bluuebunny/crossref_metadata_2025_split huggingface dataset:
MAPPING NEURAL CIRCUITS CRITICAL TO UPPER AIRWAY FUNCTION AND BREATHING‐SWALLOWING COORDINATION
Authors: Shi Huanan , Ray Russell Scott 
Published: June 2021

Upper airway control and the coordination between swallowing and breathing are essential to avoid the introduction of food or liquids into the lungs. The neural networks underlying upper airway control and swallowing coordination is poorly understood. However, perturbations to these networks may play a role in Sudden Infant Death Syndrome, obstructive sleep apnea, and neurodegenerative disorders such as Parkinson's disease where as much as 44% mortality is attributed to aspiration pneumonia. Thus, there is a clear need to better understand the neural mechanisms that underlie upper airway control, swallowing coordination, and cough reflex throughout life.Though GABAergic signaling is critical to modulate breathing, the functional organization of widespread GABAergic neurons throughout the brainstem remains unclear. We hypothesize that the adult GABAergic system is integrated into distinct functional modules within the brainstem respiratory network aligned along early hindbrain rhombomeric origins. To test this hypothesis, we aim to genetically subdivide the adult brainstem GABAergic system based on their embryonic rhombomere of origin for functional and anatomical mapping studies through the use of intersectional genetic techniques and new chemo‐genetic (DREADD) mouse lines combined with whole body barometric plethysmography and metabolic monitoring.Preliminary studies indicate that inhibitory DREADD hM4De‐mediated perturbation of systemwide GABAergic neurons (Vgat_FLPo positive neurons) results in increased respiratory output and greater breathing instability while excitatory DREADD hM3D‐mediated systemwide perturbation results in increased sighs and decreased metabolic demand. Examination of the respiratory waveform shows mid‐inspiratory pauses indicative of poor glottal control and increased incidences of cough and expiratory reflex movements. Initial results from rhombomere GABAergic mapping studies suggest that GABAergic involvement in adult chemosensory reflexes may be organized along developmental rhombomeres during embryogenesis.Support or Funding InformationMcNair Medical InstituteThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Acute hyperglycemia does not alter central respiratory CO2 chemoreflex responsiveness
Authors: Bird Jordan , Skalk Alexandra , Thrall Scott , Strzalkowski Nicholas , Day Trevor A 
Published: June 2021

The control of breathing is modulated by two distinct but interacting respiratory chemoreceptor compartments: peripheral chemoreceptors (PCRs; carotid bodies) and central chemoreceptors (CCRs; brainstem). The PCRs respond to variety of chemostimuli, including arterial oxygen, arterial carbon dioxide, glucose, insulin and temperature, and are now thought to act as metabolic sensors. However, CCRs have only been characterized as carbon dioxide/acid sensors (PCO2/[H+]). PCRs respond to chemostimulation faster than CCRs, which may mask CCR responses to stimuli like acute hyperglycemia. The aim of this study was to characterize the relationship between alterations in blood glucose concentration and central respiratory chemoreflex responsiveness via hyperoxic rebreathing in healthy humans. We hypothesized that experimentally‐induced relative hyperglycemia following an oral glucose tolerance test (OGTT; 75g, 300 ml) would (a) increase the rate of CO2 accumulation during rebreathing and (b) augment central respiratory chemoreflex responsiveness due to a synergistic effect of hyperglycemia on the CO2 sensitivity of CCR neurons. In 10 healthy participants, we measured minute ventilation (VI; L/min; pneumotachometer) and end‐tidal carbon dioxide (PETCO2; Torr; gas analyzer). We used the modified hyperoxic rebreathing test to isolate CCRs and quantify the central chemoreflex responsiveness to increases in metabolically‐derived CO2. Blood glucose levels were higher 30‐min following the OGTT beverage (i.e., glucose‐loaded) compared to fasted (7.8±1.1 vs. 4.7±0.4 mmol/L; P<0.0001). During rebreathing, the rate of end‐tidal (PET)CO2 accumulation was greater in the glucose loaded trial compared to the fasted trial (0.086±0.007 vs. 0.07±0.008 vs. Torr/sec; P=0.0002). These findings confirm the hyperglycemic stimulation between trials. However, the central respiratory chemoreflex responsiveness during rebreathing was not different between glucose loaded and fasted trials (2.3±1.4 vs. 2.5±1.8 vs. L/min/Torr CO2; P=0.59). These preliminary findings suggest that relative hyperglycemia does not affect the central respiratory chemoreflex responsive to hyperoxic rebreathing. The CCRs may be a more specialized respiratory chemoreceptor, with a phenotype to detect only metabolically‐derived accumulations in CO2.Support or Funding InformationNSERC Discovery and MRU Faculty of Science and TechnologyThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Evidence for a Role for Sestrin1 in Mediating Leucine‐Induced Activation of mTORC1 in Skeletal Muscle
Authors: Xu Dandan , Shimkus Kevin L. , Lacko Holly A. , Kutzler Lydia , Jefferson Leonard S. , Kimball Scot R. 
Published: June 2021

