bluuebunny/crossref_metadata_2025_split huggingface dataset:
Investigating the effects of thermoneutral housing on skeletal muscle SERCA efficiency in mice fed a high-fat diet with and without exercise training
Authors: Braun Jessica , Raun Steffen , Karavaeva Iuliia , Ali Mona , Møller Lisbeth , Gerhart-Hines Zachary , Fajardo Val , Richter Erik , Sylow Lykke 
Published: May 2023

Thermoneutral (TN) housing of mice is an important factor to better mimic human metabolism and optimize translational research. The sarco(endo)plasmic reticulum (SR) Ca2+ ATPase (SERCA) pump actively transports Ca2+ from the cytosol into the SR, making it a regulator of muscle relaxation and energy metabolism. In response to cold or caloric excess, SERCA inefficiency generates heat and drives the combustion of metabolic substrates in muscle; however, whether TN housing affects SERCA efficiency is unknown. Here, we determined SERCA pump efficiency in skeletal muscles of mice housed at room temperature (RT, 22°C) or TN (30°C) with and without 60%E high-fat diet (HFD) and exercise training (ET) interventions. We hypothesize that TN would increase SERCA efficiency compared to RT on a chow diet, and that HFD and HFD + ET would reduce SERCA efficiency at both housing temperatures. Mice housed at RT or TN were fed a chow or 60%E HFD for 16 weeks. Eight weeks into the diet, half of the mice on HFD were randomly assigned to either ET or remained sedentary (SED) for the remaining 8 weeks. HFD + ET increased SERCA’s affinity for Ca2+ and maximal SERCA activity trended reduced by ET compared to HFD + SED mice. Investigating SERCA efficiency at low physiological [Ca2+]free shows that TN reduced Ca2+ uptake by ~60% in HFD mice and reduced SERCA activity by ~60% in SED mice. This increased SERCA efficiency 4-fold in chow-fed mice housed at TN compared to RT and reduced SERCA efficiency in HFD mice at TN to ~80% of that of chow-fed mice at TN. Similarly, at high physiological [Ca2+]free, TN reduced Ca2+ uptake by ~40% in HFD mice and reduced SERCA activity by ~35% in SED mice, but had no effect on SERCA efficiency. Together, TN housing appears to influence SERCA efficiency especially under chow and HFD conditions at a low [Ca2+]free. In conclusion, housing mice at TN should be considered when investigating non-shivering thermogenic mechanisms and skeletal muscle Ca2+ handling. Jessica L. Braun and Steffen H. Raun contributed equally. Erik A. Richter and Lykke Sylow are co-corresponding authors. Disclosure of funding: JLB. is supported by a Canadian Institute for Health Research Doctoral grant and a Michael Smith Foreign Study Supplement. SHR is supported by the Lundbeck Foundation and the Independent Research Fund Denmark. LS is supported by the Novo Nordisk Foundation and Independent Research Fund Denmark. 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.
Neonatal hyperoxia does not exacerbate hypertension in adult obese offspring from obese mothers
Authors: da Silva Alexandre , Dai Xuemei , Larson Kaylie , Aitken Nikaela , Frierson Timia , Walker Xavier , Oppedal Kari , Omoto Ana , Wang Zhen , Li Xuan , Mouton Alan , Hall John , do Carmo Jussara 
Published: May 2023

Maternal obesity increases the risk of preterm delivery which may result in rapid transition of their offspring from a relatively hypoxemic environment to normal or elevated oxygen environment, especially if the baby receives oxygen therapy. This exposure of premature infants to increased oxygen levels could induce oxidative stress and detrimental effects on organ development and maturation. Previous studies have shown that early-life exposure to high oxygen levels (hyperoxia) induces cardiovascular disease later in life. In the present study, we tested the hypothesis that neonatal exposure to hyperoxia (HO) leads to elevated blood pressure (BP) at adulthood in offspring from lean mothers and exacerbates the adverse impact of maternal obesity on offspring BP regulation. Male (n=5-7) and female (n=5-7) offspring from lean and high fat diet-fed obese mothers were exposed to room air (21% O2) or hyperoxia (80% O2) between postnatal (P) days P3-P10, and then returned to room air. The rats were provided food and water ad libitum and followed until 12-13 weeks of age when telemetry probes were implanted to measure BP and heart rate (HR) 24-hrs/day. After 10 days of recovery from surgery, BP and HR were measured for 5 consecutive days. Contrary to our hypothesis, neonatal HO was associated with lower BP compared to control offspring from lean mothers (males: 111±1 vs. 105±1 mmHg and females: 108±0.4 vs. 102±0.4 mmHg). Neonatal HO exposure was also associated with similar reductions in BP in hypertensive obese offspring from obese mothers (males: 123±1 vs. 117±1 mmHg and females: 116±1 vs. 113±1 mmHg). Offspring exposed to neonatal HO showed a tendency for reduced HR compared to lean and obese offspring not submitted to HO with significant reduction observed in obese female offspring from obese mothers (393±3 vs. 379±2 bpm). These results suggest that exposure to hyperoxia in early postnatal life is not associated with elevated BP in adulthood and it does not exacerbate the hypertensive effects of maternal obesity on offspring BP regulation. NIDDK 1R01121411, NIGMS P20GM104357 and NIGMS U54GM115428 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.
Role of potassium ion diffusion from neurons to capillaries in neurovascular coupling: effects of astrocytic endfeet geometry
Authors: Djurich Sara , Secomb Timothy 
Published: May 2023

