The discussion includes molecular and cellular mechanisms that link obesity to several other diseases, including type 2 diabetes and atherosclerosis. Informal feedback from students in the pre-nursing course at the end of the course suggested that students shifted their thinking about obesity from a purely behavioral phenomenon to a more nuanced understanding of obesity as a multifactorial condition. Overall, devoting class time to biological mechanisms of obesity has resulted in increased student understanding of the complex nature of body weight regulation. None. 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.
Vascular Dysfunction and Inflammation in Liver Transplant Recipients
Authors: Barton Brittany , Chavez Domenico , Connelly Margery , Bohmke Natalie , Wolver Susan , Siddiqui Mohammad , Kirkman Danielle 
Published: May 2024

INTRODUCTION Liver transplant (LT) recipients have an increased risk of developing cardiovascular disease (CVD) after transplant. The physiological mechanisms driving this risk are not fully understood. Vascular endothelial dysfunction is the initial pathophysiological step in the development of atherosclerosis. The objective of this study was to characterize vascular endothelial function in LT recipients. It was hypothesized that compared to matched healthy controls (HC), LT recipients would have impaired vascular function. METHODS. Conduit artery endothelial function was measured by flow-mediated dilation of the brachial artery (FMDBA) with duplex ultrasound in 40 LT patients (18 male, 22 female; mean ± SD: Age, 56±11 years) and 10 age matched HC (4 male, 6 female; Age 51±16 years). Central aortic blood pressures were derived from radial arterial tonometry and the use of the generalized transfer function. A venous blood sample was obtained for nuclear magnetic resonance spectroscopy assessment of the inflammation biomarker GlycA, and high-density lipoprotein (HDL) particle subspecies. A novel metabolic inflammation index was derived from plasma GlycA and HDL subparticle concentrations. RESULTS. LT recipients had higher peripheral (Median [IQR]: HC vs. LT, 119 [111-136] vs. 135 [124-147] mmHg, p=0.01) and central aortic (113 [102-126] vs. 124 [116-139] mmHg, p=0.03) systolic blood pressures. LT recipients had impaired vascular endothelial function (HC vs. LT, FMDBA: 6.08 [5.01-7.61] vs. 4.54 [3.31-6.24] %, p = 0.04). In LT recipients, the inflammation index (55 [45-62] AU) was negatively associated with vascular endothelial function ( r=-0.4, p=0.03). CONCLUSIONS. Despite optimal pharmacological intervention, LT recipients had higher systolic blood pressures and worse vascular endothelial dysfunction compared to HC. In LT recipients, a higher inflammation index was associated with worse endothelial function, suggesting that chronic low-grade inflammation may partly contribute to endothelial dysfunction in this patient population. These findings provide support for the vascular endothelium as a potential therapeutic target to improve cardiovascular health in LT recipients. Supported by CTSA award No. UM1TR004360 from the National Center for Advancing Translational Sciences. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Impact of exercise training on endothelial metabolism and skeletal muscle angiogenic potential in type 2 diabetes
Authors: Moller Sophie , Hansen Maria , Wickham Kate A. , Pedersen Thomas Å. , Åkerström Thorbjörn , Helge Jørn W. , Dela Flemming 
Published: May 2024

