bluuebunny/crossref_metadata_2025_split huggingface dataset:
Contributions of ATP12A, a non-gastric proton pump alpha subunit, to the pathogenesis of idiopathic pulmonary fibrosis
Authors: Li Xiaopeng , Abdelgied Mohamed , Uhl Katie , Chen Oliver , Schultz Chad , Tripp Kaylie , Peraino Angela , Paithankar Shreya , Chen Bin , Tamae Kakazu Maximiliano , Castillo Bahena Alicia , Jager Tara , Lawson Cameron , Chesla Dave , Pestov Nikolay , Modyanov Nikolai , Prokop Jeremy , Neubig Richard , Uhal Bruce , Girgis Reda 
Published: May 2023

Background: Idiopathic Pulmonary Fibrosis (IPF) is a pathological condition of unknown etiology which results from injury to the lung and an ensuing fibrotic response that leads to the thickening of the alveolar walls and obliteration of the alveolar space. The pathogenesis is not clear and there are currently no effective therapies for IPF. Small airway disease and mucus accumulation are prominent features in IPF lungs, similar to Cystic Fibrosis (CF) lung disease. The ATP12A gene encodes the alpha-subunit of the non-gastric H+, K+-ATPase, which functions to acidify the airway surface liquid (ASL) and impairs mucociliary transport function in cystic fibrosis patients. Hypothesis: We hypothesize that the ATP12A protein may play a role in the pathogenesis of IPF. Methods: ATP12A expression level was evaluated by immunohistochemical staining and RNAscope in situ hybridization in normal and IPF human distal lungs. Primary human small airway culture model was used to elucidate the potential roles of ATP12A in the activation of latent TGF-beta activation. Viral vector mediated ATP12A overexpression was used in the bleomycin-induced lung fibrosis mouse model. A potassium-competitive proton pump blocker, vonoprazan was used to block ATP12A functions both in vitro and in vivo. Results: Our studies demonstrate that ATP12A protein is overexpressed in distal small airways from IPF patient lungs compared to normal human lungs. Potassium competitive proton pump blocker vonoprazan decreased airway surface liquid (ASL) pH and TGF-β1 activation in IPF small airway epithelial cells. In addition, overexpression of the ATP12A protein in mouse lungs worsened the Bleomycin (BLEO)-induced experimental pulmonary fibrosis. This was prevented by a potassium-competitive proton pump blocker, vonoprazan. Conclusion: Those data support that the ATP12A protein plays an important role in the pathogenesis of lung fibrosis. Inhibition of the ATP12A protein has the potential as a novel therapeutic strategy in IPF. This work was funded by the National Institutes of Health (HL153165-01A1 to X.L.), the Cystic Fibrosis Foundation (LI19XX0), Cystic Fibrosis Research Institute, and Spectrum Health-MSU Alliance Corporation funds. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
The impact of the pointless system of grading in an undergraduate physiology class
Authors: Safford Susan 
Published: May 2023

The pointless system of assessment is a relatively new concept and few papers have been published demonstrating its usefulness in higher education, particularly in STEM classes. The current study was undertaken to determine the usefulness of this pedagogy in assisting students to master physiological concepts. The hypothesis is that students will respond positively to this assessment and show improved mastery of concepts. All assignments and tests require written answers that involve explanation of concepts and mechanisms. All work, except exams, can be revised, and detailed feedback and rubrics are given for each assignment. Student work is rated as exceeds, meets or approaches expectations. Class work is divided into categories (writing, exams, case studies, lab handouts, lab reports) and each category is rated as exceeds, meets or approaches expectations depending on the overall quality of the work in each category. Final grades are awarded based on a matrix of how many categories are rated at each level as shown in Table 1. [Table: see text] This approach was used in spring 2021 under IRB# LUIRB03022021SS with a physiology class while students were remote. In 2021, all the students revised some of their work and learned from their revisions as evidenced by improved first drafts in subsequent work. Students seemed to master concepts better with this system as 85% of the students scored exceeds expectations on comprehensive mid-term and final exams. Student comments on a reflective writing exercise indicated that most of the students liked this approach despite the perceived increase in workload. Students indicated that they believed they learned the concepts better and they were less concerned about trying to remember minutia. This approach is currently being used for the second time during the spring 2023 semester in a face-to-face physiology course. One goal for this year is to see if the outcomes are similar in a face-to-face class. The first student assignments are due shortly, so summary data for this semester is not yet available. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Investigation into the role of Apj and Vegf receptor signaling in the regulation of coronary angiogenesis
Authors: Kuschel Bryce , Sharma Bikram 
Published: May 2023