Previous studies established that leucine stimulates protein synthesis in skeletal muscle to the same extent as a complete mixture of amino acids, and the effect occurs through activation of the mechanistic target of rapamycin in complex 1 (mTORC1). Recent studies using cells in culture identified a family of three proteins, Sestrins 1, 2, and 3, that bind leucine and are required for leucine‐dependent activation of mTORC1. However, the role they play in mediating leucine‐dependent activation of the kinase in vivo has been questioned because the dissociation constant of Sestrin2 for leucine is well below circulating and intramuscular levels of the amino acid. The goal of the present study was to compare expression of the Sestrins in skeletal muscle to other tissues, and to assess their relative role in mediating activation of mTORC1 by leucine. The results show that the relative expression of the Sestrin proteins varies widely among tissues, and that in skeletal muscle Sestin1 expression is higher than Sestrin3 while Sestrin2 expression is markedly lower. Analysis of the dissociation constants of the Sestrins for leucine as assessed by leucine‐induced dissociation of the Sestrin•GATOR2 complex revealed that Sestrin1 has the highest affinity for leucine and that Sestrin3 has the lowest affinity. In agreement with the dissociation constants calculated using cells in culture, oral leucine administration promotes disassembly of the Sestrin1•GATOR2 complex, but not the Sestrin3•GATOR2 complex in skeletal muscle. Overall, the results presented herein are consistent with a model in which leucine‐induced activation of mTORC1 in skeletal muscle in vivo occurs primarily through release of Sestrin1 from GATOR2.Support or Funding InformationSupported by NIH grants DK13499 and DK15658.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Interaction Between Fibrinogen and the Microglial CD11b Receptor Mediates Several Neuropathological Alterations in a Mouse Model of Alzheimer's Disease
Authors: Muthukumar Gayathri , Merlini Mario , Rafalski Victoria A. , Ryu Jae Kyu , Mucke Lennart , Akassoglou Katerina 
Published: June 2021

Alzheimer's disease (AD) is characterized by amyloid β (Aβ) deposition, tau pathology, cerebrovascular damage, and microglia‐mediated neuroinflammation. Cerebrovascular damage includes breakdown of the blood‐brain barrier leading to fibrinogen deposition in the AD brain. Fibrinogen is a blood coagulation factor that upon conversion to fibrin binds to the CD11b/CD18 receptor and induces microglial activation. Here, we show that genetic disruption of fibrinogen interaction with the CD11b/CD18 receptor in 10‐month‐old 5XFAD mice crossed with Fggγ390–396A knock‐in mice, which lack the CD11b binding site, have less neuropathology and microglial activation than 5XFAD littermates. Comparative histological analyses revealed reductions in neuronal and presynaptic terminal loss, Iba‐1+ microglia, immunostaining for the lysosomal marker LAMP‐1, and Aβ plaque burden in the hippocampus of 5XFAD:Fggγ390–396A mice. Thus, genetic inhibition of fibrinogen interaction with CD11b/CD18 receptor reduces multiple AD‐relevant neuropathological alterations in 5XFAD mice.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Elucidating the Role of DEPTOR in Cultured Glioblastoma Multiforme Cancer Cells
Authors: Ryan Patrick J , Deaver J William , Koo Sunwoo , Touissaint L Gerard , Fluckey James D 
Published: June 2021