Type 2 diabetes (T2D) is associated with vascular endothelial dysfunction and microvascular rarefaction in skeletal muscle tissue (1). Although endothelial dysfunction in metabolic disease is proposed to be associated with altered endothelial cell metabolism, there is to date a paucity of human data to support this notion. The aim of this study was to investigate the metabolism in microvascular endothelial cells derived from skeletal muscle biopsies. Moreover, as exercise training is known to reverse endothelial dysfunction and promote angiogenesis, the effect of a period of exercise training was assessed. Microvascular endothelial cells were isolated from m. vastus lateralis biopsies taken from obese individuals with (n = 7) and without (n = 8) T2D before and after 12 weeks of aerobic exercise training. Mitochondrial respiration, hydrogen peroxide (H2O2) emission, and nitric oxide (NO) formation were determined in the cells by the Oroboros Oxygraph-2K. In addition, angiogenic-, metabolic- and antioxidant enzymes and proteins, cell proliferation, and skeletal muscle capillarization were determined. At baseline, there was no difference between endothelial cells from obese control participants and T2D obese participants for any of the parameters measured: glycolytic capacity, as evidenced by a similar lactate production and PFK-1 protein content, respiratory capacity, H2O2 emission, NO emission, endothelial NO synthase protein (eNOS) content. The training period led to an overall increase in the respiratory capacity in endothelial cells from both groups (main effect, P = 0.021) whereas mitochondrial H2O2 emission remained unaltered. There was no change in glycolytic capacity, superoxide dismutase 2 or eNOS protein contents, or NO emission. Training did not influence the capillary-to-muscle fiber ratio in either group. The results of this study show that aerobic exercise training of obese control and obese diabetic subjects leads to an increase in the respiratory capacity of muscle microvascular endothelial cells. The data also indicate that there are no differences in endothelial metabolism and NO production between obese control and obese diabetic individuals. However, as the study is ongoing and only half of the subjects have been included at this time, power is limited and results may differ upon completion. Data from all subjects will be presented at the conference. Funding: The study is funded by Novo Nordisk A/S. 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.
Mitochondrial Fragmentation Increases with Aging in Rats
Authors: Alamodi Maryam , Dasgupta Debanjali , Fogarty Matthew , Mantilla Carlos B. , Sieck Gary 
Published: May 2024

The diaphragm muscle (DIAm) is the major pump muscle for breathing. Neural control of the DIAm involves recruitment of phrenic motor neurons (PhMNs) comprising motor units that vary in their mechanical and fatigue properties. Smaller PhMNs innervating fatigue resistant DIAm fibers are highly active being recruited during breathing, while larger PhMNs are infrequently recruited during more forceful expulsive behaviors. Previously, we found that to support their higher activity levels, smaller PhMNs have higher mitochondrial volume density and are less fragmented compared to larger PhMNs. With aging, larger PhMNs are more vulnerable and ~30% are lost, and those surviving display greater mitochondrial fragmentation. We also found that older rats exhibit elevated levels of the proinflammatory cytokine tumor necrosis factor alpha (TNFa), which in other tissue has been linked to mitochondrial fragmentation via activation of the IRE1a S724-mediated endoplasmic reticulum (ER) stress pathway. Accordingly, we hypothesized that in 24-month-old rats, increased TNFa levels activate the pIRE1aS724-mediated ER stress pathway, leading to XBP1s splicing, which transcriptionally increases expression of cyclin-dependent kinases (CDK1 and CDK5) that mediate phosphorylation of DRP1 at Serine 616 (pDRP1S616), and ultimately mitochondrial fragmentation. We found that serum TNFa levels increased ~3.5 fold in 24-month rats compared to 6-month rats. Consistent with elevated TNFa, we found increased pIRE1aS724 and XBP1s splicing in the cervical ventral horn of 24-month rats. In retrogradely labeled PhMNs, we found XBP1s was localized to the nucleus, consistent with transcriptional activation of gene expression. Bioinformatic analysis and ChIP assay confirmed XBP1s binding to the CDK1 and CDK5 promoter regions in rat cervical ventral horn. Both CDK1 and CDK5 mRNA and protein were elevated in the cervical ventral of 24-month rats. In aged rats, pDRP1S616 phosphorylation increased with a corresponding increase in mitochondrial fragmentation. Our results support our hypothesis that chronic inflammation (elevated TNFa levels) in older rats activate the pIRE1aS724-mediated ER stress pathway, leading to XBP1s splicing, which transcriptionally targets CDK1 and CDK5 expression mediating pDRP1S616 phosphorylation and mitochondrial fragmentation. Research Supported by NIH R01 grant AG44615. 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.
Examining the relationship between Locus coeruleus (LC) activity and breathing in response to chemical exposure
Authors: Warden Matthew , Szujewski Caroline , Browe Brigitte , Garcia Alfredo J. 
Published: May 2024

