bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nodose afferent fibers require PIEZO2 for esophageal mechanosensation
Authors: Nair SANJAY S , Hadley Stephen , Patil Mayur , Taylor-Clark Thomas 
Published: May 2024

The esophagus receives dual innervation of extrinsic afferent fibers from both the dorsal root ganglia as well as the vagal ganglia. These are polymodal sensory afferents that are able to sense a variety of stimuli that include chemical and mechanical stimuli. Previous research has demonstrated that the esophagus is innervated by low threshold mechanoreceptors arising from the nodose ganglia, which provide critical peripheral feedback that is required for proper swallowing and peristaltic reflexes. We know that in the vagal system, PIEZO2 plays a critical role in lung inflation and baroreceptor function in the aorta and carotid sinus. Hence, we hypothesize that PIEZO2 is the mechanotransducer in these nodose esophageal low threshold mechanoreceptors. We used a two-pronged approach to elucidate PIEZO2’s role in esophageal mechanosensation: first, GCaMP6s imaging and then single fiber electrophysiology to understand the kinetics of nodose esophageal afferent fiber activation. Both of these approaches used our ex-vivo intact vagal esophageal preparation. Our proof-of-principle studies were conducted in PIRT-GCaMP6s mice, obtained through the crossbreeding of Pirt-Cre (Cre expressed in all sensory neurons) mice with Cre-dependent, ROSA26 based, GCaMP6s reporter (B6.129S6-Gt(ROSA)26Sor-tm96(CAG-CGaMP6s)Hze). Our preliminary data in Pirt-GCaMP6s mice showed a profound increase in the Ca2+ influx in a subset of nodose neurons in response to mechanical distention of the esophagus at 5, 10, and 30mmHg pressures. For our knockout group, we obtained nodose-specific knockout of PIEZO2 by crossing P2X2-Cre mice (P2X2 is expressed in all nodose neurons) with PIEZO2fl/fl mice (P2X2/PIEZO2 KO mice). Upon performing our GCaMP6s imaging experiments in this group, we saw that there was a significant reduction in the number of nodose neurons that were responsive to esophageal distention (58% down to 17%). Comparing the fluorescence intensities of all esophageal neurons between the control and KO groups, we observed a significant reduction at all three intraesophageal pressures (p<0.05, n=458 and 395 neurons in control and KO groups, respectively). In our single fiber electrophysiology experiments, our control and KO groups were PIEZO2fl/fl mice and P2X2/PIEZO2 KO respectively. We were able to successfully record APs from A-fiber mechanosensitive esophageal neurons. The number of APs recorded from KO group was reduced at all the three intraesophageal pressures when compared to the control PIEZO2fl/fl mice. Our findings support the hypothesis that PIEZO2 is the mechanotransduction protein involved in vagal nodose afferent fibers innervating the esophagus. NIH. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Pulmonary Embolism Increases the Risk of Dyspnea in Pediatric Patients
Authors: Abidan Abulimiti , Robson Lydia , Pawelczyk James , Balmain Bryce N. , Babb Tony G. , Zia Ayesha 
Published: May 2024

This study investigated the association between pulmonary embolism (PE) and a subsequent diagnosis of dyspnea in pediatric patients using real world population-based data. We collected de-identified data from TriNetX, a global federated multicenter research database using both UTSouthwestern (UTSW) and Multinational Research Network. Patient ages of 8 to 21 with and without a diagnosis of pulmonary embolism (ICD-10-CM I26) were examined for associations with a new diagnosis of dyspnea (ICD-10-CM R06.0) three or more months after their initial PE diagnosis. The prevalence of PE significantly increased the risk for a new diagnosis of dyspnea after their initial PE diagnosis among all patients in the UTSW Network (risk ratio: 5.00) and Research Network (risk ratio: 6.55). In the Research Network, this risk was significantly higher for females than males (risk ratio: 6.06 Vs. 5.08) (all p<0.001). These findings suggesting that clinicians should consider PE as an independent risk factor for diagnosis of dyspnea in pediatric patients. Supported in part by NHLBI R38HL150214 (PI: Susan Hedayati). 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.
N-Methyl-D-aspartic acid (NMDA) mediated vasodilation in aorta
Authors: Yilmaz Gokhan , Alexander J. Steven 
Published: May 2024

