bluuebunny/crossref_metadata_2025_split huggingface dataset:
Roles of the nuclear receptor corepressor 1 (NCoR1) and the silencing mediator of retinoid and thyroid hormone receptors (SMRT) in the developing brain
Authors: Amano Izuki , Ninomiya Ayane , Kawabata-Iwakawa Reika , Ritter Megan , Hollenberg Anthony , Koibuchi Noriyuki 
Published: May 2023

The nuclear receptor corepressor 1 (NCoR1) and the silencing mediator of retinoic acid and thyroid hormone (SMRT) are critical coregulators of the nuclear receptor (e.g., thyroid hormone receptors and retinoic acid receptors), mediating transcriptional repression via histone deacetylation. Although they are highly homologous and have similar nuclear receptor interaction domains, they have different roles in different organs. Recently, de novo genetic variants in nuclear corepressors were found in pediatric patients with neurodevelopmental disorders. Thus, we generated the mouse models to understand the role of NCOR1 and SMRT in the central nervous system. We used the mice with conditional NCoR1 or SMRT (NCoR1lox/lox or SMRTlox/lox) alleles in combination with the mice that express Cre recombinase in a neuronal specific fashion (Snap25-Ires2-Cre). First, we performed a battery of behavioral tests to screen behavioral phenotype of mice. We found that hypoactivity, social deficits, and mild anxiety in neuronal specific NCoR1 or SMRT KO mice. In addition, NCoR1 KO mice showed high learning abilities in pairwise visual discrimination task. Next, we performed RNA-sequencing analysis with amygdala from postnatal day 21 to investigate gene expression mediated by NCoR1 and SMRT. We found that 449 genes were upregulated by SMRT deletion, whereas only 8 genes were upregulated by NCoR1 deletion. Overall, our data demonstrate for the first time that NCoR1 and SMRT have separate functions in the central nervous system. JSPS Grant-in-Aid for Early-Career Scientists 19K16486, 21K15340 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.
Cardiometabolic conflux at the carotid body
Authors: Thakkar Pratik , Pauza Audrys , Murphy David , Paton Julian 
Published: May 2023

Background: Diabetes is the fastest-growing disease in New Zealand, and when combined with high blood pressure (hypertension), so-called sweet pressure (SP) is the leading cause of mortality. However, controlling SP remains challenging clinically. One target that remains unexploited is the sympathetic nervous system (SNA). As the carotid body (CB) has a pivotal role in regulating SNA, blood pressure and blood glucose, we searched for novel signalling pathways linking the CB with metabolism. Using RNA sequencing, we discovered melanocortin type-4 receptor (MC4R) expression was upregulated in the CB of spontaneously hypertensive rats (SHR) versus Wistar rats; these receptors have an essential role in regulating cardiovascular and energy homeostasis. Hypothesis: We hypothesised that blockade of MC4R within the CB would reduce SNA and alleviate SP. Methods: The SHR was used as a hypertensive-diabetic model as it has glucose intolerance. Using a novel in situ preparation, we recorded SNA activity while injecting an MC4R antagonist (HS014) into the CB via the internal carotid artery. Results: The upregulated MC4R expression in the CB of SHR versus Wistar rat was validated using qPCR and immunocytochemistry. Antagonising MC4R within the CB lowered SNA and prevented the SNA hyperactivation triggered by hyperglycaemia (high glucose). No such responses were found in control Wistar rats. Conclusion: MC4R signalling is a novel mechanism within the CB that depresses ongoing SNA and, importantly, the elevated SNA caused by hyperglycaemia; whether this reduces blood glucose awaits testing in vivo. These data provide a potential mechanism for controlling co-comorbidity of hypertension and blood glucose. Funding: HRC, Royal Society Te Apārangi and Sidney Taylor Trust funded this research. 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 GP.Mur red cell phenotype (higher band 3 expression) affects respiratory frequency and the inspiratory/expiratory ratio in a breath cycle during exhaustive exercise
Authors: Hsu Kate , Hsu Kate , Tseng Wei-Chin , Chen Li-Yang , Chen Pin-Lung , Lu Yu-Xian , Chen Yung-Sheng , Tseng Kuo-Wei 
Published: May 2023