Objective: The control of breathing must continuously adapt in response to homeostatic changes. This is particularly important in the context of chemical exposure to substances such as opioids and anesthetic gases known to suppress the drive for breathing. While these agents suppress breathing through different modalities, how they affect neuromodulatory networks capable of influencing breathing remains unknown. This ongoing study aims to understand how exposure to the ultrapotent synthetic opioid (UPSO), fentanyl, and the anesthetic gas, isoflurane, affect the relationship between LC activity and breathing. Hypothesis: We hypothesize that fentanyl and isoflurane have divergent effects on the relationship between LC activity and breathing. Methods: Measurements were made using unrestrained whole-body plethysmography and fiber photometry in NET-cre positive mice expressing GCaMP8s while breathing room air (FiO2=21%) before and following the administration of either fentanyl (0.7 mg/kg i.p.) or exposure to isoflurane (1.5% inhaled). Post-hoc analyses were conducted using MATLAB. Results: Our analyses showed that awake mice (N=8) exhibited two types of LC activity. Type 1 LC activity coincided with high frequency respiratory transients (HFRTs); whereas Type 2 activity did not appear to coincide with changes in breathing. Both fentanyl (N=5) and isoflurane (N=3) suppressed breathing with a greater degree occurring with the UPSO. Furthermore, the frequency of LC activity increased during opioid-induced respiratory depression (OIRD) where both types of LC activity were evident. Isoflurane anesthetized mice showed decreased Type 1 LC activity and a reduction in the duration of Type 2 activity while breathing either room air or hypoxia (FiO2=10%). Conclusion: While isoflurane suppressed Type 1 LC activity in room air and hypoxia, fentanyl which caused a larger suppression in breathing, preserved Type 1 LC activity. These differential effects suggest that the contribution of LC activity to breathing fundamentally changes when exposed to either anesthesia or fentanyl, which may be relevant to understanding the physiological consequences of exposure to either agent. This work was supported by NIH: R01HL163965, R01DA057767. 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.
Identification of proteins differentially associated with Npt2a in the presence and absence of NHERF1
Authors: Lederer Eleanor , Gagnon Kenneth , Merchant Michael 
Published: May 2024

Background: NHERF1 deficient mice are hypophosphatemic and phosphaturic due to failure of functional apical membrane localization of Npt2a. Wild type (WT) and NHERF1 knock out (KO) mice show similar proximal tubule protein expression of Npt2a. Previous studies have shown that dissociation of Npt2a and NHERF1 stimulated by PTH and FGF23 results in lysosomal degradation of Npt2a. The persistence of Npt2a expression in NHERF1 deficiency suggests a defect in Npt2a forward traffcking. Hypothesis: We hypothesized that comparison of Npt2a-associated proteins from WT and KO mouse kidney cortex would identify novel proteins critical for forward traffcking of Npt2a. Methods: We immunoprecipitated homogenized kidney cortex from WT and NHERF1 KO C57Bl6 mice using a polyclonal Npt2a antibody followed by proteomic analysis using liquid chromatography-mass spectrometry and the STRING database of known and predicted protein-protein interactions. Results: We identified 31 proteins that showed statistically significantly greater association with Npt2a in WT kidney cortex and 50 proteins that showed statistically significantly greater association with Npt2a in KO kidney cortex. We did not identify greater association of Npt2a from KO kidney cortex with any of the other known PDZ proteins known to associate with Npt2a including PDZK1 and PIST. Among the proteins more highly associated with Npt2a in KO were 14-3-3 and valacyclovir hydrolase. STRING analysis of the WT-associated proteins identified membrane transport, phosphate ion homeostasis, and oxidative phosphorylation as important biological processes. Analysis of the KO-associated proteins identified DNA unwinding, regulation of cytoplasmic translation, and clathrin-dependent endocytosis were identified as important biological processes in the absence of NHERF1. Conclusions: We conclude that the aberrantly-traffcked Npt2a in KO has successfully traversed the Golgi and is correctly folded but may interact with 14-3-3 through its PDZ binding motif, preventing forward traffcking. We also conclude that the function of Npt2a may significantly change when the cotransporter does not properly forward traffc in the absence of NHERF1 expression. Support for EDL from Dept Veterans Affairs CX0001614 and the Pak Mineral Metabolism Center. 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.
Theoretical modeling of tumor angiogenesis: the opposing effects of vascular endothelial growth factor and angiopoietin-2
Authors: Nguyen Vivian , Secomb Timothy 
Published: May 2024