Coronary artery disease (CAD) is one of the leading causes of death worldwide; however, a therapeutic remedy has not been developed. Coronary angiogenesis, a process by which new coronary vessels are formed in the embryos, is primarily a function of endothelial cells which form the inner lining of the vessel wall. Therefore, understanding coronary endothelial cells' cellular and molecular biology can teach us how to effectively stimulate the repair and regeneration of damaged coronary vessels. Investigations in mice have identified the Apelin receptor (alias: APJ) and Vascular endothelial growth factor receptor 2 (VEGFR2) signaling as regulators of coronary angiogenesis. However, it is unclear whether APJ and VEGFR2 signaling interact with one another in the regulation of coronary angiogenesis. To investigate this, we performed in vitro cell culture experiments using isolated coronary endothelial cells and in vivo experiments with APJ KO mice. We hypothesize that ELABELA/APJ signaling downregulates VEGFR2 expression in coronary endothelial cells. Our expression analysis using immunostaining and qPCR show that APJ loss-of-function in coronary endothelial cells results in increased VEGFR2 expression. Collectively, our results show that ELABELA/APJ suppresses VEGFR2 signaling during coronary angiogenesis. This study is supported by the NIH R15 (1R15HL159660-01) research grant to BS. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Mice lacking angiotensin AT1A receptors in neurons exhibit a behavioral preference for decreased ambient temperature
Authors: Grobe Connie , Freudinger Bonnie , Sherman Alexander , Burnett Colin , Segar Jeffrey , Grobe Justin 
Published: May 2023

The local tissue renin-angiotensin system (RAS) within the brain is implicated in cardiometabolic control, including core temperature and resting metabolic rate (RMR). Previously we demonstrated a critical role for the angiotensin (ANG) type 1A receptor (AT1R), localized to neurons of the hypothalamic arcuate nucleus that express Agouti-related peptide (AgRP), in the control of RMR. Further, we demonstrated that mice deficient for melanocortin type 4 receptors (MC4R) for AgRP resist stimulation of RMR by ANG in the brain. Given the known projections of AgRP neurons and RMR-regulating networks within the forebrain and hypothalamus, we hypothesize that ANG in the brain acts to sensitize the animal to the sensation of cold, rather than to directly stimulate pre-autonomic functions. To test this hypothesis, we examined the consequences of genetically deleting the AT1R gene from all neurons upon ambient temperature preference, as mice with inhibited sensation of cold should prefer a colder temperature, while mice with inhibited stimulation of pre-autonomic areas should prefer a warmer temperature. We constructed a thermal gradient that consisted of four parallel lanes with opaque white polycarbonate walls (58.4 x 7.5 cm, 20.5 cm tall) and an aluminum floor. Temperature-controlled circulating water baths supplied heating/cooling blocks on opposite ends of lanes to generate a linear temperature gradient as assessed using infrared imaging (FLIR A700: gradient range 40-15°C; T=38.40-0.04091✕D, R2=0.99, where D=distance from warmed end of lane, in mm) that was similar between lanes (within 0.87±0.31°C). Mice were placed in the center of the gradient and mouse position in the gradient was analyzed continuously for 2h by video (AnyMaze, Stoelting) during the middle of the light phase. Mice with AT1R deleted from neurons ( Syn1-Cre+/- x Agtr1a F/F, n=3m+4f) and littermate controls ( Agtr1a F/F, n=3m) on the C57BL/6 background exhibited similar decaying locomotor activity for the first 90 min before reaching a nadir in activity between 90-120 min (23±13 cm/min, p=ns between groups). Between 90-120 min, the knockout mice localized to a significantly lower ambient temperature than controls (28.1±1.0 vs 31.9±0.3°C, p=0.04). Validating our approach, others have previously reported 32-33°C as the preferred light-phase ambient temperature for adult mice. Together, these findings demonstrate our fabrication and validation of a thermal gradient system for mice and support the working hypothesis that the brain RAS functions to modify the integration of cold stimuli, ultimately to influence energy homeostasis. HL134850, HL084207, DK133121, UL1TR001436, 18EIA33890055 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Isolated Human Mesenteric Arteries from Organ Donors as a Model to Determine Arterial Reactivity
Authors: Bloom Charissa , Zimmermann Rollin Isabela , McQueen Jenna , Iyer Vishnu , Breslin Jerome 
Published: May 2023

