bluuebunny/crossref_metadata_2025_split huggingface dataset:
Carotid Body O2 Sensing requires H2S-dependent Persulfidation of Olfactory Receptor 78
Authors: Peng Ying-Jie , Nanduri Jayasri , Wang Ning , Bindokas Vytautas , Fox Aaron , Vignane Thibaut , Filipovic Milos , Prabhakar Nanduri 
Published: May 2023

Hydrogen sulfide (H2S) is implicated in O2 sensing by the carotid body(CB) to stimulate breathing response to hypoxia. Present study shows hydrogen sulfide-dependent persulfidation (S-sulfhydration) of olfactory receptor 78 (Olfr78) as an integral component of carotid body O2 sensing. H2S increased cAMP production (index of Olfr78 activation) in HEK-293 cells expressing Olfr78 as measured by cAMP fluorescent biosensor, in a dose-dependent manner with an ED50 of 25μM. H2S as well as hypoxia increased persulfidation in the carotid body glomus cells and these responses were absent in cells Olfr78 as well as CTH (CSE) null mice. MS/MS analysis showed that persulfidation of Cys240 increased in a time-dependent manner with H2S. Alpha fold modelling of Olfr78 showed Cys240 in the interface of the cytosol and the membrane facilitating water accessibility of sulfur atom in cysteine. Substituting Cys240 with alanine blocked Olfr78 activation by H2S as indicated by absence of increased cAMP fluorescence in HEK-293 cells and impaired trafficking of Olfr78 protein to the cell membrane, consistent with the Alpha fold model prediction of Cys240 location near the surface of the Olfr78. Hypoxia and H2S stimulated ex vivo CB sensory activity and elevated intracellular calcium of glomus cells in wild type but not Olfr78 mutants. Intravenous administration of H2S increased efferent phrenic nerve activity in a dose-dependent manner, and the responses were absent in Olfr78 mutants. These results suggest that H2S through redox modification of Cys240 of Olfr78 participates in O2 sensing by the CB to regulate breathing. Supported by NIH-HLBI P01-HL-44454 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.
Loss of Kir5.1 disturbs acid-base homeostasis in Dahl salt-sensitive rats
Authors: Xu Biyang , Staruschenko Alexander 
Published: May 2023

Renal basolateral inwardly-rectifying potassium (Kir) channels contribute to the maintenance of the resting membrane potential and potassium homeostasis. Heteromeric Kir4.1/Kir5.1 channels are more sensitive to intracellular acidification than homomeric Kir4.1 channels. Our previous study demonstrated that genetic mutation of Kcnj16 (the gene encodes Kir5.1) causes chronic metabolic acidosis with lower blood pH and bicarbonate levels in Dalh salt-sensitive (SS) rats. Here, we aim to investigate the underlying mechanisms. We hypothesized that loss of Kir5.1 disturbs acid-base homeostasis in SS rats by impairing ammoniagenesis in the proximal tubule and HCO3- reabsorption in the distal convoluted tubule (DCT).12-week-old male SSWT and SSKcnj16-/- rats were separated into two groups (N=5 per group). At the end of the experiment, kidneys were flushed and processed for blood pH and Western blot analysis.Western blot analysis indicated that knock out of Kir5.1 causes lower expression of sodium-coupled neutral amino acid transporter 3 (SNAT3), which may indicate defective ammoniagenesis in the proximal tubule. On the other hand, increased expression of NBCe1 and NHE3 suggests enhanced HCO3- reabsorption and H+ excretion. Additionally, the expression of vacuolar ATPase (V-ATPase), which is a proton pump responsible for controlling the intracellular and extracellular pH of cells, remained the same. In the following experiments, we will further investigate the ammoniagensis in the proximal tubule as well as key bicarbonate transporters in DCT and collecting duct. Funding sources: National Institute of Health Grants R35 HL135749 (to AS), Department of Veterans Affairs grant I01 BX004024 (to AS). 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.
S1928 Phosphorylation Control CaV1.2 Spatial Distribution and Function During Angiotensin II Signaling: Implications for Hypertension
Authors: Flores Tamez Victor , Baudel Miguel , Hong Junyoung , Singhrao Navid , Ramer Victoria , Reddy Gopireddy , Man Kwun Nok Mimi , Hell Johannes , Nieves-Cintron Madeline , Navedo Manuel 
Published: May 2023