The GP.Mur red cell phenotype is characterized by the unique presence of glycophorin B-A-B hybrid protein on the erythrocyte membrane which promotes band 3 expression. Band 3, or anion exchanger-1, transports HCO3 - across the erythrocyte membrane by exchange of Cl-; this function of band 3 works in concert with intraerythrocytic carbonic anhydrase II (CAII) to facilitate blood CO2 transport. People with the GP.Mur blood type express 10-20% more band 3 protein than those without the special blood type. We thus hypothesized that respiration in people with the GP.Mur blood type might be distinctly different when being challenged. In this study, we recruited 36 age-matched male elite athletes (13 GP.Mur and 23 without GP.Mur [control]) for an incremental running test to exhaustion. While running on a treadmill, the subjects were continuously monitored using a Quark CPET (cardiopulmonary exercise testing) unit (COSMED, Italy). Two statistical methods were employed for data analysis: (1) unpaired t-test for comparison at individual timepoints; and (2) linear mixed modeling for serial cardiopulmonary measurements collected during the running test. We found that their running abilities were similar. However, the subjects with GP.Mur showed higher respiratory rates and smaller inspiratory/expiratory (I/E) ratios than the control subjects throughout the entire exhaustive running test. That is, GP.Mur+ subjects spent a larger fraction of the respiratory cycle time on CO2 excretion than inspiration; their respiration also appeared to respond faster to the same level of workload. These resulted in lower end-tidal CO2 pressure in the running GP.Mur subjects compared to the controls. In conclusion, we presented direct evidence that band 3-mediated HCO3 -/CO2 exchange at the erythrocyte level could impact the respiratory pattern of CO2 excretion. Taiwan National Science and Technology Council; MacKay Memorial Hospital 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.
Mechanotransduction meets thermosensation: Coupling of TRP channels in ventilator-induced lung injury
Authors: Michalick Laura , Zergane Meryam , Pickerodt Philipp , Kuebler Wolfgang 
Published: May 2023

Study objective: Mechanical ventilation can damage the lung by causing endothelial barrier failure, edema formation and lung injury. Yet, the exact mechanisms underlying the mechanotransduction at the microvascular barrier are still unclear. In previous work, we had identified a critical role for the endothelial Ca2+ channel transient receptor potential vanilloid 4 (TRPV4) in lung microvascular barrier failure subsequent to mechanical overventilation. Our preliminary data reveal an involvement of thermosensitive TRPV1 in this scenario, which prompted us to test for TRPV1’s contribution to TRPV4-induced Ca2+ signaling and lung injury induction in vivo, ex vivo and in vitro. Hypothesis: TRPV1 acts as amplifier of mechano- and thermosensitive TRPV4-mediated pulmonary vascular barrier failure during mechanical ventilation. Methods: Anesthetized wild type or Trpv1-/- mice were ventilated for 2 h with low (7 mL/kg) and high (20 mL/kg) tidal volumes (LVT/HVT) at different inspired gas temperatures (20-40°C) in vivo, and parameters such as edema formation, vascular permeability and inflammation was assessed . Endothelial [Ca2+]i in response to pressure elevation from 5 to 15 cmH2O was quantified in isolated-perfused lungs ex vivo, and in vitro in human pulmonary microvascular endothelial cells (HPMECs) after activation of TRPV1 and/or TRPV4 by capsaicin and/or GSK1016790A with or without pharmacological inhibition of TRPV1 and TRPV4. Additionally, we measured barrier function by ECIS ® and examined the induction of apoptosis after TRPV1/4 activation. Results: TRPV1 deficiency or inhibition, as well as reduced temperatures (< 25°C) of inspired gas attenuated VILI in vivo, and reduced the endothelial [Ca2+]i response to high pressure inflation ex vivo. In vitro HPMECs showed a characteristic increase in endothelial [Ca2+]i in response to agonism of TRPV4, yet not TRPV1 alone. In line with these findings, the dual activation of both TRPV channels amplified and prolonged the TRPV4-mediated Ca2+ response, induction of apoptosis and loss of barrier integrity. Conclusions: Here, we demonstrate a critical role for TRPV1 as amplifier of the TRPV4-mediated [Ca2+]i response and vascular barrier failure in VILI as a function of inspired gas temperature. Our findings unveil a mechano- and temperature-sensitive increase in TRPV1/4 activation, which contributes to endothelial barrier dysfunction and edema formation during mechanical ventilation and could be targeted by lower inspired gas temperatures. This study is supported by the German Centre for Cardiovascular Research (DZHK), partner site Berlin, Germany. 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.
Significance of Cell Membrane Repair in Parkinson's Disease
Authors: Goncalves Isabella , Goncalves Isabella 
Published: May 2023