Glioblastoma multiforme (GBM) is the primary malignancy of the brain, representing 45% of all central nervous system tumors. Aggressive and incurable, GBM is generally fatal within two years of diagnosis, despite the best treatment. The cause and progression of these tumors remains a mystery; however, what is known about GBM pathology indicates a role for the anabolic AKT/mTOR pathway in tumorigenesis and growth. Our group and others recently identified an endogenously produced direct inhibitor of mTOR, DEPTOR, which binds mTOR and potently inhibits its activity. As previous attempts to prevent cell growth in GBM have only been marginally successful, manipulation of an effective innate inhibitor of mTOR could provide a viable avenue toward new therapeutics for this deadly cancer. With this in mind, we set out to characterize the role of DEPTOR in cultured glioblastoma cells. Immortalized U87 glioblastoma cells were grown and harvested in cell culture, along with U87 cells selected for invasive potential to model a more aggressive subset of tumors (designated IM3), and cultured astrocytes to provide an adjacent tissue comparison. Western blot methodology was used to investigate the status of several key proteins in the AKT/mTOR axis (including DEPTOR), as well as the relative abundance and phosphorylation status of downstream targets of mTOR (S6K1 and 4EBP1). We determined that key measures of anabolic signaling were elevated in the cultured GBM cells, with double the ratio of phosphorylated to total S6K1 observed in both GBM lines versus the astrocyte, along with reductions in total 4EBP1, indicating upregulation of cap‐dependent protein synthesis. Further, DEPTOR expression was reduced five‐fold in cultured GBM cells, indicating that this “brake” on mTOR has been removed, resulting in rampant and out‐of‐control anabolism. Taken together, these findings hint that lack of DEPTOR may play a role in GBM pathology, and suggest that further investigation into the interplay between DEPTOR, mTOR, and cancer cell growth in GBM is warranted.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Role of Fatty Acid Oxidation and Glucose Oxidation in Endothelial Cell Inflammation and Permeability Associated with Acute Lung Injury
Authors: Ruiz Vania Lopez , Leonard Antony , Rahman Arshad , Fazal Fabeha 
Published: June 2021

Acute lung injury (ALI) is a common cause of respiratory failure in critically ill patients with a mortality rate of 38.5%. ALI can be precipitated by either direct insults such as pneumonia, aspiration or via indirect insults such as sepsis and multiple trauma, to the lungs. The vascular endothelium forming the innermost lining of all pulmonary blood vessels is the major barrier that protects air spaces against vascular fluid entry. Because of their localization, endothelial cells (EC) are constantly exposed to oxygen and nutrients that fuel cell metabolism. However, very little is known about the role of EC metabolism in the regulation of EC inflammation and permeability, the two major pathogenic features of ALI. Recent studies have highlighted that fatty acid oxidation (FAO) is central to the tight regulation of EC permeability required to maintain vessel functionality. The purpose of the present study is to understand the mechanistic link between cell metabolism and thrombin‐induced EC inflammation and permeability and to understand the relevance of this linkage in the pathophysiology of ALI. Human Pulmonary Artery Endothelial cells (HPAECs) were stimulated with proinflammatory mediator thrombin in the presence and absence of Etomoxir, an inhibitor of FAO or dichloroacetate (DCA), an inhibitor of pyruvate hydrogenase kinase (PHK). Our results indicate that both Etomoxir and DCA inhibited thrombin‐induced inflammatory responses as observed by decrease in the secretion of cytokines IL‐6 and IL‐8. In addition real time changes in transendothelial electrical resistance (TER) were measured to monitor endothelial permeability after exposure of HPAECs to Etomoxir or DCA, followed by thrombin treatment. Our data indicate that Etomoxir had no effect on thrombin‐induced decrease in TER however it delayed the recovery after 1 hour of thrombin challenge. DCA in contrast showed no effect on thrombin‐induced EC permeability. Together our data suggest that metabolic pathways are critical to EC inflammation and permeability induced by thrombin.Support or Funding InformationSupported by: NIH (HL130870)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Cardiovascular Responses to the Exercise Pressor Reflex in Pediatric Heart Transplant Recipients
Authors: Blushke Corey R , Boyes Natasha G , Lahti Dana S , Kosokowsky Kylee , Marciniuk Darcy , Butcher Scotty J , Erlandson Marta C , Wright Kristi D , Pharis Scott , Pockett Charissa , Tomczak Corey R 
Published: June 2021