The L-type calcium channel CaV1.2 (LTCC) is essential for vascular smooth muscle (VSM) contraction and blood pressure control. Increased vascular contractility, blood pressure, and enhanced angiotensin II (angII) signaling are hallmarks of hypertension (HTN). It has been proposed that spatial redistribution of CaV1.2 channels at the sarcolemma of VSM contributes to the potentiation of LTCC function and vascular dysfunction during HTN. However, the mechanisms underlying the spatiotemporal regulation of the CaV1.2 channels during angII signaling and HTN are poorly understood. Here, we hypothesize that CaV1.2 phosphorylation at the S1928 site is a key event mediating increased CaV1.2 channel clustering, which in turn leads to an increase in LTCC activity and vascular reactivity during angII signaling and HTN. We first demonstrated that angII-treated wild-type (WT) mesenteric arteries display increased phosphorylation at the S1928 site. Molecularly, angII redistributed CaV1.2 into larger clusters. This was correlated with elevated VSM whole-cell L-type channel currents, global intracellular Ca2+ and contraction, increased arterial tone ex vivo and in vivo in mesenteric arteries, and altered mesenteric blood flow in arteries from WT mice. These changes were prevented or significantly ameliorated in mesenteric VSM cells and arteries from a knock-in mouse expressing a mutant CaV1.2 in which serine was replaced with alanine at position 1928 (S1928A mouse) and by PKC inhibition. In angII-induced hypertensive mice, increased CaV1.2 cluster size and channel activity, enhanced arterial tone, and mean arterial pressure in WT mice were prevented or significantly reduced in S1928A mice. Altogether, these results suggest a key role for the phosphorylation of vascular CaV1.2 at S1928 in regulating LTCC spatial distribution, activity and vascular function during angII signaling and HTN. Phosphorylation of this single amino acid could be an essential regulatory mechanism that could be exploited for therapeutic intervention. This work was supported by NIH grants R01HL149127, R01HL121059, and R01HL161872 (to MFN). 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.
Oxidation in a respiratory brainstem area of an Alzheimer's rat model
Authors: Schmitz Hailey , Le Andy , Koogler Alicia , Ostrowski Daniela , Ostrowski Tim 
Published: May 2023

Alzheimer’s disease (AD) is a progressive neurodegenerative disease affecting more than 50 million individuals worldwide. Sporadic AD comprises 95% of all cases and is most commonly known for its hallmark symptoms of cognitive decline and memory degradation. In addition, respiratory dysfunction is found in up to 80% of AD patients and often manifests as sleep-disordered breathing. In the early stages of AD, increased reactive oxygen species cause widespread oxidative stress, which can damage cellular components and severely impact neuronal activity. While the respiratory dysfunction and oxidative stress is well known, there is little known about the underlying mechanisms and their potential intersection in AD patients. This study used the Streptozotocin (STZ)-AD rat model, which is the only well-established model mimicking sporadic AD with its multifactorial presentations including AD hallmark symptoms and respiratory dysfunction. Two weeks after induction of the STZ-AD rat model (2 mg/kg STZ), we analyzed targets of oxidative stress in a critical respiratory control area in the brainstem, the nucleus Tractus Solitarii (nTS). Immunohistochemistry was used to fluorescently stain brainstem sections in order to analyze for oxidation of lipids (4-hydroxynonenal, 4-HNE), DNA (8-hydroxyguanine, 8-OHG), and protein sulfhydryl groups (dimedone-tagged sulfenic acid). While there was no pronounced lipid peroxidation, the STZ-AD group had significantly increased levels of DNA oxidation when compared to the control (CTL). In addition, sulfhydryl groups, which are present on many cellular proteins, also had a significantly increased baseline oxidation in the STZ-AD group when compared to CTL. Oxidation of these sulfhydryl groups is known to be responsible for altering ion channel function and thus neuronal activity. Reducing agent Dithiothreitol (DTT) was able to revert sulfhydryl oxidation in STZ-AD to its reduced form, while CTL rats did not change from baseline. On the other hand, addition of the oxidizing agent hydrogen peroxide increased sulfhydryl oxidation in CTL, but not in STZ-AD. Overall, our results show that STZ-AD causes increased oxidation throughout a key brainstem area of respiration. This oxidation also affects protein components important for neuronal activity, which could be an underlying cause for the respiratory dysfunction in AD. Funding sources include the Kirksville College of Osteopathic Medicine Biomedical Sciences Graduate Program and the National Institutes of Health (R15AG065927). 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.
Highlighting the role of glial-specific miR-92 on synaptogenesis of developing Drosophila melanogaster
Authors: Moe Simon , McNeill Elizabeth 
Published: May 2023