Objective: Parkinson’s disease (PD) is the second most common neurodegenerative disorder and affects an estimated 10 million people worldwide. PD pathogenesis involves the death of neuronal cells due to the breakdown of their cell membranes. Membrane repair is a mechanism that appears in nearly every eukaryotic cell that repairs disruptions in the plasma membrane to maintain cell health and function. The aim of the present study was to determine the if compromised membrane repair can contribute to the progression of PD. Materials and Methods: Using a glass bead mechanical damage assay, we injured N2A neuroblastoma cells with three different conditions: GFP transfected control cells, cells expressing alpha synuclein, and cells expressing A53T, an alpha synuclein mutant linked to PD. We then measured the amount of an intracellular enzyme, lactase dehydrogenase (LDH), that was released from the cells after injury with glass beads to determine how well the membrane repaired. (n=16) We also injured the membrane of these cells with a laser injury heat damage assay. In this mechanism, a laser is used to injure the cells, and influx of FM4-64 dye into the cell is measured to determine the rate of membrane repair. (n=60) Results: In the mechanical damage assay, cells expressing alpha synuclein released more LDH, which suggests that membrane repair may be compromised in PD. In the laser damage assay, cells expressing alpha synuclein showed significantly more FM4-64 dye influx. We observed increased dye influx in WT Alpha Synuclein cells. This shows that Alpha Synuclein transfected cells do not repair as effectively as control cells when exposed to the same conditions. These findings support that membrane repair may be compromised in PD. Elucidating that membrane repair is impaired in PD leads us to investigate if existing membrane repair enhancing agents could be potential therapeutics for the disease. American Physiological Society Summer Undergraduate Research Fellowship (APS SURF) 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.
CD8+ T cells stimulate renal sodium transporters contributing to salt-sensitive hypertension
Authors: Deck Katherine , Guo Yunping , Benson Lance , Liu Yunmeng , Mora Christoph , Mu Shengyu 
Published: May 2023