Few studies have explored reactivity of isolated human arteries to chemical mediators. The purpose of this research was to establish a model utilizing mesenteric arteries isolated from donated human organs to study tone. The general hypothesis was that the arteries would be viable and would respond to stimuli such as alpha-receptor agonists, thromboxane receptor agonists, and endothelin-1. Intact human small intestines were provided by LifeLink. Mesenteric arteries were carefully dissected and cut into 2 mm rings. Then they were mounted on parallel wires of a DMT Multi Wire Myograph System Model 620M and stretched to an internal vessel circumference corresponding to native transmural pressure (13.3 kPa). The vessels were bathed in a physiological salt solution at 37°C. Viability of the vessels was tested with a physiological salt solution containing 60 mM KCl. Afterwards, the vessels were treated with increasing concentrations of one of the following vasoconstrictive agents: U46619, phenylephrine (PE), and endothelin-1 (ET-1). Potential differences between age groups, sexes, and different health conditions among donors were investigated. Concentration-response curves were constructed and the EC50 and maximum tension were determined for each drug. The results show that the arteries were nearly always viable and responded to each of the three drugs. There was no significant difference among age groups or between sex for any of the agents. There was a significant difference in the maximum of the concentration-response curve for U46619 between donors who had diabetes vs. no diabetes. Also, donors with hypertension had a higher EC50 for phenylephrine, with rightward shift in the concentration-response curve, compared to individuals who did not have hypertension. Collectively, these findings suggest that human arteries isolated from organ donor mesentery are a reliable model for evaluating arterial contractile reactivity. In addition, insights into how different disease states impact arterial function can be gained from this type of study. Supported by NIH Grant R21AA029213 and the generous donations of organs for research by LifeLink. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Investigating the effects of thermoneutral housing on skeletal and cardiac muscle function in D2 mdx mice
Authors: Wasilewicz Luc , Hamstra Sophie , Hockey Briana , Braun Jessica , Marcella Bianca , Baranowski Ryan , MacPherson Rebecca , Fajardo Val 
Published: May 2023

Since its discovery, the mdx mouse has been the foundation for research on Duchenne muscular dystrophy (DMD) and its potential therapies. Although, nearly all studies using mdx mice as an experimental model have been conducted under “standard” lab conditions using room (22C) instead of thermoneutral (TN, 30C) temperature housing. Room temperature (RT) is a mild cold stress to mice, causing metabolic adaptations that can confound experimental results, limiting their interpretation and translation to humans. This study investigated the effects of housing temperature on whole-body metabolism and skeletal and cardiac muscle function in the mdx mouse. To this end, 20 D2 mdx mice (age 5 weeks, n = 10 per group) were housed at RT and TN for 10 weeks. Metabolic cage analysis demonstrated that TN housed mdx mice displayed significantly decreased VO2 consumption and reduced food intake that was likely due to lowered daily energy expenditure. TN housed mice also had significantly lower respiratory exchange ratio values, indicative of increased fat metabolism. However, there were no differences in body mass or composition (i.e., % lean and fat mass). Treadmill-to-fatigue experiments revealed no differences in exercise performance. Furthermore, ex vivo muscle contractility analysis displayed no differences in extensor digitorum longus or soleus specific force generation between TN and RT housed mice. Analysis of cardiac structure/function demonstrated that TN housed mdx mice exhibited a reduction in cardiac output, which we attributed to diastolic dysfunction. While ejection fraction and fractional shortening were not different among the two groups, TN housing led to a significant reduction in end diastolic volume (EDV) and left ventricle internal diameter (diastole, LVID;d), as well as increased relative wall thickness (diastole, RWT;d) compared to RT housed mice. Though isovolumic relaxation time was prolonged in TN-housed mice, this did not reach statistical significance. Taken together, our results demonstrate that TN housing had minimal effects on skeletal muscle contractility, but did lead to signs of diastolic dysfunction in young mdx mice. Future studies will examine the effects of TN housing in aged mdx mice, when systolic dysfunction occurs, as well as any influence of TN housing on the efficacy of potential muscle wasting therapeutics. Overall, our results support the growing literature that highlights the importance of selecting the appropriate housing temperature when studying metabolism or muscle wasting conditions in mice. NSERC This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Protonic Action Potential: Better understanding neural stimulation by touch
Authors: Lee James 
Published: May 2023