Neurovascular coupling (NVC) refers to a local increase in cerebral blood flow (CBF) in response to increased neuronal activity. Diffusion of K+ released by neurons through the extracellular space (ECS) to capillaries may contribute to NVC. Increased perivascular K+ levels can initiate a conducted response that travels to arterioles, triggering vasodilation and increased CBF. Astrocytic endfeet almost completely cover cerebral capillaries, and K+ must diffuse through narrow clefts between endfeet to reach the capillaries. It has therefore been assumed that astrocytes form a barrier to diffusion of K+ in the ECS. The goal of this study is to determine the effects of astrocytic endfeet on the diffusion of K+ from neurons to blood vessels. Two simplified 2D geometries of the ECS, endfeet, and perivascular space (PVS) are used. The first geometry represents diffusion of K+ from a source 1 μm away from a capillary of diameter 5 μm. The second geometry represents K+ diffusion from a neuron 15 μm from the capillary, the average distance between a neuronal soma and the nearest blood vessel. A baseline [K+] of 3 mM is assumed throughout the region. K+ release from neurons is modeled as a prescribed concentration of 12 mM along the outer boundary of the ECS. The time-dependent diffusion equation is used to describe K+ diffusion through the region. Effective diffusivity of K+ is 937.5 μm2/s. Standard conditions are a PVS width of 100 nm and an astrocytic endfeet cleft width of 20 nm, with 2.5 clefts per vessel circumference such that the total width of the clefts represents 0.31% of the capillary’s circumference. In the first geometry, [K+] in the PVS approaches 12 mM within 0.05 s. Decreasing the astrocytic endfeet cleft width to 6.67 nm slows the rise in [K+] to 10 mM at 0.05 s. Increasing PVS width also slows the rise in [K+]. In the second geometry, the rise in [K+] is slower due to the greater diffusion distance and PVS [K+] approaches 12 mM within 0.5 s. Decreasing cleft width or increasing PVS width in the second geometry slightly slows the rise in [K+]. The predicted rise in [K+] at the blood vessel occurs well within the time that increased CBF is observed in NVC, 1-2 seconds. The predicted PVS [K+] levels are sufficient to cause the vasodilation seen in NVC. The present results suggest that direct diffusion of K+ through the ECS is a possible NVC signaling mechanism. Supported by NIH Grant U01 HL133362. 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.
Sex differences in proximal tubule metabolism influence hemodynamics and salt reabsorption to mediate dimorphic susceptibility to kidney diseases
Authors: Xiong Lingyun (Ivy) , MacLean Adam , McMahon Andrew 
Published: May 2023

Evidence suggests that decline in renal function is more severe in males than in age-matched females, manifesting in increased susceptibility to both chronic and acute kidney diseases among males. Our previous single-cell studies on renal transcriptomes in human and mouse demonstrated that sex differences are the most prominent in proximal tubules (PTs), where over 70% of salt reabsorption happens. However, it remains elusive how these molecular differences affect renal physiology and pathophysiology. Widely known as an indicator of renal function, glomerular filtration rate (GFR) is tightly regulated by tubuloglomerular feedback (TGF) within the nephron to optimize ultrafiltration of plasma and reabsorption of essential molecules. Importantly, GFR shows a sustained oscillatory pattern over time with a period of 30-45 seconds in rodents, and loss of GFR oscillations is associated with cessation of reabsorption activities and ischemia-reperfusion injuries in the kidney, as well as systemic hypertension. To study the relationship between intracellular events and renal function, we developed a mathematical model of TGF linking metabolic regulation within PT cells to fluid handling and salt reabsorption in the nephron, using real-time transdermal GFR readings in conscious, free-moving mice of both sexes. Bifurcation analysis on model parameters revealed that due to heightened oxidative profile to supply energy for reabsorption, male PTs operate near the critical boundary of losing oscillatory behavior in the system, hence they are prone to damage upon metabolic stress. In contrast, female PTs situate further away in the parameter space and are more resilient to failure because of biases towards an anti-oxidation state. Feminized male nephrons showed an intermediate phenotype, and inhibition of peroxisome activities improved recovery post injury. Combining single-cell genomics, physiological measurement and computational modeling of renal function, this study provides a multiscale explanation for sexual dimorphism in kidney diseases. NIDDK funding: DK126925 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.
Contrasting the production and molecular composition of venom from varying species of Belostomatidae
Authors: Preveza Natalie , Preveza Natalie 
Published: May 2023