Tumor microvascular networks are highly unstable, disorganized structures that obstruct cancer therapeutics by poorly distributing blood flow and oxygen. The elevated release of vascular endothelial growth factor (VEGF) by solid tumors has been widely implicated in pathological angiogenesis, or the growth of new blood vessels. However, how VEGF overexpression leads to the malformation of vascular networks is incompletely understood. Angiopoietin-2 (Ang2) is a destabilization factor that has been shown to promote sprouting in the presence of VEGF with hypoxia, but regression in its absence. Here, we hypothesize that the tumor environment, which sustains VEGF production under conditions of normoxia, also promotes Ang2-induced regression. A theoretical model is developed representing the 3-dimensional growth, remodeling, and pruning of microvascular networks in early-stage tumors to investigate the combined effects of VEGF and Ang2. Oxygen transport by the growing vascular network is simulated. VEGF production is induced by hypoxia and also elevated independent of oxygen levels in the expanding tumor region. Angiogenesis is stimulated in response to elevated VEGF levels. The model predicts that the release of VEGF in normoxic regions without counteracting factors results in very high tumor vascular densities compared to normal tissue, which is not observed experimentally. Introducing the regressive effects of Ang2 limits vascular density and produces greater variability in oxygen levels in the tumor region. Vascular networks in the tumor generated from the model show comparable densities to surrounding tissue, in which an elevated rate of sprouting is balanced by Ang2-induced regression. In this state, continuous turnover of vessels is predicted, while a relatively constant vascular density is maintained. These simulations suggest that the destabilizing role of Ang2 is an important factor that should be included in theoretical models for tumor angiogenesis. While Ang2 activity is already targeted in a number of clinical trials, clarifying the dynamic role of Ang2 may help advance angiogenesis-based therapeutic approaches. Supported by NIH grant HL034555. 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 potassium as a coronary metabolic vasodilator
Authors: Warne Cooper , Heard Michael , Essajee Salman , Tucker Selina , Tune Johnathan , Dick Gregory 
Published: May 2024

K+ release from the myocardium is associated with decreased coronary vascular resistance. Accumulation of extracellular K+ has been linked to mechanisms of vasodilation in the coronary circulation including activation of the electrogenic Na+-K+ pump in smooth muscle (Murray and Sparks, Circ. Res. 1977) and endothelial-mediated hyperpolarization via Kir2.1 channels (Zhao et al., PNAS 2020). Our objective was to examine K+ as a coronary metabolic vasodilator in vivo. Further, we addressed two potential shortcomings of previous studies: the short duration of the bolus K+ stimulus employed and the seemingly high concentrations required to produce vasodilation. We hypothesized that continuous, steady-state intracoronary infusions of K+ would produce sustained coronary vasodilation in a concentration-dependent manner. Our methods involved instrumenting anesthetized, open-chest Yorkshire swine (male and female, 60 kg) for measurements of coronary blood flow, as well as arterial and coronary venous blood sampling. The left anterior descending coronary artery was cannulated and perfused under the control of a pressure servo, allowing us to determine flow and infuse K+. Our results show small, but statistically significant (* represents p < 0.05), effects of K+ on coronary hemodynamics. The coronary venous K+ concentration was 4.0 ± 0.1 mM at baseline. Infusing K+ into the coronary artery at increasing rates increased coronary venous K+ to 4.9 ± 0.2*, 6.4 ± 0.2*, and 7.9 ± 0.2* mM. Higher K+ concentrations caused fatal arrhythmias. Coronary blood flow was 0.73 ± 0.14 ml/min/g at baseline. Infusing K+ into the coronary artery at increasing rates increased coronary blood flow to 0.78 ± 0.14*, 0.82 ± 0.15*, and 0.86 ± 0.16* ml/min/g. These small coronary blood flow changes were sustained during continuous K+ infusion. We conclude that K+ is a coronary vasodilator, as has been demonstrated previously. Importantly, however, we emphasize that the effects of K+ are extremely modest and the concentrations required to produce physiologically significant vasodilation are life-threatening. With the assumption that the venous K+ concentration is in equilibrium with that surrounding the smooth muscle and cardiac muscle of the working heart, we urge caution in interpreting isolated artery studies that routinely use 15-20 mM K+ to elicit hyperpolarization and vasodilation. Our data do not support the idea that K+ plays a major role in regulating coronary vascular resistance. This work was supported by National Institutes of Health grant R01 HL158723. 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.