The 2021 Nobel Prize in Physiology or Medicine was recently awarded to David Julius and Ardem Patapoutian “for their discoveries of receptors for temperature and touch.” It is now well established that touch receptors provide sensory inputs to inform the brain about objects in our environment. Touch sensation is vital for survival and, without it, even simple activities such as feeding, dressing, or standing would be exceedingly difficult to accomplish. Like hearing, balance, and proprioception, touch is initiated by mechanosensory receptor cells. These cells contain mechanotransduction channels (such as PIEZO), which convert physical stimuli into membrane potential changes, called receptor potentials, that trigger neuronal action potentials. These action potentials are transmitted by sensory afferents to the brain, where sensory percepts are formed. However, exactly how the transient ion transport activity of touch receptors can stimulate the firing of action potentials seems still not entirely clear. In this presentation, we will employ the latest transmembrane-electrostatic proton localization theory with a newly formulated membrane potential equation to better understand neural resting and action potential as the voltage contributed by the transmembrane-electrostatically localized protons/cations charges (TELC) at a neural liquid-membrane interface. Accordingly, the neural stimulation by touch can now be better elucidated through analysis of PIEZO conduction and TELC activity with the newly formulated membrane potential equation. This research was supported in part by a Multidisciplinary Biomedical Research Seed Funding Grant from the Graduate School, the College of Sciences, and the Center for Bioelectrics at Old Dominion University, Norfolk, Virginia, USA. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Novel regulatory role of post-translational structural modification in modulating Src kinase activity in pulmonary arterial hypertension
Authors: Alhawaj Raed , Ghadhanfar Elham , Cherian Susan 
Published: May 2023

Under conditions that lead to pulmonary arterial hypertension (PAH), the pro-proliferative oncoprotein Src kinase activity is elevated, contributing to pulmonary arterial smooth muscle cell remodeling, increasing vascular resistance, and leading to PAH. In addition, reactive oxygen species (ROS), including Hydrogen peroxide (H2O2), are elevated in the pulmonary vasculature under pro-PAH conditions. Therefore, we hypothesized that Src kinase is subject to redox modulation by elevated hydrogen peroxide (H2O2) under pro-PAH conditions. We intended to explore whether increased H2O2 can cause the oxidation of Src kinase thiol groups resulting in an inter-molecular disulfide bond forming Src kinase homodimer, increasing its catalytic activity. The results of this study detected evidence that Src kinase undergoes redox-induced homodimer formation as illustrated by western blot analysis under non-reducing conditions of rat MCT-induced PAH lung lysates. Furthermore, the redox-mediated Src kinase homodimer formation was associated with the increased catalytic activity of Src kinase, as seen in its intra-molecular auto-phosphorylation of its tyrosine 416 residue. This process was accompanied by activating one of Src kinase downstream substrates, STAT3, via the phosphorylation of its tyrosine 705 residue. Moreover, these mechanistic changes were associated with a PAH disease state confirmed with elevated right ventricle systolic pressure and right ventricle hypertrophy through right ventricle catheterization and the Fulton index, respectively. From the results above, we can conclude that in rat MCT-PAH lung lysates, Src kinase undergoes a redox-induced modulation that results in a structural modification associated with increased Src kinase activity, as observed in its autophosphorylation and the phosphorylation of its downstream substrate STAT3. In conclusion, under conditions that lead to PAH, Src kinase undergoes a post-translational structural modification. This modification occurs in redox-induced oxidation of Src kinase thiol groups. This process results in an inter-molecular disulfide bond formation yielding a homodimer associated with elevated Src kinase catalytic activity, further adding a mechanistic layer to Src kinase regulation in PAH. Kuwait University Research Sector This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
MCT4 Deficiency Enhances High-intensity Interval Training-induced Metabolic Adaptations in Skeletal Muscle
Authors: Tamura Yuki 
Published: May 2023

The purpose of this study was to understand the effect of increased lactate accumulation in skeletal muscle by MCT4 deficiency on the adaptation of skeletal muscle to high-intensity interval training. To address this challenge, we first developed MCT4-deficient mice with a genetic background of the Jcl:ICR strain which is capable of performing high-intensity exercise. We found that MCT4 deficiency enhances high-intensity interval training-induced improvement of endurance exercise capacity at high intensity. Furthermore, it was also shown that the combination of MCT4 deficiency and high-intensity interval training, coupled with the physiological context of such adaptation, increases enzyme activity of the glycolysis and the mitochondrial oxidative capacity of pyruvate. The findings of this study would help us understand the physiological significance of lactate accumulation in skeletal muscle with high-intensity exercise. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.