True bugs, also known by their scientific name- Hemipterans, are an order of insects that use piercing and sucking mouthparts to consume prey. Belostomatidae is one family within hempitera currently containing eight described genera. The genus Belostoma is smaller in size, and tends to feed on smaller invertebrate prey, while a second more distantly related genus, Lethocerus, is much larger in body size and known to feed on small fish, reptiles, and amphibians. We wished to know if this diversification in prey selection also represents a diversification in the venom used to hunt different animal types. To test this we extracted and analyzed the venom from multiple Belostomatid species representing an evolutionary diversity of the family: Lethocerus americanus, Lethocerus medius, Abedus herberti, and Belostoma fluminium. We then compared the relative protein size composition and functional performance of each species’ venom to determine if venoms are similar or different among genuses. We predicted that if venom composition and functionality is similar among species, larger volumes of venom will be associated with larger species.Venom was collected over 10 weeks from 2 L. americanus, 1 L. medius, 5 A. herberti, and 22 B. fluminium. We also extracted from 4 B. flumineum that were collected and raised in a different region of N. America, which were kept separate from the locally occurring B. fluminium to test for regional differences that may be indicative of speciation events. B. fluminium produced a mean mass of 0.65mg of venom per individual insect, whereas the remote B. fluminium had a mean mass of 1.08mg per individual. While the mean venom collected from the remote B. fluminium individuals was greater than local specimens, the total mass for all B. fluminium was generally smaller than that of the larger species. The mean mass of venom extracted per individual from the remaining species were as follows: A. herberti, 1.44mg, L. medius, 1.30 mg, and L. americanus, 1.47mg. From this data, we conclude that larger sized Belostomatids produce larger volumes of venom. To compare the general protein composition and functional performance of the toxins, extracted venoms were pooled, frozen, and lyophilized to stabilize protein components. An SDS PAGE gel was then run with samples to test for different size protein compositions among species. Additionally, a functional dilution analysis was performed using monocultures of chicken embryonic cells followed by a cell viability assay to compare the relative toxicity of each species’ venom. Funding for this project was provided by Union College Undergraduate Research Grants. 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.
Mirabegron-mediated vasodilation in resistance-sized arteries
Authors: Bulley Simon , Choi Young , Reinert Angela 
Published: May 2023

β3-adrenergic receptors (β3-ARs) are the most recently established member of the beta-adrenergic sub-family of receptors, however, it’s apparent that β3-ARs contribute to the regulation of the cardiovascular system, including metabolism, vasodilation, and cardiac contractility. β3-ARs have been identified in the cardiac tissue of multiple species, including canine, rodent, and human, where observations suggest that its expression is upregulated in pathological conditions, such as heart failure. Less is understood about the function of β3-ARs in resistance-sized arteries, with most studies utilizing first-generation β3-AR agonists BRL37344, CL316243, and SR58611, which between them have been shown to cause vasodilation in coronary microarteries and thoracic arteries in rodents and dogs. Preliminary Simple Western and immunofluorescence data indicate that β3-ARs are expressed in resistance-sized mesenteric artery endothelial and vascular smooth muscle cells. Mirabegron, an agonist of the more recently established β3-AR subtype, and recently FDA-approved for the treatment of overactive bladder (OAB), causes vasodilation of mesenteric arteries through a cGMP-mediated β3-AR-dependent mechanism at low concentrations, and a β3-AR-independent mechanism at higher concentrations. These data suggest that β3-AR regulates arterial tone in systemic resistance-sized arteries and that Mirabegron causes vasodilation through additional, unknown mechanisms at higher concentrations. American Heart Association 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.
An Innovative Liver-Specific GalNAc-RNAi Suppression of UGT1A1 in Obese Mice Improves Metabolic-Associated Fatty Liver Disease (MAFLD)
Authors: Bates Evelyn , Kipp Zachary , Badmus Olufunto , Xu Mei , Mitchell Zachary , Stec David , Hinds, Jr Terry 
Published: May 2023