The objective of this study was to investigate the glial specific role of miR-92 in the developing nervous system. micro-RNA (miRNA) have been implicated in many neurological and neurodegenerative disease states. Glial tissue provides a wealth of supporting roles in nervous tissue function, however their ability to mediate nervous system development through epigenetic factors is poorly understood. We predict that miR-92 expression is necessary in glial tissue for both proper development and physiology at the developing larval neuromuscular junction. Using a combination UAS/Gal4 system, highly human conserved miR-92b expression was competitively inhibited in various tissues within the third instar larval nervous system of Drosophila melanogaster. We measured developmental parameters of the nervous tissue, electrophysiological features, and explored potential genetic targets in recapitulating the loss-of-function phenotypes. Amongst the tissues encompassing the neuromuscular junction (NMJ) of larval Drosophila, loss of miR-92b expression in glial tissue recapitulates global loss phenotypes. These NMJ were characterized by fewer glutamate-releasing synaptic boutons and an increased count of underdeveloped ghost boutons. These same flies have a decreased mEJP frequency in abdominal muscles 6/7, but a normal EJP. Inhibition of miR-92b in the subperineurial glia subtype, which function as the blood-brain barrier, can mimic these synaptic phenotypes. Administration of a dextran dye show that the subperineurial glia of the CNS have increased permeability in miR-92b inhibited flies. Target analysis predicted a V-ATPase gene (Vha55) downstream may be driving these phenotypes. Future work will explore Vha55 as a possible candidate driving these neuronal phenotypes. The importance of glial specific miRNA in modifying neurological systems is very promising for both therapeutic markers and potential treatments. 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.
Brief angiotensin converting enzyme inhibition early in life delays the onset of albuminuria in sheep born with a solitary functioning kidney
Authors: Denton Kate , McArdle Zoe , Moritz Karen , Schreuder Michiel 
Published: May 2023