Pediatric heart transplant recipients (HTR) have reduced exercise tolerance despite normal systolic ventricular function. A slower heart rate adaptation to exercise in HTR due to cardiac denervation is commonly observed in HTR patients, which explains, in part, the exercise intolerance. We tested the hypothesis that the cardiovascular response to exercise pressor reflex activation from handgrip exercise would be blunted in HTR.MethodsSix pediatric HTR (3f/3m; mean±SD, 10±3 yrs) and five healthy‐matched controls (CTL; 3f/2m; 10±2 yrs) were studied. After 3 min of resting baseline, subjects performed 2 min of isometric handgrip (HG) exercise at 40% maximal voluntary contraction, followed by 3 min post‐exercise circulatory occlusion (PECO). Beat‐by‐beat mean arterial pressure, heart rate, and modelflow stroke volume and cardiac output were recorded. Data were analysed as the change (Δ) from rest using two‐way repeated measures ANOVA (2 × 3; group × condition) and Holm‐Sidak multiple comparisons analysis. Significance was accepted at P<0.05.ResultsMean arterial pressure increased in HTR (Δ17±15 mmHg) and CTL (Δ13±16 mL) during HG (P<0.001) and remained elevated above baseline during PECO (HTR: Δ10±10 mmHg; CTL: Δ11±9 mmHg; P<0.05), with no between group differences. Heart rate did not significantly increase during HG in HTR (Δ4±5 bpm, P=0.235) but did in CTL (Δ14±11 bpm, P<0.001), and was 9 bpm lower in HTR vs CTL (P=0.005). Heart rate was not different during PECO from rest in HTR and CTL. Stroke volume increased in HTR (Δ3±1 mL) and CTL (Δ3±3 mL) during HG (P<0.001) and remained elevated above baseline during PECO (HTR: Δ3±2 mL; CTL: Δ4±3 mL; P<0.001), with no between group differences. Cardiac output did not significantly increase during HG in HTR (Δ0.34±0.21 L/min, P=0.074) but did in CTL (Δ0.71±0.54 L/min, P<0.001), and was 0.37 L/min lower in HTR vs CTL (P=0.035). Cardiac output was not different during PECO from rest in HTR and CTL.ConclusionsOwing to the impaired heart rate response during handgrip exercise, cardiac output was lower in pediatric HTR compared to healthy‐matched controls in response to exercise pressor reflex activation.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Effects of Paracrine and Intracellular Angiotensin II on Protein Kinase C, MAP kinase ERK1/2, and Nuclear Factor‐κB Signaling Responses in Mouse Glomerular Mesangial cells
Authors: Leite Ana Paula Oliveira , Li Xiao C. , Zhuo Jia L. 
Published: June 2021

Angiotensin II (ANG II) acts not only as a vasoconstrictor, but also as a growth‐promoting cytokine and chemokine, proinflammatory and profibrotic factor in the kidney. Glomerular mesangial cells (MC) are a key target for endocrine, paracrine, autocrine, and intracrine ANG II. Augmentation of local paracrine and intracrine ANG II generation in MCs may induce glomerular injury by promoting MC cell growth, hypertrophy and fibrosis. In the present study, we performed phosphoproteomic characterization of ANG II‐induced protein kinase C (p‐PKCα), MAP kinase ERK1/2 (p‐ERK1/2), p38 MAPK, and nuclear factor‐κB (p65 and p50 subunits) signaling responses in murine glomerular MCs. Murine mesangial cells (MES‐13, ATCC) were grown to ~80% confluence in 6‐well plates in DMEM and Ham's F‐12 medium, containing 5% fetal bovine serum, and 1% penicillin‐streptomycin, maintained at 37°C and 95% O2/5% CO2. After starved at a serum‐free medium for 24 h, MCs were then treated with low to high levels of ANG II (0.1 to 100 nM) for 5 to 20 min, or transfected with a mitochondria‐targeting intracellular ANG II for 48 h (mito‐ECFP/ANG II, 4 μg/well), with or without pretreatment with the AT1 receptor blocker losartan (1 μM), AT2 receptor blocker PD123319 (1 μM) or both blockers. Proteins were extracted for Western blot analysis of p‐PKCα, p‐ERK1/2, p38 MAPK, and p65 and p50 subunits of NF‐κB, respectively. ANG II significantly increased p‐ERK1/2 and p‐PKCα in both dose‐ and time‐dependent manners, with peak responses to ANG II occurred at 0.1 and 1.0 nM, 5–10 min (p<0.05), respectively. ANG II also increased p38 MAPK response, but it peaked at 1 nM, 20 min (p<0.05). By contrast, ANG II appeared to decrease the NF‐κB responses at 1 nM, 10 min, which were reversed by losartan and PD123319. The expression of mito‐ECFP/ANG II selectively in the MC mitochondria significantly increased mitochondrial complex proteins (CI‐CV), which were blocked by losartan (p<0.01). Our results suggest that both paracrine and intracellular ANG II may activate AT1 receptors to induce important intracellular PKC, MAP kinase ERK1/2, p38 MAPK, and NF‐κB signaling responses in MCs, which may contribute to ANG II‐induced glomerular injury in hypertension and kidney diseases.Support or Funding InformationSupported by National Institute of Health grants, 2R01DK067299‐10A1 and 2R01DK102924‐03A1 to Zhuo, and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior ‐ CAPES to Leite.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The Influence of GATOR1 Sub Complex NPRL2 on Anabolic Signaling During Insulin Resistance in Rats
Authors: OReilly Colleen , Greene Nicholas , Wiggs Michael , Fluckey James 
Published: June 2021