Several population studies have found lower serum bilirubin levels to be associated with the pathology of metabolic-associated fatty liver disease (MAFLD). Yet, treatments to target this metabolic trend have not been explored. In our study, we hypothesized that inhibition of hepatic UGT1A1 would increase serum bilirubin levels and improve conditions like MAFLD and hepatic insulin resistance. Therefore, we designed an RNAi targeting murine Ugt1a1 expression in the liver. The RNAi molecule was constructed by conjugating it with an amino sugar derivative of galactose, N-Acetylgalactosamine (GalNAc) [GalNAc-UGT1A1-RNAi]. GalNAc covalently linked to the siRNA enables delivery through the asialoglycoprotein receptor (ASGPR)-mediated targeting to hepatocytes in vivo. Hence, the treatment of the GalNAc-UGT1A1-RNAi primarily targets the liver. In this study, male C57BL/6J mice were fed a high-fat diet (HFD, 60%) for 30 weeks for diet-induced obesity (DIO) and were treated subcutaneously with GalNAc-UGT1A1-RNAi (3mg/kg, n=7) or sham control (n=6) once weekly the final 4 weeks while on the HFD. The results show that GalNAc-UGT1A1-RNAi treatment significantly raised serum bilirubin levels compared to sham control-treated (0.38±0.01 vs. 1.36±0.08 mg/dL, Sham vs. GalNAc-UGT1A1-RNAi, p<0.05), decreased hepatic fat content (26 ± 1.4 vs. 18 ± 1 %, p<0.05) and hepatic triglycerides (17±1.5 vs. 11.5±1 nM, p<0.05), and improved fasting blood glucose (261±11 vs. 201±8 mg/dL, p<0.05) and insulin (9.9±0.1 vs. 3.5±0.3 ng/ml, p<0.05) levels. We performed extensive kinase activity analyses using PamGene PamStation technology and found a significant increase in insulin receptor downstream mediators such as SRC, AKT, and ERK kinase families with the GalNAc-UGT1A1-RNAi treatment, indicating improved hepatic insulin sensitivity. These results show that GalNAc-UGT1A1-RNAi improves MAFLD, increases serum bilirubin, reduces its catabolized produce urobilin in the plasma, and reduces hyperglycemia and hyperinsulinemia. These indicate that UGT1A1 antagonism might serve as a treatment for MAFLD and hepatic insulin resistance, which could improve obesity-associated comorbidities. This work was supported by the National Institutes of Health 1R01DK121797-01A1 (T.D.H.) and 1R01DK126884-01 (D.E.S.), the National Heart, Lung and Blood Institute K01HL-125445 (T.D.H.) and P01 HL05197-11 (D.E.S.), and the National Institute of General Medical Sciences P20GM104357-02 (D.E.S.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. 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.
Altered autonomic control or coronary artery blood flow by the aortic body chemoreceptors in conscious normotensive and hypertensive sheep
Authors: Shanks Julia , Pen Dylan , Abukar Yonis , Ramchandra Rohit 
Published: May 2023

Peripheral arterial chemoreceptors monitor the chemical composition of the blood. While, the carotid bodies located at the bifurcation of the common carotid arteries have been extensively studied. The physiological role of the aortic bodies located in the walls of the aortic arch remains relatively under-studied, and its role in hypertension is unexplored.We hypothesized that activation of the aortic bodies would increase coronary blood flow in the normotensive state and that the parasympathetic nerves to the heart would mediate this.Experiments were conducted in conscious and anesthetized ewes instrumented to record arterial pressure, coronary blood flow, and cardiac output. Two groups of animals were studied, one made hypertensive using a 2 kidney one-clip model (HTN. n=6) and a sham-clipped normotensive group (Con. n=6). Unilateral renal clipping increased resting mean arterial pressure (Con: 84±5 vs HTN 115±6 mmHg). The aortic body chemoreceptors were stimulated by a bolus infusion of potassium cyanide (KCN; 10-30 μg/kg) into the left ventricle.Activation of the aortic bodies in the normotensive and hypertensive animals resulted in a significant increase in coronary blood flow ( P<0.05, 2-way ANOVA, interaction effect), which was not different between groups. In normotensive sheep, the aortic body chemoreflex-mediated coronary vasodilation was attenuated by atropine infusion. Interestingly, the coronary vasodilation in hypertensive animals was not altered by the blockade of muscarinic receptors but was attenuated after propranolol infusion ( P<0.05, interaction effect). Bilateral vagotomy is not possible in conscious animals; under anesthesia, the coronary blood flow response to aortic body stimulation was significantly attenuated in normotensive sheep. Neither atropine nor propranolol affected the aortic body chemoreflex meditated changes in either group's blood pressure, heart rate, or cardiac output. This data suggests that the aortic bodies play an important role in modulating coronary blood flow and that their effector mechanism is altered in hypertension. Many patients with hypertension are on beta-blockers. Our finding indicates that the aortic bodies modulate coronary blood flow via a beta-adrenergic mechanism in hypertension, which may have important implications for regulating coronary blood flow during exertion in hypertensive patients. Work is supported by the Health Research Council (HRC) of New Zealand. 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.