Impaired salt handling by the kidneys acts as one source of hypertension. However, the exact identity of this kidney defect remains unknown. As established recently, the adaptive immunity, T cells in particular, acts as an important contributor to the pathogenesis of hypertension. In this regard, our laboratory has reported that CD8+ T cells (CD8Ts), when adoptively transferred from salt-sensitive hypertensive mice to normotensive mice, stimulate Sodium Chloride Cotransporter (NCC). Through this stimulation, sodium retention occurs, and salt-sensitive hypertension develops. However, whether other sodium transporters within the nephron are affected by hypertensive CD8Ts and contribute to this pathogenesis of hypertension remains uncharacterized. We hypothesize hypertensive CD8Ts will also have an impact on other sodium channels. Here, we demonstrate the impact of hypertensive CD8Ts on sodium-potassium-co-transporter (NKCC) and epithelial sodium channel (ENaCs) in the kidney and the potential of these regulations contributing to salt-sensitive hypertension.Through in vivo studies, we employed a CD8T-adoptive transfer model as described in our previous publications. The kidneys from mice receiving adoptive transfer of hypertensive CD8Ts were harvested and protein levels of NKCC, αENaC, βENaC, and γENaC were analyzed by western blot. With in vitro studies, we co-cultured mouse CD8Ts with Collecting Duct epithelial cells (CDs, M1 cells) to examine the direct interaction between CD8Ts and CDs in media containing various levels of corticosteroids. Similar western blots were performed after this co-culture, as well as measurement of sodium retention through an intracellular sodium indicator and flow cytometry, as reported previously.In the results of in vivo studies, we found that the kidneys of mice receiving adoptive transfer of hypertensive CD8Ts demonstrated higher expression of NKCC, βENaC and γENaC, but no change in αENaC. In the results from in vitro studies, we further found that in charcoal-stripped co-culture conditions, pre-activated CD8Ts stimulate higher expression of ENaC subunits and ENaC-mediated sodium retention in M1 cells. However, these effects are masked in culture conditions with physiological hormone levels or with additional corticosteroids.Overall, our results suggest that, as a potential kidney defect, hypertensive CD8Ts strongly stimulate NCC and NKCC in the kidney to mediate excessive salt retention. Although CD8Ts themselves can increase ENaC, this effect might be masked in physiologic conditions. NIH R01-HL146713 (Mu), AHA 15BGIA25730047 (Mu), and SPaT T32-GM10699 (Deck) 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.
Microvascular Function in Skeletal Muscle of Acute Adiponectin Knockout Mice
Authors: Medarev Steven , Faal Madikay , Asher Andy , Smith Cole , Qasim Muhammad , Belenko Jasen , Hendrickson Dylan , Mitchell Logan , Ojah-Maharaj Jayden , Faynberg Victor , Cannon Nicole , Muller-Delp Judy 
Published: May 2023

Adiponectin contributes to the regulation of vascular and metabolic functions in skeletal muscle. Although circulating adiponectin is known to increase with aerobic exercise training, a direct role for adiponectin in adaptation of microvasculature of skeletal muscle to aerobic exercise training has not been documented. We exercise trained young adult mice with normal circulating adiponectin (wild type, WT) and mice in which adiponectin was acutely deleted (Cre-Lox conditional knockout system induced with Tamoxifen chow, AdipoKO) before undergoing 8 weeks of exercise training. Sedentary WT and AdipoKO mice were housed under similar cage conditions for 8 weeks. We determined skeletal muscle oxidative capacity, exercise tolerance, lean and fat mass, and we assessed reactivity of 1A arterioles from the gastrocnemius muscle. Exercise training increased exercise tolerance in both WT and AdipoKO mice. Exercise training increased lean mass and reduced fat mass in both WT and AdipoKO mice. Myogenic constriction to intraluminal pressure changes was increased by exercise training in gastrocnemius muscle 1A arterioles from both WT and AdipoKO mice. In contrast, phenylephrine-induced contractile responses were increased by exercise training in WT, but not AdipoKO mice. These data suggest that adiponectin is an important contributor to adaptations of contractile function that occur in skeletal muscle in response to exercise training; however, the training-induced increase in exercise tolerance and muscle mass that occurred in both WT and AdipoKO mice suggests that loss of adiponectin impacts smooth muscle function independently of metabolic adaptations in skeletal muscle. NIH R56AG068156 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.
Spinal microglial morphology in a rat model of Pompe Disease
Authors: Deegan Kyle , Martinez Robert , Rana Sabhya , Byrne Barry , Fuller David 
Published: May 2023