Skeletal muscle metabolism plays a significant role in dysregulation of protein synthesis signaling pathways in skeletal muscle is a contributing factor in multiple disease states including Type 2 Diabetes (T2D). In insulin resistant rats, there is a well‐documented increase in mammalian target of Rapamycin (mTOR) activity, in contrast to observed muscle mass losses. In several types of cancer, the same mTOR increases were attributed to a deficiency in at least one of the GATOR1 sub complexes (DEPDC5, NPRL2, NPRL3). GATOR1 is a GTPase activating protein, which when active, is an mTOR inhibitor. When one or more of these sub complexes are deficient, GATOR1 will not inhibit mTOR. NPRL2 is specifically associated with the Gap activity observed with Gator1 and it's mTOR inhibition. It has been shown that specific knockout of NPRL2 in mouse skeletal muscle resulted in increased mTORC1 activity. While this deficiency and its relationship to downstream targets of mTOR are documented in multiple cancer models, the relationship of GATOR1 sub complexes with insulin resistance is less clear. The purpose of this study was to determine the relationship between NPRL2 and the observed mTOR response to insulin resistance as well as this relationship with or without exercise.METHODSMale obese and lean zucker rats were given twelve days of acclimation and then assigned to control or exercise groups blocked for lean mass. The exercise groups were put through 4 bouts of resistance exercise over an eight day period using the “squat” resistance model.RESULTSOur results indicate NPRL2 content is lower in the obese rats with or without prior exercise. This corresponds to higher mTOR activity, demonstrated by phosphorylation of p70S6k, being higher in the obese rats than in the lean rats.CONCLUSIONThese results contribute to the understanding of insulin resistance and muscle's metabolic role in that resistance. NPRL2 and the GATOR1 complex may be another key player in the understanding of the mTOR dysregulation with metabolic disease.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Skeletal Muscle Anabolic Response Following Incubation with Protein Kinase C Activator OAG
Authors: Deaver J William , O'Reilly Colleen L , Cross Kristina M , Fluckey James D 
Published: June 2021

PurposeFor years, there has been a growing interest in the role of lipids in the progression of type 2 diabetes. Specifically, molecules such as diacylglycerol have garnered attention due to its concomitant increase with the progression of insulin resistance and type 2 diabetes. These experiments aim to further characterize the role of diacylglycerol in cellular metabolism by using the diacylglycerol mimetic, 1‐oleoyl‐2‐acetyl‐sn‐glycerol (OAG) alongside mTOR inhibitors rapamycin or Torin 1.MethodsC2C12 myoblasts were grown and maintained in 10 cm plates with high glucose DMEM growth media until reaching ~80% confluence, at which point they were transitioned to a high glucose differentiation media to encourage myotube formation. Six days following differentiation, plates were randomly assigned to treatment groups (n=3) and treated in the presence of 4% deuterium oxide for 24 hours. Myotubes were harvested with cell scrapers in the presence of Norris lysis buffer, and cellular contents were fractionated for measures of both protein synthesis rates and anabolic signaling via western blot analysis.ResultsPresence of OAG (20 μM) did not significantly alter 24 hour rates of protein synthesis (1.728%/hr) compared to controls (1.630%/hr) (p = 1.000). Rapamycin (1.333%/hr) and Torin 1 (1.187%/hr) treatments significantly reduced protein synthesis rates compared to controls (p = 0.003 and p < 0.001 respectively). However, OAG did not have any statistically significant effect on mitigating the suppressive effects of rapamycin (OAG+Rapamycin 1.380%/hr) (p=1.000) or Torin 1 (OAG+Torin 1 1.158%/hr) (p=1.000).ConclusionsOAG is known to be a potent activator of Protein Kinase C as a cell permeable analog of diacylglycerol. These data indicate that a 24‐hour incubation with OAG is not sufficient to significantly perturb fractional rates of protein synthesis in murine skeletal muscle myotubes.Support or Funding InformationWork by this author was partially supported by the Sydney & J.L. Huffines Institute for Sports Medicine & Human Performance, and a Texas A&M College of Education and Human Development Graduate Research award.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.