Children with solitary functioning kidney (SFK) have an increased risk of hypertension and kidney injury from early in life. Hypertrophy and hyperfiltration are compensatory adaptations in the remaining kidney that may contribute to kidney injury over time. Angiotensin-converting enzyme inhibitors (ACEi) have reno-protective and blood pressure (BP) lowering properties. This study examined if brief ACEi early in life in sheep born with a SFK altered compensatory kidney hypertrophy and prevented elevation in BP and albuminuria. SFK was induced by unilateral nephrectomy in male fetal sheep at 100 days gestation (term=150 days; n=19) or sham surgery performed (n=10). Between 4 to 8 weeks, some SFK lambs received enalapril (n=10; 0.5mg/kg/day, once daily, orally) and others received vehicle (water; n=9). At 2, 6 and 20 months kidney volume was assessed using magnetic resonance imaging. At 8, 14 and 20 months, BP, renal functional reserve and albuminuria were examined. In SFK sheep, kidney volume was lower (~20%) than sham at 2 and 6 months but similar at 20 months. ACEi in SFK sheep reduced kidney volume at 2 months (~13%) but not at 6 or 20 months. SFK sheep had higher BP than sham at all ages and ACEi did not prevent the rise in BP. SFK sheep had higher urinary albumin and reduced RFR at all ages compared with sham. ACEi increased RFR and prevented albuminuria at 8 months in sheep with SFK but not at 14 and 20 months. In conclusion, brief and early ACEi in sheep with SFK did not prevent elevations in BP but delayed the onset of kidney injury in the short-term. This was likely associated with a reduction in the level of kidney hypertrophy early in life. Brief postnatal ACEi may delay loss of renal function in children born with one kidney and warrants further investigation. The Netherlands Organization for Health Research and Development (ZonMW Vidi 016.156.454) 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.
Evaluation of gastrocnemius motor evoked potentials induced by trans-spinal magnetic stimulation following tibial nerve crush in rats
Authors: Vinit Stephane , Michel-Flutot Pauline , Jesus Isley , Bonay Marcel , Auré Karine , Lee Kun-Ze , Mansart Arnaud 
Published: May 2023

Peripheral nerve injuries induce long-lasting physiological and severe functional impairment due to motor, sensory, and autonomic denervation. Preclinical models allow us to study the process of nerve damage, evaluate the capacity of the peripheral nervous system for spontaneous recovery, and test diagnostic tools to assess the damage and subsequent recovery. Methods: In this study on Sprague-Dawley rats, we: 1) compared the use of two different anesthetics (isoflurane and urethane) for the evaluation of motor evoked potentials (MEPs) induced by trans-spinal magnetic stimulation (TSMS) in gastrocnemius and brachioradialis muscles; 2) monitored the evolution of gastrocnemius MEPs by applying paired-pulse stimulation to evaluate the neuromuscular junction activity; and 3) evaluated the MEP amplitude before and after left tibialis nerve crush (up to 7 days post-injury under isoflurane anesthesia). The results showed that muscle MEPs had higher amplitudes under isoflurane anesthesia as compared with urethane anesthesia in the rats, demonstrating higher motoneuronal excitability under isoflurane anesthesia evaluated by TSMS. Following tibial nerve crush, a significant reduction in gastrocnemius MEP amplitude was observed on the injured side, mainly due to axonal damage from the initial crush. No spontaneous recovery of MEP amplitude in gastrocnemius muscles was observed up to 7 days post-crush; even a nerve section did not induce any variation in residual MEP amplitude, suggesting that the initial crush effectively severed axonal fibers. These observations were confirmed histologically by a drastic reduction in the remaining myelinated fibers in the crushed tibial nerve. These data demonstrate that TSMS can be reliably used to noninvasively evaluate peripheral nerve function in rats. This method could therefore readily be applied to evaluate nerve conductance in the clinical environment. This research was funded by the Chancellerie des Universités de Paris (Legs Poix) (SV, MB), the Fondation de France (SV), the Fondation Médisite (SV), INSERM (MB, SV, AM), Université de Versailles Saint-Quentin-en-Yvelines (SV, AM) and Ministry of Science and Technology 109-2636-B-110-001 (KZL). 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.
Hemodynamic response to different contractile speeds of resistance exercise in adults with sarcopenic obesity
Authors: Hsu Kuo-Jen , Huang Sheng-Yun , Chen Chiao-Nan 
Published: May 2023