Although N-Methyl-D-aspartic acid (NMDA) mediated vasodilation has been extensively studied in cerebral circulation, there are limited studies that address the NMDA-mediated vascular responses at the peripheral vascular system. In this study our objective is to address the peripheral vascular responses mediated by NMDA. Vascular responses were obtained via in vitro myography on thoracic aorta segments isolated from C57BL/6 wild type male mice. NMDA at the concentration range of 100 micromolar to 1 millimolar in aortic segments precontracted by 1 micromolar phenylephrine. Maximal vasodilation of 75% in reference to baseline prior to drug application was observed at 3mM NMDA. NMDA receptor blockade by MK-801 did not change NMDA-induced vasodilation (55% vs 58%). Neither vehicle of NMDA, nor corresponding osmolar solutions of mannitol to NMDA concentrations induced vasodilation. Nitric oxide synthase (NOS) inhibition by 100 micromolar m Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME) reduced 3mM NMDA induced vasodilation from 75% to 16%. Removal of endothelial cell layer did not change the vasodilation mediated by NMDA. NMDA at millimolar concentrations relaxes vascular smooth muscle via non-endothelium dependent and NMDA-receptor independent mechanisms. Vasodilatory response to NMDA appears partially mediated by NOS. It is possible that NMDA is exerting its vasodilatory effects via non-NMDA receptors on the vascular smooth muscle. Whether NMDA-induced vasorelaxation is observed in resistance arteries remains warranted. PSC CUNY 66608-00 54. 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.
Myeloid Ptpn2 Deficiency in Mice Causes Functional Iron Deficiency
Authors: Lei Hillmin , Spalinger Marianne , Santos Alina , Crawford Meli'sa , Shawki Ali , McCole Declan 
Published: May 2024

Background: Anemia is the most prevalent extraintestinal complication of inflammatory bowel disease (IBD) and is associated with the manifestation of Crohn’s disease. Anemia significantly reduces the quality of life, increases hospitalization visits, and increases medical care expenses of IBD patients. Iron deficiency is the leading cause of anemia in IBD; however, the physiological mechanisms involved are still poorly understood. Macrophages significantly contribute to iron homeostasis by mechanisms including iron recycling by phagocytosing senescent erythrocytes and damaged cells, and nurturing erythropoiesis in the bone marrow. In this study, we investigated the role of the IBD candidate gene, protein tyrosine phosphatase non-receptor type 2 ( PTPN2), in regulating macrophage iron homeostasis. Methods: Myeloid cell-specific knockout mice ( Ptpn2LysMCre) and control littermates ( Ptpn2fl/fl) were analyzed for serum iron content and liver and spleen non-heme iron. Duodenal epithelial cell (DEC) proteins were assayed by Western blotting. Localization of the brush border ferrous iron transporter, DMT1, and the coupled ferrous iron absorption driver, NHE3, in duodenal tissue was determined by immunohistochemistry (IHC). Gene expression profiles of macrophages were analyzed by Nanostring. Results: Ptpn2LysMCre mice had reduced serum iron ( p<0.0001; n=12) and reduced spleen non-heme iron (p=0.0017; n=6), whereas liver non-heme iron was unaltered (n=6), indicating iron deficiency in select tissues. DMT1 (n=8) and NHE3 (n=5) protein expression in DECs was unaltered and IHC confirmed the unaltered localization of DMT1 and NHE3 (n=6) in the duodenal epithelium of Ptpn2LysMCre mice, suggesting the reduction in serum iron was not due to an impairment in intestinal non-heme iron uptake. Nanostring analyses revealed that the gene expression of the iron transporter Dmt1, iron exporter Fpn, and iron importer Tfr1 were significantly downregulated (p<0.05; n=5) in macrophages from Ptpn2LysMCre mice, indicating an iron sequestering phenotype. Conclusions: Loss of myeloid Ptpn2 in mice causes functional iron deficiency. These findings indicate a major role of myeloid PTPN2 in regulating systemic iron homeostasis. 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.
Liposomal Nanocarriers of Preassembled Glycocalyx Restore Venular Permeability in Sepsis: Assessed Quantitatively with a Novel Microchamber System
Authors: Ishiko Shinya , Koller Akos , Deng Wensheng , Huang An , Sun Dong 
Published: May 2024