Pompe disease is a monogenic neuromuscular disorder caused by a mutation in the gene encoding the lysosomal enzyme acid alpha-glucosidase. This leads to widespread glycogen accumulation, cardiorespiratory failure, and early mortality. There is clear evidence for neurodegeneration and neuroinflammation in animal models of Pompe disease (Turner et al., Resp. Phys. Neurobio., 2016) as well as human Pompe tissues (Fuller et al., J. Neurophys., 2021). However, the appearance of microglia has not been comprehensively evaluated in Pompe disease. Here we examined this question using a rat model of Pompe disease. Mid-cervical spinal cord tissue sections of 10-13 mo old male Pompe ( Gaa null, n=3) and Sprague Dawley rats (n=3) were histologically evaluated. We focused on the mid-cervical spinal cord because this region contains the phrenic motoneurons which innervate the diaphragm muscle. Immunohistochemical processing was performed on coronal spinal cord sections using a neuronal nuclear protein (NeuN) antibody to label neurons, and an ionized calcium-binding adaptor molecule 1 (IBA-1) antibody to label microglia. Robust and reliable staining of neurons and microglia was observed in white and grey matter regions of the spinal cord section using fluorescent imaging. Putative motoneurons in the Pompe mid-cervical ventral grey matter had the “prototypical appearance” of motoneurons in lysosomal storage diseases. This included a considerably enlarged (“swollen”) soma and extensive vacuolization. Spinal cord microglia in Pompe tissues had a fundamentally different appearance as compared to Sprague-Dawley. Specifically, microglia appeared with increased density in Pompe spinal cord sections and were frequently observed to be in immediate proximity (e.g., “wrapping around”) to ventral spinal neurons which displayed a swollen and vacuolated morphology. Pompe microglia also showed a rounded appearance that is consistent with the “reactive” state known to occur during neuroinflammation. These histological data are consistent with neurodegeneration and ongoing microglia-driven phagocytosis of neurons in the mid-cervical spinal cord of adult Pompe disease rats. R01HD052682 (DDF and BJB) 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.
Circadian timing of grape intake and the oxidative stress response
Authors: Blanton Cynthia , Aghazadeh-Habashi Ali , Ghimire Biwash , Khajeh Pour Sana 
Published: May 2023

Background: The immune system displays circadian rhythm and timing of the ingestion of foods with immunoactive properties may modify their impact. Objective: The purpose of this investigation was to evaluate the effect of time of day of grape consumption on oxidative stress. Hypothesis: We hypothesized that the oxidative stress response to a high-fat meal would be 1) greater in the a.m. vs. p.m. and that 2) this response would be blunted by ingestion of a grape vs. placebo drink. Methods: The study followed a 2 x 2 factorial randomized, controlled, double-blind design wherein healthy men and women (n=32) consumed either a grape (equivalent to 1.5 servings of fresh grapes) or placebo drink with a high-fat meal (an oxidative challenge) in either the morning (7:00 a.m.) or evening (6:00 p.m.). Urine was collected for a measure of oxidative stress (F2-isoprostane) at baseline and post-meal at hour 1 and batched over hours 1-6. F2-isoprostane concentration was determined using Liquid Chromatography-Tandem Mass Spectrometry and values were normalized to creatinine levels determined by enzyme-linked immunoassay. Results: ANOVA showed a significant increase above baseline in urine F2-isoprostane levels (ng/mg creatinine) at hour 1 and hours 1-6 (P<0.0001) that were significantly greater in the a.m. vs. p.m. (P=0.04) but were not significantly different between grape and placebo. Expressed as % baseline, F2-isoprostane levels at hour 1 and hours 1-6 tended to be lower in the grape vs. placebo group (P=0.058) and were significantly higher in the a.m. vs. p.m. (P=0.01). Total isoprostane excretion expressed as % baseline showed a significant increase in the a.m. placebo group (P=0.03) that was prevented by grape ingestion. Conclusions: 1) Grape may suppress the oxidative stress response to a high-fat meal and 2) The oxidative stress response to a high-fat meal appears greater in the morning vs. evening. Thus, timing the consumption of immunoactive food may alter the immune response. Funding and grape/placebo powders were provided by the California Table Grape Commission. 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.