This study aimed to compare the effects of high-speed and low-speed resistance exercise on hemodynamics in adults with sarcopenic obesity. We hypothesized that high-speed resistance exercise induces greater/longer cardiovascular stress than low-speed resistance exercise. Forty-five individuals with sarcopenic obesity (64.0±6.0 years) were randomized to the low-speed resistance exercise group (LSRE; n=24) and the high-speed resistance exercise group (HSRE; n=21). All participants performed one-session of resistance exercises [squatting, chest press, and upright row; 3 sets of 10 repetitions at 60% of 1 repeated maximum]. Participants in the LSRE group performed the exercises with a 4:4 second concentric-eccentric contraction cycle controlled by a metronome while participants in the HSRE group performed the exercise with a 1:4 second concentric-eccentric contraction cycle. Systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), and arterial stiffness (brachial-ankle pulse wave velocity; baPWV) were determined before exercise (resting), immediately after exercise (P0), 15-min after exercise (P15), and 30-min after exercise (P30). Two-way repeated measure analysis of variance was used to examine the effect of different contractile speeds of resistance exercise on outcome variables. The significant level was set at 0.05. We found that the HR at P0 was higher than the resting values for both groups, with 10.9 bpm and 14.0 bpm of increases for the LSRE group and HSRE group, respectively. HR was back to the resting level at P15 in the LSRE group; however, HR was back to the resting level until P30 in the HSRE group. For both groups, SBP was significantly higher at P0 compared to resting (12.5 mmHg of increase for the LSRE group and 11.9 mmHg of increase for the HSRE group) and back to the resting level at P15. PWV at P0 was higher than the resting and back to the resting level at P15 in the LSRE group. PWV levels did not change with exercise in the HSRE group (p>0.05). DBP did not change significantly with exercise in both groups (p>0.05). In conclusion, the influence of HSRE on HR is longer than that of LSRE. LSRE, but not HSRE, results in transient changes in arterial stiffness in adults with sarcopenic obesity. This study was supported by the Ministry of Science and Technology, Taiwan [grant numbers: MOST-109-2314-B-010 -036 -MY3 (Chen, C.N.)]. 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.
A potential role for GPR160 and its ligand, CART, in the modulation of feeding behavior in Prader-Willi Syndrome
Authors: Bocke Colleen , Bocke Colleen , Yosten Gina , Samson Willis 
Published: May 2023

Hyperphagia is a hallmark of Prader-Willi syndrome (PWS). Managing the extreme hunger and insatiability associated with PWS remains a considerable challenge to PWS patients and their caregivers. Appetite and feeding behavior are governed by numerous neural circuits, several of which are potentially disrupted when some or all of the Prader-Willi critical region on chromosome 15 is lost. Previous research has focused on well-established feeding circuits in an effort to uncover the physiology underlying PWS hyperphagic behavior; however, due to the complex interplay between these circuits, much is left to be explored. We have previously demonstrated that interactions between GPR160 and its ligand cocaine and amphetamine regulated transcript (CART) are important in the control of feeding behavior. Several groups have reported that CART exerts anorexigenic properties when injected into areas of the brain that are important to feeding behavior, including regions of the brainstem and hypothalamus. The prohormone convertase PSCK1, which is responsible for post-translational processing of the CART prohormone, appears to be reduced in PWS patients, suggesting that CART could play a role in the pathophysiology of PWS. Using a rat model of PWS supplied by the Foundation for Prader-Willi Research (Magel2- deficient), we seek to investigate this potential role of CART and GPR160 in PWS-associated hyperphagia. Through the use of continuous monitoring of food and water intake, we were able to define meal patterning differences between wild type and paternally Magel2-deficient rats. In addition to evaluating baseline meal patterning, we also administered CART centrally and recorded CART-induced changes in feeding behavior. Lastly, we determined physiologic changes in levels of GPR160, CART, and PSCK1 in the pituitary, hypothalamus, amygdala, and brainstem from WT and paternally-deficient Magel2 rats in the setting of metabolic stress (fasting). Although additional studies must be performed to better define the role of CART and GPR160 in the feeding behavior of PWS patients, we anticipate that this ligand-receptor pair has the potential to serve as a novel therapeutic target for the treatment of PWS-associated hyperphagia. Foundation for Prader-Willi 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.