Background: The endothelial glycocalyx (EG), covering the luminal side of endothelial cells, regulates vascular permeability and senses wall shear stress. In sepsis, EG undergoes degradation leading to increased permeability and edema formation. We hypothesized that restoring EG integrity using liposomal nanocarriers of preassembled glycocalyx (LNPG) will restore normal venular permeability in a lipopolysaccharide (LPS)-induced sepsis model of mice. Methods: To test this hypothesis, we designed a unique perfusion microchamber in which the vascular permeability of isolated and cannulated mice mesenteric venules could be assessed by measuring the concentration of Evans blue dye (EBD) by fluorescent spectroscopy in microliter-samples of extravascular solution (ES). Results: Histamine-induced time- and dose-dependent increases in EBD in the ES could be measured, confirming the sensitivity of the microchamber system. Notably, the histamine-induced increase in permeability was significantly attenuated by histamine receptor (H1) antagonist, triprolidine hydrochloride. Subsequently, mice were treated with LPS, or LPS + LNPG. Compared to control mice, venules from LPS-treated mice showed a significant increased permeability, which was significantly reduced by LNPG administration. Moreover, in the presence of wall shear stress, intraluminal administration of LNPG significantly reduced the permeability in isolated venules from LPS-treated mice. Conclusion: Our newly developed microchamber system can quantitatively measure the permeability of isolated venules. LPS-induced sepsis increases permeability of venules that is attenuated by in vivo LNPG administration, which is also reestablished endothelial vasomotor responses to shear stress. Thus, LNPG presents a promising therapeutic potential for restoring EG function and thereby mitigating the increased permeability in sepsis. Support: National Institute of Health [grant number: HL144528, Dong Sun] and the Uehara Memorial Foundation [grant number: 202241049, Shinya Ishiko) and Hungarian Academy of Sciences Post-Covid 2021-34 (AK) and MIT of Hungary, National Research, Development, and Innovation Fund, OTKA K 132596 (AK). 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.
Discovery and mechanistic studies of a novel BKCa channel modulator inducing long openings
Authors: Lee Na Young , Jung Jun-Hyung , Lee Narasaem , Park Chul-Seung 
Published: May 2024

The large-conductance Ca2+-activated K+ channel (BKCa channel) plays critical roles in various tissues. In the smooth muscle of the urinary bladder, BKCa channel is highly expressed and regulates the spontaneous action potentials that control muscle contraction. Thus, the chemical activators for BKCa channel have their therapeutic potential against overactive bladder syndrome. Preveiously, we conducted a screening of a chemical library comprising 9,938 compounds in search of novel activators of the BKCa channel and performed structure-activity relationship study through hit compounds by using a cell-based fluorescence assay. Among the optimized compounds, DBTB-1 (N-[4-(2,4-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)-1,3-thiazol-2-yl]benzamide) displayed a robust activation of macroscopic BKCa channel currents in Xenopus oocytes. In contrast to other BKCa channel activators, DBTB-1 mainly influenced deactivation kinetics of the channel without affecting channel activation significantly. At the single-channel level, DBTB-1 increased the open-state probability compared to vehicle without affecting its single-channel conductance, indicating the delayed closing of the channel in the presence of the drug. Furthermore, analysis of the open dwell-time showed an additional population of long openings induced by DBTB-1. Thus, these unique characteristics of DBTB-1 can be useful in designing a new class of BKCa channel activators and might be utilized in developing therapuetics targeting specific aspect of the channel function. This research was supported by Korea Drug Development Fund funded by Ministry of Science and ICT, Ministry of Trade, Industry, and Energy, and Ministry of Health and Welfare (RS-2023-00258812). 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.
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.